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Studies on cardiac pacing : emphasis on pacemaker sensors and cardiac resynchronizationtherapy
Erol-Yilmaz, A.
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Citation for published version (APA):Yilmaz, A. (2005). Studies on cardiac pacing : emphasis on pacemaker sensors and cardiac resynchronizationtherapy. Amsterdam: Amsterdam University Press.
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Download date: 19 Jun 2019
Studiess on Cardiac Pacing Emphasiss on Pacemaker Sensors and Cardiacc Resynchronization Therapy
Author:: A Erol-Yilmaz
ISBN:: 90-9019108-9
Coverr and Lay-out; Chris Bor, Medische Fotografie en illustratie
AMC,AMC, The Netherlands.
Printedd by: Buijten & Schipperheijn, Amsterdam. The Netherlands
Studiess on pacing. Emphasis on pacemaker sensors and cardiac resynchronization
therapy. .
Thesiss University of Amsterdam, The Netherlands.
Copyrightt © A, Erol-Yilmaz. Amsterdam, The Netherlands. All rights reserved. No
partt of this publication may be reproduced or transmited in any form or by means,
electronicc or mechanical, including photography, recording, or any information
storagee and retrieval system without permission in writing of the copyright owner.
Thiss thesis has been made possible through unrestricted research grants
providedd by (alfabetic order) Guidant BV Nederland. Medtronic BV Nederland
andd Vitatron.
Thee printing of this thesis was financially supported by Jacques H. de Jong Stichting,
J.. E, Jurriaanse Stichting. Guidant BV Nederland, Medtronic BV Nederland,Vitatron,
Hollandd Medical, St Jude Medical Nederland BV. Biotronik Nederland BV. Orbus
International,, Pfizer BV, Sanofi-Synthelabo. Astra Zeneca, Guerbet Nederland BV
Farmasel. .
Studiess on Cardiac Pacing Emphasiss on Pacemaker Sensors and
Cardiacc Resynchronization Therapy
ACADEMISCHH PROEFSCHRIFT
terr verkrijging van de graad van doctor
aann de Universiteit van Amsterdam
opp gezag van de Rector Magnificus
prof.. mr. P.F. van der Heijden
tenn overstaan van een door het college voor promoties ingestelde
commissie,, in het openbaar te verdedigen in de Aula der Universiteit
opp 18 maart 2005. te 10.00 uur
door r
Aytenn Yilmaz
geborenn te C icekdagi (Turkije)
Promotiecommissie: :
promotor: :
co-promotor: :
overigee leden:
Prof.dr.. A.A.M. Wilde
Dr.. R. Tukkie
Prof.dr.. C. Ince
Prof.dr.. J.M.Tde Bakker
Prof.dr.. J.H. Ravesloot
Prof.dr.. N.M. van Hemel
Prof.dr.. M.J. Schalij
Dr.. N. Sulke
Faculteitt Geneeskunde
Financiall support by the Netherlands Heart Foundation for the printing of this
thesiss is gratefully acknowledged.
Anneme e
Voorr mijn moeder
Contents s
Chapterr 1 8
Introduction,, aims and outline of the thesis.
Parti i
Chapterr 2 30
Iss manual rate response optimization necessary in current rate
adaptivee pacemakers?
SubmittedSubmitted for publication
Chapterr 3 56
Heartt rate profiles during two types of exercise testing in healthy
individuals. .
Chapterr 4 74
Individuall optimization of pacing sensors improves exercise
capacityy without influencing quality of life.
PACEPACE 2005: 28:17-24
PresentedPresented at world congress of pacing and electrophysiology.
20032003 Hong Kong and Cardiostim 2004 Nice, Accepted for
presentationpresentation at the American College of Cardiology, Orlando 2005.
Chapterr 5 94
Cerebrall blood flow velocity and cardiac output at the onset of
dynamicc exercise at two settings of pacemaker determined heart rate.
SubmittedSubmitted for publication
PresentedPresented at first joint meeting of the European Federation of Auto-
nomicnomic Societies (EFAS) & American autonomy society {AAS). 2004
Amsterdam.Amsterdam. Finapres Medical System travel fellowship award.
Chapterr 6 112
Directt comparison of a contractility and activity pacemaker sensor
duringg treadmill exercise testing.
PACEPACE 2004: 27:1-7
PresentedPresented at Cardiostim 2004 Nice.
Partt II
Chapterr 7 128
Cardiacc resynchronization induces favorable neurohumoral changes.
AcceptedAccepted for publication in PACE
PresentedPresented at Cardiostim 2004 Nice; 51th annual meeting of the Society
ofof Nuclear Medicine, 2004 (Philadelphia. USA): Accepted for presenta-
tiontion American College of Cardiology. Orlando 2005.
Chapterr 8 144
Cardiacc resynchronization improves microcirculation.
SubmittedSubmitted for publication
AcceptedAccepted for presentation American college of cardiology, Orlando 2005
Chapterr 9 158
Reversedd remodeling of dilated left sided cardiomyopathy after upgrad-
ingg from WIR to WIR biventricular pacing.
EuropaceEuropace 2002; 3: 445-449
Chapterr 10 170
Summaryy and conclusions
Chapterr 11 180
Samenvattingg en conclusies
Dankwoordd 192
Curriculu mm Vitae 200 0
Introduction,, aims and outlinee of the thesis
Chapterr ]
Introductio n n
Thee development of the cardiac pacemaker as an implantable device to sustain heart
rhythmm has revolutionized the treatment of bradyarrhythmia's. After the first
permanentt pacemaker implantation in 1958, the initial developments in pacemaker
technologyy were aimed at improving the longevity and the reliability of their
performance.11 The standard method of pacing in these early years was a single
chamberr ventricular pacemaker, which was effective as a life saving therapy.
Overr the past two decades, however, there have been tremendous advances in
pacemakerr technology resulting in the availability of complex, multiprogrammable,
multii chamber and rate-adaptive pacemakers to meet the haemodynamic needs of
ann individual patient. In addition, recent years generated wide interest in multisite
pacing,, alternative site pacing, preventive pacing for atrial fibrillation, biventricular
pacingg and the development of digital pacemakers.
Inn this chapter, a brief history of cardiac pacing, indications for pacing therapy and
thee rationale for cardiac resynchronization therapy (CRT) are described. At the end
off this introduction, the research aims of this thesis are formulated and the
structuree of this thesis is outlined.
Pacingg history
Ass early as 1580. Mercuriale Geronimo of Padua (Italy) described a syncope
associatedd with a slow pulse, an event now known as the typical Adams Stokes
attack.22 Galvani discovered in 1791 the fundamentals of electrical stimulation of the
heart.33 In 1798, Bichat in Paris examined hearts of decapitated men and showed that
humann hearts reacted to electrical stimuli.4 In a horrific experiment in 1819,
Aldidnii tried to stimulate the heart of criminals soon after their death penalty with
aa pen through the thorax. He realized from these observations that the heart rhythm
couldd be sustained by artificial stimulation.5
Betweenn 1929 and 1932, Albert and Charles Hyman invented an electromechanical
devicee and coined the term pacemaker. It consisted of a magnetic generator
weighingg 7.2 kg. A spring motor could spin the generator for 6 minutes and the
pulsee frequency could be fixed at 30, 60, or 120 impulses per minute.
AA transcutaneously introduced special needle with a noninsulated bare tip
stimulatedd the left ventricle. Paul Zoll was the first who accomplished in 1952
transcutaneouss cardiac pacing and until 1957 transcutaneous closed chest cardiac
stimulationn was the only available approach for cardiac st imulat ion/
Inn 1958. the first pacemaker was implanted by Ake Senning in a 40-year old patient.1
Thee implanted pulse generator had a rechargeable nickel-cadmium battery. Senning
andd his associate Rune Elmqvist had developed and tested this pacemaker between
19566 and 1958.s Although the first pulse generator failed within few hours, a
successorr lasted already for about 6 weeks. This first patient died eventually at the
agee of 86 years after receiving 27 pacemakers during his lifetime.1
Twoo years later, W.M. Chardack carried out the first successful implantation of a
pacemakerr with limited programmable functions.9 The amplitude of the electrical
currentt and the pacing rate could be adjusted using a needle electrode through the
skin.. Engineer Wilson Greatbatch had worked together with Chardack in designing
thiss device.9 This achievement of Chardack and Greatbatch has since been
recognizedd as a defining moment in the history of pacing. A few weeks later, Paul
Zolll and associates implanted a pacemaker of somewhat similar design.10
Clearly,, the idea for an implantable pacemaker was not the exclusive property of any
groupp but was 'in the air,' At that time, implantation required a left anterior
thoracotomyy and exposure of the myocardium: thus training in thoracic or
cardiovascularr surgery was a necessity, Complications from generator failure, rapid
batteryy exhaustion, packaging defects, electrode disruption and infection plagued
thiss endeavor.
Thee problems faced by these pioneers in cardiac pacing have today been largely
overcome,, although some of these problems, but fortunately less frequently, are
stilll encountered.
Comparedd to the early days, cardiac pacing is now a routine procedure in most parts
off the world. A recent world-wide survey of cardiac pacing showed that in The
Netherlandss in one year (2001) 314 new pacemakers per millio n of the population
weree implanted.11 Germany had the highest number of new implants per millio n of
thee population (837/million). followed by The United States with 786 /million. High
degreee atrioventricular block and sick sinus syndrome remain the two major
indicationss for pacemaker implantations. In 2 % of cases, biventricular pacing was
thee mode of pacing in those countries that implanted such systems in 2001. There
hass been an increased use of DDDR systems in most countries.
12 2
Chapterr 1
Pulsee generator
Thee earliest implantable pacemakers delivered stimuli at a fixed rate, regardless of
anyy intrinsic electrical activity. Hence, this early kind of pacing was known as
asynchronouss pacing (later coded VOO) with the objective simply to sustain an
adequatee rhythm. David Nathan approached the Cordis Corporation with the idea
forr an atrial synchronous (or VAT) pacemaker.12 Devices that restored atrial
synchronyy were described as early as 1957, and the first human system was
implantedd by Nathan and co-workers in 1963.12 This device was capable of sensing
intrinsicc atrial electrical activity. Dwight Harken implanted in 1966 the standby
pacer."" today's WI pacemaker.13 Non-competitive pacing was an important step
towardss current dual-chamber pacemakers, which can sense and pace in one or both
cardiacc chambers and are thus capable of mimicking normal physiologic rhythm.
Atrioventricularr (AV)sequential (DVI pacing mode) pacing became popular in the
latterr half of the 1970s and Funke et al. developed in 1977 the first DDD
pacemaker.. Today, the modern rate- responsive DDDR pacemakers have adjustable
sensorss to respond to the patient's metabolic need and contain numerous
programmablee automatic features. We will address in detail the issue of rate
adaptivee pacing by artificial sensors in chapter 2, 4 and 6. Figure 1 illustrate the
evolutionn of pacemakers,
Seymourr Furman and his associates were active from the mid-1960s in designing
instrumentss that assisted the physician to assess the functioning of the pacemaker
att implantation and afterwards.'5 From this work, the Montifore group went on in
19699 to describe the first practical techniques for routine monitoring of pacemaker
ratee by telephone. Transtelephonic monitoring became popular in the United States
duee to the long distances to the hospital. In 1972, Cordis introduced the
Omnicorr line of pacemakers, the first adjustable pacers under noninvasive
electronicc control (see figure l).18 This pacemaker could be non-invasively
reprogrammedd for rate (six choices) and output (four choices). The Omnicor also
containedd a miniature magnetic reed switch. This was the ancestor of today's
externall programmers.
13 3
Figuree 1. The development of pacemakers 1: Demo of the first human pacemaker implanted in 1958:: 2: Chardack Greatbatch pacemaker with adjustable sensitivity (Medtronic Inc. Minnesota. USA).. 3: Siemens Elema (Sollna, Zweden) pacemaker with connection possibilities for a bipolar lead.. 4: Ventricor fixed rate pacer with a rate of 70/min (Cordis. Florida, USA). 5: One of the first WII pacemakers (Medtronic Inc. Minnesota. USA). :6 0mni-Stanicor R-wave inhibited programmable cardiacc pacemaker (Cordis. Florida. USAl 7: Single lead VDR pacemaker (Sorin Biomedica. Sallugia. Italy).. 8: A modern DDDR pacemaker (Guidant Insignia. Guidant. Minneapolis. USA). 9: Cardiac resynchronizationn device (Guidant Contak Renewal TR 2. Guidant. Minneapolis. USA).
M M
Chapterr 1
Pacemakerr leads
Permanentt pacing leads contain five major components: I) the pacing electrode, 2)
thee conductor. 3) the insulation. 4) the connector pin and 5) a fixation mechanism.
Thee pacing lead remains the weakest link of the whole implantable pacing system.
Leadd failures have been a major issue from the beginning of pacemaker therapy.19
Permanentt transvenous pacing first appeared in the early 1960s but did not achieve
generall acceptance in the United States until after 1965. Chardack developed a
helical-coiledd conduction wire, a great advance over earlier lead designs when
introducedd by Medtronic Inc. in 1962,20 Hunter et al. constructed in 1959 a bipolar
myocardiall electrode, which stabilized the resistance over the myocardial-electrode
interfacee after an initial rise.
Thee lead and the Iead-myocardial interface play a major role in pacemaker battery
consumption.. The search for low-threshold, high-impedance leads by fractionate tip
technology,, steroid-eluting designs, and small spherical electrode tip designs are
majorr contributions in this respect. An early approach to improve the handling
characteristicss and downsize the lead diameter was successfully achieved by the
Vitatronn Slimtine high performance silicone-insulated bipolar lead (Vitatron,
Arnhem.. The Netherlands). Intermedics introduced a different approach with the
Thinlinee lead (Angleton, Texas, USA). The leads based on coated wire technology
openedd a new era in lead design. These leads use a single radial conductor coil with
interconductorr electrical insulation provided by a coating of ethylene tetrafluor
ethylenee fluoropolymer on each wire.
Thee earliest transvenous pacing leads had large stimulating electrode surface areas
off approximately 100 mm2 resulting in pacing impedances of about 250 ohms.22 '29
Byy the late 1970s most pacing lead designs had cathodes with reduced surface areas
inn the range of 8-12 mm2 (pacing impedance of 400-800 ohms).23 Today high
impedancee leads (> 1000 ohms) with less than 2 mm2 surface area are available.
Thee conductor of a pacing lead is composed of wire that conducts the electrical
currentt from the pulse generator to the stimulating electrode. Unipolar leads
requiree one conducting coil whereas bipolar leads require two. Conductors are also
responsiblee for transfer of the sensed cardiac signals from the electrodes to the
sensingg amplifier of the pulse generator. The development of coated wire
technologyy enabled that bipolar leads have now outside diameters as small as those
off unipolar leads. The lead insulation extends from the lead connector to the
15 5
cathodee tip and, in a bipolar lead, is interrupted by the anode-ring.
Thee lead connector connects the lead to the pulse generator. The original pacing
leadss had no specialized connector. A major improvement in lead connectors was
thee low profile, in-line bipolar design. An in-line connector places both electrical
terminalss on a single lead pin, with an insulating barrier separating the anode from
thee cathode. The development of the international standard 1 (IS-1), UNI. for
unipolarr leads, and IS-1 BI for bipolar leads as lead connector standard, has been a
majorr improvement in the clinical practice of cardiac pacing. There is a proposal to
developp an international standard connector (IS-IV) with connections for sensing,
pacingg and two shock coils in cardioverter defibrillators. This connector could also
bee used in single lead VDD pacemakers.
Thee ideal pacing lead should have an electrode with a small radius (to increase
currentt density) and a large surface area (to improve sensing). The solution to these
conflictingg considerations for optimal stimulation and sensing characteristics has
beenn sought in the development of electrodes with a small radius but having a
complexx surface structure, The use of electrodes with a textured surface has
resultedd in a dramatic increase in the surface area of the electrode without an
increasee in radius. The textured surface of modern leads minimizes polarization and
improvess sensing and stimulation efficiency. A further advance in permanent pacing
leadd technology has been the development of electrodes that elute small amounts of
thee corticosteroid dexamethason sodium phosphate.24 The steroid-eluting leads are
characterizedd by a minimal change in stimulation threshold from implantation to a
follow-upp period of several years due to the reduction of scar tissue at the lead-tip.
Too provide good tissue contact, two fixation methods of leads are available, so called
passivee and active fixation. Passive fixation mechanisms include tines, fins, helices,
orr conical structures that are extensions of the silicone or polyurethane insulation.
Tiness are the predominant passive fixation mechanism currently used in permanent
pacingg leads. Of the active fixation methods with a screw, barb or hook, the screw
methodd is the one most used. Figure 2 shows the different fixation mechanisms.
Thee recent survey by Mond et al. shows a predominance of transvenous, bipolar
passivee fixation leads. They also observed an increased use of active-fixation leads
inn the atrium.
16 6
Chapterr 1
Figuree 2. Different fixation mechanisms of various types for endocardial and epicardial leads from leftt to right.
2.a.. Atrial endocardial leads.
2.b.. Right ventricular endocardial leads.
I I I I
2.c.. Epicardial leads.
17 7
Pacemakerr batteries
Thee mercury zinc cell, originally developed by Ruben during the Second World War
largelyy for military operations, was patented in 1947.5 Although, initiall y used in
implantablee pacemakers, the longevity limitations of this battery was recognized in
1970.. The mercury zinc cell was replaced by the lithium iodine cell, which continues
too be the prominent battery to date. The litiu m iodine cell was patented in 1972
withh the battery technology largely attributed to Greatbach et al.25 The various
batteriess based on lithium chemistry had somewhat different properties and varied
actuariall survival performance, but all enjoyed significant advantages over mercury.
Thee output voltage of the lithium-iodine cell decreases gradually rather than
abruptlyy as in the mercury zinc cell, giving the physician ample warning of the need
too replace the pulse generator. Finally, the new battery generated no gas as a
chemicall byproduct, so the entire pulse generator could at last be hermetically
sealed. .
Anotherr alternative to the mercury-zinc battery, the nuclear generator, was
conceivedd in the 1960s and brought to clinical function in the early 1970s.
Thee initiative for the nuclear pacemaker came from Parsonnet in 1965-26 For the
youngerr patient likely to live many years with an implanted pacemaker, the nuclear
generatorr had the obvious advantage that the power source would last as long as the
patient.. But by the mid-1970s, the nuclear generator was competing with a new kind
off pulse generator that combined lithium batteries, low current drain, hermetic
encapsulation,, and more advanced circuitry. Nuclear pacemakers worked to
perfection,, but progress in other pacemaker components eventually rendered them
obsolete. .
Pacemakerr indications
Inn the early days of pacing, the primary indication for the implantation of a
pacemakerr was the so-called symptomatic sick sinus syndrome and atrioventricular
block.. In recent years, pacing indications have expanded tremendously. Interest
focusedd on multisite pacing to alleviate dyssynchrony and preventive pacemaker
therapyy to reduce the burden of atrial fibrillation. The efficacy of pacing (especially
atriall septal) in preventing atrial fibrillation has to be established in the future.
18 8
Chapterr 1
Pacingg for neurocardiogenic syncope with application of rate-drop algorithms and
pacingg with short AV delay for symptomatic obstructive hypertrophic
cardiomyopathyy resulted in contradicting data. The AHA and ACC guidelines for
implantationn of cardiac pacemakers updated in 2002, now include several of these
newerr indications.27
Pacemakerr modes
Thee physician has now a wide range of options when selecting a pacemaker for a
givenn patient, depending on a variety of clinical parameters and preferences.
However,, there is uncertainty as to which pacing mode offers most benefit, single
orr dual-chamber. In recent years, in the era of evidence based medicine, several
largee scale randomized trials have tried to answer this question.28
Twoo large-scale randomized trials, the Canadian Trial of Physiologic Pacing (CTOPP)
andd the Mode Selection Trial (MOST), included patients with sinus node
dysfunctionn (MOST) trial and patients with symptomatic bradycardia who needed a
firstt permanent pacemaker without atrial fibrillation (CTOPP) trial.29'31 These two
largee trials demonstrated that AV synchronous dual-chamber pacing does not reduce
thee incidence of stroke or improve survival when compared with ventricular pacing
alone.29"511 However, dual-chamber pacing did reduce the incidence of atrial
fibrillationn and in patients with sinus node dysfunction reduced the incidence of
heartt failure when compared with ventricular pacing.50,32
Otherr studies performed to assess the effect of pacing mode on morbidity and
mortalityy were the Danish study, PAcemaker Selection in the Elderly (PASE), United
Kingdomm Pacing. Cardiovascular Events (UK-PACE) and the Dual Chamber and WI
Implantablee Defibrillator (DAVID) trial.33 34 The treatment arms in the Danish study
weree AAI or 'physiologic'pacing vs. WI pacing in patients with sick sinus
syndrome.355 This trial was the only trial that showed a mortality benefit of
physiologicc pacing over WI pacing. The PASE trial compared DDDR and WIR pacing
inn elderly patients (> 65 years) with a pacing indication for prevention or treatment
off bradycardia. No statistically significant difference was found in quality of life
betweenn DDDR and WIR pacing, although there was a trend towards improved
qualityy of lif e in patients with sinus node dysfunction randomized to dual chamber
pacing.. The UK-PACE trial also compared DDD with WI pacing indicated in elderly
19 9
patientss (>70 years) with AV block. Again, this trial showed no significant
differencee between pacing modes in the primary endpoint of all cause mortality.7
Dataa are accumulating that right ventricular pacing, especially in the right
ventricularr apex, is harmful and care should be taken to minimize the amount of
ventricularr pacing. The DAVID trial supports this concept.54 The DAVID trial tested
thee hypothesis that the atrio-ventricular pacing mode would produce improved
hemodynamicss and total mortality compared to backup ventricular pacing in
patientss indicated for implantable defibrillator therapy. The striking finding of this
triall was that ventricular backup pacing produced less than 3% ventricular pacing.
whilee atrioventricular pacing produced approximately 60% atrial and ventricular
pacedd heart beats, resulting in increased mortality compared to the ventricular
backupp pacing group. The results of the DAVID trial suggest that, especially in
patientss with left ventricular dysfunction, prevention of interventricular
dyssynchronyy is mandatory. Considering the magnitude of the deleterious effects
associatedd with right ventricular pacing in this trial, future studies should explore
thee possibility that left ventricular stimulation may be the only pacing mode
capablee of preventing bradycardia without increasing death and congestive heart
failure.. Two trials {DANPACE and SAVE-PACE) are currently underway that wil l
clarifyy the clinical significance of reducing forced ventricular desynchronization.
Thee results of these trials may direct pacemaker physicians away from the right
ventricularr apical lead toward a new imperative of atrioventricular and right
ventricular-leftt ventricular synchrony.51
Biventricularr pacing history
Wiggerss et al. described in 1925. the importance of the sequence of electrical
activationn of the ventricles for optimal cardiac performance by using artificial
electricall stimulation of the heart.1 Kosowsky et al. showed that right ventricular
apexx pacing reduced the pump function, but that His-bundle pacing maintaining the
normall activation sequence did not.57
AA cardiothoracic surgeon (P. Bakker, from the HLCU of Utrecht, The Netherlands)
presentedd in 1994 preliminary finding of one of the first clinical studies showing
beneficiall effects of biventricular pacing in patients with congestive heart failure.
Inn 5 patients with dilated cardiomyopathy (NYHA HI and IV, left ventricular (LV^
ejectionn fraction 5-23%. complete left bundle branch block and prolonged PR
20 0
Chapterr 1
interval),, a triple chamber pacemaker was implanted. An endocardial right
ventricularr and an epicardial LV lead were connected to the ventricular channel. The
pacemakerr was programmed to DDD-biventricular pacing with an intraoperatively
determinedd optimal AV delay (70-100 msec). Differences in preoperative and 3
monthss postoperative NYHA class, diuretic dose. LV ejection fraction and
echocardiographicc parameters were determined. The investigators showed that
biventricularr pacing significantly improved functional NYHA class from 4 to 2.5 and
exercisee capacity in patients with end-stage dilated cardiomyopathy and LBBB.39
Mosss et al. were one of the first to use of the coronary vein for pacing indications in
1974.400 Later this technique became the preferable way to position a pacing lead for
Figuree 3. Examples of coronary sinus leads for cardiac resynchronization therapy.
3.aa Medtronic Attain ™ OTW Model 4193 iMedtronic Inc.. Minneapolis,USA), b The Aescula LV left-heartt Lead (St Jude Medical, California. USA),c. The EASYTRAK® coronary venous leads (Guidant, Minnesota,, USA).
LVV pacing. Despite advances in percutaneous techniques (lead material, guiding
sheats),, LV lead implantation fails approximately in 10-15% of the patients, and lead
dislodgementt occurrs in an additional 11 %. Therefore lead implantation in the
coronaryy sinus branches remains a challenging procedure (see figure 3. for
exampless of coronary sinus leads).
Heartt failure and rationale for biventricular pacing
Inn heart failure patients, conduction delay progressively develops and is associated
withh a poor outcome. Conduction delay, usually present at different levels, namely
atrioventricular,, interventricular and/ or intraventricular, is associated with
paradoxicall septal movement, presystolic mitral regurgitation, disturbed left
ventricularr AV-timing and reduced diastolic fillin g time. Asynchronous activation
leadss to long-term adaptation of the myocardium, usually referred to as remodeling.
21 1
Rightt ventricular pacing leads to ventricular dilatation and asymmetric hypertrophy,
fiberr disarray, increased myocardial catecholamine concentrations and disturbed
perfusionn tsee figure 4).41 The disturbed delayed electrical activation in patients
withh heart failure results in an abnormal contraction pattern and abnormal
mechanicall loading conditions of the myocardium with increased wall stress and
myocardiall oxygen consumption. The reduced pump function increases
neurohumorall activity, which is beneficial on short term, but on long term this
increasee has many deleterious effects.
Inn this thesis, we report on studies that attempted to further elucidate the
beneficiall effects of CRT on the neurohumoral imbalance (chapter 7) and whether
microcirculatoryy changes could be observed with CRT (chapter 8).
Thee rationale for biventricular pacing in heart failure patients is: 1) to reverse the
mechanicall dyssynchrony by improving the atrio-ventricular, interventricular and
intraventricularr dyssynchrony and 2) to correct the asymmetric activation of the
mitrall papillary muscles with reduction of mitral valve insufficiency. Improved
Neurohumoral l activation n
Regional l Differences s
Mechanicall work
Asynchronouss electrical activation T^
I I —— Dyscoordinate contraction
___J J Reducedd pump function
Rightwardd shift Increased pressuree volume relation wall stress
Ventricularr dilatation
-> Hypertrophy
Longerr conduction pathh length
f t t
Molecular/cellular r changes s
Asymmetric hypertrophy
Figuree 4 Proposed relation between events following onset of asynchronous electrical activation (modifiedd from Vernooy et al. with permission.1~"
22 2
Chapterr I
synchronouss activation of the heart leads to earlier activation, earlier relaxation and
earlierr rapid fillin g with increased left ventricular fillin g time and as consequence
ann increased left ventricular ejection fraction. In responders to biventricular pacing
(700 to 80% of the patients) an acute reduction of mitral regurgitation and long term
reversedd remodeling of the myocardium can be achieved.42
Clinicall trials on CRT
Severall trials provided clinical evidence for the beneficial effects of CRT.43'45 These
beneficiall effects of CRT include: improvement in quality of life, 6-minute walking
distance.. NHYA functional class, peak oxygen consumption, treadmill exercise time,
cardiacc geometry, ejection fraction and reduction of hospitalizations for heart
failure.. In most of these trials, inclusion criteria required heart failure patients to
bee in NYHA III or IV. sinus rhythm. QRS > 120 msec of left bundle branch block type.
andd left ventricular ejection fraction < 35%.
Thee PAcing THerapies for Congestive Heart Failure (PATH-CHF) and MUltisite
STimulationn In Cardiomyopathy (MUSTIC) studies had a cross-over design, whereas
thee Multicenter Insync RAndomized CLinical Evaluation (MIRACLE) and CONTAK
CDD trials are parallel arm studies with controls (device implanted but pacing
inactivated).455 The Comparison of Medical therapy. Pacing aNd defibrillatlON in
heartt failure (COMPANION) trial randomized 1520 patients in a 1:2:2 ratio to receive
optimall pharmacological therapy alone or in combination with CRT with either a
pacemakerr or a pacemaker-defibrillator.46 The primary composite end point was the
timee to death from or hospitalization for any cause. This study showed that in
patientss with advanced heart failure and prolonged QRS interval, CRT decreases the
combinedd risk of death from any cause or first hospitalization and, when combined
withh an implantable defibrillator, also significantly reduces mortality.47 A recent
meta-analysiss suggests that CRT also without implantable defibrillator back-up
reducess mortality from heart failure.48 The ongoing Cardiac Resynchronization in
Heartt Failure (CARE-HF) study is powered to detect a beneficial effect of CRT on all
causee mortality.49
Nowadays,, patients are selected mainly on electrocardiographic criteria. However,
thee standard EKG is less reliable in the characterization of the extent of
dyssynchrony.. since even patients with normal QRS duration on EKG can have
markedd dyssynchrony. while 20-30% of patients with wide ORS complexes do not
respondd to CRT.50 Patient selection using advanced tissue Doppler>maging
techniquess is likely to improve the response rate to CRT.51
Outlin ee of this thesis
Thee first part of this thesis (chapter 2 to 6) concerns the clinical evaluation of
pacemakerr sensors, especially the effect of individual optimization of pacemaker
sensorss on exercise physiology and quality of life. The second part of this thesis
(chapterr 7 to 9) concerns the effect of cardiac resynchronization therapy on cardiac
function,, the neurohumoral system and the microcirculation in patients with heart
failure.. To gain insight into these issues, research concerning rate-adaptive
pacemakerss and cardiac resynchronization therapy has been performed and the
thesiss has been outlined accordingly.
Partt I Studies on pacemaker sensors
Chapterr 2 studied the literature whether manual rate adaptive optimization is
necessaryy in current rate response pacemakers. The various types of sensors, the
effectss of manual sensor optimization, tools for rate response optimization,
pacemakerr automaticity and automatic optimization of sensors are reviewed.
Inn chapter 3 heart rate curves of healthy individuals of various ages are described
duringg the chronotropic assessment exercise protocol and 6- minute hall walk test
withh focus on the achieved time to maximal heart rate, achieved maximal heart rate
andd achieved exercise duration.
Chapterr 4 investigated the influence of individual optimization of sensors on
qualityy of life and exercise tolerance in a randomized, single blind study in patients
withh WIR, DDDR or AAIR pacemakers.
Inn chapter 5 programming the pacemaker to default is compared to optimizing the
pacemakerr sensors with regard to the effects on blood pressure, cardiac output,
strokee volume and mean flow velocity in the middle cerebral artery during graded
ergometryy cycling.
Chapterr 6 provides a direct comparison of the chronotropic functions of two types
off sensors: the peak endocardial acceleration (PEA) and the activity sensor.
24 4
Chapterr ]
Partt II Studies on biventricular pacing
Chapterr 7 examined whether cardiac resynchronization therapy induces
neurohumorall improvements in patients with heart failure and cardiac
dyssynchrony. .
Chapterr 8 investigated the sub-lingual microcirculatory changes in heart failure
patientss as a result to cardiac resynchronization therapy and right ventricular
pacingg by use of orthogonal polarization spectral imaging.
Chapterr 9 described one of the first patients who was upgraded to biventricular
pacingg after worsening of his heart failure with increase of mitral regurgitation due
too WIR pacing after His bundle ablation. This chapter also reviews the literature
concerningg reversed remodeling of the left ventricle after biventricular pacing.
Chapterr 10 and 11 summarizes and discusses the main findings derived from the
studiess described in the previous chapters (english and dutch).
25 5
References s
1.. Senning A. Cardiac pacing in retrospect. Am } Surg. 1983:145:733-9-2.. Mercuriale G. De cognoscendis e curandis humani corporis affectibus. opera postuma.
1606:238.. 242. 243. 3.. Galvani L. De viribus electricitatis in motu musculari commentaris. Bologna Instit Scient.
1771. . 4.. Bichat X. Recherches physiologiques sur la vie et la mort. Paris:Brosson. Gabon & Cie. 1800. 5.. Jeffrey K, Parsonnet V. Cardiac pacing, 1960-1985: a quarter century of medical and industrial
innovation.. Circulation. 1998;97:1978-91. 6.. Hyman A. Resuscitation of the stopped heart by intracardial therapy. Experimental use of an
artificiall pacemaker. Arch Intern Med:50:283-305-7.. Zoll PM. Resuscitation of the heart in ventricular standstill by external electric stimulation. N
EnglEngl J Med. 1952:247:768-71. 8.. Elmqvist R. Review of early pacemaker development. Pacing Clin Electrophysiol. 1978:1:535-6. 9.. Chardack WM, Gage AA. Greatbatch W. A transistorized, self-contained, implantable pacemak-
err for the long-term correction of complete heart block. Surgery. 1960:48:643-54. 10.. Zoll PM, Frank HA. Zarsky IX Linenthal AJ, Belgard AH. Long-term electric stimulation of the
heartt for Stokes-Adams disease. Ann Surg. 1961:154:330-46. 11.. Mond HG, Irwin M. Morili o C, Ector H. The world survey of cardiac pacing and cardioverter
defibrillators:: calendar year 2001. Pacing Clin Electrophysiol. 2004:27:955-64. 12.. Nathan DA, Center S, Wu CY, Keiler W. An implantable synchronous pacemaker for the long
termm correction of complete heart block. Am J Cardiol. 1963:11:362-7. 13-- Zuckerman W. Zaroff LI. Berkovits BV, Matloff ]M. Harken DE. Clinical experiences with a new
implantablee demand pacemaker. Am J Cardiol. 1967;20:232-8. 14.. Funke H. Optimized sequential pacing of atria and ventricles: A new concept in treatment of
bradycardiacc dysrhythmias. Herz Kreislauf. 1978:10:479-483. 15.. Furman S. Schwedel JB. An intracardiac pacemaker for Stokes-Adams seizures. AT Engl J Med.
1959:261:943-8. . 16.. Furman S, Parker B. Escher DJ. Schweldel [B. Instruments for evaluating function of cardiac
pacemakers.. Med Res Eng. 1967:6:29-32. 17.. Furman S, Parker B, Escher DJ. Transtelephone pacemaker clinic. N YState ]Med.
1971:71:1931-2. . 18.. Parsonnet V. Cuddy TE. Escher DJ. Furman S, Morse D, Gilbert L. Zucker IR. A permanent
pacemakerr capable of external non-invasive programming. Trans Am Soc Artif Intern Organs. 1973:19:224-8. .
19.. Ellenbogen KA. Cardiac pacing. 1996:66-88. 20.. Chardack WM. A Myocardial Electrode for Long-Term Pacemaking. Ann N Y Acad Sci.
1964:111:893-906. . 21.. Hunter SW, Roth NA. Bernardez D, Noble JL. A bipolar myocardial electrode for complete
heartt block. J Lancet. 1959:79:506-8. 22.. Ellenbogen K. Wilkoff . Clinical cardiac pacing and defibrillation. 2000:127-147. 23.. Mond HG. Unipolar versus bipolar pacing—poles apart. Pacing Clin Electrophysiol.
1991;14:1411-24. . 24.. de Voogt WG. Pacemaker leads: performance and progress. Am J Cardiol. 1999:83:187D-191D. 25.. Greatbatch W. Lee JH, Mathias W, Eldridge M, Moser JR, Schneider AA. The solid-state lithium
battery:: a new improved chemical power source for implantable cardiac pacemakers. IEEE TransTrans Biomed Eng. 1971:18:317-23.
26.. Parsonnet V, Myers GH, Gilbert L, Zucker IR. Clinical experience with nuclear pacemakers. Surgery.Surgery. 1975:78:776-86.
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27.. Gregoratos G, Abrams J. Epstein AE, Freedman RA. Hayes DL. Hlatky MA, Kerber RE. Naccarel-lii GV. Schoenfeld MH, Silka MJ. Winters SL, Gibbons RI. Antman EM. Alpert JS, Hiratzka LF, Faxonn DP. Jacobs AK. Fuster V, Smith SC. Jr. ACC/AHA/NASPE 2002 guideline update for im-plantationn of cardiac pacemakers and antiarrhythmia devices; summary article. A report of thee American College of Cardiology/American Heart Association Task Force on Practice Guide-liness tACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines), J Cardiovasc ElectiophysiolElectiophysiol 2002:13:1183-99.
28.. Hayes DL. Furman S. Cardiac pacing: how it started, where we are. where we are going. Pacing ClinClin Electrophysiol 2004:27:693-704.
29.. Skanes AC, Krahn AD, Yee R. Klein G). Connolly SJ. Kerr CR. Gent M, Thorpe KE Roberts RS. Progressionn to chronic atrial fibrillation after pacing: the Canadian Trial of Physiologic Pacing. CTOPPP Investigators. J Am Coll Cardiol. 2001:38:167-72.
30.. Newman D. Lau C. Tang AS. Irvine J. Paquette M. Woodend K, Dorian P, Gent M, Kerr C, Con-nollyy SJ. Effect of pacing mode on health-related quality of lif e in the Canadian Trial of Physi-ologicc Pacing. Am Heart J. 2003:145:430-7.
31.. Hussein SJ, Hennekens CH, Lamas GA, An update on clinical trials in pacing: is dual chamber pacingg better? Curr Opin Cardiol 2004:19:12-8.
32.. Lamas GA, Lee KL, Sweeney MO, Silverman R, Leon A. Yee R. Marinchak RA, Flaker G, Schron E.. Orav EJ, Hellkamp AS, Greer S, McAnulty J, Ellenbogen K, Ehlert F, Freedman RA. Estes NA, 3rd,, Greenspon A, Goldman L. Ventricular pacing or dual-chamber pacing for sinus-node dys-function,, N Engl J Med. 2002:346:1854-62.
33.. Lamas GA. Orav EJ, Stambler BS. Ellenbogen KA, Sgarbossa EB. Huang SK, Marinchak RA, Estes NA.. 3rd, Mitchell GF, Lieberman EH, Mangione CM, Goldman L. Quality of lif e and clinical out-comess in elderly patients treated with ventricular pacing as compared with dual-chamber pac-ing.. Pacemaker Selection in the Elderly Investigators. N Engl J Med. 1998:338:1097-104.
34.. Wilkoff BL. The Dual Chamber and WI Implantable Defibrillator (DAVID) Trial: rationale, de-sign,, results, clinical implications and lessons for future trials. Card Electrophysiol Rev. 2003;7:468-72. .
35.. Andersen HR, Thuesen L, Bagger JP, Vesterlund T, Thomsen PE. Prospective randomised trial of atriall versus ventricular pacing in sick-sinus syndrome. Lancet. 1994:344:1523-8.
36.. Toff WD, Skehan JD. De Bono DP, Camm AJ. The United Kingdom pacing and cardiovascular eventss (UKPACE) trial. United Kingdom Pacing and Cardiovascular Events. Heart. 1997:78:221-3.
37.. Kosowsky BD, Scherlag BJ, Damato AN. Re-evaluation of the atrial contribution to ventricular function:: study using His bundle pacing. Am J Cardiol. 1968:21:518-24.
38.. Bakker PF dJN, van Mechelen R. Wittkampf F. Mower M, Thomas A. Beneficial effects of biv-entricularr pacing incongestive heart failure. PACE. 1994:17:20.
39.. Bakker PF MH, de Jonge N, van Mechelen R, wittkampf F, Mower M. Thomas A. Beneficial ef-fectss of biventricular pacing in congestive heart failure. PACE. 1994; 17:20,
40.. Moss A, Rivers R. Jr, Kramer D. Permanent pervenous atrial pacing from the coronary vein. Long-termm follow-up. Circulation. 1974:49:222-225-
41.. Prinzen FW, Delhaas T, Arts T, Reneman RS. Asymmetrical changes in ventricular wall mass by asynchronouss electrical activation of the heart. Adv Exp Med Biol. 1993:346:257-64.
42.. Erol-Yilmaz A, Tukkie R. Schrama TA. Romkes HJ. Wilde AA. Reversed remodelling of dilated leftt sided cardiomyopathy after upgrading from WIR to WIR biventricular pacing. Europace. 2002;4:445-9. .
43.. Auricchio A, Stellbrink C, Sack S, Block M. Vogt J, Bakker P. Mortensen P. Klein H. The Pacing Therapiess for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of aa prospective randomized multicenter study. Am ƒ Cardiol. 1999;83;130D-135D.
44.. Auricchio A. Stellbrink C, Sack S. Block M, Vogt J. Bakker P, Huth C, Schondube F, Wolfhard U, Boekerr D. Krahnefeld O, Kirkels H, Long-term clinical effect of hemodynamically optimized cardiacc ^synchronization therapy in patients with heart failure and ventricular conduction delay.. J Am Coll Cardiol. 2002;39:2026-33.
45.. Lau CP, Barold S, Tse HF, Lee KL, Chan HW. Fan K, Chau E. Yu CM. Advances in devices for car-diacc ^synchronization in heart failure, ƒ Interv Card Electrophysiol. 2003;9:167-81,
21 21
46.. Salukhe TV, Francis DP, Sutton R. Comparison of medical therapy, pacing and defibrillation in heartt failure {COMPANION! trial terminated early: combined biventricular pacemaker-defi-brillatorss reduce all-cause mortality and hospitalization. Int f Cardiol. 2003:87:119-20.
47.. Bristow MR, Saxon LA. Boehmer J, Krueger S, Kass DA. De Marco T. Carson P. DiCarlo L. DeMetss D. White BG. DeVries DW. Feldman AM. Cardiac-resynchromzation therapy with or withoutt an implantable defibrillator in advanced chronic heart failure. NT Engl J Med. 2004:350:2140-50. .
48.. Bradley DJ, Bradley EA, Baughman KL. Berger RD. Calkins H, Goodman SN. Kass DA, Powe NR. Cardiacc resynchronization and death from progressive heart failure: a meta-analysis of rand-omizedd controlled trials. Jama. 2003:289:730-40.
49.. Cleland JG. Ghosh J, Khan N, Hurren S. Kaye G. Ongoing trials of cardiac resynchronisation. MinervaMinerva Cardioangiol. 2003:51:197-207.
50.. Peichl P. Kautzner J, Cihak R, Bytesnik J. The spectrum of inter- and intraventricular conduc-tionn abnormalities in patients eligible for cardiac resynchronization therapy. Pacing Clin Elec-trophysiol.trophysiol. 2004:27:1105-12.
51.. Bax [J. Ansalone G. Breithardt OA, Derumeaux G, Leclercq C, Schalij M], Sogaard P, St John Suttonn M. Nihoyannopoulos P. Echocardiographic evaluation of cardiac resynchronization therapy:: ready for routine clinical use? A critical appraisal. ƒ Am Coll Cardiol. 2004;44:1-9.
52.. Vernooy K, Verbeek XA. Peschar M, Prinzen FW. Relation between abnormal ventricular impulsee conduction and heart failure. / Interv Cardiol. 2003:16:557-62.
x x
Iss manual rate response optimization necessaryy in current rate adaptive
pacemakers? ?
Aytenn Erol-Yilmaz MD and Raymond Tukkie MD PhD
SubmittedSubmitted for publication
Abstract t
Background d
Automaticc functions are increasing in rate adaptive pacemakers. Whether we can
relyy on these automatic functions in daily practice is limited described. We
thereforee review in this article various types of sensors and try to answer the
questionn if manual rate response (RR) optimization improves patient outcome and
iss still necessary with the existing automaticity in RR pacemakers,
Material ss and methods
AA literature search was performed in journal articles published in Medline using the
keywordss rate adaptive pacemakers, sensors, automaticity, optimization, quality of
lif ee (QOL) and exercise.
Results s
Despitee sophisticated sensor systems and algorithms, today there is still as yet no
sensorr system that can simulate ideal sinus rhythm behavior. The majority of
pacemakerss are programmed in default sensor setting, although there is evidence
thatt individual optimization of sensors is beneficial. Limited studies are done
clarifyingg the clinical benefit of automatic features. Although exercise tests and
QOLL questionnaires are most used for evaluating of RR optimization internationally,
clearr guidelines for optimization are lacking.
Conclusions s
Automaticc features can be helpful in reducing time during follow-up of pacemakers,
howeverr individually adjustment of pacing sensors is still necessary.
32 2
Chapterr 2
Introductio n n
Thee first rate adaptive pacemaker, capable of altering paced rate on the basis of
inputt from a sensor incorporated in a pulse generator was proposed by Krasner in
1966.11 In 1982, the first rate adaptive (RR) pacemakers were implanted for treatment
off chronotropic incompetence in bradyarrythmias and they became available for
generall use in the United States in 1986.
Onee of the aims of a pacemaker sensor is to simulate normal sinus response.
Despitee large number of implantable sensors to detect exercise that have been
proposedd or instrumented in pacing devices, there is as yet no single sensor that
cann simulate ideal sinus node behavior.2 Many sensors have failed to demonstrate
adequatee chronotropic response after experimental or preliminary clinical studies:
oxygenn saturation, and central venous temperature.3"5 In the surviving artificial
sensorss (activity, OT interval, minute ventilation, peak endocardial acceleration
(PEA)),, several limitations have been observed, related mainly to sensor
characteristics:: speed of response, sensitivity to exercise versus no exercise
stimulation,, specificity to increases in oxygen demand, proportionality and
responsee to different exercise modalities.2 6"9 However, optimal operation of these
pacemakerss depends on correct functioning and programming of the implanted
sensor.. In the future, the role of sensors could expand to include functions other
thann rate augmentation, such as monitoring of cardiac hemodynamics during heart
failure,, which is beyond the scope of this article.
Automaticc functions are increasing in RR pacemakers. Whether we can rely on these
automaticc functions in daily practice is limitedly described. The last review about
RRR pacing dates from 2000,7 The purpose of this review is to outline if manual RR
optimizationn improves patient outcome and is still necessary with the existing
automaticityy in RR pacemakers. The various types of sensors, the effects of manual
sensorr optimization, the tools for RR optimization, automaticity and automatic
optimizationn of sensors are reviewed. Search is performed in journal articles
publishedd between 1966 and 2004 indexed in Medline using the keywords rate
adaptivee pacemakers, sensors, automaticity. optimization, QOL and exercise.
33 3
Algorithmss and rate response
Ratee adaptive pacemakers have two basic components, the sensor Is) and
algorithms.. Sensors detects raw physical and physiological changes and algorithms
transformm these raw sensor data into a corresponding heart rate.2'8 Q The obtained
raww sensor data are first filtered to exclude unwanted signals and then modified
appropriately.. These filtered signals are then converted into a rate response (RR)
curvee e.g. linear, curvilinear or tri-phasic. In accessible pacemakers, the physician
cann modify the RR by changing this filter.
Twoo different algorithms are used in practice: 1) counting energy-peaks, which pass
throughh the threshold according to the programmable thresholds 'low, medium or
high'.. 2) integrating the voltage graph over a standardized interval. Corresponding
too the programmable threshold, a specific value is subtracted from the computed
integral.. The remaining signal is transformed into the stimulation rate.
Theree are two ways (open or closed loop systems) in a RR pacemaker, which can
drivee an algorithm to induce an HR. An open loop system detects a physiological or
physicall change and is used in most currently available sensors. This change in turn
initiatess an algorithm where after a HR is created. Dependent on how sensor
settingss are programmed by the physician a specific HR wil l be produced. An open
loopp system is easily implemented and usually does not require special pacing
electrodes.. An example is an activity sensing system that detects body movements.
AA closed loop system detects a physiological change, for instance blood
temperature,, and reacts with a negative feedback. This negative feedback induces a
physiologicall change in opposite direction, so that the physiological variation
responsiblee for the rate change wil l return to the baseline condition. The
physician'ss role in obtaining a clinically desired rate is in this system minimal.
Activityy based sensors
ActivityActivity sensor
Jacquess and Pierre Curie first discovered piezoelectricity in 1880 when they struck
quartzz with a hammer and noticed an electric signal. Today most piezoelectric
materialss are ceramics like barium titante or lead zirconate, however they are still
calledd crystals, and work in the same way: bending or deforming the crystal
34 4
Chapterr 2
producess an electric signal. By means of a piezoelectric crystal attached to the inside
off the pacemaker can (see figure la), vibrations above a programmable threshold are
treatedd as counts, the frequency of which can then be converted into a pacing rate
byy a series of programmable slope of rate responses. This is a mechanical sensor,
whichh detects physical activity signals in a range of 1-5 Hz so electrical inputs
intoo the enclosure, such as myopotentials. are not sensed. In the LIVIN G I (Sorin
Biomedica.. Sallugia, Italy) is the physical activity sensor of a gravitational type and
thereforee particularly sensitive to vertical displacement of the body. Functioning of
thiss sensor is based on the opening/closing of a mobile contact consisting of a
droplett of mercury of appropriate inertial mass. The physical/dimensional
characteristicss of the sensor and associated electronic circuit are designed to select
signalss with rates typical of physical activity (2-5 Hz).
Humenn et al. reported the initial clinical experience of 6 patients implanted with
thee piezoelectric crystal.' Improvement in cardiac output was observed in all
patientss in the rate responsive mode. However, they were unable to demonstrate
improvementt of exercise capacity in their patients because exercise tolerance of
somee patients was limited by noncardiac factors such as intermittent claudication.
Inn subsequent larger studies, improvement of exercise capacity has been
demonstratedd beside the reported symptomatic benefit.11 '2
Thee main advantage of the activity sensor is the rapid onset of RR at the onset of
isotonicc exercise. A disadvantage of this sensor is that the RR of the sensor does not
correlatee closely with sinus rate (see table I and 2). Especially during walking up an
inclinee or cycling, inadequate low HR are achieved with this sensor while riding a
carr can induce inappropriate high HR.13 Thus although activity-sensing RR pacing
givess a prompt increase in pacing rate and improves maximum exercise tolerance,
furtherr refinement is necessary because detection of vibrations as indicator of
activitiess does not correlate well with the level of exertion. 14 These limitations
aree probably due to direct attachment of the crystal to the pacemaker can and to
nonselectivee processing of vibration signals.
Electronics s
Activity y
Figuree l.a: Activity sensor mounted inside in the pacemakerr can.
Battery y
35 5
Accelerometer Accelerometer
Measurablee acceleration forces applied to the human body during different types of
physicall stress were published for the first time in 1988.1:,Accelerometer-based RR
stimulatorss were then developed using sensors directly mounted on the hybrid
circuitt (plate with electronic circuitry of the pacemaker without battery) coupled
withh low pass filters, see figure lb.1 3 , 1 6'18
Betweenn accelerometers there are differences in: 1) which direction of the body
accelerationn is measured: 2) range of the low pass filters used (1-10 Hz) and 3) the
designn of the accelerometer. The different directions nowadays used for body
accelerationn are anteroposterior, horizontal, vertical or biaxial. There are also
triaxiall accelerometers but as far as we now not yet used in pacemakers.1
Triaxiall accelerometers can have advantages in RR pacing due to improvement in
describingg physical activity and as a consequence the RR. Steele et al. showed that
thee triaxial accelerometer has the potential to provide more precise measurement of
dailyy physical functioning in COPD patients.
Thee response of the accelerometer to exercise is rapid and can accommodate brief
activities,, such as running and stair-climbing in which a brisk increase in HR is
requiredd and adapts pacing rates during treadmill exercises independent of
treadmilll speed or slope better than those controlled by a conventional housing
pressuree or vibration sensor.~' However, physiological activities such as handgrip,
valsalvaa maneuver, are not associated with significant vibrations, therefore the
pacingg rate does not correlate well with the level of exertion. Furthermore,
accelerationn signal amplitudes could vary up to 20% from patient to patient during
comparablee treadmill tests.22 Different walking behaviors or inclinations of the can
onn the prepectoral area could account for these variations.23 Also the nature of
patient'ss footgear could influence acceleration levels. 2A Therefore, individually
calibratingg the accelerometer signals seems crucial.
Figuree l.b: Sensor mounted on hybrid circuit.
Accelerometer r Battery y
Electronics s
36 6
Chapterr 2
Physiologicc sensors
QTQT sensor
Rickardss et al. established the principle of using the paced evoked QT interval
(figuree 3) to determine pacing rate in 1983.2b This parameter has been used in the
developmentt of a QT sensing pacemaker (Vitatron, Arnhem, The Netherlands). The
pacedd QT (stimulus-t) interval is measured from the pacemaker spike to the
maximumm negative deflection of first derivate of the endocardial T wave (see figure
2).. An algorithm converts the change in stimulus-T interval into a change of pacing
rate.. There is a non-linear relationship between pacing and evoked QT intervals.
Thee principle of the evoked QT interval is that the QT interval shortens during
physicall exercise and mental stress. Approximately half of this shortening is
broughtt about by an increase in HR. but the other half is probably related to direct
effectt of catecholamines, such as those induced by emotional stress.27 2& Drugs,
myocardiall ischemia, and electrolyte changes vary also the duration of QT interval
andd hence the HR in the absence of changes on metabolic demand.29
Althoughh response to stress appears physiological, a potential disadvantage of this
sensorr could be undesirable tachycardia mediated by an increased sympathetic
tone,, occurring in stressful situations like angina pectoris or acute myocardial
infarction.30,311 Another disadvantage of this sensor is the slow response especially
inn the first stage of exercise, even though in new QT software with dynamic slopes
theree is a reduction of t ime delay of RR and also an improved correlation between
thee sinus activity and pacing rate in the dynamic algorithm. Close follow-up and
frequentt reprogramming, guided by results of exercise tests and holter monitoring,
mayy be necessary to adjust for chronic changes in QT parameters to ensure that the
sensorr continues to function optimally. Particularly because under identical
conditions,, the HR/QT and HR rate /stimulus-T interval relations vary significantly
inn different patients and in the same subject from one occasion to another,32
Thee QT sensor can also be used for AV- interval optimization which was
demonstratedd by Ishikawa et al.35 They studied the relationship between AV delay
andd evoked QT interval and cardiac function in 13 elderly patients with an
implantedd QT-driven DDDR pacemaker. A special pacemaker software module was
downloadedd into the pacemaker memory for evoked QT interval data logging.
37 7
AVV delay was set at 100, 120, 150, 180, 210 and 240 ms. Cardiac output was
measuredd by continuous wave Doppler echocardiography. The cardiac output was
maximall when AV delay was set at the AV delay at which the evoked QT interval was
maximal,, They conclude that the optimal AV delay can be predicted from the evoked
QTT interval sensed by an implanted pacemaker and automatic setting of the optimal
AVV delay can be achieved by the OT sensor of an implanted pacemaker.
kk >1 QTT interval
Figuree 2. OT-interval after a ventricular stimulus.
MinuteMinute ventilation sensor
Rossii et al. have shown that changes in the respiratory rate correlate significantly
withh changes in HR during exercise. 34 First respiratory pacemakers sensed the
respirationn rate using an auxiliary lead, which was implanted subcutaneous and
weree susceptible to erosion. Nappholtz et al. have shown the possibility of
intracardiacc measurement of MV using impedance measuring. Impedance is a
measuree of electric resistance and derived by measuring the resistance from an
injectedd electric current across a tissue (see figure 3). The impedance principle has
beenn used extensively for measuring respiratory parameters. Minute ventilation
(MV,, the product of respiratory rate and tidal volume) is derived in the pacemaker
byy using current pulses, injected between the proximal ventricular or atrial
electrodee and the pacemaker casing.
Lauu et al. described the initial clinical experience with the MV sensor in the Meta
pacemakerr (Telectronics-Cordis. Colorado, USA). They showed that rate modulated
pacingg by sensing MV resulted in better exercise capacity and symptomatology. ' In
thee new generation pacemakers, for example the Insignia ™ (Guidant Minnesota,
38 8
Chapterr 2
USA).. MV is still measured by transthoracical impedance changes. The sensed MV
changess are translated into a rate change using slope or RR factor. The main
disadvantagee of this senor is the initial delay of 30 seconds at the onset of exercise
beforee RR is observed, although nervous activity results in an almost instantaneous
changee of ventilation.
Differentt conditions with no direct relevance to cardiac output may affect
respiration,, and hence, the RR behavior of MV sensor. For example, Cheyne-Stokes
breathingg may be associated with inappropriate tachycardia during the rapid
breathingg phase. MV may be interrupted if the patient is talking during exercise and
duee to patient activities, such as upper limb and in particular arm movement. Other
factorss which can influence the RR obtained by the MV sensor are: concomitant
heartt failure, pulmonary disease, posture difference, breathing patterns, type of
exercise,, phonation and coughing.'8 Especially in patients with for example
hyperventilation,, pacemakers with other sensors may be preferable because
otherwisee accurate RR adjusting can be difficult .
Figuree 3- Transthoracic impedance mesurement. 1= current. V = voltage
PeakPeak endocardial acceleration sensor
Thee PEA sensor mounted at the tip of the right ventricular pacing lead, can measure
thee mechanical vibrations generated by the left ventricular myocardium during the
isovolumetricc contraction phase. The sensor detects natural heart acceleration,
whichh represents the endocardial acceleration at the interface between the lead tip
andd the myocardial wall (see figure 4). The peak-to-peak amplitude of the
39 9
endocardiall acceleration signal is detected during the isovolumetric ventricular
contractionn phase. Although the PEA parameter is a time period and not an actual
volumee measurement, PEA and stroke volume are closely related, and PEA gives an
indirectt indication of the contractility of the myocardium.39Contractility is sensitive
too adrenergic stimulation that accompanies increase in metabolic needs and can
supplyy relevant information regarding the patient's hemodynamics.39 The PEA
signall is not influenced by HR but is significantly increased by emotional stress,
exercisee stress, inotropic stimulation and follows linearly the changes in maximum
leftt ventricular dP/dt. In addition this sensor appears to measure global left
ventricularr contractile performance rather than regional mechanics.
Dataa from the European multicenter study of 1-month and 1-year confirmed that
PEAA is a stable long-term parameter that can be used for physiological driving of a
RRR pacemaker. The evaluation of the study confirmed the absence of adverse long-
termm effects, and the reliability of the sensor, lead sensing and pacing performances
remainedd within the expected range.6,40,41 Clementy et al. validated the PEA sensor
withh serial standardized exercise testing and showed that PEA sensor successfully
restoredd chronotropic response in a population of paced patients with severe
chronotropicc incompetence.42
Rickardss et. al. suggest that the PEA reflects the underlying contractile state of the
entiree heart and is not sensitive to local myocardial properties at the location of the
accelerometer,, however it must be considered that they worked with favourable
conditionss like normal geometry of the ventricles. Interpreting the results of the
PEAA measurements can be more difficult in patients with heart failure with valve
insufficiencyy or regional contractile dysfunction. Another limitation in general, is
thee use of uniaxial acceleration measurements because ventricle displacement and
thereforee acceleration follows a very complicated three-dimensional trajectory. The
possibilityy that the three-dimensional amplitude response may be different from
thee one dimensional measurement cannot be ruled out although in some studies,
PEAA is described as insensitive to local myocardial properties or the location of the
accelerometerr lead."13
Besidee appropriate use in RR pacing, the PEA signal results in new options such as
automaticc AV delay optimization. Previous studies showed a close relationship
betweenn PEA, first heart sound, and the AV delay. A louder first heart sound is
observedd with short AV delays as the ventricle contracts after atrial emptying.44 45
Dupuiss et al. showed that the optimal AV delay estimates obtained by the PEA
40 0
Chapterr 2
analysiss during automatic AV delay scanning are consistent with those obtained by
echocardiography.. 45 Recent clinical trials have shown that selected patients with
recurrentt vasovagal syncope may benefit from permanent pacing with a PEA sensor.
Thee authors demonstrated using head-up til t testing that increase in sympathetic
activityy preceding syncope could be sensed by a PEA sensor. 4 A1 The PEA sensor is a
promisingg tool for long-term hemodynamic monitoring and serial evaluation of the
effectss of multisite ventricular pacing in heart failure patients.48 Another possibility
withh the PEA signal is the estimation of the aortic diastolic pressure with the PEA II
signall ( = the abrupt deceleration of the moving aortic blood mass).49 Disadvantages
off the sensor are mostly related to the lead characteristics (lead body size) and the
sensorr location. The PEA sensor is located at the lead tip. consequently sensor
failuree necessitates a new lead insertion.
Forcee transducer Electronics s
Pacingg tip Rigidd and hermetic can Microo mass
Inert iall acceleration
Figuree 4. PEA sensor system.
Sensorr combination
Thee achieved rate profile during treadmill exercise testing resulting from dual
sensorr pacing (with complementary properties) is improved over single sensor
pacingg because sensor combination provides improvement in speed,
proportionality,, sensitivity and specificity.9 5 Combinations include association of
ann activity sensor giving an aggressive response for exercise that is light and/or of
shortt duration and a non-activity sensor, e.g., OT interval or minute ventilation,
addedd to provide a delayed but proportional and stable acceleration to sustained
exercisee and deceleration during recovery.2
Thee association of two sensors allows compensation of failure of one by the other.
41 1
Combiningg sensors is theoretically superior, but no clinical study has yet
demonstratedd this superiority in terms of quality of life. As far as proportionality
andd speed of RR are concerned, the current sensor combinations are an
improvementt over single sensor pacing.
Sensorr blending and cross-checking
Combiningg sensors with different RR properties requires adequate blending of
respectivee sensor activities. The sensor blending could be performed in several ways.
Blendingg can be performed at signal production as for example in the blending system
usedused in the Vitatron devices (Vitatron, Arnhem. The Netherlands), combining QT
intervall and activity in 5 different possibilities (activity, activity > QT interval,
activity=QTT interval, activity <QT interval, QT interval). This blended signal is
transmittedd to the algorithm working with a variable automatic slope. The resulting
signall that is transmitted to the algorithm is a mixture of a percentage of activity
sensorr signal with an inverse percentage of QT sensor signal.51
Anotherr possibility for sensor blending is prioritisation as in Medtronic Kappa series.
Thee activity sensor initially accelerates the rate from the lower rate to a daily life
plateauu (programmable 90-95 beats/min). The rate returns to the lower rate if effort
stopss or is accelerated proportionally from the plateau by the MV sensor up to the
maximumm sensor rate, which then is in charge of the recovery rate decrease. Sensor
crosss checking is used to avoid inappropriate rate increase.
Thee insignia I (Guidant, Minnesota, USA) combines quantitative blending and
prioritisationn with cross checking.52 At the beginning of an effort, the signal of the
activityy sensor is usually faster than the MV sensor signal. At lower rates, the
influencee of the acceleration sensor is higher than MV. As long as the activity signal
iss higher than the MV signal, the magnitude of the RR provided by the activity signal
iss still higher then the influence of activity sensor controlled by the MV sensor
(prioritisation).. If. at maximum sensor rate, the activity signal is still higher, then
thee influence of accelerometer is lower than MV (cross checking). When the MV
signall is higher than the activity signal, a steady state or recuperation is assumed
andd RR is based on MV dependence. The physiologic relationship between MV and
ratee is approximately bilinear. During exercise levels up to the anaerobic threshold,
thiss relationship can be approximated by a linear relationship. At exertion levels
abovee the anaerobic threshold, the slope becomes less pronounced. The
42 2
Chapterr 2
relationshipp between the secondary slope and the primar y slope varies from person
too person and depends on several factors such as gender, age, and exercise
frequencyy and intensity.
Thee importance of optimized programming is illustrated by the study of Lau et al.
Hee studied the effect of sensor cross-checking in a dual sensor system with an
activit yy and QT sensor in 4 patients. Rate response setting of each sensor was
individuall yy optimized, and an equal rate contributio n for the OT and activity
sensorss (QT=activity ) was used. Three maximal treadmil l exercise tests were
performedd in random order in three different sensor blending setting, QT only.
QT=activity .. and in activity only. In the dual sensor mode, the time for onset of RR
(delayy time) was reduced compared with OT only. However, the time to reaching
50%% of RR in the low activity threshold dual sensor mode was delayed compared to
sensorr blending setting (QT = activity) and was similar to the QT only mode. Lau et
al.. showed that programming the activity threshold to low. results in sensor
crosscheckingg at rest, which limit s the speed of RR onset.
Tablel.. Advantages and disadvantages of currently available sensors
Sensors s Advantages s Disadvantages s
Activity/accelee rome ter #
QT T
Conventionall lead and implantt procedure Fastt response to changes inn exercise Simplee to program
Standardd bipolar pacing lead Metabolicc demandf Reactss to mental stress
-- Compromised ability to adapt too different workload levels
-- No response to emotion -- Displays not a circadian variation -- Occasional sensing of mechanical signalss unrelated to activity
-- Post-activity response dictated by pacemakerr circuitry
-- Operates only with paced events -- Can be used only in the ventricle -- Slow reaction*
MV V Closee relationship to oxygen - Pulmonary disease alters MV consumptionn response mechanism Metabolicc demandf - Slow reaction*
PEA A Metabolicc demandf Reactss to mental stress
Sensorr at lead tip Sensorr failure necessitates a neww lead insertion Sloww reaction*
#-Aaelerometerr has the same advantages and disadvantages as the activity sensor but with improvedd reaction on physical activity compared with the activity: MV-minute ventilation; PEAA = peak endocardial acceleration: slow reaction* = slow reaction especially at the beginning and cessationn of exercise: Metabolic demandf = Proportional to metabolic demand and circadian variation.
43 3
Tablee 2. Sensor characteristics
Sensorr Proportionality Speed Sensitivity Specificity
Activityy - + + Accelerometerr - + - -QTT - + MVV + + -PEAA + +
•-not :: +=good- + + = very good; = moderate ariation
Manuall rate response optimization
Essentiall factors for successful RR optimization are to inventarize: 1} the individual
needss of the patient, 2) the medical history, 3) the programmable parameters of the
pacemaker,, in particular the sensor behavior and 4) evaluation of the effect of RR
optimization. .
Vitall elements in recording the needs of the patient are to comply gender, age,
medicall history and activity level. Detailed information about the activity level in
dailyy life is of utmost importance. A helpful tool can be the activity log in the new
developedd pacemakers such as in the Insignia plus pacemaker (Guidant, Minnesota.
USA}.. This feature is especially important in patients with heart failure, because
reducedd daily activity has been identified as an independent marker of poor
prognosis. .
P rogrammablee pa r ame te r s
Mainn programmable variables of rate modulation are: pacing mode, responsiveness,
sensorr status, threshold, minimum and maximum HR, slope and recovery time.
Sensorr status informs about the possible programmable variables of the sensors such
ass sensor blending and cross-checking. Threshold determines the minimal level of
senorr input required to produce a HR. Minimum and maximum HR is dictated in a
pacemakerr by the lower rate limit (LRL) and the upper rate limit (URL). Slope governs
thee HR change within a time period for a given sensor input. Recovery time governs
thee time required to return to minimum HR after cessation of work.
Theree is little attention for the LRL in daily practice, however programming the LRL
accuratee can limit unnecessary developments of symptoms and contributes to a
smoothh exercise and energy saving. 28
44 4
Chapterr 2
Thee estimation of the maximal HR has been largely based on the Astrand formula
(maximumm HR-220-age).:n~sq Despite the acceptance of this formula, Robergs and
Landwehrr showed in research spanning more than two decades, the large error
inherentt in the estimation of maximum HR with this formula.60 Considering the
manyy factors which can influence the achieved maximal HR, careful programming of
thee maximal HR is needed.61 It bears repeating that this is only an estimate of an
individuall patient's maximum HR. Better methods need to be developed to estimate
especiallyy the HR responses at sub maximal levels because patients needing a
pacemakerr are of an age group where they may have disabilities limitin g their
physicall work capacity.
Scrutinyy the functioning of the pacemaker sensor(s) is indispensable. Detailed insight
inn direct reaction of sensors and the long- term adjustment of the algorithm to
changess of sensor settings is vital. For example in the dual sensor pacemakers of
Vitatronn (Arnhem, Netherlands) with the QT and the activity sensor there is 4 to 6
weekss needed to achieve maximal effect of the changed sensor blending When
evaluationn is prior to week 4, the physician has to take into account that the maximal
effectt is not yet achieved. Furthermore application of a ramdump of the manufacturer
cann be helpful in understanding the autoslope function from this system.
Evaluat ionn of sensor op t im iza t ion
Effectss of sensor adjustment can be evaluated with serial exercise testing and
qualityy of lif e questionnaires (QOL-q).
ExerciseExercise tests
Forr pacemaker optimization, tests are in use with largely isotonic (dynamic or
locomotory)) exercise. These exercise tests can be divided in: in-hospital and out-
hospitall exercise tests.
Fromm the in-hospital tests, the chronotropic assessment exercise protocol (CAEP)
exercisee test according to Wilkof f and the 6-minute walk test are frequently used.7 62
Otherr in hospital tests, which are not frequently used, are the LITE walk protocol.
shuttlee walk test, and the Kaltenbach test. Main disadvantage of in-hospital testing
iss that the tests poorly represent daily activities. Especially a treadmill test is not
ann ideal exercise test for pacemaker patients, because in pacemaker patients.
45 5
exercisee is often limited by loss of muscle strength and mass rather than
cardiopulmonaryy capacity. This loss of muscle strength is particularly apparent
whenn exercise testing is performed on a bicycle or treadmill. The CAEP exercise test
hass non-linear characteristics. The first 10 minutes requires low metabolic
workload,, beyond which the workload abruptly increases. Patients with preserved
functionall capacity, capable of exercising for more than 10 minutes, may quit before
reachingg maximal 02 uptake, mainly because of excessive increments in workload
nearr the end of the test. thus, being limited by mechanical rather than metabolic
barriers.. Caution is needed in the application of the CAEP protocol which is also
illustratedd by Freedman et al.6^ They showed that specifically failure in attaining
maximumm exercise could create the appearance of sub-optimal pacemaker
performance. .
Thee limited studies evaluating exercise duration and sensor optimization show no
significantt improvement in exercise duration after sensor optimization and
guideliness are lacking how to evaluate pacemaker function with exercise tests.
Thee guidelines of American College of Cardiology on exercise testing, only mention
thatt the optimum protocol for any test should last 6 to 12 minutes and should be
adjustedd to the subject's needs. International guidelines are needed to
standardizee pacemaker sensor optimization in all chronotropic incompetent
patients.. First, we suggest to adjust the pacemaker sensors individually. Second, to
adjustt the sensors separate in dual sensor systems to gain insight in the
contributionn of each sensor. Third, using preferably the holter capacities of the
currentt pacemakers, monitoring sensor function during daily activities at home,
mayy visualize the true activity level of the patients better.
QualityQuality of life
Qualityy of lif e is a relatively new scientific measure to evaluate effectiveness of
treatment.. QOL reflects the patients perceived health and may considerably
improvee the evaluation of optimal RR.
Usingg OOl-q in international studies is a challenge since interpreting the data could
posee several difficulties. Most important is that the generalizability of health
conceptss between different countries and cultures are being assumed without data
basedd evaluations. This complicates comparing studies using different OOL-q's
andd methods for assessing OOL (transtelephonic, self administered at hospital by
46 6
Chapterr 2
researcherr /patient). Therefore, it is advisable to interpret QOL data in pacemaker
patientss cautiously. b 9 ' °
Inn general, there is a lack of validated pacemaker patient specified OOL-q.' To date.
onlyy two questionnaires were specifically developed for pacemaker patients
(Hacettepee Qol-q71, Aquarel QOL-q).72 Oto et al. developed the Hacettepe OOL-q,
whichh is a pacemaker patient specific QOl-q. In his study. 11 patients were
randomlyy assigned to a crossover study in order to assess their overall exercise
capacityy and OOL scores. They concluded that WIR pacing offers a better QOL in
additionn to an improved exercise capacity, compared to WI pacing.
Thee Karolinska QOL-q and the recently developed Aquarel QOL-q are also disease
specific.72'744 The Aquarel Qol-q is specifically designed for the pacemaker patient.
Thee Karolinska QOL -q is in our opinion complex to fil l in because of the use of
manyy visual analogue scales. The Hacettepe OOL-q and the Aquarel QOl-q were only
usedd domestic with few patients and the Hacettepe Ool-q has a lack of questions on
arrhythmias/ /
Thee study of Sulke et al. is yet the only study, which primarily assessed the effect of
RRR pacing on OOL. Appropriate, over and under programming of the RR in both dual
andd single chamber activity sensor rate adaptive pacemakers was evaluated with
visuall analogue scales and specific activity questionnaires. 5 Symptoms were least
inn the appropriate programmed pacemakers after 2 weeks of follow up.75
Inn addition, in most pacemaker studies their is a discrepancy in results attained
fromm exercise tests and QOL-q. ' •" Improvement in exercise capacity is not always
achievedd together with improvements in QOL-q. For example, studies on cardiac
resynchronisationn therapy have shown only minor changes in exercise capacity yet
majorr changes in QOL. This can be explained by several factors: 1) QOl-q used are
nott sensitive enough for measuring the effect of optimization as described above. 2)
typee of in-hospital exercise tests are different compared to the type of exercise in
dailyy activities. We therefore think that evaluating RR optimization using daily
activitiess is superior to the known in-hospital exercise tests.
Effectss of manual vs. automatic RR optimization
Automaticityy in antibradycardia pacemakers started in the early 1960s with the
introductionn of inhibited ventricular pacing mode. '8 Today, numerous new-
automatedd features and algorithms have been developed.'' ' The introduction of
47 47
digitall pacemakers promises new possibilities in the future. Automaticity could
helpp in reducing follow up time and simplify programming. Accessibility of
pacemakerss remains crucial to verify that RR pacemakers respond correctly.
Thee majority of pacemaker sensors remain at the original programmed settings of
thee manufacturer and are never reprogrammed during their entire lifespan, despite
thee fact that several studies have shown the benefit of appropriate programming of
RR.. ^ '83 Table 3 summarizes the studies affecting manually vs. automatic RR
optimization.. It is striking that most studies do not clarify how RR optimization was
performed.. RR optimization was carried out with instructions of the manufacturer
andd or to the discretion of the physician without using standardized protocols for
optimization,, Most studies focus on programming the URL and do not describe how
otherr RR parameters such as threshold and slope were changed. Thereby the
influencee of the programming sequence of RR parameters is also not described.
Inn most trials, in-hospital exercise tests are used for the evaluation of RR. which has
disadvantages,, as described before in this review. Other limitations of these studies
aree the lack of randomised trials and the predominance of single sensor systems.
Onee of the first studies on autoprogrammability was the study of Mahaux et al.24
Hiss group descibed in 11 patients the autoset function of the Sensolog 703 and
evaluatedd after 6 and 10 months of follow-up whether manual adjustment was still
needed.. The autoset function was time consuming (15-48 min) and in most patients
manuallyy optimization was still necessary. Other larger studies comparing
automaticc with manual adjustment confirmed these results that manual
adjustmentss remained needed. Automatic adjustment lowered in the study of
Kloniss follow-up time in contrast to the first study on autoprogrammability of
Mahauxx et al.24'84-85
Schuchertt et al. showed in a study with 37 patients after 1 month follow up. no
differencee in complaints or activity level when randomized to fixed activity RR
programmingg according to the physicians judgment of patient's life style and
automaticc RR programming in the Thera DR (Medtronic. Minneapolis. USA). &b
Leungg et al.' compared automatic sensor adaptation with individually optimization
inn 9 patients with DX2 pacemakers (Medtronic. Inc., Minneapolis, USA) with ACT
andd MV dual sensor systems. ' The accuracy of rate profile optimization versus
manuall programming was assessed at 1 month and there was no significant
differencee between the two methods of programming. The lack of demonstrating
anyy differences in these two studies between automatic vs. manual adjustment of
48 8
Chapterr 2
pacemakerr sensors may be related to some limitation s of the studies. First, the
follow-upp period of 1 month in both studies could be short to evaluate RR
optimization,, longer follow-up may be needed to detect some differences. Second,
Tablee 3. Summary of studies with manual and automatic sensor optimization
Study y
Mahaux, ,
19892'1 1
NN = ] l
Sulke. . 1990 ^
NN = 20
Lau. .
19966 "
NN = 4
Gentzler. .
1996" "
NN = 93
Schuchert t
199S7t t
NN = 37
Leung. .
19988 ^7
N=9 9
Studyy aim
Too study if manually
adjustmentt is
neededd with autoset
functionn of Sensolog
7Ü3 3
Too study die effect of
appropriate,, under
andd over-program-
mingg of RR
Too study the effects
off manually
adjustmentt of
activityy sensor on RR
kineticss of a OTand
activityy dual sensor
systemm with sensor
cross-- checking
algorithm m
Too evaluate the
automaticc sensor
adjustment t
Too compare the
continouss auto-
maticc adjustment of
activityy RR with
fixedd activity RR
programming g
Too study the
accuracyy of auto-
maticc RR optimiza-
tionn vs manual
programming g
Usedd test/
parameter r
AÜL L
Hoo I ter
TT T
Histograms s
TT T
ADL L
QOL L
TT T
ADL L
Briskk 1-
minutee test
Sensor r
indicatedd rate
histogram m
ADL L
Halll walk
'IT T
ADL L
Optimization n
guide e
Automatic c
withh MG
Manual l
withh MG
Manual l
withh DP
Automatic c
withh DP
Manuall with
DP/Automatic c
Manuall with
DP/Automatic c
Parameters s
optimized d
Reactionn time
Threshold d
Slope e
Recoveryy time
Reactionn time
Threshold d
Slopee URL
Sensorr blending
(QT/activity) )
Slope e
Activit yy ra te|
LRL L
Threshold d
Slope e
Recovery y
URL L
Fu u
6.10 0
months s
22 weeks
Direct t
1.3.6 6
months s
11 month
1.3 3 months s
Conclusion n
Automatic c
programmingg is time
consuming. .
Manuallyy adjust-
mentt needed in
mostt patients.
Appropriate e
programmingg is
betterr than under
andd overprogram-
ming g
Programmingg the
activityy threshold to
loww can induce
cross-checkingg at
rest,, which gives
delayedd RR onset
76%% of patients had
appropriate e
autoslope e
Noo difference in
complaintss or
activityy level of
patients s
Automaticc and
Manuall RR
optimizationn are
comparable e
TableTable continued on next page
49 9
Tablee 3. (continued)
Study y
Garrigue. .
20022 "*
N'' = 66
Kloms. .
200 ^ "
KK = S7
Studyy aim
Too study the auto-
maticc calibration
functionn of Opus G*
accelerometer r
comparedd to
manuallyy adjusted
activityy sensors and
healthyy controls
Too compare
automaticc with
manuaii sensor
adjustment t
Usedd test.
parameter r
Rapidd walking
Stairr climbing
Walkk test.
Sensor r
indicatedd rate
Histogram m
Optimization n
tluiJe e
Manuall with
DP-Automatic c
Manuall with
DP/Automatic c
Parameters s
optimized d
Acceleration n
time e
Slope e
Recoveryy time
URL L
Threshold d
Slope e
FF Li eva-
luation n
1.. 3
months s
1,3.6 6
months s
Conclusion n
Automatic c
calibrationn of Opus
GG pacemaker better
thann manual
adiustment t
Autoo sensor
adiustment t
requiress less time
comparedd to
manuall optimized
MG== manufacturers guide: DP= discretion of the physician: ADL= activities daily life; TT =
treadmilll test; MV = minute ventilation: RR=rate response; Fu = follow-up; * -W I R pacemaker. Ela
Medical.. Montrouge. France); Activity ratef = according to patients life style (active, moderate active
orr less active), FU = follow-up.
inn the study of Schuchert et al., the participating physicians were highly
experiencedd in pacemaker follow up and changed already at discharge in most
patientss the nominal RR to an individual setting.86 Therefore, these study results
cannott be applied to patients in whom the activity-triggered RR generally remains at
nominall values.
Garriguee et al, is the only study which showed better daily life performances with
ann automatic sensor function (autocalibration function of the Opus G WIR
pacemaker.. Ela medical) than without.88 In 43 patients with the autocalibration
function,, the provided daily life performances (rapid walking, stair climbing) were
closerr to those of healthy controls, than 23 patients with activity sensor controlled
pacemakerss without the autocalibration function.88
Inn summary these study results, confirm that manual adjustment of pacemaker
sensorss is beneficial and illustrate that automatic RR optimization can reduce
follow-upp time
Chapterr 2
Conclusions s
Thee majority of pacemaker sensors remain at the original programmed settings of
thee manufacturer, however there is evidence that individually adjustment of
pacemakerr sensors improves exercise capacity and quality of life. It is preferable to
matchh the type of sensor with the individual patient before pacemaker
implantation.. The improvements in automaticity with sophisticated sensor systems
cann be helpful in reducing follow-up time of pacemakers. The development of a
sensorr system that can simulate the ideal sinus rhythm behaviour remains a challenge
forr scientists and manufacturers. International guidelines are needed to standardize
pacemakerr sensor optimization in all chronotropic incompetent patients.
Acknowledgments s
Thee authors thank Tim Schrama (pacemaker technician) for the fruitful discussions.
51 1
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41.. Clementy }. Dual chamber rate responsive pacing system driven by contractility; final assessmentt after 1-year follow-up. The European PEA Clinical Investigation Group. Pacing ClinClin Electrophysiol. 1998:21:2192-7.
42.. Clementy J, Kobeissi A. Garrigue S, Jais P, Le Metayer P. Haissaguerre M. Validation by serial standardizedd testing of a new rate-responsive pacemaker sensor based on variations in myocardiall contractility. Europace. 2001:3:124-31.
43.. Rickards AF. Bombardini T, Corbucci G. Plicchi G. An implantable intracardiac accelerometer forr monitoring myocardial contractility. The Multicenter PEA Study Group. Pacing Clin Electrophysiol.Electrophysiol. 1996:19:2066-71.
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53 3
45.. Dupuis JM. Kobeissi A. Vitali L. Gaggini G, Merheb M, Rouleau F. Leftheriotis G. Ritter P. Victorr J. Programming optimal atrioventricular delay in dual chamber pacing using peak endocardiall acceleration; comparison with a standard echocardiographic procedure. Pacing ClinClin Electrophysiol. 2003:26:210-3.
46.. Deharo JC, Brunetto AB, Bellocci F, Barbonaglia L. Occhetta E. Fasciolo L. Bocchiardo M, Rognonii G. DDDR pacing driven by contractility versus DD1 pacing in vasovagal syncope: a multicenter.. randomized study. Pacing Clin Electrophysiol. 2003:26:447-50.
47.. Deharo JC, Peyre JP. Chalvidan T. Thirion X. Valli M. Ritter P. Djiane P. Continuous monitoring off an endocardial index of myocardial contractility during head-up til t test. Am Heart ƒ. 2000:139:1022-30. .
48.. Bordachar P. Garrigue S, Reuter S. Hocini M. Kobeissi A. Gaggini G, Jais P. Haissaguerre M. Clementyy J. Hemodynamic assessment of right, left, and biventricular pacing by peak endocardiall acceleration and echocardiography in patients with end-stage heart failure. Pacing ClinClin Electrophysiol, 2000:23:1726-30.
49.. Plicchi G. Marcelli E. Pariapiano M. Bombardini T. PEA I and PEA II based implantable haemodynamicc monitor: pre clinical studies in sheep. Europace. 2002;4:49-54.
50.. Avery P. Banning A. Lawson T. McGurk L, Buchalter M. Physiological pacing improves symptomss and increases exercise capacity in the elderly patient. Int J Cardiol. 1994:46:129-33.
51.. Clarity reference guide VMBV. 1999:31-33. 52.. Insignia I Plus rg, Guidant Corporation. 2001. 53.. Lau CP. Leung SK. Lee IS. Delayed exercise rate response kinetics due to sensor cross-checking
inn a dual sensor rate adaptive pacing system: the importance of individual sensor programming.. PacingClin Electrophysiol. 1996:19:1021-5.
54.. Walsh IT, Charlesworth A. Andrews R, Hawkins M, Cowley A]. Relation of daily activity levels inn patients with chronic heart failure to long-term prognosis. Am J Cardiol. 1997:79:1364-9.
55.. Astrand. Aerobic work capacity its relation to age. sex. and other factors, circulation research. 1967:20:1-2111 1-217.
56.. Astrand I, Astrand. PO, Rodahl K. maximal heart rate during work in older men. Journal of appliedapplied physiology. 1959:14:562-566.
57.. Astrand I. Aerobic work capacity in men and women with special reference to age. Acta Physio!Physio! Scand. 1960;49(Suppl 1Ó9H-92.
58.. Astrand I. Aerobic work capacity its realtion yo age, sex. and other factors. Circ Res. 1967:XX:1-211-217. .
59.. Astrand PO. Ryhming I. A nomogram for calculation of aerobic capacity (physical fitness) from pulsee rate during sub-maximal work. J Appl Physiol. 1954:7:218-21.
60.. Robergs R.A. LR. The surprising history of the "Hrmax = 220-age" EQUATTION. JEPonline. 2002;5:1-10. .
61.. Cooper KH PJ. White Sr. et al. Age-fitness adjusted maximal heart rate. Med Sport 1977:10:78-88. 62.. Kay GN. Quantitation of chronotropic response: comparison of methods for rate- modulating
permanentt pacemakers, ƒ Am Coll Cardiol. 1992:20:1533-41. 63.. Freedman RA. Hopper DL. Mah J, Hummel J. Wilkoff BL. Assessment of pacemaker
chronotropicc response: implementation of the Wilkoff mathematical model. Pacing Clin Electrophysiol.Electrophysiol. 2001:24:1748-54.
64.. Page E, Bonnet JL. Durand C. Comparison of metabolic expenditure during CAEP versus a test adaptedd to aerobic capacity (Harbor test) in elderly healthy individuals. Pacing Clin Electrophysiol.Electrophysiol. 2000:23:1772-7.
65.. Sulke N. Dritsas A. Chambers J. Sowton E. Is accurate rate response programming necessary? PacingClinPacingClin Electrophysiol. 1990:13:1031-44.
66.. Fletcher GF. Balady GJ. Amsterdam EA. Chaitman B. Eckel R. Fleg J, Froelicher VF, Leon AS. Pinaa IL. Rodney R. Simons-Morton DA, Williams MA, Bazzarre T. Exercise standards for testingg and training: a statement for healthcare professionals from the American Heart Association.. Circulation. 2001;104:1694-740.
67.. Gibbons R], Balady GJ. Bricker JT. Chaitman BR. Fletcher GF. Froelicher VF. Mark DB. McCallisterr BD, Mooss AN, O'Reilly MG. Winters WL, Jr.. Antman EM. Alpert JS. Faxon DP. Fusterr V, Gregoratos G. Hiratzka LF. Jacobs AK. Russell RO, Smith SC. Jr. ACC/AHA 2002 guidelinee update for exercise testing: summary article: a report of the American College of
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Cardiology/Americann Heart Association Task Force on Practice Guidelines (Committee to Updatee the 1997 Exercise Testing Guidelines). Circulation. 2002;106:1883-92.
68.. Linde C. Quality-of-life in pacemaker and implantable cardioverter defibrillator recipients. PacingPacing Clin Electrophysiol, 2000:23:931-3.
69.. Linde C. How to evaluate quality-of-life in pacemaker patients: problems and pitfalls. Pacing ClinClin Electrophysiol. 1996:19:391-7.
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71.. Oto MA. Muderrisoglu H. Ozin MB. Korkmaz ME, Karamehmetoglu A. Oram A. Oram E, Ugurluu S. Quality of lif e in patients with rate responsive pacemakers: a randomized, cross-overr study. PacingClin Electrophysiol. 1991;14:800-6.
72.. Stofmeel MA. Post MW. Kelder JC. Grobbee DE. van Hemel NM. Psychometric properties of Aquarel,, a disease-specific quality of lif e questionnaire for pacemaker patients, ƒ Clin Epidemiol.Epidemiol. 2001:54:157-65.
73.. Stofmeel MA. Post MW. Kelder JC, Grobbee DE, van Hemel NM. Changes in quality-of-life afterr pacemaker implantation: responsiveness of the Aquarel questionnaire. Pacing Clin Electrophysiol.Electrophysiol. 2001:24:288-95.
74.. Linde-Edelstam C. Nordlander R. Unden AL. Orth-Gomer K. Ryden L. Quality-of-life in patientss treated with atrioventricular synchronous pacing compared to rate modulated ventricularr pacing: a long-term, double-blind, crossover study. Pacing Clin Electrophysiol. 1992:15:1467-76. .
75.. Lopez-Jimenez F, Goldman L, Orav EJ. Ellenbogen K, Stambler B. Marinchak R, Wiikoff BL. Mangionee CM. Yoon C. Vitale K, Lamas GA. Health values before and after pacemaker implantation.. Am Heart]. 2002:144:687-92.
76.. Huth C, Friedl A. Klein H, Auricchio A. [Pacing therapies for congestive heart failure consideringg the results of the PATH-CHF study]. Z Kardiol. 2001:90 Suppl 1:10-5.
77.. Newman D, Lau C, Tang AS. Irvine J. Paquette M. Woodend K. Dorian P, Gent M, Kerr C, Connollyy SJ. Effect of pacing mode on health-related quality of lif e in the Canadian Trial of Physiologicc Pacing. Am Heart J. 2003:145:430-7.
78.. Chawla NP, Rea W, Shapiro W. The use of an implanted demand pacemaker in bradyarrhythmias.. Arch Intern Med. 1969:124:593-9.
79.. Saoudi N. Appl U, Anselme F, Vogiimacci M, Cribier A. How smart should pacemakers Be? Am JJ Cardiol. 1999;83:180D-186D.
50.. Jones BR. Kim J. Zhu Q. Nelson JP, KenKnight BH. Lang DJ. Warren JA. Future of bradyarrhythmiaa therapy systems: automaticity. Am ƒ Cardiol. 1999:83:192D-201D.
51.. Neuzner J. Schwarz T. Sperze! J. Pacemaker automaticity. Am ƒ Cardiol. 2000:86:K104-K110. 82.. Griffi n JC. Schuenemeyer TD. Hess KR. Glaeser D, Anderson BJ. Romans E. Jenkins MA.
Nielsenn AP. Pacemaker follow-up; its role in the detection and correction of pacemaker system malfunction.. PacingClin Electrophysiol. 1986:9:387-91.
83.. Ribeiro AL, Rlncon LG. Oliveira BG. Mota CC. Pires MT. Enhancing longevity of pacemakers throughh reprogramming. Underutiiization and cost-effectiveness. Arq Bras Cardiol. 2001:76:437-44. .
84.. Klonis D, Zhang X. Patel U. Gulamhusein S. Patel J. Hurwit H. Banish D, Marco D. Automatic sensorr algorithms expedite pacemaker follow-ups. Pacing Clin Electrophysiol. 2003:26:225-8.
85.. Gentzier RD, Lucas EH. Automatic sensor adjustment in a rate modulated pacemaker. North Americann Trilogy DR + Phase I Clinical Investigators. Pacing Clin Electrophysiol. 1996:19:1809-12. .
86.. Schuchert A, van Langen H. Michels K, Meinem T. A prospective randomized comparison betweenn fixed rate response programming and automatic rate response optimization in activity-triggeredd DDDR pacemakers. Thera Pacemaker Study Group. Cardiology. 1998:89:25-8.
87.. Leung SK, Lau CP. Tang MO. Leung Z, Yakimow K. An integrated dual sensor system automaticallyy optimized by target rate histogram. Pacing Clin Electrophysiol. 1998:21:1559-66,
88.. Garrigue S. Gentilini C. Hofgartner F. Mouton E. Rousseau A, Clementy J. Performance of a ratee responsive accelerometer-based pacemaker with autocalibration during standardized exercisee and recovery. Pacing Clin Electrophysiol. 2002:25:883-7.
55 5
Heartt rate profiles during two types off exercise testing in healthyy individuals
Aytenn Erol-Yilmaz MD. Raymond Tukkie MD PhD and Arthur Wilde MD PhD
Abstract t
Background d
Thee normal values concerning heart rate (HR) profiles during two frequently used
exercisee tests are limited described in literature, especially in elderly healthy
persons.. Data is lacking about which test is better for pacemaker sensor optimiza-
tionn purposes, Therefore, we studied the HR responses of healthy individuals (HI)
off different age categories using the chronotropic assessement exercise protocol
(CAEP)) and the 6- minute hall walk test (6-HWT).
Materiall and methods
HII of different age categories without co-morbidity and medication were included
andd randomized to either CAEP or 6-HWT exercise test. The age categories were 20-
300 years (groupl). 30-40 years (group 2). 40-50 years (group 3). 50-60 years (group 4)
andd > 60 years (group 5). HR at rest, HR at 1 minute of exercise, time to peak HR,
maximall achieved HR, HR at 1,3 and 10 minutes recovery period, exercise duration,
andd METS or achieved distance (meters) were measured.
Results s
Hundred-seventy-fivee HI (87 men, 88 female) were included in the several age
categories.. Ninety-one HI were randomized to the CAEP and 79 HI to the 6-HWT,
Numberr of HI in each categorie were: 30 in group 1 (mean age 25 2 years), 29 in
groupp 2 (mean age 35 3 years), 40 in group 3 (mean age 44 3 years), 41 in group
44 (mean age 55 2 years) and 30 in group 5 (mean age 66 5 years) respectively.
Thee achieved HR at one minute of exercise was significantly higher and the time to
peakk HR significantly shorter during 6-HWT compared to CAEP. although the
achievedd maximal HR was comparable. There are no gender differences in HI
randomizedd to 6-HWTand minimal gender differences in HI randomized to CAEP.
Thee predicted maximal HR according to the Astrand formula (220-age) was not
significantlyy different compared to the achieved maximal HR in both tests.
Conclusions: :
Thee HR rate profiles can be used to further optimization of the pacemaker sensors.
Thee Astrand formula (220-age) can still be used for prediction of the maximal HR.
Thee 6-HWT is preferable for pacemaker sensor optimization.
58 8
Chapterr 3
Background d
Physicianss are accustomed to decision-making on the basis of knowledge of normal
rangess and normal responses to (diagnostic) tests. Several exercise tests are used for
pacemakerr sensor optimization (the chronotropic assessment of exercise protocol
(CAEP),, 6 minute hall walk test (6- HWT), stair climbing, Kaltebach step test, daily
activities).. The normal values concerning heart rate (HR) profiles during two most
frequentlyy used exercise tests are limited described in literature, especially in the
elderlyy healthy persons.1'31
Thee CAEP protocol according to Wilkoff is designed for pacemaker patients and is one
off the most used exercise test in this patient category beside the 6- HWT. ' In
addition,, data is lacking about which test is better for pacemaker sensor optimization
purposes.. Therefore we studied the HR responses of healthy individuals (HI) of
differentt age categories using the CAEP and the 6-HWT exercise test. These data were
laterr used for pacemaker sensor optimization in chapter 4. We also tried to answer
whichh exercise test is the optimal test for pacemaker sensor optimization.
Material ss and methods
Healthyy individuals
Healthyy individuals (HI) of different age categories without co-morbidity and
medicationn were included and randomized to one of the exercise test protocols.
Thee age categories were 20-30 years (groupl), 30-40 years (group 2), 40-50 years
(groupp 3). 50-60 years (group 4) and > 60 years (group 5)- The two exercise tests used
weree the six minute hall walk test (6-HWT), and the chronotropic assessment
exercisee protocol (CAEP) according to Wilkoff.29 The subjects were exercised until
fatigue,, symptomatic or end of the protocol, but no systematic effort was made to
encouragee exercise to exhaustion. Also the HR response to postural change was
measured.. The HI were recruited by advertising in the local newspaper, on the
severall outward-clinics of our hospital.
59 9
Posturee change
Alll HI were examined in the same conditions (before noon, uniform room tempera-
turee and footgear (subject's own shoes)). After instrumentation, subjects rested
supinee on an examination table with one pillow for 5 minutes. They then elevated
too the sitting position and immediately to the standing position.
Exercisee test protocols
ChronotropicChronotropic assessment of exercise protocol
Healthyy individuals randomized to the CAEP according to Wilkoff underwent a
symptomm limited treadmill test,29 One MET equals 3.5 ml oxygen uptake/kg body
weight/min,, representing the approximate metabolic cost to stand quietly. In his
protocol,, oxygen consumption and carbon dioxide production was not measured,
andd thus metabolic workload (METS ) was not directly measured during exercise.
Rather,, metabolic levels during each stage of exercise were estimated using tread-
milll grade and speed.
SixSix minute hall walk test
Afterr 5 minutes of rest, HI were brought to the parcour. A parcour of 100 m was
createdd by attaching stickers each meter in an oval form showing the walk distance.
Normalss were instructed to walk or run for 6 minutes at the parcour after hearing
thee start sign. After the symptom limited 6-HWT, the HI were brought back to the
testt room for a recovery period of 10 minutes.
Measurements s
Beatt to beat HR was recorded during the physical tests with the Polar advantage
systemm using electrodes mounted in a belt (Polar Electro OY. Kempele. Finland). The
firstt 10 HR of each minute were averaged. During the CAEP exercise test, HI were
alsoo continuously monitored by 12-lead electrocardiographic recordings. HR at rest,
HRR at 1 minute of exercise, time to peak HR, maximal achieved HR, HR at 1,3 and 10
60 0
Chapterr 3
minutess recovery period, exercise duration, and METS or achieved distance (meters)
weree measured.
Statistics s
Firstt the Kruskal-Wallis test was used to analyse differences between the different
agee categories. When the Kruskall-Wallis test was significant, the nonparametric
dataa were analyzed using the Mann- Whitney U test and the parametric data were
analyzedd using the paired sample t test. All data are expressed as mean SD. A P
valuee <0.05 is considered statistically significant.
Results s
Normall population
Hundred-seventy-fivee HI (87 men. 88 female) were included in the several age
categories.. Ninety-one HI were randomized to the CAEP (42 men, 49 female) and 79
HII to the 6-HWT (42 men, 37 female). Number of HI in each categorie were: 30 in
group.. 29 in group 2, 40 in group 3, 41 in group 4 and 30 in group 5 respectively. Of
fourr HI 3 in the HWT (66, 63. 32 years) and 1 in the CAEP (28 year) data derived from
thee Polar advantage system could not be analyzed due to technical disturbance of
thee system. One HI in group 5, a 65 year old female, developed atrial fibrillation
duringg the CAEP and stopped the exercise test.
Exercisee tests
ChronotropicChronotropic assessment exercise protocol
Restt rate
Thee resting HR in HI randomized to the CAEP was not significantly different be-
tweenn group I to 5 (see table 1 and figure 1).
61 1
HRR at one minute of exercise
Thee HR at one minute of exercise was not significantly different between group 1 to
55 (see table 1).
Timee to peak HR
Inn each group the time to peak HR increased. The achieved time to peak HR in group
11 was significantly longer compared to group 4 (p= 0,004) and 5 (p<0.001). The
achievedd time to peak HR in group 2 was significantly longer compared to group 4
(p== 0.07) and 5 (p<0.001). The achieved time to peak HR in group 3 and 4 were
significantlyy longer compared to group 5 (p<0.001. see table 1).
Maximall HR
Thee maximal HR diminished in each group with increasing age. The achieved
maximall HR in group 1 was significantly higher compared to group 3. 4 and 5
(p<0.009.. see table 1, figure ), The achieved maximal HR in group 2 was significant-
lyy higher than in the groups 4 and 5 (p = 0.07. p<0.001). The achieved maximal HR
inn group 3 and 4 was significantly higher compared to group 5 (p=0.004. p = 0,03)-
Thee percentage difference between the achieved and predicted maximal HR was the
largestt in group 1 and 5 (184 10 vs. 195 bpm, A in bpm -6% and 144 36 vs, 154.
AA bpm =6% respectively). In group 2, 3 and 4 the percentage difference between the
achievedd and predicted maximal HR differed minimal (181 15 vs. 185 bpm, A in
bpmm = 2%, 172 13 vs. 176 bpm. A in bpm =3%. 167 10 vs. 165, A in bpm = 2%
respectively). .
Recovery y
Thee HR at 1 minutes of recovery was significantly higher in group 1 compared to
groupp 3, 4 and 5 (p-0.06, p = 0.003, p = 0.03). The achieved HR at 10 minutes was
significantlyy higher in group 2 compared to group 4 (p —0.001). The achieved HR at
1,3.. 10 minutes of recovery in group 3 compared to group 5 was significantly
higherr (p< =0.06).
62 2
Chapterr 3
Exercisee duration and METS
Thee exercise duration of the HI in group 1 was significantly longer than in group 3.
44 and 5 (p = 0.05. p = 0.006, p<0.001). The exercise performance of the HI in group 2,
33 and 4 were significantly higher compared to group 5 (p< 0.03. see table 1).
Thee achieved METS were significantly higher in group 1 and 2 compared to group 4
andd 5 (p<0.001). The achieved METS were also higher in group 3 and 4 compared to
55 (<0.001. see figure 3.d).
6-6- minute hall walk test
Restt rate
Thee resting HR in HI randomized to the 6-HWT was not significantly different
betweenn group 1 to 5 except for group 2 compared to 3 (55 12 vs. 64 7 bpm,
pp = 0.02. see table 2. and figure 2).
HRR at one minute of exercise
Inn contrast to the CAEP test, differences existed in the achieved HR at one minute of
exercisee between the groups. The achieved HR at one minute of exercise was
significantlyy higher in the group 1 compared to 4 (p-0.009). The achieved HR at one
minutee of exercise was significantly higher in group 2 compared to 3.4 and 5
(p<0.05).. The achieved HR at one minute of exercise was significantly higher in
groupp 3 compared to 4 (p-0.006, see table 2 and figure 2).
Timee to peak HR
Thee achieved time to peak HR was only significantly longer in group 1 compared to
44 and 5 (p<0.03, table 2).
63 3
Maximall HR
Thee maximal HR diminished with each age category. The achieved maximal HR in
groupp 1. 2 3. 4 was significantly higher than in group 5 (p<0.009, see table 2, figure 2).
Thee percentage difference between the achieved and predicted maximal HR (Astrand
formule== 220-agel is the largest in group 1 and 2 (179 19 vs. 195 bpm. A in bpm
=8%.. 175 7 vs. 154, A bpm =5%)- In group 3. 4 and 5 the percentage difference
betweenn the achieved and predicted maximal HR minimally differed (175 2 vs. 185
Tablee 1. Heart rate during rest, exercise and recovery with CAEP
Age e
(years) )
266 3 igroup D
355 3 (group 2}
455 3 Igroup 3)
555 2 (group 41
677 5 (group5 )
Resrr rate
(hr/min) )
666 10
600 12
677 12
622 10
655 10
HRatt 1 Ibpml l
911 16
866 13
800 11
833 14
900 18
TIPP HR (mini i
21 2
20 3
19 3
188 3
166 3
Exercise e
MHR R (bpm) )
1844 10
1811 15
1722 13
1677 i 10
1444 + 36
Duration n min n
222 2
211 4
200 3
199 3
177 3
METS S iml/'kg'min) )
16.66 3
16.22 2
14.99 i 3
13-55 2
10.33 3
Tablee 1. CAEP = chronotropic assessment exercise protocol HRR = heart rate: TTPHR = timc to peak heart rate; MHR = maximal heart rate; METS= oxygen uptake/kgg body weigh t/min. min = minute: bpm=beats per minute.
Tablee 2. Heart rate during rest, exercise and recovery with 6-HWT
Age e
(years) )
244 2 (group 11
355 2 (group 21
444 3 \group 31
555 3 '(group 4
666 5 igroup 5)
Restt rate
(hr/min.) )
611 9
555 12
644 7
644 13
622 10
MRR at 1 (bpm) )
1422 19
1522 12
1411 0
1244 17
1311 10
TTPP HR min n
4.33 1.7
33 1.7
377 1.6
2.88 16
2,99 i 1-3
Exercise e
MHR R (bpm) )
33 79 19
1755 7
1755 12
1688 12
1511 17
Duration n min n
66 0
66 0
66 0
5.88 0.7
5.77 0-7
METS S (ml/'kg/min) )
12366 236
1116.. 278
9833 181
10066 178
7811 281
Tablee 2. 6-HWT = 6 minute hall walk test; HR^heart rate: TIP HR = time to peak heart rate: MHRR = maximal heart rate: bpm = beats per minute; min= minutes: m = meters.
64 4
Chapterr 3
bpm.. A in bpm =0.6%. 168 12 vs. 176 bpm. A in bpm = 2%. 151 17 vs. 165, A in
bpmm =2% respectively.
Recovery y
Thee HR at 3 and 5 minutes of recovery was significantly higher in group 1 compared
too 2 (p < 0,03) • The achieved HR at 1 and 3 minutes of recovery was significantly higher
inn group 1 and 3 compared to group 5 (p<0,05). The achieved HR at 3 and 5 minutes
Recovery y
HRR at 1 min HR at 3 min HR at 5 min HR at 10 min (bprrOO (bpm) (bpm) (bpm)
1488 21 105 0 95 16 93 15
1366 6 106 17 97 2 96 9
1311 4 106 22 92 1 89 2
1277 6 98 17 90 4 88 2
1199 6 95 18 89 4 3
Recovery y
HRatt 1 min HR at 3 min HRat 5 min HR at 10 min
(bpm)) (bpm) (bpirO (bpm)
1377 22 108 0 98 13 95 15
1222 8 89 6 86 6 85 10
1355 8 108 15 96 2 93 2
11 104 4 95 2 86 0
1133 2 94 6 92 5 89 6
65 5
CAEP P 200 0
Minute s s
Figuree 1. Changes in heart rate \mean during CAEP of the different age categories \male and female!.
6-HWT T
99 12 Minute s s
Figuree 2. Changes in heart rate imean1 during 6-HWT of the different age categories (malee and female)
wass significantly higher in group 2 compared to 3 (p<0.05). The achieved HRat 1
minutess of recovery was significantly higher in group 4 compared to 5 (p=0.05).
Exercisee duration and distance
Alll HI exercised for 6 minutes except one HI in group 4 and one in group 5. they
stoppedd before the end of the test due to fatigue. The achieved distance was signifi-
ed d
Chapterr 3
cantlyy longer in group 1 compared to 3. 4 and 5 (p<0.01) and also the achieved
distancee was significantly longer in group 2 and 3 compared to 5 (p<0.04).
Genderr differences
HII randomized to 6-HWT showed no differences between females compared to
maless in the different age categories. Females compared to males in group 2 rand-
omizedd to CAEP showed significant differences in resting HR (52 9 vs.68 9 bpm,
p=0.09).. achieved maximal HR (178 4 vs. 182 8 bpm. p=0.025). exercise
durationn (20 2 vs. 21 4 min. p = 0.046) and achieved METS (14 2 vs. 17.2 1.8
METS,, p = 0.028). Within group 3 and 4, the achieved METS significantly differed
(12.55 1 vs. 17.6 1.8. p=0.001 vs. 12.6 1.8 vs. 14.7 2 METS. p=0.03). In group
5.. achieved maximal HR (134 41 vs. 162 16 bpm, p = 0.035), HR at 3 minutes of
recoveryy {88 14 vs. 106 18 bpm, p = 0.042), HR at 5 minutes of recovery (84 4
vs.. 97 12 bpm, p=0.036) and HR at 10 minutes of recovery (82 13 vs. 93 10
bpm,, p=0.066) were significantly different between men and women.
CAEPP vs. 6-HWT
Thee achieved HR at 1 minute of exercise and the achieved time to peak HR were
significantlyy different between CAEP and 6-HWT for all age categories (86 5 vs. 138
5 bpm. p<0.001 and 18.8 0.9 vs. 3-3 0.3 min, p<0.01). The rest rate, maximal
HRR and HR at 1, 3. 5 and 10 minutes of recovery were not significantly different.
Discussion n
Optimall programming of pacing variables is important in rate adaptive pacemakers
too improve exercise capacity and reduce symptoms. Individual programming should
bee adapted to the age of patients and to associated medical conditions, as well as to
overalll functional capacity. For pacemaker optimization, tests are in use with largely
isotonicc (dynamic or locomotory) exercise. These exercise tests can be divided in:
in-hospitall and out-of hospital exercise tests. From the in-hospital tests, the CAEP
exercisee test according to Wilkof f and the 6-minute walk test are frequently
67 7
used.266 ,2° However, recent data are lacking concerning normal values of HR respons-
ess in different age categories with CAEP and 6-HWT. In addition, data are lacking if
duee to the increasing height and weight during the last century, the HR response is
changedd in HI and whether the Astrand formula (220-age) for prediction of the
maximall HR can still be used. We therefore describe the HR response of 170 HI
withoutt apparent disease and medication during CAEP and 6HWT.
Thee disadvantages of in-hospital testing with standardized tests such as treadmill
andd bicycle ergometry is that these tests are time consuming and not always feasi-
blee in patients with pacemakers (as they are often elderly persons, with physical
limitations)) and the tests poorly represent daily activities.32 Especially the treadmill
testt is not an ideal exercise test for pacemaker patients, because in pacemaker
patients,, exercise is often limited by loss of muscle strength and mass rather than
cardiopulmonaryy capacity. This loss of muscle strength is particularly apparent
whenn exercise testing is performed on a bicycle or treadmill. The CAEP exercise test
hass non-linear characteristics. The first 10 minutes requires low metabolic work-
load,, beyond which the workload abruptly increases. Patients with preserved
functionall capacity, capable of exercising for more than 10 minutes, may quit before
reachingg maximal 02 uptake, mainly because of excessive increments in workload
nearr the end of the test, thus, being limited by mechanical rather than metabolic
barriers.. Caution is needed in the application of the CAEP protocol which is also
illustratedd by Freedman et al.32 They showed that failure in attaining maximum
exercisee could create the appearance of sub-optimal pacemaker performance.
Onee of the first studies which performed an in-hospital walk test was done in
patientss with chronic obstuctive pulmonary disease.7 The in-hospital HWT is
describedd in pacemaker patients with different duration (2. 6. 12 minutes) and most
off them used brisk walking, which is in contrast to our study. In our study the HI
weree allowed to run and they stopped because of maximal exhaustion, with symp-
tomss or end of the protocol. Therefore it is difficult to compare the HR response of
HII to the limited existing literature. Provenier et al. validated the six- minute walk
testt in rate response pacemakers. In his study, the six-minute walk test was per-
formedd in a corridor 45 m long with 1 (m) and 5 (m) marks on the floor.2
Thee 13 HI in his study the achieved a maximal rate of 73% of the predicted maximal
HR,, corrected for age (220-age). The HI in our study achieved almost their predicted
maximall HR, The HWT has several advantages when compared to the CAEP. The
08 8
Chapterr 3
HWTT is short, cheap, has a better practicability and uses a natural way of moving
duringg the walk with good correlation to other types of exercise at home,i q
Inn our study, the achieved HR at one minute of exercise was significantly higher and
thee time to peak HR significantly shorter during 6-HWT compared to CAEP, al-
thoughh the achieved maximal HR was comparable. We therefore think, considering
thee advantages of the 6-HWT that the 6-HWT is the prefered test for pacemaker
sensorr optimization.
Thee difference in body mass index of our HI compared to other studies is minimal
(0-11 kg/m2). even when we compared with the dated studies, which can be explained
duee to the increased height together with the increased weight. '-0'10 1213.15.20.24.27.28
Thereforee the achieved peak HR, which is correlated the body mass index, is not
significantlyy different compared to the dated literature, ^ó-1012^-^.20.24.27.2s
Thee estimation of the maximal HR has been largely based on the Astrand formula
(maximumm HR=220-age). In 13-507 healthy men from several studies, the predicted
maximall HR differed only 4.3 beats per minute compared to the achieved maximal
HRR in our study. 1-6.10.12.13,15.20.24.27.28 Considering the many factors which can
influencee the achieved maximal HR, careful programming of the maximal HR is
needed.333 It bears repeating that this is only an estimate of an individual patient's
maximumm HR. Better methods need to be developed to estimate especially the HR
responsess at sub maximal levels because patients needing a pacemaker are of an age
groupp where they may have disabilities limiting their physical work capacity.
Inn a meta-analysis, Londeree and Moeschberger showed that although 73% of the
variabilityy of the peak HR response could be attributed to age. and 5% to some other
factorss that were examined, the remaining variability could not be accounted for. 23
Thee other minor variables, which have been shown to have some influence on the
maximall HR include: gender, fitness and cardiac illness.18 Fitness and training cause
somee slowing of HR for a given external workload,115
Inn our study there were surprisingly no gender differences in HI randomized to the
6-HWT.. HI randomized to the CAEP had minimal gender differences in the groups 2
too 5. This is in contrast to the studies described before, which showed that females
hadd a higher HR at all levels of exercise. J'
InIn chapter 4. we showed that pacemaker sensor optimization improved exercise
capacityy (METS). However, the HI in this study achieved higher HR than patients
despitee individual optimization, probably because current sensors are still hypo-
69 9
chonotropicc and physicians need to program conservative due to concomitant heart
disease.. The elderly patients in the pacemaker sensor optimization study achieved
muchh lower METS (7.6 vs. 10.3) compared to the elderly HI from this study. These
dataa underline that exercise capacity can be improved in pacemaker patients by
pacemakerr sensor optimization, although other factors such as co-morbidity and
fitnesss also plays a major role. The HI were more active and had no co-morbidity
comparedd to the patients in our study.
Conclusions s
Wee describe the heart rate profiles during two types of exercise testing in 170
healthyy individuals. Only the heart rate at 1 minute of exercise and time to peak
heartt rate are significantly different when these two tests are compared. Surprising-
ly,, there are no gender differences in healhy controls randomized to 6-minute hall
testt and minimal gender differences in healthy individuals randomized to the CAEP.
Inn addition, the body mass index is not significantly changed during the last
century,, The Astrand formula (220-age) can still be used for prediction of the
maximall heart rate, however precaution is needed in the elderly pacemaker patients
withh co-morbidity. Furthermore, our data confirm that the 6-minute hall walk test is
preferablee for pacemaker sensor optimization because of the ease of implementa-
tionn and the natural way of moving during the walk with good correlation to other
typess of exercise at home. These heart rate profiles can be used to further optimize
thee pacemaker sensor.
70 0
References s
Chapterr 3
1.. Astrand PO, Ryhming I. A nomogram for calculation of aerobic capacity (physical fitness) from pulsee rate during sub-maximal work, j Appl Physiol. 1954:7:218-21.
2.. Astrand I, Astrand. PO, Rodahl K. maximal heart rate during work in older men. journal of ap-pliedplied physiology. 1959;14:562-566.
3.. Astrand I. Aerobic work capacity in men and women with special reference to age. Acta Physi-olol Scand. 1960;49(Suppl 169):l-92.
4.. Astrand I. Aerobic work capacity its realtion yo age. sex, and other factors. Circ Res. 1967:20:1-211-217. .
5.. Bowyer AF. Thomas RA. Bowyer SR. Heart rate response to exercise in normal women. Meth-odsods InfMed. 1993;32:206-10.
6.. Bruce RA, Fisher LD. Cooper MN, Gey GO. Separation of effects of cardiovascular disease and agee on ventricular function with maximal exercise. Am J Cardiol. 1974;34:757-63.
7.. Butland RJ. Pang ]. Gross ER. Woodcock AA. Geddes DM. Two-, six-, and 12-minute walking testss in respiratory disease. Bi Med j {Clin Res Ed). 1982;284:1607-8.
8.. Cardus D. Spencer WA. Recovery time of heart frequency in healthy men: its relation to age andd physical condition. Arch Phys Med Rehabil. 1967;45:71-7.
9.. Casaburi R. Spitzer S. Haskell R. Wasserman K. Effect of altering heart rate on oxygen uptake att exercise onset. Chest. 1989:95:6-12.
10.. Cooper K. Purdy JG. White SR. Age-fitness adjusted maximal heart rates, medicine sport. 1977:10:78-88. .
11.. Crook B. Nijhof P, van der Kemp P. Jennison C. The chronotropic response of the sinus node too exercise: a new method of analysis and a study of pacemaker patients. Eur Heart}. 1995;16:993-8. .
12.. Ellestad MH. stress testing principles and practice. Tirth edition:567-573-13.. Ellestad M. Allen W. Wan M. Kemp G. Maximal treadmill stress testing for cardiovascular eval-
uation.. Circulation. 1969:39:517-522. 14.. Greig CA, Young A. Skelton DA. Pippet E, Butler FM, Mahmud SM. Exercise studies with elder-
lyy volunteers. Age Ageing. 1994:23:185-9-15.. Hammond HK. Froelicher VF. Normal and abnormal heart rate responses to exercise. Prog Car-
diovascDis.diovascDis. 1985;27:271-96. 16.. Higginbotham MB. Morris KG. Williams RS. Coleman RE. Cobb FR. Physiologic basis for the
age-relatedd decline in aerobic work capacity. Am j Cardiol. 1986;57:1374-9. 17.. Higginbotham MB. Morris KG. Williams RS. McHale PA, Coleman RE. Cobb FR. Regulation of
strokee volume during submaximal and maximal upright exercise in normal man. Circ Res. 1986;58:281-91. .
18.. Jonsson BG. Astrand I. Physical work capacity in men and women aged 18 to 65- Scand j Soc Med.Med. 1979;7:131-42.
19.. Langenfeld H. Schneider B. Grimm W. Beer M, Knoche M, Riegger G. Kochsiek K. The six-minutee walk—an adequate exercise test for pacemaker patients? Pacing Clin Electrophysiol. 1990;13:1761-5--
20.. Lester M, Sheffield LT, Trammell P. Reeves TJ. The effect of age and athletic training on the maxima]] heart rate during muscular exercise. Am Heart], 1968:76:370-6.
21.. Lewalter T, MacCarter D. Jung W. Schimpf R, Manz M. Luderitz B. Heart rate to work rate rela-tionn throughout peak exercise in normal subjects as a guideline for rate-adaptive pacemaker programming.. Am ƒ Cardiol. 1995;76:812-6.
22.. Loeppky )A, Greene ER, Hoekenga DE. Caprihan A, Luft UC. Beat-by-beat stroke volume assess-mentt by pulsed Doppler in upright and supine exercise, ƒ Appl Physiol. 1981:50:1173-82.
23.. Londeree B. Moeschberger ML. Influence of age and other factors on maximal heart rate, ƒ CardiacCardiac Rehabil. 1984:4:44-9-
24.. Master A. a simple exercise tolerance test for circulatory efficiency eith standard tables for normall individuals. American journal of the medical sciences. 1929:177:223-243.
71 1
25-- Page E, Bonnet JL, Durand C. Comparison of metabolic expenditure during CAEP versus a test adaptedd to aerobic capacity (Harbor test) in elderly healthy individuals. Pacing Clin Electro-physiol.physiol. 2000:23:1772-7.
26.. Provenier F, Jordaens L. Evaluation of six minute walking test in patients with single chamber ratee responsive pacemakers. Br Heart J. 1994:72:192-6.
27.. Robinson S. Experimental studies of physical fitness in relation to age. zeitschrift fur die physiologiephysiologie der menschen beiarbeit. 1938:10:251-323.
25.. Sue DY, Hansen JE. Normal values in adults during exercise testing. Clin Chest Med. 1984;5:89-98. .
29.. Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment, Cardiol Clin. 1992:10:705-17. .
30.. Wilkoff B. Corey ], blackburn G. a mathematical model of the Cardiac chronotropic response too exercise. Journal of electrophysiology. 1989:3:176-180.
31.. Meine M, Achtelik M, Hexamer M. Kloppe A. Werner ]. Trappe HJ. Assessment of the chrono-tropicc response at the anaerobic threshold: an objective measure of chronotropic function. PacingPacing Clin Electrophysiol. 2000:23:1457-67.
32.. Freedman RA, Hopper DL. Mah J, Hummel J. Wilkoff BL. Assessment of pacemaker chrono-tropicc response: implementation of the Wilkoff mathematical model. Pacing Clin Electrophys-iol.iol. 2001:24:1748-54.
33.. Cooper KH PJ. White Sr. et al. Age-fitness adjusted maximal heart rate. Med Sport. 1977:10:78-88.
72 2
Individuall optimization of pacing sensorss improves exercise capacity withoutt influencing quality of life
Aytenn Erol-Yilmaz MD. Tim A, Schrama, Jutta Schroeder Tanka*, MD PhD, Jann G. Tijssen PhD, Arthur A. Wilde MD PhD, and Raymond Tukkie MD PhD
Fromm the department of Clinical and Experimental Cardiology, Academic Medical Centerr and the department of Cardiology. Sint Lucas-Andreas hospital*, Amsterdam,
Thee Netherlands.
PACEPACE 2005;28:17-24
Abstract t
Introductio n n
Programmablee pacemaker sensor features are frequently used in default setting.
Limitedd data are available about the effect of sensor optimization on exercise
capacityy and quality of life (QOL). Influence of individual optimization of sensors
onn QOL and exercise tolerance was investigated in a randomized, single blind study
inn patients with WIR. DDDR or AAIR pacemakers.
Materiall and methods
Patientss with >75% pacing were randomized to optimized sensor settings (OSS) or
defaultt sensor setting {DSS). Standardized optimization was performed using three
differentt exercise tests. QOL questionnaires {OOL-q: Hacettepe, Karolinska and
RAND-36)) were used for evaluation of the sensor optimization. One month before
andd after optimization, exercise capacity using CAEP and the three QOL-q were
assessed. .
Results s
Fifty-fourr patients (26 men. 28 female) with a mean age of 65 16 years were
enrolledd in the study. In each group (OSS and DSS) 27 patients were included. One
monthh after sensor optimization the achieved maximal HR and METS were signifi-
cantlyy higher in OSS compared to DSS (124 28 vs. 108 20 bpm, p=0.036; 7.3 4
vs.. 4.9 4 METS, p = 0.045). Highest HRand METS were achieved in patients with
pacemakerss with accessible sensor algorithms. In patients with automatic slope
settingss (33 %). exercise capacity did not improve after sensor optimization. QOL
didd not improve in OSS compared to DSS.
Conclusions s
Afterr 1 month of individual optimization of rate response pacemakers, exercise
capacityy was improved and maximum heart rate increased, although QOL remained
unchanged.. Accessible pacemaker sensor algorithms are mandatory for individual
optimization. .
6 6
Chapterr 4
Introductio n n
Thee normal heart adapts its rate in response to the body's changing metabolic
demandss and is therefore chronotropically competent. Earlier generation of pace-
makerss provided constant rate and were unable to maintain or restore chronotropic
competence.. Since the first permanent pacemaker implantation in 1958, there have
beenn tremendous advances in pacemaker technology with the availability of com-
plex,, multiprogrammable, dual chamber and rate adaptive pacemakers which could
meett the haemodynamic needs of an individual patient.1"3 Rate adaptive pacing
improvess cardiac output, exercise tolerance and a sense of well-being compared to
fixedd rate pacing.4
Normall sinus node function is used as the golden standard for the development of
thee ultimate pacemaker sensor. Sinus node behavior can be described with several
methods:: exercise testing protocols, the mathematical model according to Wilkoff
andd Holter monitoring in daily life. These methods together with evaluation of the
obtainedd quality of lif e (QOL) associated with a given sensor can all be used to
assesss the efficacy of a pacemaker sensor. The American college of cardiology
guideliness of exercise testing used for evaluating rate adaptive pacing advices
adjustmentt of the exercise test for the subjects need and however several exercise
testss (CAEP, LITE, Bruce, six minute walk test, Kaltenbach step test, stair climbing)
aree described, consensus lacks about the ideal exercise test protocol for pacemaker
sensorr optimization. 8"10' I4"19
Programmablee pacemaker sensor features are frequently used in default sensor
settingg (DSS) in daily practice, although rate responsive pacing has been reported to
improvee the physical capacity and QOL compared to fixed rate pacing. It is un-
knownn whether individual optimization of rate response is a necessary factor to
improvee QOL and exercise capacity with the existing sophisticated sensor technolo-
gyy compared to the default sensor setting (DSS) of the manufacturer.8 Therefore,
wee tested the effect of optimized sensor setting (OSS) with a standardized individu-
all optimization protocol and DSS on exercise capacity and QOL in patients with
AAIR,, W1R and DDDR pacemakers in a prospective single blind randomized trial.
Material ss and Methods
Patientt population
Fifty-fourr consecutive patients with >75% pacemaker sensor driven HR with mean
agee of 65 16 years (range 27 to 89 years), New York Heart Association (NYHA) class
I-- II. stable medication, stable psychosocial conditions and commercially available
pacemakerss (Medtronic Minneapolis USA. Guidant Minnesota USA, Vitatron Arn-
hemm The Netherlands) were included at least 3 months after pacemaker implanta-
tion.. Pacemaker type and pacing indication are described in table 1.
Fromm our existing institutional database of exercise testing in healthy controls (HO
withoutt co-morbidity and medical therapy , we selected nineteen age and exercise
typee matched individuals (mean age 66.5 6). All patients gave written informed
Tablee 1. Demographics and clinical variables
Patients s
Numberr of patients Agee (year) Sexx Imale/femalel [%) BMII ikg/m2} NYHAA class \l-4) LVEFF (normal/reduced. %) History y
CoronaryCoronary artery disease (%' HeartHeart valve insufficiency (%) Atria!Atria! fibrillation {%)
Medication n DigoxwDigoxw (%l ^-blocker^-blocker (%) CalciumCalcium antagonist {%} AmiodaroneAmiodarone {%)
Facemakerr type VitatronVitatron \%) MedtronicMedtronic (!fci GuidantGuidant i%1
Pacemakerr indication SSSW SSSW AVV nodal block (%i AFAF with AV nodal disease [%) AFAF with His bundle ablation iV Other Other
DSS S
27 7 066 16
59/41 1 299 6
1.77 0.9 89/11 1
4 4 6 6 42 2
4 4 10 0 6 6 2 2
41 1 33 3 26 6
15 5 15 5 11 1 52 2 7 7
OSS S
27 7 655 15 37/63 3 266 4 1.88 9 89/11 1
6 6 12 2 58 8
4 4 14 4 10 0 2 2
60 0 29 9 11 1
22 2 15 5 18 8 42 2
3 3
Tablee 1. DSS= default sensor setting: OSS= optimal sensor setting: BMI - body mass index: NYHAA = New York Heart Association: LVEF= left ventricular ejection fraction: SSS~sick sinus syndrome.. AV = atrioventricular: AF = atrial fibrillation.
78 8
Chapterr 4
consentt and the ethics committee of our institutio n approved the study.
Randomizationn protocol and study design
I nn thi s s ingle bl in d prospect ive randomized trial , pat ients were firs t randomized to
OSSS or DSS. Primar y endpoint of the study is exercise capacity. Patients in OSS were
thenn randomized to one of three exercise protocols used for opt imizat ion of the
sensor.. The three exercise tests were the six minut e hall walk test (6-HWT) , six
m inu t ee hall walk test wi t h stair c l imbin g (6-HWT+SC) and the chronotropi c assess-
mentt exercise protocol (CAEP) according to Wilkoff. 11
Al ll pat ients underwent at basel ine a CAEP exercise test wi t h posture change (PC)
andd sui tcase lift in g (SL) wi t h their pacemakers programmed in default sett ing. The
pacemakerss of the pat ients in OSS group were individual l y opt imized 1 month after
basel ine.. The CAEP test was repeated after 2 mon ths in OSS and DSS groups.
Qual i t yy of l i f e quest ionnaires (QOL-q) were assessed in all pat ients, 1 month before
andd after sensor opt imizat ion (see figur e 1).
Patients s
Baseline: : Groupp OSS (n = 271
CAEPP + PC+ SL in default
Groupp DSS (n = 27)
22 months
Afterr I month optimization using ++ QOL
Afterr 2 months: QOL +
t t
HWT T
t t
HWTT + SC
CAEPP + PC+ SL CAEP++ PC+ SL
Figuree 1. Randomization and flowchart of the study. OSS- optimalized sensor setting: DSS-defaultt sensor setting: CAEP- chronotropic assessment exercise protocol; PC- posture change:: SL- suitcase lifting: QOlq = quahty of lif e questionnaires: 6-HWT= 6 minute hall walk lest: SC== staircase ascent and descent.
79 9
Sensorr optimization
Alll sensor optimizations were done by one investigator (A-E.Y). The optimized
pacemakerr sensor setting was individually determined by 3 parameters: 1) detailed
analysiss of HR curve obtained with the exercise test after 1 month (onset of exer-
cise,, slope, total exercise time, time to peak HR, maximal HR). One of the three
exercisee tests (depending on randomization) were used for optimization (CAEP, 6-
HWTT or 6-HWT+SC). HR curves of 19 age matched HC (see figure 2) and the availa-
blee literature about normal HR during exercise were used as reference.12 2) upper
ratee limi t was programmed according to Astrand (220 - age)13 and 3) development of
complaints,, Threshold, lower rate limi t (LRL), upper rate limi t (URL), slope and
sensorr specific settings (sensor blending in dual sensor systems) were adjusted to
obtainn the predicted optimal sensor setting.
HR R
180 0 - * -- 6-HWT
-•-CAEP P
CAEP-HC C
- * -- 6-HWT-HC
i—i—i—i—n—i— rr r r t i i i—i—r~i—i—i—r—i—i—i—n—!—I—i—i—i—i—i—i— r
11 4 7 10 13 16 19 22 25 28 31 34 Minutes s
Figuree 2. Changes in heart rate ImeanV HR-heart rate; 6-HWT= 6 minute hall walk test: CAEP = chronotropicc assessment exercise protocol. HC = healthy controls.
SO O
Chapterr 4
Exercisee test protocols
PosturePosture change and suitcase lifting
Alll patients were examined in the same conditions (before noon, uniform room
temperaturee and footgear (patients own shoes)). After instrumentation, patients
restedd supine on an examination table with one pillow for 5 minutes. They then
elevatedd to the sitting position and immediately to the standing position for 2
minutes.. The patients raised a standard suitcase (9 kg weight and measuring 47 cm
xx 37 cm x 15 cm) from the floor onto the examination couch (a height of 100 cm)
usingg their preferred arm (left, right, both).
ChronotropicChronotropic assessment of exercise protocol
Alll patients underwent a symptom limited treadmill test using the CAEP protocol
accordingaccording to Wilkoff .
Onee MET equals 35 ml oxygen uptake/kg body weight/min. representing the
approximatee metabolic cost to stand quietly. In his protocol oxygen consumption
andd carbon dioxide production was not performed, and thus metabolic workload
(METSS ) was not directly measured during exercise. Rather, metabolic levels during
eachh stage of exercise were estimated using treadmill grade and speed.
SixSix minute hall walk test
Afterr 5 minutes of rest patients were brought to the parcour. A parcour of 100 m
wass created by attaching stickers each meter in an oval form showing the walk
distance.. Patients were instructed to walk or run for 6 minutes at the parcour after
hearingg the start sign. After the symptom limited 6-HWT, the patients were brought
backk to the test room for a recovery period of 10 minutes.
StaircaseStaircase descent and ascent
First,, the patients descended 5 flights of stairs as rapidly as possible (82 steps, with
totall horizontal distance of 41.5 m and vertical distance of 15 m). After 2 minutes of
rest,, the patients then ascended the same flights as fast as they could.
81 1
Qualityy of lif e
Too compensate for the limited pacemaker patient specific OOL-q, we used 3 OOL-q.
Thee Rand-36 consisting 9 domains (physical functioning, social functioning, role
functioningg physical problems, role functioning emotional problems, mental health,
energy,, domains bodily pain, general health perception and change in general
health)) was used as a generic core module. The Rand-36 was evaluated using the
scoree system from 0 to 100 % in each domain (0% =low OOL to 100% = high QOL). H
Thee second questionnaire assessed was the Hacettepe QOL-q. which is a pacemaker
patientt specific questionnaire with 8 domains (general well-being, physical activity
andd symptoms, sleeping dysfunction, appetite, sexual functioning, cognitive
functioning,, social participation and work performance). The scores of each domain
aree between 3-50 points. (3 = low QOL and 50 = high OOL).
Fromm the final questionnaire, the Karolinska OOL-q only A domains (chest pain,
palpitations,, dizziness, dyspnoea) were used as complementary to the other two
questionnaires.. The 4 domains of the Karolinska QOL-q were evaluated using Visual
Analogg Scales and required patients to place a mark along a line of 10 cm in length
fromm a minimum of 0 (no complaints) to a maximum of 10 (maximal grade of
complaints).. The results were expressed as a percentage of the distance from the
discretee minimum point to the position of the mark divided by the length of the
line.155 In the Rand-36 and the Hacettepe QOL-q a high score means a high OOL and
inn the Karolinksa QOL-q a high score means a low QOL.
Measurements s
Beatt to beat HR was recorded during the physical tests with the Polar advantage
systemm using electrodes mounted in a belt (Polar Electro OY, Kempele, Finland).
Duringg the CAEP exercise test patients were also continuously monitored by 12-lead
electrocardiographicc recordings. HR at rest, time to peak HR, maximal achieved HR.
HRR at 10 minutes recovery period, exercise duration and METS were measured, The
OOL-qq was assessed after 1 and 2 months of inclusion.
82 2
Chapterr 4
Statisticall analysis
Powerr analysis was performed on the primary endpoint of the study, exercise
capacityy in METS. Assuming that the common standard deviation is 35 and a mean
differencee in achieved METS is 3 (the difference between mean DSS l and OSS, JJL2
inn METS ), we calculated the power of 80 % using a two group t-test with a 0.05 two-
sidedd significance level. A sample size of 23 patients in each group DSS vs. OSS had
aa power of 80% to detect a difference in means of 3. Parametric data was analysed
usingg the Student's t-test while nonparametric data was analysed using the Mann-
Whitneyy U test. All data are expressed as mean SD. A P value <0,05 is considered
statisticallyy significant.
Results s
Fifty-fourr patients (26 men, 28 female) with a mean age of 65 16 years (range 27
too 89 years) were enrolled in the study. In each group (OSS and DSS) 27 patients
weree included. Demographics and baseline characteristics between both groups
weree not significantly different (see table 1).
Fivee patients (1 in OSS and 4 patients in DSS) withdrew from the study. The patient
inn group OSS stopped because of diagnosis of a pulmonary tumour. In group DSS,
threee patients stopped after programming to DSS because of symptoms of heart
failure.. The forth patient withdrew for psychosocial reasons.
Pacemakerr and sensor type
Thee majority of patients (58% in OSS group vs. 39% in DSS group) had pacemakers
equippedd with dual sensor systems of Vitatron (QT and activity. Vitatron. Arnhem
Thee Netherlands). Activity sensors were the most frequent used sensors in the
singlee sensor systems, The OSS group had 31% of activity sensors of Medtronic
(Medtronic.. Minneapolis USA), while the DSS group had 35% Medtronic and 9%
Guidantt (Guidant. Minnesota USA) activity sensors. Accelerometers of Guidant
(Guidant,, Minnesota USA) were used 17% in the DSS group and 11% in OSS.
83 3
Tciblee 2. Pacemaker optimization settings
Mode e Baseline e
WIRR i%! WII i%* DDDRR i%i ODDD i%l AAIRR i% AAII i%l
4 4
26 6 9 9 4 4 7 7
fticemakerfticemaker settings changed Baseline
Afterr optimization
59 9 0 0 35 5 0 0 6 6 0 0
Afterr optimization Frequency of change (%)
LRMbprrO O URLL ibpm) THH ilow, medium/low. medium,, medium/high, high' S l o pee [*•)
Sensor r
60 0 1211 4.4f medium m
I I
default t QT=ACT T
611 2.7
14544 14.31 low,, medium/low
moree agressive OKACT.. ACT
12 2 92 2 11 1
15 5 31 1
Tablee 2. LRL = lower rate limit ; URL = upper rate limit : TH^threshold: QT= OT sensor: ACT = activityy sensor: \*) dependent of the manufacturer: response factor, response time or acceleration time:: blending OT=ACT-> 50:50. QT<ACT-> 25:75: t URL after optimization is significantly different,, p <0.001.
Sensorr optimization
Ratee response was programmed on in all patients. The LRL was changed in 12% of
thee patients but increased not significant. The URL was programmed higher in 92%
off patients, from 121 4.4 to 145.4 14.3 bpm, (p<0.001). The threshold was
changedd in 11% of the patients: from medium to medium/ low in 4% vs. medium to
loww in 7 % and the slope settings were changed in 15 % of the patients. The re-
sponsee factor vs. response time vs. acceleration of the slope was programmed in a
moree aggressive setting: from factor 8 to 14 in 7 % vs. 30 to 10 seconds in 4 % vs.
standardd to fast in 4 %. In 33% of patients, the slope settings could not be adjusted
duee to the autoslope setting inVitatro n pacemakers (Arnhem, the Netherlands),
despitee the need for a more aggressive slope setting. Sensor blending was changed in
311 %. In 12% the default sensor blending setting (QT = ACT) of the Vitatro n pacemak-
erss (Arnhem, the Netherlands) were programmed to activity only and in 19 % to
OT<ACT ,, see table 2.
84 4
Chapterr 4
Tablee 3. Summary of HR during rest, exercise and recovery
Restingg rate ibpm.1-Timee to peak HR ymui' Programmedd maximum Achievedd maximum HR 100 mill recovery ibpm.1
METS S
Exercisee duration mini. M.tximall HR during SI. Posturee change
HRR \bpm l
^bpm.1 1
DSS S
Baseline e
vn-27^ ^ Default t
677 14
100 5 1211 4
1099 21 744 10 66 4 111 5
711 12 722 11
22 months
li ii = 231 Default t
633 29 100 7
I21 4" 11 OS 20 #
666 6 4.99 4"
100 5 688 10
688 + 6
Baseline e
inn = 27 Default t
711 14
n 5 121 4
1144 15 777 10
7 4
5 5 711 13 700 10
inn = Q CAEP P
700 13 111 +. 0
1477 + I4f I I SS 9 699 15
66 + 4 111 5
7 6 + 17 7
766 5
OSS S
22 months
inn = 81 6-HWT T
666 + 7 100 4
1422 12 S 128++ 34
65 7 7.88 4*
122 5 9 9
67 6
m-Ql l &-HWTT + SC
666 9 1 1 +5 5
1477 18+ * 1233 29 #
62 8
7.99 4* 133 * 4 68 8 67 7
P-value e
ns s ns s
t<0 .001 1 -*1== 0.036
ns s
0.045* * ns s ns s nn s
Tablee 3. HR= heart rate; bpm = beats per minute: min = minutes; DSS = default sensor setting. OSSS = optimalized sensor setting: CAEP= chronotropic assessment exercise protocol; 6-HWT = 6 minute halll walk test; SC= staircase ascent and descent; SL = suitcase lifting; #-11= the achieved maximal heart ratee is significantly higher in the total group of OSS compared to DSS, p = 0.036; * = the achieved METS wass significantly improved in the subgroups 6-HWT and 6-HWT +SC compared to These three exercise testss iCAEP. 6-HWT and ó-HWT +SO were used for optimization. DSS. p = 0.045.
HR R
140 0
1300 -
120 0
110 0
100 0
90 0
80 0
70 0
60 0 50 0
40 0
-*-DSS-B B -•—DSS-- 2 months
Rest t Exercise e Recovery y ~ii i r r T r ~!! T
33 6 9 12 15 18 21 24 27 30 33 36 Minutes s
Figuree 3. Changes in heart rate tinea nV HR = heart rate. DSS-B = default sensor setting at baseline.
S5 S5
HR R 160 0
140 0
120 0
100 0
SO O
60 0
40 0
-è^^ OSS-B 22 months
Rest t Exercise e Recovery y
- x -- -x--x-
11 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 Minutes s
Figuree 4. Changes in heart rate (mean). HR-heart rate: OSS-B- optimalized sensor setting at baseline.. *P = 0.036.
Exercisee test protocols
PosturePosture change, suitcase lifting
Thee achieved maximal HR during posture change and suitcase liftin g were compara-
blee in OSS and DSS at baseline and after 2 months (see table3). One patient could
nott lif t the suitcase.
chronotropicchronotropic assessment exercise protocol
Thee achieved maximal HR and METS after sensor optimization were significantly
higherr compared to DSS (124 28 vs. 108 20. p = 0.036: 7.3 4 vs. 4.9 4 METS,
p=0.045). .
Highestt increase in maximal HR, METS and exercise duration was achieved in the
subgroupss whereby the sensor was adjusted with 6-HWT (128 34 vs. 7.8 4 vs.12
86 6
Chapterr 4
5)and6-HWT +SC (123 29 vs. 7.9 4 vs. 13 4) compared to the subgroup
CAEPP (118 19 vs. 6 4 vs. 11 5Ï-
Otherr measured parameters between the groups and subgroups like resting rate,
timee to peak HR, HR at 10 minute recovery, maximal HR during suitcase liftin g and
posturee change were comparable between the two CAEP tests (see table 3, figure 3
andd figure 4).
Qualityy of lif e
Thee achieved scores from all the three QOL-q (RAND-3Ó, Hacettepe and Karolinska)
onee month after optimization compared to DSS were not significantly different.
Alsoo scores attained within the subgroups of the three QOL-q were not significantly
different. .
Discussion n
Exercise e
Ourr study shows that individual optimization of pacemaker sensors results in
improvedd exercise capacity. Also, after sensor optimization the reason for stopping
thee exercise test shifted to concomitant restrictions (e.g. physical activity level of
thee elderly pacemaker patients) rather than cardiovascular limitations. The in-
creasedd METS and HR indicate that patients have an improved exercise capacity
afterr sensor optimization
Thee highest benefit from optimization in achieved METS and maximal HR was
obtainedd with the 6-minute HWK and 6-minute HWK+ SC. In the CAEP subgroup,
theree were 33% more pacemakers with automatic slope settings, which could not be
individuallyy adjusted. Other possible factors, which could influence the exercise
capacityy between the groups. like medical history and medical therapy, were not
significantlyy different. These results underline the importance of individually
adjustmentt of pacemaker sensors and the necessity of accessible pacemaker
algorithms. .
Too date, limited studies investigated the effect of sensor adjustment and to the best
87 7
off our knowledge: our study is the first and largest randomized controlled study,
comparingg DSS with OSS in detail. Previous studies mainly compared different
sensorss and were not primarily designed to evaluate individual adjustment,5
Sulkee et al. showed that appropriate programming of sensors is crucial in rate
responsivee pacing. & In 20 patients the effects on exercise and QOL of appropriate,
overr and under programming of the sensor were assessed. In contrast to our study,
onlyy activity sensors were evaluated and the sensors were optimized according to
thee manufacturer's instructions without detailed insight in these instructions. In
anotherr study, Klonis et al. investigated whether automatic algorithms for sensor
optimizationn could reduce clinical follow up time compared to manual adjustment.
Usingg the activity level of patients (more active, the same, or less active) they
concludedd that automatic adjustment is less time consuming than manual adjust-
ment,, This study supports the current trend in increasing automaticity in pacemak-
ers,, although it is disputable if such a rough guide as three levels of activity can be
usedd as a guide for sensor optimization. In general, sensor optimization methods
aree poorly described, mostly referring to the manufacturers advice.
Inn agreement with previous reports, exercise duration was not significantly im-
provedd after sensor optimization.8 2D This can partly be explained by the category of
patientss in need of permanent pacing (elderly and relatively sedentary). In these
patients,, exercise is often limited by loss of muscle strength and mass rather than
cardiopulmonaryy capacity. This loss of muscle strength is particularly apparent
whenn exercise testing is performed on a bicycle or treadmill. The CAEP exercise test
consistt nonlinear characteristics. The first 10 minutes it requires a low metabolic
workload,, beyond which it increases abruptly. Patients with preserved functional
capacity,, capable of exercising for more than 10 minutes, may quit before reaching
maximall 02 uptake, mainly because of excessive increments in workload near the
endd of the test, thus, being limited by mechanical rather than metabolic barri-
ers.12211 In our study there is a trend to increase of exercise duration with a mean of
11 5 minutes. This increased exercise duration results in a higher achieved speed
andd steeper slope on the CAEP. And this longer exercise duration is achieved due to
thee higher achieved heart rate. The symptom limited 6 minute hall walk test resem-
bless closer daily activities and less time consuming compared to the treadmill or
bicyclee exercise tests. 22
Thee healthy controls achieved higher HR than patients despite individual optimiza-
tion,, probably because current sensors are still hypochonotropic and physicians feel
88 8
Chapterr 4
reluctancee to program such high upper rates due to concomitant heart disease. The
maximall HR in the default setting is generally too low, well below the age predicted
maximall HR of the mean age of a typical pacemaker patient of 70 year, according to
thee Astrand formula (220-age). An inappropriately low programmed maximum sensor
ratee and failure to reach maximum exercise will result in sensor indicated pacing rates
duringg exercise testing below the calculated expected HR. The clinician may attempt
too compensate for this by programming more aggressive rate response parameters
whichh may result in excessive rate response behavior of the pacemaker during the
patient'ss normal ambulatory activities.0
Qualityy of lif e
Qualityy of life did not improve with individual sensor optimization. Specific sub-
groupss that derived benefit were not observed, including stratified to device indica-
tion,, age or specific complaints. Again, only the study of Sulke et al. assessed the
effectt of rate responsive pacing on QOL. Appropriate, over and under programming
off the rate response were evaluated in both dual and single chamber activity sensor
ratee adaptive pacemakers with visual analog scales and specific activity question-
naires.. Symptoms were least in the appropriate programmed pacemakers after 2
weekss of follow up. The found differences between both studies could be explained
duee to the greater programming steps in Sulke's study (rate response off, appropri-
atee programming and aggressive programming). Another explanation for the failure
too improve QOL after sensor optimization could be the relatively good baseline
functionall capacity, because patients with relative preserved functional capacity at
enrollmentt show the lowest improvement in health related values.25
Alsoo in large pacemaker trials, improvements in QOL were minimal. The PAcemaker
Selectionn in the Elderly study (PASE, n=407) showed only in the subgroup with sick
sinuss syndrome a moderate improvement in QOL in patients with dual chamber
pacingg as opposed to ventricular pacing, whereas in the Canadian Trial Of Physiolog-
icc Pacing investigating (CTOPP, n = 172II only the global well being score was better
inn the physiologic vs. WIR mode.
Inn general, there is a lack of validated pacemaker patient specified quality of life
QOL-q.244 To date, only two questionnaires were specifically developed for pacemak-
err patients (Hacettepe Qol-q2\ Aquarel QOL-q). This complicates comparing
studiess using different QOL-q's and methods for assessing QOL (transtelephonic,
89 9
selff administered at hospital by researcher /patient). Therefore, it is advisable to
interprett QOL data in pacemaker patients cautiously.15 A The recent developed
Aquarell Qol-q is an accurate QOL-q for study design as our present study, therefore
wee suggest to use this OOL-q in future studies. We could not use this QOL-q for our
studyy because it was not available.
Inn this study we showed an improvement in exercise capacity without improvement
inn QOL. The reverse is shown in cardiac resynchronization therapy studies with
onlyy minor changes in exercise capacity yet major changes in QOL. The PATH-CHF
studyy there was only a minor improvement of 60 meters after cardiac resynchroniza-
tionn therapy while QOL improved clearly.2' These disconnect between exercise
capacityy and QOL can be explained possibly due to several factors. The pacemaker
implantationn has already a large impact and therefore it is more difficult to obtain
moree additional improvement. In this study we compared in hospital tests with
evaluationn of QOL based on the activities at home. As described above the in- hospital
testss are artificial, therefore it would be theoretically and scientifically better when
wee compared the sensor function at home using holter registration with QOL.
Conclusions s
Afterr 1 month of individual optimization of rate response pacemakers, exercise
capacityy and maximum HR was improved, although QOL remained unchanged.
Accessiblee pacemaker sensor algorithms are mandatory for individual optimization,
althoughh automatic features are indisputably important in the pacemaker sensor
development. .
Developmentt of sensor algorithms which create the possibility for monitoring
sensorr behavior in detail at home is a great challenge to overcome the disadvantages
off hospital exercise tests for sensor optimization.
Acknowledgments s
Thee authors thank Wandena Ramsoekh. pacemaker technician for the technical
supportt and Michael Kortz, MD (department of Cardiology, Flevohospital. Almere.
Thee Netherlands) for helping with the inclusion of patients.
Q0 0
References s
Chapterr 4
1.. Lass J, Kaik J, Meigas K, Hinrikus H, Blinowska A. Evaluation of the quality of rate adaptation algorithmss for cardiac pacing. Europace. 2001:3:221-8.
2.2. Sack S. [Modern pacemaker therapy]. Herz. 2001;26:1. 3.. Elmqvist R. Review of early pacemaker development. Pacing Clin Electtophysiol. 1978:1:535-6. 4.. Leung SK. Lau CP. Tang MO. Cardiac output is a sensitive indicator of difference in exercise
performancee between single and dual sensor pacemakers. Pacing Clin Electrophysiol. 1998;21:35-41. .
5-- Zegelman M. Cieslinski G, Kreuzer J. Rate response during submaximal exercise: comparison off three different sensors. Pacing Clin Electrophysiol. 1988:11:1888-95.
6.. Freedman RA, Hopper DL, Mah J. Hummel ). Wilkoff BL. Assessment of pacemaker chrono-tropicc response: implementation of the Wilkoff mathematical model. Pacing Clin Electrophys-iol.iol. 2001:24:1748-54.
7.. Lau CP. Leung SK. Guerola M, Crijns HJ. Comparison of continuously recorded sensor and si-nuss rates during daily lif e activities and standardized exercise testing: efficacy of automatical-lyy optimized rate adaptive dual sensor pacing to simulate sinus rhythm. Pacing Clin Electro-physiol.physiol. 1996;19:1672-7.
8.. Sulke N. Dritsas A. Chambers J. Sowton E. Is accurate rate response programming necessary? PacingClinPacingClin Electrophysiol. 1990:13:1031-44.
9-- Strobel JS, Kay GN. Programming of sensor driven pacemakers. Cardiol Clin. 2000:18:157-76. ix. 10.. Kay GN. Quantitation of chronotropic response: comparison of methods for rate- modulating
permanentt pacemakers. J Am Coll Cardiol. 1992:20:1533-41. 11.. Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment, Cardiol Clin. 1992:10:705-
17. . 12.. Ellestad MH. stress testing principles and practice.tirth edition:567-573-13.. Astrand. Aerobic work capacity its relation to age, sex. and other factors, circulation research.
1967;20:1-2111 1-217. 14.. Hays RD, Sherbourne CD, Ma2el RM. The RAND 36-Item Health Survey 1.0. Health Econ.
1993:2:217-27. . 15.. Linde C. How to evaluate quality-of-life in pacemaker patients: problems and pitfalls. Pacing
ClinClin Electrophysiol. 1996:19:391-7. 16.. Klonis D. Zhang X, Patel U. Gulamhusein S, Patel J, Hurwit H. Banish D. Marco D. Automatic
sensorr algorithms expedite pacemaker follow-ups. Pacing Clin Electrophysiol. 2003:26:225-8. 17.. Sulke N, Pipilis A, Bucknall C. Sowton E. Quantitative analysis of contribution of rate re-
sponsee in three different ventricular rate responsive pacemakers during out of hospital activi-ty.. Pacing Clin Electrophysiol. 1990;13:37-44.
18.. Bellamy CM, Roberts DH, Hughes S, Charles RG. Comparative evaluation of rate modulation inn new generation evoked QT and activity sensing pacemakers. Pacing Clin Electrophysiol. 1992:15:993-9. .
19.. Mahaux VA. Verboven Y], Waleffe A, Kulbertus H. Stepwise analysis of the calibration proce-duree of an accelerometer-based pacemaker. PacingClin Electrophysiol. 1994;17:1955-9-
20.. Hasegawa A. Hatori M, Amano M, Iijima T. Adachi H, Yamaguchi E. Fukuda T, Murata K. Nagai R.. Adequacy of pacing rate during exercise in rate responsive ventricular pacing. Pacing Clin Electrophysiol.Electrophysiol. 1997:20:307-12.
21.. Page E. Bonnet JL, Durand C. Comparison of metabolic expenditure during CAEP versus a test adaptedd to aerobic capacity (Harbor test) in elderly healthy individuals. Pacing Clin Electro-physiol.physiol. 2000;23:1772-7.
22.. Hayes DL, Von Feldt L, Higano ST. Standardized informal exercise testing for programming ratee adaptive pacemakers. Pacing Clin Electrophysiol. 1991;14:1772-6.
23.. Lopez-Jimenez F, Goldman L. Orav EJ. Ellenbogen K. Stambler B, Marinchak R, Wilkoff BL, Mangionee CM. Yoon C, Vitale K, Lamas GA. Health values before and after pacemaker implan-tation.. Am Heart J. 2002;144:687-92.
24.. Stofmeel MA. Post MW. Kelder JC. Grobbee DE, van Hemel NM. Quality-of-life of pacemaker patients:: a reappraisal of current instruments. Pacing Clin Electrophysiol. 2000:23:946-52.
91 1
25.. Oto MA, Muderrisoglu H, Ozin MB. Korkma2 ME. Karamehmetoglu A. Oram A, Oram E. Ugur-luu S. Quality of lif e in patients with rate responsive pacemakers: a randomized, cross-over study.. Pacing Clin Electrophysiol. 1991:14:800-6.
26.. Stofmeel MA. Post MW, Kelder JC. Grobbee DE, van Hemel NM. Psychometric properties of Aquarel,, a disease-specific quality of lif e questionnaire for pacemaker patients, ƒ Clin Epide-miolmiol 2001:54:157-65.
27.. Huth C. Friedl A, Klein H. Auricchio A. [Pacing therapies for congestive heart failure consider-ingg the results of the PATH-CHF study]. Z Kaidiol. 2001:90 Suppl 1:10-5.
92 2
Cerebrall blood flow velocity and cardiacc output at the onset of
dynamicc exercise at two settings of pacemakerr determined heart rate
Aytenn Erol-Yilmaz MD1, Lysander W.J. Bogert MD,2 Raymond Tukkie MD PhD1, Arthur A.. Wilde MD PhD1. Wouterr Wieling MD PhD2 and Johannes J. van Lieshout MD PhD 2
Clinicall and Experimental Cardiology1, Department of Internal Medicine2. Academicc Medical Center. Amsterdam, The Netherlands.
Dr.. Erol-Yilmaz and Dr. Bogert contributed equally to the article
SubmittedSubmitted for publication
Abstract t
Background d
Inn cardiac patients, the increase in the transcranial Doppler determined middle
cerebrall artery (MCA) mean flow velocity (Vmean) during exercise depends on the
abilityy to increase cardiac output (Q), The aim of this study was in six patients (66
(49-76)) yr.) with complete heart block and ventricle rate adaptive pacemakers to
evaluatee whether variation in heart rate (HR) affects the increase in MCA V m e an and
OO during exercise.
Material ss and methods
Thee effect of setting the pacemaker to "default" (DSS) vs. "optimized" (OSS) on
bloodd pressure (BP).Q, stroke volume (SV1 and MCA Vmean was evaluated during
gradedd ergometry cycling. During the first 3 min. of exercise in OSS vs. DSS at 25
andd 75 W the rise in HR (26 (1-59) vs. 13 (0-25) bpm; P<0.05 and 43 (0-83) vs. 27 (2-
43)) bpm: P<0,05, respectively) was larger. However, with OSS the increment in SV
wass smaller at 75 W( + 33 (-4-71)% vs. +51 (18-88)%: P<0.05) resulting in a compa-
rablee rise in Q (+95 (73-109)% vs. +101 (58-119)%). For both OSS vs. DSS there was
noo significant increase in MCA V m e an during exercise. The manipulation of the
pacemakerr setting had no effect on the maximal workload (133 (100-225) vs. 129
(75-200)) W).
Conclusions s
Thee results indicate that in patients provided with a rate adaptive pacemaker. MCA
VV , changes in cardiac output and work capacity do not depend on the increase
inHR. .
96 6
Chapterr 5
Introductio n n
Inn both animals 8 and humans cerebral blood flow (CBF) 14 A& and middle cerebral
arteryy (MCA) mean flow velocity (Vmean)22 24 increase —25% on the transition from
restt to moderate exercise.14'i q 25 33 However, the increase in MCA Vmean becomes
attenuatedd when the ability to raise cardiac output (Q) is limited as in patients with
atriall fibrillation23 and in patients with heart failure in whom the substantial
reductionn in CBF is reversed by cardiac transplantation15 Normally both chronotrop-
icc and inotropic cardiac adaptive mechanisms are driving Q in the early stages of the
circulatoryy adaptation to exercise heart rate (HR) being responsible for as much as
—75%% of the increase.4
Withh such a large contribution of HR to the increase in Ó at the onset of exercise,
thee setting of pacemakers may be critical for the patient's ability to maintain daily
activities.. Manipulation of HR is possible with rate-adaptive pacing and the ability to
increasee may be improved6 40 Rate adaptive pacemakers are used in patients with
atrioventricularr (AV)-nodal block and the rate-adaptive pacing is considered preferable
forr patients with chronotropic incompetence.31 Patients with complete heart block
followingg curative AV ablation for atrial fibrillation are provided with a rate-modulat-
edd pacemaker, i.e. the pacing rate is modulated based on one or more internal sensors
thatt detect exercise and metabolic need.31 In these patients there are several ways to
programm the pacemaker and evaluate the effects on HR and Q.
Thee increase in Q and blood pressure (BP) during dynamic exercise is preserved
whenn there is littl e change in HR, such as in patients with a heart transplant or in
healthyy individuals following autonomic blockade,30 32 35 We considered in patients
dependentt on permanent rate adaptive ventricular pacing, whether manipulation of
thee HR response would enhance the HR response to exercise and in turn MCA Vmean.
QQ and work capacity.
Methods s
Studyy Population
Sixx ventricular paced untrained patients (66 (49-76) years) with permanent program-
mablee ventricular rate adaptive pacemakers (Vitatron, Arnhem Netherlands, or
97 7
Guidant,, Minnesota USA) participated in the investigation (table 1). Pacemakers were
placedd because of drug resistant atrial fibrillation with His bundle ablation [n = 5). and
sickk sinus syndrome (n=Il. On the basis of history, medical and echocardiographical
examinationn of myocardial function all but one patient were considered without any
evidencee of inotropic dysfunction. One patient with a history of myocardial infarction
usedused amiodarone for recurrent non-sustained ventricular tachycardia and had a left
ventricularr ejection fraction of 25%. Separate analysis of the study data of this patient
revealedd no significant differences in any of the cardiovascular responses to exercise
andd data from this patient were included in the group analysis. All patients received a
verball and written explanation of the objectives and techniques of measurements and
riskss and benefits associated with the study and provided written informed consent
inn accordance with the Helsinki Declaration.
Tablee 1. Patient characteristics and pacemaker settings
Patient t no. .
1 1 2 2 3 3 4 4 5 5 6 6
Age e (yeaa rs)
69 9 49 9 76 6 67 7 58 8 57 7
Sex x IM/Ft t
M M F F M M F F M M F F
Diagnosis s
AF F AF F AF F AF F SSS S AF F
Defa a Sensor r
OT=ACT T OT=ACT T QT=ACT T ACTT only QT=ACT T ACTT only
ultt setting URL L
120 0 120 0 120 0 120 0 120 0 130 0
TH H
Med d Med d Med d Med d Med d Med d
Optimizedd setting Sensor r
OT<ACT T QKACT T OT<ACT T ACTT onlv QT=ACT T ACTT only
URL L
150 0 170 0 150 0 150 0 150 0 170 0
TH H
L L Med d MH H Med d Med d ML L
Tablee 1. URL; upper rate limit ; TH; threshold: M: male; F; female; AF: atrial fibrillation with His bundlee ablation; SSS: sick sinus syndrome; L: low: Med; medium: MH: medium high: ML: medium low;; QT; QT-sensor; ACT: activity sensor OT = ACT: equal contribution of each sensor on the pacing rate;; OT<ACT: 25% contribution of OT and 75% contribution of ACT sensor on pacing rate.
Heartt rate
Duringg consecutive runs of symptom limited exercise, using a chronotropic assess-
mentt exercise protocol ^ the pacemaker sensor setting was optimized in accord-
ancee with a database ^ to produce a physiological HR response to exercise derived
fromm electrodes mounted in a belt (Polar advantage system. Polar Electro OY. Kem-
pele.. Finlandl. The pacemakers were provided with an activity sensor that uses a
piezoelectricc crystal for detection of body movement and also a OT sensor, which uses
ratee independent shortening of the OT interval during increased sympathetic activity
ass input. In the pacemakers with a OT sensor during a learning procedure, lasting
98 8
Chapterr 5
severall weeks, software incorporated in the pacemaker correlates the longest QT
intervall and zero activity counts to an individual at rest, and the shortest OT interval
andd the maximum number of activity counts to the maximum level of exercise.
Ultimately,, the rate moves between the lower rate and the maximum sensor rate.
Thee HR response to exercise was used to vary the level of input between the activity
sensorr and the QT sensor, and the threshold of the activity sensor was adjusted to
thee minimal level of vibration required for producing a rate response. With succeed-
ingg series of exercise, pacemaker output was adjusted in a stepwise manner until
thee derived HR curves (optimized sensor sett ing= OSS) approached the reference
curvess 52. OSS was established further by increasing the URL from 122 (SD 4) to 157
(SDD 10) beats per min {bpm) (table l) with the upper rate limi t (URL) set as
(220-age)) bpm,3
Studyy protocol
Afterr completion of the sensor learning period and at least 2 months following
sensorr optimization, patients were admitted to the laboratory for exercise testing,
afterr being fitted with a headgear for transcranial Doppler (TCD) measurement of
MCAA velocity. After a resting period of 15 min in the seated position, resting data
weree collected and the patients performed graded ergometry cycle exercise with
pacemakerr settings in the manufacturers default setting (DSS) and with OSS.
Uprightt exercise was performed on an electrically braked stationary cycle ergometer
fromm rest to maximal exertion with a constant pedaling speed of 60 rpm. Exercise
startedd at 25 W for 3 min. From then on each stage increased wattage from the
previouss stage by 25 W and lasted 2 min in duration. The exercise was stopped
whenn the patients were no longer able to maintain 60 rpm. Then, they rested in the
supinee position for at least 45 min to allow cardiovascular variables to return to
baselinee levels. Thereafter, the pacemaker settings were switched from OSS to DSS
orr vice versa. The order of the pacemaker settings was fixed in 4 of the 6 patients
accountingg for the requested OT sensor learning time and these patients started
exercisee with the pacemaker in OSS. Both the patients and the observer were
blindedd for the settings of the pacemaker.
99 9
Cerebrall and Central Hemodynamic Measurements
Bloodd pressure was measured non-invasively by photoelectric plethysmography
withh a Finapres [Model 5; Netherlands Organization for Applied Scientific Research,
Biomedicall Instrumentation, TNO-BMI, Amsterdam, The Netherlands) with the
fingerr cuff on the mid-phalanx of the middle finger of the dominant hand. To avoid
hydrostaticc level differences, the hand was held at right-atrial level in the mid-
axillaryy line. In the Finapres device, a built in expert system (Physiocal) was in
operationn to establish and adjust a proper volume clamp set point (17). During
progressivee exercise to fatigue there is no significant difference in the intercept
valuee from zero between systolic [SBP), mean (MAP), and diastolic blood pressure
(DBP)) between radial and finger arterial pressure with validity correlations ranging
fromm 0,93 to 0.99 (9. 11. 44). Left ventricular ejection time (LVET) was the time from
upstrokee to dicrotic notch.
Thee SV was determined by a three-element model of arterial input impedance (53)
whichh provides accurate estimates of changes in SV during postural stress (17).
Modell simulated (modelflow) Qfrom radial or finger arterial pressure follows
changess O in as determined by thermodilution in direction and degree during
cardiacc surgery, postural stress, and shock (17, 29. 53). Changes in Doppler echocar-
diographyy determined SV are tracked by model SV during the Valsalva maneuver,
passivee til t and exercise (38, 45. 51). If accurate absolute values are required, the
methodologyy needs calibration against a standard method (28, 50); otherwise, O is
expressedd as changes from control with the same precision in O (17. 27. 37). Q was
Restt Exercise 25W DSSS OSS DSS OSS
MAPP immHg) PPP tmmHgl HRibpmï ï LVET T SV% % Qi%l l TPRR t%l Pp.,CO,, immHg!
ff i tri in ')
899 173-105) 588 \34-73) 700 160-76)
0.277 (0.24-0.32 100 0 100 0 100 0 333 \29-371 466 137-62) 166 d 2-20)
933 175-1081 599 (37-72) 733 105-87)
0.277 t0.24-0.3r 100 0 100 0 100 0 333 L29-371 466 i35o6) 166 (12-191
92 2
85 5
83 3 0.29 9 136 6
161 1 66 6
35 5 48 8
20 0
\76-112* *
152-106H H 165-9911 t
(0.25-0.35^ ^
i l 2 I - 1 5 D t t
i l41-196) t t (50-7311 j .30-37) )
i83-66^ ^
112-27)) t
103 3 81 1
99 9 0.27 7
115 5 154 4
71 1
37 7 50 0
21 1
186-120)*" " (55-109) )
174-128)) * * f l0.22-0.3411 *
87-13«)** *
1128-170)) t (65-8511 t 132-4211 j
144-63' '
i !! 7-251 t
100 0
Chapterr ~>
SVV times HR. Total peripheral resistance iTPR) was the rati o of BP and Q expressed as
changess from its starting value in the sitting resting position prior to exercise (37).
Changess in cerebral perfusion were evaluated by following the blood flow velocity
inn the MCA by insonating its proximal segment (Multido p X. DWL, Sipplingen,
Germany)) through the posterior temporal "window " (1). When the optimal signal-
to-noisee rati o was obtained the probe was secured with a headband (Mark 600,
Spencerr Technologies. Seattle WA, USA), End-tidal C02 (PETC02) as an estimate of
arteria ll C02 tension (PaC02) and breathing frequency (f) were obtained from the
capnogramm by means of a nose tubing connected to a sampling infrare d C02 analyz-
err (Datex Normocap 200. Helsinki. Finland).
Analysis s
Forr off-lin e analysis signals of arterial pressure, MCA velocity and capnogram were
analogue-to-digitall converted at a sampling rate of 100 Hz and stored on disk. Beat-
to-beatt SBP and DBP values were derived. MAP and MCA V were obtained, mean n
respectively,, as the integral of pressure and velocity divided by the corresponding
beatt interval . Pulse pressure was the SBP- DBP-difference and HR was obtained from
thee pulse pressure interval . The HR responses produced with DSS and OSS were
evaluatedd according to the maximal HR attained and to the slope of the regression
off HR vs. time durin g the first 3 min of exercise.
Forr comparison data were transformed to equidistantly re-sampled data at 2 Hz by
polynomiall interpolation and expressed as 10 s averages. Baseline measurements
Tablee 2. Values are expressed as mean and range. DSS: defaultt sensor setting: OSS; optimized sensor setting, MAP:: mean arterial pressure, PP: pulse pressure, HR: heartt rate, LVET: left ventricular ejection time. . SV: strokee volume. ; cardiac output, TPR: total peripheral resistance.. P^CO.,: end-tidal COr f: breathing frequency. Vm.ir]:: cerebral mean blood velocity-. DSS vs. OSS * p<0.055 ** p<0.01 rest vs. exercise f p<0.05, J p<0.01.
94 4 104 4
97 7 0,26 6
151 1 20] ]
56 6
36 6 44 4 22 22
Exercis ee 75W DSS S
171-105) ) (78-123) )
(67-117)) t i0.22-0,33^ ^ (118-186) )
\\\\ 58-2274
i53-8D* * \32-42) )
i41-491 1 (16-294 4
100 0 102 2
116 6 0.24 4 132 2
195 5 56 6
37 7
45 5 23 3
OSS S
(79-1151** * 172-1161 1
(73 -152 ) + n n (0.20-0.3011 * 1 191-172)* *
(176-208)* * 148-66)) t
02-451 1 \42-51) )
(17-33)1 1
101 1
Exercisee in DSS
,0 0
0Ü 0Ü
1755 "
11 50-
1255 "
11 00
755 "
50--
5. .
OS S EC C
1755 -
150 0
125--
100 0
755 "
50 0
-- -
00 300 600
Timee (s)
Exercisee in OSS
300 300 600 0
Timee is)
Figuree 1. HR responses to exercise at two levels of pacemaker rate response. Individual (thin lines) andd group averaged (thick lines). HR during default Ueft panel) and optimized (right panel) settings off the pacemaker during exercise. DSS: default sensor setting, OSS: optimized sensor setting. HR: heartt rate.
aree averaged values over a 1 min resting period seated on the bicycle prior to
exercise.. If data fitted a normal distribution as determined by Kolmogorov-Smirnov
testt with Lilliefors' correction they were examined by paired t-test and otherwise by
Wilcoxonn signed-rank test. Data are expressed as mean and range in tables and as
meann S.E.M in figures. A p-value <0.05 was taken to indicate a difference.
102 2
Chapterr 5
w> > _. . --B B
. .
220 0
140 0
100 0
60 0
, - i . ' '
s s > >
,--fci fci u. . oS S
::: :
40 0
0 0
160 160
140 0
100 0
80 0
60 0
220 0 L80 0 140 0 100 0 60 0
66 54 3 2
I JJ I 1
. . . . . . . . . . . . . . . . . . . . . . .
w i ÉÉ , Ï • • • t • • • • • • • * * 8 * • i
,, 4 . * * * * H oo Q 9 2 9 9 22 5 V 2 f ? ^
< <
a a
2200 -
1800 -
140 0
100100 -
600 -
66 C
--
88 o o 0 0 * ö ö Ó
* * 88 5 8 ? * ? !
OWW 25W 50WW 75W
Workloadd (Watt)
Figuree 2. Cerebral and central hemodynamic response at two levels of heart rate. Meanss and SEMs for systemic and peripheral hemodynamics. Arrows indicate a patient that had to stopp exercising. White circles indicate values obtained in optimized settings, black in default settings.. BP: arterial pressure (systolic, mean and diastolic). V: cerebral velocity (systolic, mean and diastolic).. HR: heart rate. SV: relative stroke volume from baseline. Q. relative cardiac output from baseline. .
Results s
Inn the resting sitting condition prior to exercise in DSS and OSS, HR 70 (60-76) vs.
733 (65-87) bpm and MAP 89 (73-105) vs. 93 (75-105) mmHg were comparable. Also
Vmean .. PETCO, and breathing frequency were not affected by the pacemaker setting
(tablee 2). The increase in HR with OSS vs. DSS during the first 3 min of exercise at
255 W was larger and this difference remained at 75 W (Fig. 1). SV increased less with
103 3
50WW 100W 150W 200W 25W W 50WW 75 W ÏOOW
25W W 50W W 75W W 25W W 55 OW
25W W 50WW 75W ÏOOW 125W 25WW 50W 75W ÏOOW 125W
Figuree 3- Individual difference ^optimized - default curves for hemodynamic variables during exercise.. Differences in HR. SV and O during exercise for the individuals. The steeper increase in HRR is compensated by a less steeper increase in SV in the optimized settings. HR: heart rate. SV: strokee volume, O: cardiac output. O: optimized. D: default.
104 4
Chapterr ~>
OSSS with a comparable rise in Q (table 2). Resting LVET was comparable for OSS and
DSS,, while during exercise the decline with OSS was larger at 25 and 75W.
Withh OSS the increase in BP was larger while MCA Vmean did not change (table 2 and
fig.. 2). The individual difference curves for Q and SV at two levels of HR are given in
fig.. 3. The HR response did not modify maximal achieved exercise workload or
exercisee duration in OSS vs. DSS: 133 (100-225) vs. 129 (75-200) W, 684 (355-1476)
vs.. 642 (360-1384) s.
Discussion n
Thee purpose of this study was to determine in patients with a rate adaptive pace-
makerr the contribution of two settings of pacemaker determined HR to the cardiac
outputt and cerebral blood velocity response during exercise. The data indicate that
inn these patients with generally normal heart function, the ability to elevate cere-
brall perfusion during exercise is affected. Enhancing the HR response to exercise
didd not augment O with a larger HR response balanced by a proportional attenua-
tionn of the increase in SV The following discussion details the assumptions and
evidencee that underlie these conclusions.
Normally,, in healthy individuals during exercise an increase in Q provides for the
increasedd tissue oxygen demand with a graded increase in local and regional cere-
brall perfusion corresponding to the MCA territory8- Ï A 18 1Q- 22 24- 2b " • 4 8 In turn,
pharmacologicall reduction of the exercise related increase in Q by cardioselective
bj-adrenergicc blockade reduces the increase in MCA Vmean without affecting MAP or
PETC02 .255 This suggests that during dynamic exercise a reducedQ has an effect on
thee cerebral circulation and in patients with heart failure physical exercise may
evenn reduce cerebral perfusion.20
Wee considered that during dynamic exercise diastolic cardiac volume is secured by
venouss return43 and that in pacemaker dependent patients manipulation of the HR
responsee during rate adaptive pacing allows to study the contribution of HR to the
cardiacc and cerebral response to exercise. Our study has, however, several potential
limitations. .
Rightt ventricular apical pacing results in an asynchronous ventricular contraction'1
andd Q may possibly have been lower due to asynchronous activation. However,
105 5
sincee each patient was his/her own reference this possible restriction applies for
bothh HR responses. During exercise, Q is tightly controlled by and linearly related to
oxygenn uptake and in this study workload, duration of exercise and attained Q
weree comparable for the two levels of HR response. By design the two exercise
protocolss were performed in a fixed order to allow for the required QT sensor
learningg period and although both patients and observer were blinded for the actual
pacemakerr setting we cannot exclude an influence on the outcome.
Thee increase in MAP during exercise with OSS was larger. Increasing the pacing rate
enhancess peripherally measured systolic, diastolic and mean arterial pressures
relatedd to alterations in the timing of pressure wave reflection without modifying
centrall systolic pressure.54
Wee assumed that changes in MCA Vmean reflect changes in cerebral blood flow,
whichh is true only in so far the diameter of the vessel does not change. The large
cerebrall arteries are conductance rather than resistance vessels and changes in MAP
withi nn the physiological range appear to have negligible effects on the diameter of
thee insonated artery.42 49 More direct observations made during craniotomy reveal
thatt the vessel diameter does not change significantly during variations in MAP
andd changes in MCA V„ seem to follow cerebral Xe clearance. ' Also, in °° mean
healthyy adults who performed at 60% of their maximum exercise capacity, cerebral
norepinephrinee spillover was not increased making an increase in brain sympathet-
icc activity as a cause of constriction of the MCA unlikely.24
PaC022 is an important denominator of CBF. From the supine to the upright position,
aa reduction in O and a gravity-induced V/O mismatch both affect PETC0213 and from
restt to peak exercise the arterial to end-tidal gradient for CO, increases with exer-
cisee intensity47 questioning PETC02 as an estimate of PaC02. We consider that the
exercise-relatedd increase in P£ TC02 was comparable for both settings of HR making a
significantt contribution of this gradient to the MCA Vmean responses at the moder-
atee exercise intensity of this study less likely.
Inn response to exercise intensities of about 40-60% of maximal oxygen uptake the
increasee in O results from both chronotropic and inotropic cardiac responses, i.e. an
instantaneouss increase in HR and a more gradual rise in SV. 2 21 39 At higher work-
loadss the increase in SV reaches a limi t or SV may even fall and especially older
endurance-trainedd patients have an impaired ability to maintain SV at high levels of
exercise.. Such a decline in SV during prolonged exercise is influenced by an
106 6
Chapterr 5
increasee in HR, i.e. with the rise in HR inhibited by b-adrenergic blockade the
declinee in SV is less conforming that during exercise at higher HR, SV may no longer
bee maintained.10 These findings, taken together with the present data may indicate
ann intrinsic relationship between HR and SV during exercise exposed by pacing at
twoo levels of pacemaker determined HR response.16
Thee finding that Vmean did not increase when exercising from 75 Watt to the maxi-
mumm workload indicates a subnormal increase in Q 2t and a steeper increase in HR
duringg exercise was not translated in an enhanced Q. Several mechanisms may be
responsiblee for this phenomenon. At first, while training allows for a larger increase
inn SV during exercise Al the patients were sedentary and untrained. Second, there was
noo atrial contribution to Q which is probably of significance to restingQ. 3I 4 At an
elevatedd HR level an increase in SV would be caused by a decrease in end-systolic
volumee (increased contractility). We attribute the larger increase in SV at the lower HR
levell during exercise to enhanced ventricular fillin g time (Frank-Starling mechanism).
Inn conclusion, in older sedentary pacemaker dependent patients with complete
heartt block, the ability to elevate cerebral perfusion during exercise is affected by
ann impaired capacity to increase cardiac output. Enhancing the heart rate response
too exercise does not augment cardiac output by a proportional offset of the exercise-
inducedd increase in stroke volume.
Acknowledgments s
LWJJ Bogert is a research fellow supported by the Netherlands Heart Foundation
(grantt 99182). A Erol-Yilmaz is a research fellow supported by unrestricted research
grantss supplied by pacemaker companies Guidant BV. Nieuwegein. The Netherlands,
Metronicc BV. Heerlen, The Netherlands and Vitatron, Arnhem. The Netherlands.
107 7
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]] 10
Directt comparison of a contractility andd activity pacemaker sensor during
treadmilll exercise testing
Aytenn Erol-Yilmaz MD, Raymond Tukkie MD PhD, Job de Boo* MD, Tim Schrama andd Arthur Wilde MD PhD
Fromm the department of Clinical and Experimental Cardiology. Academicc Medical Center Amsterdam and the department of Cardiology
Oosterscheldehospitall Goes. The Netherlands.
PACEPACE 2004; 27:1-7
Abstract t
Introductio n n
Theree are limited data about the chronotropic capacity of the peak endocardial
accelerationn (PEA) sensor. This study directly compared the chronotropic function
fromm the PEA and the activity (ACT) sensor.
Methods s
Thee study included 18 patients (73 7 years) with > 75% pacemaker driven heart
ratee (HR) and a PEA sensor and 11 healthy individuals (HI, 67 7 years) underwent a
CAEPP exercise test with the pacemaker patients in WIR mode after programming
thee sensors in the default setting, with adjustment of the upper sensor rate as an
agee related maximum value (220-age). The ACT sensor was externally strapped on
thee thorax.
Results s
Achievedd exercise duration for the patients and controls was, respectively 92 3
vs.. 18.4 4 min. (p<0.001). The maximal achieved HR with the PEA sensor 124
255 beats/min, versus the ACT 140 23, versus the controls with 153 26 bpm,
(p<0.0011 between the groups). For the PEA, ACT and controls, the time to peak HR
was,, respectively, 11 3. 7 36, and 18 4 (p<0,001 between the groups) and HR
afterr 10 minutes recovery was, respectively. 80 20, 65 15, and 82 4 beats/min
(p<0.0011 between the groups).
Conclusions s
Thee PEA sensor functions hypochonotroop during exercise programmed as a single
sensorr system. It is, therefore, preferable to combine the PEA sensor with an
activity-basedd sensor in a dual sensor system. Although both groups had normal left
ventricularr functions, the exercise capacity of pacemaker patients is significantly
lowerr than in healthy individuals.
114 4
Chapterr ó
Introductio n n
Manyy pacemaker sensors have been developed in the last decade with the ultimate
aimm to imitate the sinus node function.1 From these sensors are the non-physiolog-
ic,, activity based (activity, accelerometer) and the physiologic based (QT, minute
ventilation,, peak endocardial acceleration (PEA)) still in use. The activity-based
sensorr is still in use because of the obvious advantages (sensitive, no necessity for
ann extra lead, housing in the pacemaker can, ease in implementation) although
oftenn combined with one of the physiological- based sensors in a dual sensor
system. .
Thee PEA sensor (Sorin Biomedica, Salugia, Italy) incorporated in the tip of a pacing
leadd is a unique sensor, which measures the peak-to-peak amplitude of the endocar-
diall acceleration signal detected during the isovolumic ventricular contraction
phase.. The PEA values differ from patient to patient, the values reflect the varia-
tionss in sympathetic activity due to physical and mental stress in each patient and
cann be changed by medication or pathological events, 2 Previous experiments
showedd that PEA is related to dP/dt. increases during adrenergic stimulation along
withh dP/dt and reflects whole heart contractility. There is limited data about the
chronotropicc capacity of the PEA sensor and wether the sensor alone is capable to
mimicc sinus node function.2"4 No studies are available which compares the PEA
sensorr with another sensor in the same patient, This study, directly compared the
chronotropicc function offered with the PEA sensor and ACT sensor in WIR mode
duringg treadmill exercise test in default setting with adjustment for the maximum
heartt rate (HR) and compared this with healthy individuals (HI).
Patientss and Methods
Patientt population and healthy individuals
Eighteenn (S men. 10 women; mean age 73 8 years) consecutive patients with > 75%
pacemakerr driven rhythm and commercially available pacemakers with PEA sensor
weree included after informed consent. The pacemaker driven patients had minimal
co-morbidityy but a significant part used some medication. From the existing institu-
115 5
tionall database of exercise testing with HI without co-morbidity and medical
therapy.. 11 (6 men, 5 women; mean age 67 ) age- and exercise type- matched
(chronotropicc assessment exercise protocol (CAEP)) HI were selected. The patients
weree in New York heart association (NYHA) class I- II . The activity levels of patients
andd HI were divided into three grades of activity. Minimally active was defined as
havingg a sedentary lif e style, moderately active when one sports ones a week, and
veryy active when one sports twice a week. Pacemaker implantation was indicated
duee to sick sinus syndrome, atrioventricular (AVI block, atrial fibrillation with His-
bundlee ablation or chronotropic incompetence (see tablel).
Tablee 1. Pacemaker indication, mode and sensor settings
Indication n
Mode e
DDDRR t%) WIRR {%)
ssss w AVV blok [%)
Hiss bund le ablat ion i%)
Otherr (%Ï
Baseline e
28 8
72 2
3Q Q
33 3
12 2
16 6
Testt set t ing
W I R R
W I R R
PEAA and ACT Sensor set t ings
LRMPEAandd ACT1 60
USRR iPEAand ACT) 220-age
PEAA sensit iviy med ium
PEAA upward slope med ium
PEAA downward slope med ium
ACTT threshold Low
ACTT accelerat ion 15 sec
ACTT decelerat ion ] 0 min
Tablee 1,Values are given as mean SD or percentage.; SSS= sick s inus syndrome: PEA— peak
endocardiall accelerat ion; ACT = activity sensor: LRL = lower rate l imit : USR upper sensor rate
Pacemakerr devices and optimization
Alll patients underwent a symptom limited CAEP exercise test according to Wilkof f
andd Miller ' in WIR mode after programming the sensors in the default setting.
withh exception of the upper sensor rate that was programmed 220-age in years. 5
Thee Sorin Living 1 and the Minilivin g D (Sorin Biomedical with a PEA sensor were
used.. These pacemakers are DDDR systems with two sensors: along with the micro
accelerometerr of the PEA sensor there is also a gravimetric sensor, which was
116 6
Chapterr ó
switchedd Off during this study to avoid any interference (which is also in accord-
ancee with the default setting of the pacemakers). The pacing leads were the Best
andd the Minibest leads (Sorin Biomedical. The Best leads had a total length of 62 cm
andd a cylindrical shaped tip. The surface area of this tip is 6 mm2 with a 2,1 mm tip
diameter.. The Pt/Ir electrodes are coated with porous platinum. The sensor sensitiv-
ityy is 50 Hz, 6.8 1.3 mV/g. The lead was inserted through a 13 Fr introducer. The
Minibestt leads differ only in a thinner diameter tip of the lead (1.85 mm) compared
too the Best leads. The lead position in relation to the diaphragm was computed in
thee anteroposterior view on the chest x-ray.
Inn eight patients with the Sorin Living 1, beat-to-beat values of PEA and HR were
telemetricallyy transmitted and recorded by an external PEA recorder. These data
weree analyzed with the Living 1 tool software (Sorin Biomedica). In the other ten
patientss with the Minilivin g D pacemaker, PEA was recorded with an internal Holter
becausee an external PEA recorder is not connectible with this type of pacemaker.
Thee HR derived from the PEA signal was analyzed thoroughly for HR driven due to
intrinsicc versus paced beats.
Simultaneously,, a Medtronic Kappa DR 733 (Medtronic, Minneapolis, MN, USA)
withh an ACT sensor (piezoelectric crystal) was strapped to the contralateral side of
thee internal pacemaker on the upper anterior thorax region in exactly the same
mannerr in each patient. Particular emphasis was placed on uniformly stable attach-
mentt of the external pacemaker; large area adhesive strips were used for this
purpose.. It has been previously shown that behaviors of implanted and externally
strappedd conventional activity-based pacemakers do not differ significantly,6 The HR
drivenn by the PEA and the ACT sensor was monitored with a 12 lead electrocardio-
graphh (ECG). The two lead ports of the externally attached ACT sensor were connect-
edd with the ECG leads V1 and V2, which then reflect the ACT sensor induced rate
responsee and the other ECG leads reflect the PEA sensor induced rate response.
Posturee change and exercise protocol
Alll patients and HI were examined in the same conditions (before noon, uniform
roomm temperature and foot gear (patients own shoes)). After instrumentation,
patientss rested supine on an examination table with one pillow for 5 minutes. Then
thee patients and the HI underwent a CAEP protocol.7' Total exercise time. PEA
117 7
signalss and for both sensors: time to peak HR and maximal achieved HR. HR at 10
minutess recovery were measured.
Statisticall Analysis
Alll results are presented as the mean SD of the group. The pacemaker patients
wit hh the PEA and ACT sensor were compared to HI with the paired sample t-test.
AA P value <0.05 was considered significant.
Results s
Clinicall parameters
Al ll patients were in NYHA class 1 and 2 wit h various activity levels and most
patientss used medication for supraventricular tachyarrytmias. The HI had a higher
activit yy level then the patients and used no medication. The comorbidity of the
Tablee 2. Demographics and clinical variables
Agee (year Sexx (male/female) BMII ikg/m^ NHYAA class [\-4) Activit yy level
MinimallyMinimally active i%) ModerateModerate active i%i VeryVery active {%]
LVEF;%I I
History y
MI(%) MI(%) CABG(%) CABG(%) AtrialAtrial fibrihtion (%)
Medication n DigoxinDigoxin {%) ji-blockerji-blocker {%) calciumcalcium antagonist [%<l
amiodaroneamiodarone \%)
Patients s
733 6.8 8/10 0
25.44 3.6 1.66 0.6
6 6 67 7 27 7
63.11 4
11 1 5.6 6 22 2
5.6 6 50 0 11 1
5.6 6
HI I
6776/5 5
24.55
1 1
75 5 24 4 NA A
0 0 0 0 0 0
0 0 0 0 0 0 0 0
Tablee 2 Values arc given as mean SD or percentage = healthy individuals; BMI= body mass index;; NYHA = New York Heart Association; I.VEF = left ventricular ejection fraction: NA- not available:: Ml= myocardial infarction: CABG = coronary artery bypass grafting; MR= mitral regurgitation. .
i l 8 8
Chapterr 6
patientss was minimal and the HI had no comorbidity. The patients versus HI
stoppedd with the exercise test, respectively. 71 % versus. 90 % due to fatigue, in 17 %
versuss 10 % due to dyspnea, in 6% versus. 0 % due to discomfort to their legs and in
6%% versus 0 % due to dizziness (table 2).
PEAA sensor
Duee to the strict inclusion criteria intrinsic beats were minimized. At rest 2 % and
duringg exercise 8% of the total HR of 18 patients were driven due to intrinsic beats.
Duringg the recovery period 2.7 % of the total beats were fusion beats.
Thee pacemaker leads were all located in the right ventricular apex. The angle of the
leadd tip in relation to the diaphram on the anteroposterior view of chest-x-ray was
30.33 13 degrees. During exercise, the PEA increased from 0.24 0.05 at rest to
0.65 0.14 (g) at maximal load, whereas HR increased from 65 7 to 120 25 beats/
min.. The PEA decreased during recovery to 0.45 0.10 (g), whereas HR decreased to
800 19 beats/min (figure 1. figure 2 table 3).
Onee patient showed an inappropriately low PEA value (0.1 g), which resulted in
pacingg at the lower rate limi t of 60. In this patient, the PEA sensor remained pro-
grammedd On with faster slope settings and also the gravimetric sensor was pro-
grammedd On.
Inn three other patients, an inappropriately high PEA value was measured (3.4 0.3
g),, which resulted in pacing at the upper sensor rate limit of 140. In these 3 pa-
tients,, it was necessary to program the rate response Off to stop the high sensor
rates,, because of palpitations. In the recovery period, HR increases in the PEA group
firstt (while normally the HR decreases immediately) partly due to the inappropriate
highh sensor rates of the above-mentioned patients.
CAEPP exercise test
Restt rate
Thee achieved resting HR with the PEA sensor was significantly higher compared to
thee ACT sensor and HI (80 8 vs. 65 7 vs. 8 beats/min, respectively, see
figuree 1 and table 3).
119 9
Timee to peak HR
Thee ach ieved t ime to peak HR w i t h PEA sensor was s igni f icant ly longer compared to
thee ACT sensor b ut s igni f icant ly sho r ter than in HI 111 3 vs. 7 3-6 vs. 18 4
min. respect ive ly,, see f igure 1 and table 3).
Tablee 3. Summary of HR of normals, the activity and PEA sensor during rest, exercise and recovery.
Restingg rate (bpm.) Timee to peak pacing rate (min) Maximumm HR (bpm.) 100 min. recovery (bpm.) Exercisee duration (min.)
PEA A
800 8*t 111 3 * t
1244 25 * t 800 20 *f 9-22 3 *
ACT T
655 7 # 77 3.6 #
1400 23 # 655 15 #
HC C
655 8 18 8
1533 26 822 4
18.44 4
P-value e
** t = s. # = ns
** t # = s ** + # = s
** # = s. t = n s '' - s
Tablee 3.Values are given as mean SD.HC = healthy controls: ACT = activity sensor-, PEA= peak endocardiall acceleration: HR= heart rate: bpm=beats per minute: min= minutes. * = PEA vs ACT t == PEAvs HC; # =ACT vs HC; s = p<0.001: ns = p>0.05-
Maximall HR
Thee ach ieved max imal HR w i t h PEA sensor was s igni f icant ly lower compared to the
ACTT sensor and HI (124 25 vs. 140 23 vs. 153 26 beats /min . respect ive ly, see
f iguree 1 and table 3).
HRR (bpm)
160 0
140 0
120 0
100 0
80 0
60 0
40 0
20 0
'PEA A
'ACT T
HC C
Rest t Exercise e Recovery y
<< MIC << > I '
11 3 5 7 9 11 13 15 17 19 21 23 25 21 2Q 31 33 Timee (min)
n(P)) = 18 17 16 14 12 9 8 6 4 3 2 1
n(HC)== ii x e 4 2
Figuree 1. Changes in heart rate (mean SD) PEA vs ACT vs HC. ACT = activity sensor; PEA= peak endocardiall acceleration sensor: HC= healthy controls-. P= patients: n (p) = number of patients remainingg during exercise: n (HC) number of healthy controls remaining during exericse.
120 0
Chapterr 6
90 0
22 ss Figure 2. Changes in PEA vs. heart ££ rate. PEA= peak endocardial activity.
155 20 255 33
Timee imin)
Recovery y
Thee achieved HR at 10- minute recovery with the PEA sensor was significantly
higherr compared to the ACT sensor but comparable to the HI (80 20 vs. 65 8 vs.
822 4 beats/min, respectivelysee figure 1 and table 3).
Exercisee duration
Thee exercise performance of the pacemaker patients with the PEA sensor was signifi-
cantlyy lower compared to HI (9-2 3 vs. 18.4 4 min, see figure 1 and table 3).
Discussion n
Normall sinus node behavior is the ultimate tool to evaluate sensor characteristics.
Severall methods have been used to describe the sinus node behavior and thus the
efficiencyy of different sensors: 1), by measuring the chronotropic response with
differentt exercise testing protocols (CAEP, Bruce, six minute walk test, Kaltenbach
stepp test, stair climbing),2). by measuring the rate response with Holter monitoring
inn daily lif e and 3) by evaluation of the obtained quality- of- lif e (OOL) associated
withh a given sensor.
Inn limited previous studies, the PEA sensor was validated with supposed high
12: :
correlationn with normal sinus rhythm.49"11 Therefore, the PEA sensor is appropriate
too use in rate adaptive pacing2'4'9 10 Also, the PEA signal results in new options; 1)
automaticc AV delay optimization, The studies before showed a close relationship
betweenn PEA, first heart sound, and the AV delay. A louder first heart sound is
observedd with short AV delays as the ventricle contracts after atrial emptying12'13
Dupuiss et al. 13 showed that the optimal AV delay estimates obtained by the PEA
analysiss during automatic AV delay scanning are consistent with those obtained by
echocardiography;; 2) recent clinical trials have shown that selected patients with
recurrentt vasovagal syncope may benefit from permanent pacing with a PEA sensor.
Thee authors demonstrated using head-up til t testing that increase in sympathetic
activityy preceding syncope could be sensed by a PEA sensor.1415 and 3) the PEA
sensorr is a promising tool for long-term hemodynamic monitoring and serial
evaluationn of the effects of multisided ventricular pacing in heart failure patients.16
Anotherr possibility with the PEA signal is the estimation of the aortic diastolic
pressuree with the PEA II signal (the abrupt deceleration of the moving aortic blood
mass).1'' Beside these advantages, a number of critical remarks can be made, disad-
vantagess of the sensor are mostly related to the lead characteristics (lead body size)
andd the sensor location. The PEA sensor is located at the lead tip; consequently
sensorr failure necessitates a new lead insertion. Langenfeld et al.2 showed in a
multicenterr trial with 105 patients uncomplicated lead implantation in all patients.
Att a mean follow-up of 22.1 months no pacing or sensing failure was reported.
Uncomplicatedd function of the sensor was reported in 98% of the patients after 1-
yearr follow- up. Although Vitali et al.18 showed that the lead size is significantly
reducedd in size from 11 to 9 Fr introducer, placement of the lead could pose some
difficultyy in small patients, when multiple leads are used or when using the cephal-
icc vein. Long-term lead survival has to be followed carefully. The lead localization,
size,, and the relative short follow -up period described in the restricted studies of
thee PEA sensor limits the benefit of the PEA sensor.2
Noo studies are available that directly compare the PEA sensor with another sensor
typee in the same patient during exercise. The present study clearly demonstrates
thee hypochonotropic function of the PEA sensor compared with the ACT sensor and
withh HI. 5 1922 in addition, the programmed upper rate limi t is not achieved with
thee PEA sensor in contrast to maximum achieved HR by the ACT sensor which came
closee to the achieved maximal HR of the HI, The findings are in accordance with the
studyy of Clementy et al.11 They compared the chronotropic function offered by the
122 2
Chapterr 6
Bestt Living system in patients suffering from chronotropic incompetence with that
off normal sinus rhythm measured in matched normal subjects (n= IS). They also
showedd that a single PEA sensor successfully restored chronotropic response in a
populationn of paced patients (n= 14) with severe chronotropic incompetence after
optimall programming of the sensor. They showed a physiological chronotropic
modulationn of the paced rate with the PEA sensor during exercise, although the
overalll rate response remains hypochonotropic (the configuration of the HR curve
derivedd from the HI was comparable but lower HR were achieved with the PEA
sensor).. As previously described, 23"25 the present study also showed the main
characteristicss of the hyperchonotropic ACT sensor namely: prompt rise of pacing
ratee with the onset of physical exercise, higher achieved maximal HR which is less
proportionall to exercise and a relative rapid recovery compared with the HI and the
PEAA sensor. In the commercially available pacemakers with the PEA sensor, the ACT
iss programmed Off in the default setting. The disadvantages of the PEA induced rate
responsee can be compensated by programming the ACT sensor On, in combination
withh the PEA sensor and adequate programming of the sensor parameters (e.g.
sensorr cross-checking, sensor blending). The advantages of sensor combination
(ACTT and another existing physiological sensors) considering improved rate re-
sponsee curves during exercise compared with one of the sensors alone, is described
before.. 26 For example, Leung et al. 27 showed an improved cardiac output with
combiningg the ACT sensor with the QT sensor compared to the sensors alone.
Itt remains mandatory to individually optimize the PEA sensor because PEA values
differr from patient to patient, the values reflect the variations in sympathetic
activityy due to physical and mental stress in each patient and can be changed by
medicationn or pathological events.2 28
Itt remains to be proven if all efforts in optimizing pacemaker sensors are expressed
inn an improvement in QOL.29
Thee exercise capacity of patients in the present study were significantly lower
comparedd to HI. The lower exercise capacity of the pacemaker patients compared to
thee HI were possibly due to interaction with the used negative inotropic drugs (a-
blockerr 50%, calcium antagonist 11 %), asynchronous activation of the myocard with
WIRR pacing and absence of AV synchrony.
Surprisingly,, the authors found a high percentage of abnormal PEA signals (22 %
comparedd to 3% in the study of Langenfeld).2 One patient had a very low PEA value
andd three patients had high PEA values and inappropriately high sensor signals
123 3
withoutt efficient rate response function.
Thee low values are possibly explainable due to mechanical contact disturbances of
thee PEA lead tip since the patient had a previous inferior myocardial infarction. The
veryy high PEA values in the present study are possibly induced by overshoot of the
sensor.. In one patient a different acceleration of the heart and thus a different first
heartt sound due to a mechanical mitral valve could explain the overshoot of the
sensor.. Other reasons to explain the overshoot of the sensor, like catch up of the
intrinsicc HR, deviation of the lead position, and the type of the lead, can be exclud-
edd for several reasons. First, the patients in the present study had pacing induced
HRR and usually such high PEA values were only demonstrated in studies after
dobutaminee infusion.2,11 17 Second, all leads were located in the right ventricular
apexx with a comparable angle of insertion of the lead tip. Third, the study of
Rickardss et al.4 showed that the PEA signal is insensitive to local myocardial proper-
tiess or the location of the lead, although other investigators have suggested that
theree are possible limitations in the use of an uniaxial acceleration transducer
becausee ventricular displacement follows a three- dimensional trajectory.
Conclusions s
Thee PEA sensor functions hypochonotroop during exercise programmed as a single
sensorr system, therefore, it is preferably to combine the PEA sensor with a hyper-
chonotroopp functioning activity-based sensor in a dual sensor system.
Acknowledgments s
Thee authors thank Robert Pilage (Holland Medical, Kerkrade. The Netherlands) for
thee technical support, the Department of Cardiology from the Oosterschelde
hospitall for creating facilities to perform the study and Jan Paul Van Mantgem from
thee Amstelveen hospital for selecting patients for the study.
124 4
References s
Chapterr 6
1.. Leung SK, Lau CP. Developments in sensor-driven pacing. Cardiol Clin. 2000:18:113-55. ix. 2.. Langenfeld H, Krein A, Kirstein M, Binner L. Peak endocardial acceleration-based clinical test-
ingg of the "BEST" DDDR pacemaker. European PEA Clinical Investigation Group. Pacing Clin ElectrophysiolElectrophysiol 1998:21:2187-91.
3.. Clementy J. Dual chamber rate responsive pacing system driven by contractility: final assess-mentt after 1-year follow-up. The European PEA Clinical Investigation Group. Pacing Clin Elec-trophysiol.trophysiol. 1998;21:2192-7.
4.. Rickards AF, Bombardini T, Corbucci G. Plicchi G. An implantable intracardiac accelerometer forr monitoring myocardial contractility. The Multicenter PEA Study Group. Pacing Clin Elec-trophysiol.trophysiol. 1996:19:2066-71.
5.. Wilkoff BL. Miller RE. Exercise testing for chronotropic assessment. Cardiol Clin. 1992:10:705-17. .
6.. Mianulli M BD. Markowitz T. A comparison of strap-on versus implanted activity based rate responsivee pacemakers: Are strap-on studies valid? PACE:iA-.732.
7.7. Oto A Ts. Ozin B et al. The use of rate response function during daily lif e in patietns with ratee adaptive pacemakers with two different sensors. EUR. j.P.E. 1993:1:59-62.
&.&. Stofmeel MA, Post MW, Kelder JC. Grobbee DE, van Hemel NM. Ouality-of-life of pacemaker patients:: a reappraisal of current instruments. Pacing Clin Electrophysiol. 2000:23:946-52.
9-- Greco EM, Ferrario M. Romano S. Clinical evaluation of peak endocardial acceleration as a sensorr for rate responsive pacing. Pacing Clin Electrophysiol. 2003;26:812-8.
10.. Occhetta e PA. Rognoni G, et al. Experience with a new myocardial acceleration sensor during dobutaminee infusion and exercise test. Eur JCPE. 1995:5:204-209.
11.. Clementy J. Kobeissi A, Garrigue S. Jais P. Le Metayer P. Haissaguerre M. Validation by serial standardizedd testing of a new rate-responsive pacemaker sensor based on variations in myo-cardiall contractility. Europace. 2001:3:124-31-
12.. Ritter P. Padeletti L, Gillio-Meina L. Gaggini G, Determination of the optimal atrioventricular delayy in DDD pacing. Comparison between echo and peak endocardial acceleration measure-ments.. Europace. 1999:1:126-30.
13.. Duputs JM. Kobeissi A, Vitali L. Gaggini G. Merheb M, Rouleau F. Leftheriotis G, Ritter P, Vic-torr ]. Programming optimal atrioventricular delay in dual chamber pacing using peak endocar-diall acceleration: comparison with a standard echocardiographic procedure. Pacing Clin Elec-trophysioltrophysiol 2003;26:210-3.
14.. Deharo JC, Brunetto AB. Bellocci F, Barbonaglia L. Occhetta E. Fasciolo L, Bocchiardo M. Rog-nonii G, DDDR pacing driven by contractility versus DDI pacing in vasovagal syncope: a multi-center,, randomized study. Pacing Clin Electrophysiol. 2003:26:447-50.
15.. Deharo JC. Peyre [P. Chalvidan T, Thirion X, Valli M, Ritter P, Djiane P. Continuous monitoring off an endocardial index of myocardial contractility during head-up til t test. Am Heart J. 2000:139:1022-30. .
16.. Bordachar P. Garrigue S. Reuter S. Hocini M, Kobeissi A, Gaggini G. Jais P. Haissaguerre M. Clementyy J. Hemodynamic assessment of right, left, and biventricular pacing by peak endocar-diall acceleration and echocardiography in patients with end-stage heart failure. Pacing Clin Electrophysiol.Electrophysiol. 2000:23:1726-30.
17.. Plicchi G, Marcelli E. Pariapiano M, Bombardini T. PEA I and PEA II based implantable haemo-dynamicc monitor: pre clinical studies in sheep. Europace. 2002:4:49-54.
18.. Vitali L, Gaggini, G, Ceron, C. Improved hemodynamic sensor and lead. 2002. 19.. Freedman RA. Hopper DL. Mah J, Hummel ], Wilkoff BL. Assessment of pacemaker chrono-
tropicc response: implementation of the Wilkoff mathematical model. Pacing Clin Electrophys-ioliol 2001:24:1748-54.
20.. Kay GN, Quantitation of chronotropic response: comparison of methods for rate-modulating permanentt pacemakers. J Am Coll Cardiol 1992:20:1533-41.
21.. Page E. Defaye P. Bonnet JL, Durand C. Amblard A. Comparison of the cardiopulmonary re-sponsee to exercise in recipients of dual sensor DDDR pacemakers Versus a Healthy control group.. Pacing Clin Electrophysiol. 2003;26:239-43.
125 5
22.22. Ellestad MH. stress testing principles and practice.tirth edition:567-573-23.. Mehta D. Lau CP, Ward DE. Camm AJ. Comparative evaluation of chronotropic responses of
QTT sensing and activity sensing rate responsive pacemakers. Pacing Clin Electrophysiol. 1988:11:1405-12. .
24.. All E. Kriegler C, Fotuhi P, Willhaus R. Combs W, Heinz M. Hayes D. Feasibility of using intrac-ardiacc impedance measurements for capture detection. Pacing Clin Electrophysiol 1992;15:1873-9. .
25.. Alt E. Matula M. Holzer K. Behavior of different activity-based pacemakers during treadmill exercisee testing with variable slopes: a comparison of three activity-based pacing systems. Pac-inging Clin Electrophysiol 1994:17:1761-70.
26.. Werner J, Hexamer M. Meine M. Lemke B. Restoration of cardio-circulatory regulation by rate-adaptivee pacemaker systems: the bioengineering view of a clinical problem. IEEE Trans Bi-omedomed Eng. 1999:46:1057-64.
27.. Leung SK, Lau CP. Tang MO. Cardiac output is a sensitive indicator of difference in exercise performancee between single and dual sensor pacemakers. Pacing Clin Electrophysiol. 1998;21:35-41. .
28.. Sulke N, Dritsas A. Chambers J, Sowton E. Is accurate rate response programming necessary? PacingPacing Clin Electrophysiol. 1990:13:1031-44.
29.. Clementy J. Barold SS. Garrigue S. Shah DC. Jais P. Le Metayer P, Haissaguerre M, Clinical sig-nificancee of multiple sensor options; rate response optimization, sensor blending, and trend-ing.. Am } Cardiol 1999:83:l66D-171D.
30.. Wood JC, Festen MP. Lim M], Buda AJ, Barry DT. Regional effects of myocardial ischemia on epicardiallyy recorded canine first heart sounds, f AppI Physiol. 1994:76:291-302.
126 6
Cardiacc synchronization induces favorablee neurohumoral changes
Aytenn Erol-Yilmaz MD.1 Hein J, Verberne MD,2 Tim A. Schrama,1 Jana Hrudova MD,1
Robbertt J. de Winter MD PhD,1 Berthe L.F van Eek Smit MD PhD,2
Riannee de Bruin.' Jeroen ]. Bax MD PhD,3 Martin }. Schalij MD PhD.3
Arthurr A. Wilde MD PhD1 and Raymond Tukkie MD PhD1
Fromm the departments of Clinical and Experimental Cardiology ' and Nuclear Medicine2,, Academic Medical Center, Amsterdam: and the department of Cardiologyy , Leiden University Medical Center.3Leiden, the Netherlands.
AcceptedAccepted for publication in PACE
Abstract t
Aims s
too examine whether Cardiac resynchronization therapy (CRT) induces improve-
mentss in the neurohumoral system.
Methodss and methods
Thirteenn patients with heart failureHF (left ventricular (LV) ejection fraction <35%)
weree included. Before and after 6 months of CRT, myocardial 123I-metaiodobenzyl-
guanidinee (123I-MIBG) uptake indices, used as an index of neural norepinephrine
reuptakee and retention, and brain natriuretic peptide (BNP) levels, used as an index
off LV end-diastolic pressure. NYHA classification and echocardiographic indices
weree assessed.
Results s
Sixx months of CRT resulted in significant improvement in 1) NYHA classification
andd reduction in QRS width (p<0.001, 2) decrease of LV end diastolic diameter
(p=0.005),, LV end systolic diameter (p= 0.005), septal to lateral delay (p = 0.01) and
mitrall regurgitation. (MR, p=0.04), 3) Delayed 123I-MIBG heart/mediastinum ratios
improvedd (p=0.03) and 123I-MIBG washout decreased (p=0.001) 4), and BNP levels
decreasedd (p=0.001).
Conclusions s
Parallell to significant functional improvement and echocardiographic reverse
remodelingg and resynchronization. our data indicate that CRT induces favorable
changess in the neurohumoral system.
130 0
Chapterr 7
Background d
Heartt failure (HF) is a complex clinical syndrome resulting from any structural or
functionall cardiac disorder that impairs the ability of the ventricle to fil l with or eject
blood'' The reduction in cardiac performance induces a series of neurohumoral
adjustments,, including an increase in atrial natriuretic peptide, brain natriuretic
peptidee (BNP), and activation of the renin-angiotensin-aldosterone system. Brain
natriureticc peptide is mainly synthesized in the ventricles of the heart and reflects the
leftt ventricular (LV) end-diastolic pressure, LV end-systolic and LV end-diastolic
volumee index.2 Initially , the activation of the neurohumoral system functions as a
compensatoryy mechanism but long term activation has many detrimental effects. The
activatedd neurohumoral system is reversibly correlated with the worsened prognosis
off (HF) patients. Also, elevated catecholamines have a direct cardiotoxic effect and are
importantt predictors of HF mortality and morbidity.2
Largee scale pharmacological trials in HF patients have shown that treatment with ACE-
inhibitors.. p-blockers and aldosterone inhibitors improves the imbalance in the
neurohumorall system and thereby improve the prognosis of patients with HF.
Cardiacc resynchronization on top of optimal pharmacological therapy has already
beenn shown to improve the symptoms of HF. reduce hospital admission and improve
LVV function.0 A recent meta-analysis suggests that cardiac resynchronization therapy
(CRT)) also reduces mortality from HF. ' This is confirmed by theCOMPANION study,
thee largest prospective trial yet.s However, limited data are available whether func-
tionall improvement, induced by CRT. is related to changes in the neurohumoral
system.55 6
Cardiacc adrenergic nerve activity can be estimated using several techniques: first,
usingg iodine-123metaiodobenzylguanidine (125 I MIBG) as a noradrenaline ana-
logue.00 123I-MIB G is a guanethidine analogue that shares the same uptake, storage
andd release pathway as norep inephr ine and has the potential to reflect the whole
myocardiall adrenergic pathway.0, i0 123I-MIB G myocardial uptake indices can be used
ass a predictor of prognosis in patients with chronic HF.11"14 Second, BNP may have a
sympathoinhibitoryy effect on the sympathetic nerve activity.
Wee prospectively studied a group of chronic HF patients to determine the 6 months
effectss of CRT on the neurohumoral system using 123 I MIBG scintigraphy and BNP.
131 1
Methods s
Patientt population
Thirteenn consecutive patients with chronic symptomatic HF referred for implantation
off a CRT device were included in the present study after informed consent. Patients
receivedd CRT according to the accepted criteri a of ejection fraction < 35%. QRS width
>> 120 ms, and severe HF in NYHA functional classes II I or IV despite maximally
toleratedd medical treatment for HF (American Heart Association Pacing / ICD guide-
lines).. 5 Patients were studied before pacemaker implantation (baseline) and 6
monthss after biventricular pacing. NYHA classification, QRS width . LV functional
parameterss using echocardiography. 125 I MIBG myocardial uptake indices and BNP
weree assessed. Medical therapy was unchanged durin g the follow up of 6 months.
Tablee I . Demographics and clinical variables
Agee (year) 63.6 12,8 Sexx (male/female) {%) 61/39 lHD/non-IHDD 1%) 23/77 NYHAA 37 0.4 QRSS duration vmsl 182.4 18.2 Medication n
ACEACE inhibitor [%) 92 B-biocket[%)B-biocket[%) 50 DiureticsDiuretics i%) 69 SpironolactoneSpironolactone (%J 54 DigoxinDigoxin (%) 38
Valuess are given as mean SD or percentage: IHD - ischemic heart disease: NYHA - New York Heartt Association.
Pacemakerr system and implantation technique
Commerciallyy available biventricular pacemakers were used (Guidant. Minnesota.
USA;; Medtroni c Minneapolis USA: St Jude Medical. Californi a USA). The right atrial
leadd was positioned in the right atrial appendix and the ventricular lead was posi-
tionedd in the right ventricular apex. The LV pacing lead was positioned in a posterior
orr lateral branch of the coronary sinus in all patients. A biventricular DDDR system
wass used in 10 patients. In 3 patients the implantation of an internal defibrillato r was
alsoo indicated.l 5 In these patients a combined device was implanted.
132 2
Chapterr 7
Cardiacc MIBG imaging
Patientss underwent myocardial scintigraphy to determine 123I-MIBG uptake, used as
ann index of neural norepinephrine reuptake and retention. The analysis of the
myocardiall scintigraphy at baseline and after 6 months was blinded. To block
thyroidd uptake of free 123I. all patients received 100 mg potassium iodide orally, one
hourr prior to the injection of I23I-MIBG. After a subsequent resting period of at least
300 minutes, patients were injected intravenously with approximately 185 MBq of 123"I-MIB GG (Amersham Health, Eindhoven, the Netherlands). Twenty minutes (early
imaging)) and 4 h (delayed imaging) after MIBG administration, a 10-min planar
anteriorr image of the chest was acquired using a dual-head gamma-camera (e-cam,
Siemens,, Hoffman Estate, Illinois, USA). A 20% energy window was centered on the
1599 keV photopeak of 123I . Images were acquired using a medium energy collimator
andd stored in 128 xl28 matrix. 123I-MIBG myocardial activity was measured using a
manuallyy drawn region of interest around the LV. Mediastinal activity was measured
usingg a fixed 20 x 20 pixel region of interest placed over the upper mediastinum.
Mediastinall and myocardial values are expressed as mean counts/pixel. To evaluate 123I-MIBGG myocardial uptake the H/M ratio was calculated from the early and
delayedd images. Myocardial I23I-MIB G WO was defined as the percentage of change
inn activity from the early and delayed images: ((H early-H delayed) / H early) x 100,
HH values being corrected for 123I physical decay.
Echocardiography y
Patientss were imaged in the left lateral decubitus position using 2 D, M mode and
color-dopplerr and tissue doppler echocardiography {Vivi d 7, GE-Vingmed Ultra-
sound.. Horten Norway). The left ventricular end-diastolic diameter (LVEDD) and left
ventricularr end-systolic diameter (LVESD) were measured from the parasternal long
axiss view. Mitral regurgitation was classified semi-quantitatively in eight degrees
(0== none, 1= minimal. 1.5= minimal to mild, 2= mild. 2.5= mild to moderate. 3 =
moderate.. 3-5= moderate to severe, 4 = severe). The left ventricular ejection frac-
tionn is echocardioghraphically measured.
Whenn available tissue doppler data were obtained in the apical four-chamber view
att frame rates above 100 fps. The resulting digital cine loops where transferred to a
computerr for offline analysis (Echo-Pac software. Ge-Vingmed Ultrasound. Horten
133 3
P== 0.001
Norway).. The simultaneous velocity curves of 2 selected (septal, lateral) LV seg-
mentss were compared (using the 4-chamber view) for a mean of two consecutive
beatss to minimize the variability between measurements. The LV tissue velocities
WOO (%}
700 -
60 0
50 0
40 0
30 0
20 0
10 0
0 0 Baselinee 6 months CRT
Figuree 1. '^ MIBG Cardiac washout (wo) before and after 6 months of CRT.
weree measured during systole. Indicator of LV asynchrony is considered as the
differencee between the timing of the peak systolic velocities of the septum and
laterall LV. For each patient the atrioventricular interval was individually adjusted
too maximize the mitral inflow duration using pulsed doppler echocardiography on
thee first postoperative day.
BNP-concentration n
Bloodd for determination of the plasma BNP concentration was sampled from an
intravenouss canula. Patients were resting in supine position for at least 30 minutes
beforee blood collection. The samples were withdrawn into evacuated ethylenedi-
aminetetraaceticc acid (EDTA) tubes and centrifuged at 4°C at 4000 rpm for 10 min.
Thee samples were stored at -70CC until assay. Plasma BNP (pg/mL) was measured
withh the Triage BNP Test (fluorescence immunoassay device, Biosite San Diego,
USA).1''' Using the Triage BNP test, the upper level of normal BNP was 100 pg/mL.
134 4
Chapterr 7
Statisticall analysis
Thee data are expressed as mean SD. The two-paired sample t-test was applied
comparingg the 123I-MIBG myocardial uptake indices and echocardiography parame-
terss of LV function before and after 6 months of CRT. Changes in BNP measure-
mentss were expressed as percentage change from baseline. The one sample t-test
wass used to compare changes in BNP levels. A probability value of P < 0.05 was
consideredd to indicate a significant difference, The Pearson test (2-tailed) was used
too test the correlation between MIBG indices and BNP.
Results s
Patientt Population
Thirteenn patients were included in the study, 77 % with non-ischemic heart disease.
Tablee 1 shows the demographics and clinical variables, including medication. All
patientss were in sinusrythm except one patient who was in chronic atrial fibrilla-
tionn with slow atrioventricular conduction.
Clinicall Parameters
NYHAA classification improved after 6 months CRT at least one class in all patients
fromm 3-7 0.4 to 2.2 0.6 (p< 0.001). The QRS duration decreased significantly
fromm 182.7 17 to 155-0 14,6 msec {p<0.001). Medication was not altered during
thee pacing period but for furosemide, which had to be withdrawn in one patient
andd low dose digoxin. which was started in another patient.
Echocardiography y
Biventricularr pacing resulted in significant reduction of LVEDD from 73-7 8,9 to
67.66 9.9 mm (p=0.005) and LVESD from 65-8 7.5 to 58.5 12.2 mm (p = 0.005).
Alsoo mitral regurgitation decreased from 2.9 0.6 to 2.2 0.9 (p = 0.04). The left
ventricularr ejection fraction increased from 14 7 to 21 8 % (p = 0.007). There
135 5
Tablee 2. Echocardiography data,ir?l-MIB G data and BNP before and after CRT.
Patients s
1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 Q Q
10 0 11 1 12 2 13 3
Total l {mean} } l ii SD)
LVEDD D
(mm) )
83 3 84 4 66 6 76 6 68 8 69 9 79 9 72 2 56 6 71 1 74 4 88 8 78 8
73.7 7 7 7
LVESD D
{mm) )
76 6 76 6 57 7 60 0 63 3 64 4 73 3 64 4 52 2 68 8 66 6 75 5 68 8
65.8 8
7.5 5
Valuess are given as mean SD. . endd diastolic diameter; LVESD = EF-- ejection fraction: S-L-
MI I
(1-4) )
3.5 5 2.5 5 2.5 5 0 0
3.5 5 2 2
3.5 5 3.5 5 3,5 5 3 3 0 0 2 2 3 3
2.9 9 0.6 6
EF F
(%) )
10 0 10 0 20 0 21 1 10 0 15 5 15 5 15 5 15 5 10 0 13 3 10 0 15 5
14 4 7 7
Baseline e
SL L delay y (msec) )
95 5
97 7 93 3 ----
90 0 90 0 97 7
933 3 3.3 3
CRTT = cardiac ^synchronization tr == left ventricular end
septall to lateral. dinee heart/ mediastinum: WO -
weree no sign
non ischemic c
laterall delay
(p=0 .01.. see
i ff i cant clif f ere
pat ients. .
decreased d
tablee 2).
[ n o o
-- washout. --
BNP P
(pg/ml) )
316 6 2140 0 576 6 110 0
2140 0 1040 0 529 9 152 2 614 4 2420 0 1013 3 1024 4
1006.2 2 806 6
wo o
i%) )
55.8 8 51.4 4 373 3 35.8 8 36.5 5 64.0 0 43.8 8 27.3 3 48.1 1 24.1 1 30.0 0 30.3 3 38.3 3
40.2 2 12.0 0
Latee ]2\ MIBGG H/M
ratio o
1.2 2 1.1 1 1.6 6 1.3 3 1.3 3 1.1 1 13 3 1.4 4 1.1 1 1.3 3 1.5 5 13 3 1.1 1
1.3 3 0.2 2
ïerapy;; LVEDD - left ventricular systolicc diameter: MR -mitrall regurgitation;
r;,l-MIBGH/MM = 123-iodine-metaiodobenzylguam-== not available.
ncess be tween the ejectionn fr a : t io nn for the ische
pat ientss t issue doppler data were obtained. Se
afterr 6 months off pac ingg fro m 93.3 39.3 to 26
;mi cc and
ptall to
26.55 msec
--- —
Cardiacc MIBG imaging
Afterr 6 months of biventricular pacing, early l23I-MIB G H/M ratio remained unchanged
(fromm 1.4 0.1 to 1.5 0.1, p=0,224). Late 1231-M1BG H/M ratio increased from 1.3
0.22 to 1.4 0.2 (p = 0.03). 1231-MIBG washout significantly decreased from 40.2 12.0
too 28.3 6.1 (p=0.001, see figure 1 and table 2). The change in H/M ratios and
myocardiall washout were not significantly different for ischemic (H/M earlv: 0.0: H/M
l a t e:0.1:: washout:12 %) and nonischemic (H/M early: 0.1; H/M l a t e;0.1; washout: 11 %)
heartt failure patients.
136 6
Chapterr 7
LVEDD D
(mm! !
82 2 85 5 59 9 59 9 67 7 61 1
59 9 56 6 63 3 68 8 74 4 78 8
67.6 6 9.9 9
LVESD D
imml l
75 5 77 7 51 1 37 7 61 1 52 2
52 2 46 6 54 4 58 8 70 0 69 9
58.5 5 12.2 2
BNP(pg/ml) )
25000 J
2000 ^
1500 ^
1000 ^
5000 -
u u
Ml l
11-41 1
3.5 5 25 5 2 2 0 0
3.5 5 1 1
1 1
2.5 5 2.5 5 0 0 2 2 2 2
2.2 2 0.9 9
Baseline e
Figuree 2. BNP before and after 6
Afterr 6
EF F
i%) )
10 0 15 5 35 5 29 9 10 0 30 0
25 5 25 5 20 0 13 3 20 0 20 0
21 1 8 8
monthss of CRT
monthss of CRT
SL L delay y (msec) )
20 0
25 5 26 6
35 5 30 0 20 0
23.8 8 5 5
BNP P
\pg/mll l
275 5 1340 0 133 3 58 8
1440 0 110 0 236 6 41 1 474 4 180 0 131 1 115 5
377.8 8 487.2 2
WO O
{%) {%)
38.0 0 38.6 6 22.3 3 27.0 0 34.9 9 26.4 4 30.2 2 23.6 6 34.8 8 24.5 5 18.6 6 292 2 24.1 1
28.3 3 6.1 1
PP <0.001
66 months CRT
Latee 123I-MIBGG H/M
ratio o
1.3 3 1.2 2 I I 1 1 1 1 1 1 1 1 1 1 I I 1 1
4 4 5 5 3 3 3 3 4 4 7 7 4 4 4 4
1.4 4 1.8 8 1.4 4
1.4 4 0.2 2
137 7
BNP-concentration n
BNPP levels decreased significantly 1006.2 806 to 377.8 487.6 pg/mL (p<0.001)
att 6 months. There was a great interindividual variability in the measured BNP
values,, expressed by the large SD. The normalized BNP level (baseline value set at
100%)) decreased at least 13 %, not exceeding 93% with a mean of 53-4 29.7%
(p<0.001)) after 6 months of biventricular pacing (see figure 2), In one patient
BNPP could not be measured for technical reasons. We tested with the Pearson test
(2-tailed)) whether a correlation is between MIBG indices and BNP and could not
showw any correlation.
Discussion n
Thiss study showed that CRT induced improvement of functional parameters in a
patientt group with severe HF and broad QRS is accompanied by favorable changes in
neurohumorall system. These favorable changes are illustrated by a significant
decreasee of BNP combined with a reduction of 123I-MIBG washout and improved
delayedd H/M ratio. In accordance with previous studies clinical improvement was
alsoo obtained, indicated by the lower NYHA class, increase of LV ejection fraction
decreasee of mitral regurgitation, echocardiographic reversed remodeling and «syn-
chronizationn of the LV. 6 J 6 1 8 19 All patients responded clinically to CRT, This was
predictedd by the large septal to lateral delay and the very broad QRS complexes.
CRTT and 123I-MIB G
Previouss studies have shown that 123I-MIBG is capable of visualizing the improved
neurohumorall status in HF patients treated with b- blockers and ACE- inhibitors.3'4
Inn these studies, 123I-MIBG WO decreased and late 123I-MIBG H/M ratio increased.
Agostinii et al. showed an increased cardiac 123I-MIBG uptake after 6 months treat-
mentt with carvedilol in HF patients (NYHA 2 or 3)3 Somsen et al. observed a similar
increasee in myocardial 123I-MIBG uptake after 6 weeks of treatment with the ACE-
inhibitorr enalapril.20 In addition, Fukoka et al. found a decrease in I23I-MIB G WO
afterr therapy with metoprolol."1 Our findings show analogue to these studies an
increasee of cardiac 123I-MIBG uptake and less competition between plasma no-
138 8
Chapterr 7
radrenalinee and 123I-MIBG reflected by a decreased washout after 6 months of CRT.
Thiss may also reflect a restoration of pre-synaptic cardiac sympathetic nerve func-
tion.. In addition, also the decrease of isolated, nonischemic mitral regurgitation can
inducee the favorable neurohumoral changes.19 The favorable changes found in this
studyy are at least on top of ACE-inhibitors and in half of the patients also on top of
B-blockers,, In contrast to these favorable changes after CRT, previous studies
showedd worsening of 123I-MIBG parameters after sole right ventricular pacing.22
Ourr data supports that CRT induces reduced sympathetic activity as expressed by an
improvedd 123I-MIBG WO. The recent study of Adamson et al. reported that CRT
inducess a relative shift in cardiac autonomic balance toward a more favorable
profilee that is less dependent on sympathetic activation.25 However, they failed to
showw a clear reduction in sympathetic activity since they did not find a change in
plasmaa catecholamines. This difference in findings might be explained by differ*
encee in patient population and used measurements of sympathetic activity. Moreo-
ver,, more severe asynchrony may have been present in our patient population given
thee wider ORS-complex and larger LV diameters. Another striking difference be-
tweenn our study and the study of Adamson et al is the longer pacing period of 6
monthss compared to 3 months. Whether this difference can explain the differences
inn plasma catecholamines, remains unclear.
Thee improvement in 125I-MIBG parameters may have prognostic implications.
Decreasee of MIBG uptake is probably a late event in the history of the disease,
explainingg its prognostic value in end-stage HF. It has been shown that cardiac 123I-MIBGG imaging, especially cardiac 123I-MIBG WO, has prognostic value in patients
withh chronic HF.U1A 123I-MIBG WO is more useful as an index of adrenergic nervous
activityy because it is independent of the number of neurons available, whereas the 123l-MIBGG H/M activity ratio is not. Therefore, although the 1Z3I-MIBG H/M activity
ratioo and 123I-MIBG WO represent different functions of adrenergic presynaptic
activity,, washout may be a more accurate marker of severity of HF.
CRTT and plasma BNP
Inn our study, plasma BNP levels decreased significantly after 6 months of CRT
(p<0.001)) in all patients, although there were important interindividual differences,
ass frequently observed in HF patients. Pressure and volume overload of the cardiac
chamberss stimulate enhanced production and release of natriuretic peptides. These
139 9
peptidess result in natriuresis, diuresis, vasodilatation and the suppression of the
renin-angiotensin-aldosteronee system in the cardiovascular system and are the
commonn denominator present in patients with systolic or diastolic dysfunction,
volumee overload, and HF, regardless of the underlying cardiovascular disease.25
Atriall and brain natriuretic peptides are elevated in patients with HF, and these
peptides,, especially BNP, are independent prognostic parameters.26"28 Not only are
thee natriuretic peptides important predictors of HF mortality and morbidity, but
changess in these neurohormones over time are associated with corresponding
changess in mortality and morbidity.2 Among the neurohumoral parameters (nore-
pinephrine,, renin activity, aldosterone, arginine-vasopressin and endothelin) BNP is
thee strongest marker for LV dimensions and LV ejection fraction in patients with
systolicc HF.29
Ass has been previously shown, short term CRT results in a significant decrease in
BNPP levels in HF patients, but long term data about the effects of CRT on BNP are
limited.23,300 31 Sinha et al. studied the usefulness of BNP release as a surrogate
markerr of the efficacy of 6 months effect of CRT in 17 patients. After already 6
monthss of pacing, CRT was inactivated using a backup mode (WI 40 beats/min) for
100 days 3 days and then reinitiated using the same stimulation parameters. BNP
levelss were measured after 6 months of pacing just before discontinuation CRT, at
thee last day before and 10 days after CRT reinitiating. Although in the study of Sinha
ett al., the baseline BNP levels (before CRT) was not measured, they showed that BNP
levelss significantly increased immediately after short-term CRT termination and
decreasedd again after CRT reinitiating. In addition to the data of Sinha. we showed
thatt already in the first 6 months the BNP level is reduced. These data indicate that
BNPP might be a reliable marker to assess the effect of CRT and also guide medical
interventionn in case of worsening HF during CRT therapy. Furthermore, we could
nott show a correlation between MIBG indices and BNP levels. Possibly this lack of
correlationn between the two tests may be synergistic, with each test perhaps
examiningg a different aspect of the sympathetic nervous system.
Limitations s
Theree are some potential limitations to the present study. It has been shown that
somee beta-adrenoreceptorblockers and it has been suggested that some ACE-
inhibitorss may influence myocardial 123I-MIBG uptake. As medication was obviously
140 0
Chapterr 7
nott withdrawn in the present study, this could have influenced absolute myocardial 123I-MIBGG uptake measurements. On the other hand as medication was not altered,
measuredd differences in I23I-MIBG uptake will still reflect the effect of CRT.
Anotherr possible limitation might be that in the present study we did not perform
tomographicc imaging. However, especially in patients with end-stage HF it is
extremelyy difficult to obtain adequate tomographic acquisitions, due to poor
contrastt between myocardium and surrounding tissue.
Furthermore,, the present study might be limited by the lack of a control group.
However,, in light of clinical evidence, it is not ethical to withheld CRT in a control
groupp with severe HF and clear indications for CRT.
Conclusions s
Cardiacc resynchronization therapy induces favorable changes in the neurohumoral
systemm already within the first 6 months in patients with severe HF.
Acknowledgments s
Wee thank Irma de Groot, Jim Vleugels and Denise Samson for their technical assist-
ancee with the echocardiography. The authors also thank Christel Feenstra for her
technicall assistance with the myocardial 123I-MIBG scintigraphy.
141 1
References s 1.. Hunt SA, Baker DW. Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management
off Chronic Heart Failure in the Adult: Executive Summary A Report of the American College off Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revisee the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed inn Collaboration With the International Society for Heart and Lung Transplantation; Endorsed byy the Heart Failure Society of America. Circulation 2001:104:2996-3007.
2.. Anand IS, Fisher LD. Chiang YT, et al. Changes in brain natriuretic peptide and norepine-phrinee over time and mortality and morbidity in the Valsartan Heart Failure Trial iVal-HeFT1. Circulationn 2003:107:1278-83.
3.. Agostini D. Beltn A. Amar MH. et al. Improvement of cardiac neuronal function after carvediloll treatment in dilated cardiomyopathy: a 123I-MIBG scintigraphic study. ] Nucl Med 2000:41:845-51. .
4.. Kawai H, Fan TH, Dong E. et al. ACE inhibition improves cardiac NE uptake and attenuates sympatheticc nerve terminal abnormalities in heart failure. Am ] Physiol 1999;277:H160Q-i7.
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6.. Auricchio A. Stellbrink C. Sack S, et al. Long-term clinical effect of hemodynamically opti-mizedd cardiac ^synchronization therapy in patients with heart failure and ventricular con-ductionn delay. J Am Coll Cardiol 2002;39:2026-33.
7.. Bradley D]. Bradley EA, Baughman KL, et al. Cardiac ^synchronization and death from pro-gressivee heart failure: a meta-analysis of randomized controlled trials. Jama 2003:289:730-40.
5.. Bristow MR. Saxon LA. Boehmer ]. et al. Cardiac-resynchronization therapy with or without ann implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004:350:2140-50. .
9,, Zhao C, Shuke N, Yamamoto W, et al. Comparison of cardiac sympathetic nervous function withh left ventricular function and perfusion in cardiomyopathies by (123U-MIBG SPECT and (99mlTc-tetrofosminn electrocardiographically gated SPECT. J Nucl Med 2001:42:1017-24,
10.. Somsen GA, van der Wall EE, van Vlies B. Borm ]], van Royen EA. Neuronal dysfunction in heartt failure assessed by cardiac 123-iodine metaiodobenzylguanidine scintigraphy. Int 1 Card Imagingg 1996:12:305-10.
11.. Cohen-Solal A. Esanu Y, Logeart D, et al. Cardiac metaiodobenzylguanidine uptake in patients withh moderate chronic heart failure; relationship with peak oxygen uptake and prognosis, f Amm Coll Cardiol 1999:33:759-66.
12.. Ebina T, Takahashi N. Mitani I. et al. Clinical implications of cardiac il23U-meta-iodobenzyI-guanidinee scintigraphy and cardiac natriuretic peptides in patients with heart disease. Nucl Medd Commun 2002:23.795-801.
13.. Yamada T. Shimonagata T. Fukunami M, et al. Comparison of the prognostic value of cardiac iodine-1233 metaiodobenzylguanidine imaging and heart rate variability in patients with chronicc heart failure: a prospective study. J Am Coll Cardiol 2003;41:231-8.
14.. Ogita H. Shimonagata T, Fukunami M. et al. Prognostic significance of cardiac Ll23)I metaio-dobenzylguanidinee imaging for mortality and morbidity in patients with chronic heart fail-ure;; a prospective study. Heart 2001:8b:656-60.
15.. Gregoratos G. Abrams J. Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implan-tationn of cardiac pacemakers and antiarrhythmia devices: summary article, A report of the Americann College of Cardiology/American Heart Association Task Force on Practice Guidelines ACC,, AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines J Cardiovasc Electro-
physioll 2002:13:1183-99. 16.. Bax J]. Marwick T.H. Molhoek S.G. Left ventricular dyssynchrony predicts benefit of cardiac
^synchronizationn therapy in patients with end-stage heart failure before pacemaker implan-tation.. Am ] Cardiol 2003. in press.
17.. Shapiro BP. Chen HH. Burnett JC. Jr.. Redfield MM. Use of plasma brain natriuretic peptide concentrationn to aid in the diagnosis of heart failure Mayo Clin Proc 2003:78:481-6.
142 2
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18.. Bax J]. Molhoek SG. van Erven L, et al. Usefulness of myocardial tissue Doppler echocardiog-raphyy to evaluate left ventricular dyssynchrony before and after biventricular pacing in pa-tientss with idiopathic dilated cardiomyopathy. Am J Cardiol 2003:91:94-7.
19.. Tsutsui H. Ando S, Kubota T. et al. Abnormalities of cardiac sympathetic neuronal and left ventricularr function in chronic mitral regurgitation: assessment by iodine-123 metaiodoben-zylguanidinee scintigraphy. Am ] Card Imaging 1996:10:14-22.
20.. Somsen GA, van Vlies B, de Milliano PA. et al. Increased myocardial [12311-metaiodobenzyl-guanidinee uptake after enalapril treatment in patients with chronic heart failure. Heart 1996:76:218-22. .
21.. Fukuoka S. Hayashida K. Hirose Y. et al. Use of iodine-123 metaiodobenzylguanidine myocar-diall imaging to predict the effectiveness of beta-blocker therapy in patients with dilated cardi-omyopathy.. Eur J Nucl Med 1997:24:523-9.
22.. Simantirakis EN, Prassopoulos VK. Chrysostomakis SI, et al. Effects of asynchronous ventricu-larr activation on myocardial adrenergic innervation in patients with permanent dual-chamber pacemakers;; an H123)-metaiodobenzylguanidine cardiac scintigraphic study, Eur Heart J 2001;22:323-32. .
23.. Adamson PB. Kleckner KJ. VanHout WL, Srinivasan S, Abraham WT. Cardiac ^synchronization therapyy improves heart rate variability in patients with symptomatic heart failure. Circulation 2003:108:266-9. .
24.. Merlet P, Valette H, Dubois-Rande JL, et al. Prognostic value of cardiac metaiodobenzylguani-dinee imaging in patients with heart failure. J Nucl Med 1992:33:471-7.
25.. Levin ER. Gardner DG, Samson WK. Natriuretic peptides. N Eng] J Med 1998;339:321-8. 26.. Tsutamoto T. Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac
natriureticc peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptidee concentration in patients with chronic symptomatic left ventricular dysfunction. Cir-culationn 1997;96:509-16.
27.. Swedberg K. Eneroth P. Kjekshus J. Wilhelmsen L. Hormones regulating cardiovascular func-tionn in patients with severe congestive heart failure and their relation to mortality, CONSEN-SUSS Trial Study Group. Circulation 1990:82:1730-6.
2&.2&. Gottlieb SS. Kukin ML, Ahern D, Packer M. Prognostic importance of atrial natriuretic peptide inn patients with chronic heart failure. J Am Coll Cardiol 1989:13:1534-9.
29.. Groenning BA. Nilsson JC. Sondergaard L. Kjaer A, Larsson HB, Hildebrandt PR, Evaluation of impairedd left ventricular ejection fraction and increased dimensions by multiple neurohu-morall plasma concentrations. Eur J Heart Fail 2001:3:699-708.
30.. Filzmaier K SA. Breithardt OA, Stiegler H. Short-term effects of cardiac ^synchronisation on brainn natriuretic peptide release in patients with systolic heart failure and ventricular conduc-tiunn disturbance. J Am Coll Cardiol 2002:39:104.
31.. Sinha AM, Filzmaier K, Breithardt OA, et al. Usefulness of brain natriuretic peptide release as aa surrogate marker of the efficacy of long-term cardiac ^synchronization therapy in patients withh heart failure. Am f Cardiol 2003;91:755-8.
143 3
Cardiacc resynchronization improvess microcirculation
Aytenn Erol-Yilmaz MD,1 Bektas. Atasever MD,2 Keshen Mathura.2
Jeromee Lindeboom MD.5 Arthur Wilde MD PhD.1 Can ince PhD.2
andd Raymond Tukkie MD PhD1
Fromm the Department of Clinical and Experimental Cardiology,1 the Department of Physiologyy 2 and the Department of Oral and Maxillofacial Surgery ? Academic
Medicall Center, University of Amsterdam, Amsterdam, The Netherlands,
SubmittedSubmitted for publication
Abstract t
Background d
Althoughh it is known that CRT in HF patients improves systemic circulation, its
acutee effects on microcirculation are as yet unknown. Therefore we investigated the
sub-linguall microcirculatory changes in heart failure (HF) patients due to cardiac
^synchronizationn therapy (CRT) and right ventricular pacing (RV) by use of orthogo-
nall polarization spectral (OPS) imaging.
Material ss and methods
Twelvee consecutive HF patients with a CRT device and 10 healthy individuals were
included.. Acute microcirculatory changes were assessed by functional capillary
densityy (FCD) and capillary velocity (CV) after previous six months of CRT. FCD and
CVV were measured in HF patients sub-lingually after 15 minutes of programming in
onee of the pacing modalities (no pacing, RV pacing, and CRT) in dual chamber mode.
Results s
FCDD was significantly higher in healthy individuals (10.9 1.9. cm/cm2) compared
too HF patients with RV pacing (8.9 1,9. cm/cm2, p = 0.025) and no pacing
(8.33 2.4, cm/cm2, p = 0.008), CRT (12.1 2.2. cm/cm21 significantly increased FCD
inn HF patients compared to RV pacing (8.9 1.9 cm/cm2, p=0.03) and no pacing
(8.33 2.4, cm/cm2. p=0.018). CV was normal in all patients with or without pacing.
Conclusions s
CRTT improves microcirculatory function as assessed by OPS imaging.
146 6
Chaprerr S
Introductio n n
Heartt failure (HF) is a complex clinical syndrome resulting from any structural or
functionall cardiac disorder that impairs the ability of the ventricle to fil l with or
ejectt blood.1 The symptoms of HF can be explained in terms of microvascular
dysfunctionn within the tissues, either inadequacy of nutritive flow or failure to
preservee tissue fluid economy,23
Cardiacc resynchronization therapy (CRT) on top of optimal pharmacological therapy
hass already been shown to improve cardiac and systemic hemodynamics. CRT
inducess reduction of symptoms of HF. reduction of hospital admission, improves
exercisee capacity, V02 max and left ventricular (LV) function,4
Soo far. imaging of the human microcirculation in patients with HF has been limited
too observations in nailfold and conjunctiva,235 Orthogonal polarization spectral
(OPS)) imaging is a recent technique for non-invasive observation and quantification
off microcirculatory function in patients. The OPS imaging, which uses green
(wavelengthh 550 nm) polarized light that is guided through a set of lenses, was
originallyy introduced by Slaaf et al. The OPS technique was validated in previous
studiess with septic shock, brain tumors, nailfold skin and comparing OPS with
conventionall capillary microscopy in healthy volunteers. In addition, other studies
weree performed to assess the effects of no rep inephr ine and dopamine on human
intestinall mucosal perfusion. 7 1 0 13
Thee OPS imaging technique provides the unique opportunity to quantify measure-
mentss of relevant physiological parameters in the microcirculation such as function-
all capillary density (FCD) and capillary flow (CV). FCD is defined as the length of
capillariess perfused with red blood cells per observation area and is given in cm/
cm2.. Since red blood cells are taken into account in the FCD measurements. FCD is a
directt measure of nutritional tissue perfusion and an indirect measurement of
oxygenn delivery to tissue.1^
AA recent study using OPS imaging, identified abnormal microcirculatory flow
alterationn in patients with severe HF.7 However, studies examinating the effect of
CRTT on microcirculation in patients with severe HF are lacking. In this study, we
testedd the hypothesis that in patients known to respond to CRT, CRT also improves
microcirculationn in these patients by observation of sub-lingual microcirculation
withh OPS.
147 7
Material ss and methods
Studyy population
Twelvee consecutive patients (9 male, 3 female. 64.5 5 years) with chronic
symptomaticc HF referred for implantation of a CRT device were included in the
presentt study after informed consent. Ten age matched healthy individuals (HI)
withoutt co-morbidity and medical therapy (10 women: 61.4 2.3 years) were
includedd to confirm the hypothesis that HF patients have an impaired microcircu-
lation.. Patients received CRT to the criteria of device implantation according to
ACC/AHAA criteria (ejection fraction < 35%. QRS width > 120 ms, and severe HF in
NYHAA functional classes III or IV despite maximally tolerated medical treatment for
HF)) and measured echocardiographic LV asynchrony (septal to lateral delay >60 ms)
ass previously described.' l5 Between 2000 and september 2004. in 53 patients CRT
devicess were implanted in our hospital. Due to the criteria used in our academic
centerr for implantation of CRT devices lower than 10% of the patients with a CRT
devicee are non-responders. So the majority of the patients are responders. Five
patientss had a history of managed hypertension and 2 patients had also type II
diabetess mellitus.
Randomizationn protocol and study design
Beforee pacemaker implantation (baseline) and 6 months after CRT, NYHA classifica-
tion.. QRS width, left ventricular (LV) functional parameters using echocardiography
parameterss were assessed. Standard biventricular pacemaker implantation was
performedd using available biventricular pacemakers (Guidant, Minnesota, USA:
Medtronicc Minneapolis USA). The right atrial lead was positioned in the right atrial
appendagee and the ventricular lead was positioned in the right ventricular apex. The
LVV pacing lead was positioned in a posterior or lateral branch of the coronary sinus
inn all patients. A biventricular DDDR system was used in 11 patients. In 1 patient
thee implantation of an internal defibrillator was also indicated and a combined
devicee was implanted. The echocardiographically optimized sensed AV delays were
betweenn 100-120 msec.
Echocardiographyy parameters were measured with a Vivid 7 ultrasound device
14S S
Chapterr 8
(GE-Vingmedd Ultrasound, Horten Norway). Patients were imaged in the left lateral
positionn using 2 D, M mode, color-doppler and tissue doppler echocardiography.
Thee left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic
diameterr (LVESD) were measured from the parasternal long axis view. Mitral regur-
gitationn was classified semi-quantitatively in four degrees (I = mild, II - moderate,
IIII = moderate to severe. IV = severe).
Alll patients responded beneficially to CRT. FCD and CV were measured after 6
monthss of CRT in an acute setting using OPS imaging. In each patient FCD was
measuredd in one session at random with 1) no pacing in HF patients, 2) RV pacing
andd 3) biventricular pacing. The heart rates in the RV and biventricular pacing mode
weree programmed to fixed 60 beats/min. Measurements were done after fifteen
minutess of pacing in the at random programmed mode and with no pacing. In each
patient,, the systolic and diastolic blood pressure was measured once with a mercury
sphygmomanometerr 15 minutes after each pacing modality. In 10 healthy individu-
alss also the FCD and the CV were measured.
Orthogonall polarization spectral imaging
Thee OPS imaging device uses the absorption of hemoglobin to visualize the micro-
circulationn using a polarized light technique as described before.59,12 16 The subject
mediumm is illuminated with light that has been linearly polarized in one plane,
whilee imaging the remitted light through a second polarizer oriented in a plane
preciselyy orthogonal to that of the illumination. In order to make the image, the
lightt is collected , passed through a spectral filter to isolate the wavelength region,
andd linearly polarized.
Functionall capillary density and capillary velocity
Alll patients and HI were examined in the resting sitting condition in the afternoon
withh uniform room temperature. The sublingual microcirculation was observed by
OPSS imaging (Cytoscan A/RII (Cytometrics. Philadelphia, Pa), with a 5 X objective
providingg a 166 X final magnification as previously described.0 l2Ab For FCD meas-
urements,, three sublingual regions of interest were selected. From each region two
imagess with the best visual quality in every subject were analyzed. Measurements
weree digitally videotaped for 1 minute. All computed aided analyses was performed
149 9
usingg Cap-image computer computer programme (Cap-image; H Zeintl, Heidelberg,
Germany99 10). FCD was measured as the length of capillaries perfused with red
bloodd cells per observation area given in cm/cm2 as described previously. '
Twoo independent blinded investigators analyzed the perfusion in the microcircula-
toryy bed semi-quantitatively as described elsewhere.12 The perfusion was scored in
low.. normal and high flow at each measurement.
Statisticall analysis
Thee non-parametric data were analyzed using the Mann- Whitney U test. All data were
expressedd as mean SD. A P value <0.05 was considered statistically significant.
Results s
Patientt Population
Twelvee patients were included in the study, of which 8 had non-ischemic heart
disease.. All patients were in sinus rhythm except one patient who was in chronic
atriall fibrillation with slow atrioventricular conduction. All of the patients used
diuretics.. 83% ace-inhibitors. 42% p-blocker. 25% amiodarone and 8% calcium-
antagonist.. All patients were responders to CRT indicated by a significant decrease
inn NYHA classification from 3.6 0,5 to 2.3 0.6 (p< 0.001), decrease in QRS width
fromm 179 17 to 156.0 14 msec (p<0.001). increased LV ejection fraction from 14
too 22% (p<0.001), reduction of LVEDD from 73 9 to 67 9 mm (p = 0.005) and
LVESDD from 64.8 7 to 57.5 12.2 mm (p = 0.005). In addition, mitral regurgitation
decreasedd from 3 0.5 to 2.2 0.8 (p = 0.04). Mean blood pressure in the HF
patientss with biventricular pacing was 125 13 mm Hg, with RV pacing 121 9 mm
Hgandd no pacing 114 7 mm Hg (p = 0.786).
Functionall capillary density and capillary velocity
Inn four patients pacing could not be terminated because of inadequate intrinsic
rhythm.. During intrinsic rhythm FCD was the lowest [&. 2.4 cm/cm2). Biventricular
150 0
Chapterr S
Figuree 1, Functional capillary density off heart failure (HF) patients with intrinsicc rhythm (INT), with cardiac ^synchronizationn therapy (CRTV right ventricularr pacing (RV) and of healthy individualss (HI). HF vs. CRT = pp = 0.018: HF vs. HI =p = 0.008; CRT vs. RVV = p = 0.03: RVvs. HI =p = 0.025.
HF-INTT HF-CRT HF-RV HI I
Figuree 2.a.: Images of the microcircu-lationn with the CRT device pro-grammedd Off.
Figuree 2.b.: Images of the microcircu-lationn with the CRT device pro-grammedd On. Notice that the capillary densityy is higher when the CRT device iss programmed On.
- : :
TableTable 1, Functional capillary density of HF patients, duringg right ventricular pacing and CRT.
Patients s
1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9
10 0 11 1 12 2
HF-INT T
8.7 7 11.5 5 7.1 1 8.8 8 3-8 8 7.2 2 9,5 5 8.9 9
RV V
8.8 8 11.4 4 6.4 4 7.7 7 6.2 2 8.8 8 7,7 7 8 8
12.3 3 10.6 6 8.8 8
10.5 5
CRT T
93 3 14.1 1 12 2 9.3 3
14.5 5 10.1 1 14 4 13 3 14.9 9 138 8 10.4 4 10.1 1
HF-INTT = heart failure patients with intrinsic rhythm; RV== right ventricular pacing: CRT = cardiac ^synchronizationn therapy: -notavailable.
pacingg significantly increased FCD compared to RV pacing (12,1 2.2. cm/cm2) vs.
(8.99 1.9 cm/cm2, p = 0.03) and no pacing in HF patients (8.3 2.4, cm/cm2.
p=0.018,, see table 1, figure 1). Figure 2.a and 2.b are representative figures showing
thee capillaries during pacemaker programmed off and with CRT on, Age matched HI
hadd significantly higher FCD than HF with the intrinsic rhythm; 10.9 2.0 vs. 8.3
2.44 cm/cm2, p = 0.008. The FCD in age matched HI compared to FCD induced by CRT
weree not significantly different {10.9 2.0. vs. 12.1 2.2, cm/cm2). Capillary
velocityy was normal in all patients in each pacing modality and also when the
pacemakerr was programmed off.
Discussion n
Inn this study, we showed for the first time that cardiac resynchronization therapy
acutelyy improves microcirculatory perfusion. Today, the beneficial effects of CRT on
topp of optimal pharmacological therapy, regarding HF symptoms, hospital admission
ratess and LV function together with systemic circulation, are well establised. The
MUSTICC study showed the maintenance of clinical and hemodynamic benefits after
122 months of CRT and an improvement of left ventricular ejection fraction.1' Acute
hemodynamicc studies with CRT showed improvement in systolic blood pressure,
pulmonaryy capillary wedge pressure, dp/dt, V02 max and cardiac output.18 19 In the
152 2
Chapterr S
PATH-CHFF study, CRT decreased the left ventricular end diastolic pressure signifi-
cantlyy and increased dp/dt.4 Stroke volume and ejection fraction increased within 2
dayss after CRT in the recently published study by Gorscan et al. 18 The microcircula-
toryy changes in our study were already reached within 15 minutes, while previous
studiess showed also that the macrocirculatory changes could be observed within 20
minutes.44 20 The improvement in microcirculation likely contributes to the ob-
servedd beneficial clinical respons and may explain why some patinets with marked
functionall benefit despite limited objective increase in LV ejection fraction im-
prove,, since improvement in microcirculation means more oxygen delivery to the
tissuess (like muscles).
Thee present study confirmed recent observations by De Backer et al, 7 of decreased
microcirculationn in HF patients imaged with the OPS technique. Main changes in
microcirculatoryy in patients with HF are reduction of capillary density and blood
velocityy as described in previous reports using several other techniques,3 21 22 The
mechanismm for the changes is not clear yet. Influencing factors for these changes
couldd be various inflammatory mediators, increase of tumor necrosis factor, reactive
oxygenn species, increase of adrenergic agents, and increase of sympathovagal
imbalance.. 3' 5 Whether long term CRT can undo these negative changes by e.g.
reducingg sympathovagal imbalance and by improving cardiac output has to be
investigatedd in the future.
Inn the present study, the FCD increased significantly with CRT. A possible explanation
forr the direct increase of the FCD with CRT is the improvement of tissue perfusion by
ann increase in dp/dt and stroke volume, because microcirculatory control mechanisms
activelyy respond to changes of cardiac output as the heart similarly reacts to altera-
tionss in pre- and afterload. However, clinical studies showed that improvement of
macrocircualtionn does not necessarily result in improvement of microcirculation.7 21
Nevertheless,, in our opinion improving microcirculation might be more important
thann improving macrocirculation as illustrated in the study of De Backer et al. These
investigatorss showed that in patients with acute severe HF and cardiogenic shock, the
proportionn of especially perfused small vessels was higher in patients who survived
thann in patients who did not survive, although the perfusion of large vessels was
preservedd in all patient groups.
Similarr improvement in FCD was observed in a recent OPS study by Creteur et al. in
septicc patients where correction of systemic hemodynamic parameter also led to an
improvedd FCD. Treatment by catecholamines of septic shock patients also resulted
153 3
inn capillary recruitment.
Thee capillary velocity in our patients were normal and did not change with CRT and
RVV pacing. Which is in contrast to the study of the Backer et al,7The difference in
resultss could be explained by the different methods used for the analysis. They
recordedd 20 seconds, whereas we recorded 1 minute. Furhtermore, the patient
populationn in the study of De Backer et al. have more severe heart failure compared
too the patients in our study. Namely 77% of the patients were in cardiogenic shock
usingg inotropics Idobuatmine, dopamine, noradrenaline) with dilating effect on
capillariess with as consequence lower flow. However, in our patients there was
alreadyy normal flow but new capillaries are recruited.
Limitations s
AA limitation to the present study might be the fact, that we were not able to investi-
gatee stroke volume and dp/dt simultaneously with the OPS measurements. These
dataa could provid more detailed information about the correlation of systemic
hemodynamicss and microcirculatory changes. Furthermore, measurements were
donee for 15 minutes only in responders to CRT and only after device implantation.
Futuree research should investigate whether non-responders show no or reduced
microcirculatoryy changes. In addition, it would be of interest to know whether
microcirculatoryy changes at implant could predict beneficial response to CRT and
whetherr CRT induces beneficial long-term microcirculatory changes. The study
populationn is too small to directly correlate the improvement in microcirculation to
thee observed clinical benefit.
Itt is known that hypertension and diabetes mellitus can induce microcirculatory
alterations.277 2S However, in our opinion the role of these possible alterations have
noo significant role in our study for several reasons. First, the patients had no severe
hypertensionn or complicated diabetes. Second, each patient was his/her own
reference.. Third, patients with hypertension and diabetes mellitus responded with
aa identical microcirculatory changes to the switch in pacing mode compared to the
otherr patiens.
154 4
Chapterr 8
Conclusions s
Ourr data confirm that heart failure patients have a disturbed microcirculation
comparedd to healthy individuals. Cardiac resynchronization therapy induced an
acutee improvement of microcirculation as assessed by OPS.
Acknowledgement t
B.Ataseverr has been supported by Netherlands Heart Foundation (gr.2001B142).
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lii GV Schoenfeld MH. Silka MJ. Winters SL. ACC/AHA/NASPE 2002 Guideline Update for Im-plantationn of Cardiac Pacemakers and Antiarrhythmia Devices—summary article: a report of thee American College of Cardiology/American Heart Association Task Force on Practice Guide-liness iACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Am Coll Car-dioldiol 2002:40:1703-19.
2.. Tassi G. Maggi G. de Nicola P. Microcirculation in the elderly. Int Angiol 1985:4:275-83. 3-- Houben AJ. Beljaars JH. Hofstra L, Kroon AA, De Leeuw PW. Microvascular abnormalities in
chronicc heart failure: a cross-sectional analysis. Microcirculation. 2003:10:471-8. 4.. Auricchio A. Stellbrink C, Sack S. Block M. Vogt J, Bakker P. Huth C, Schondube F. Wolfhard U,
Boekerr D. Krahnefeld O, Kirkels H. Long-term clinical effect of hemodynamically optimized cardiacc resynchronization therapy in patients with heart failure and ventricular conduction delay.. J Am Coll Cardiol 2002:39:2026-33.
5.. Duprez D, De Buyzere M, Dhondt E. Clement DL. Impaired microcirculation in heart failure. IntInt j Microcirc Clin Exp. 1996:16:137-42.
6.. Slaaf DW. Tangelder G], Reneman RS, Jager K, Bollinger A. A versatile incident illuminator for intravitall microscopy. Int J Microcirc Clin Exp. 1987:6:391-7.
7.. De Backer D, Creteur J, Dubois MJ, Sakr Y, Vincent JL. Microvascular alterations in patients withh acute severe heart failure and cardiogenic shock. Am Heart J. 2004;147:91-9-
8.. Lindert J. Werner J. Redlin M, Kuppe H. Habazettl H. Pries AR, OPS imaging of human micro-circulation:: a short technical report, J Vase Res. 2002:39:368-72.
9.. Mathura KR, Ince. C. First clinical use of orthogonal polarization spectral imaging. Prog Appl Microcirc.Microcirc. 2000;24:94-101.
10.. Mathura KR. Vollebregt KG Boer K, De Graaff JC. Ubbink DT. Ince C. Comparison of OPS imag-ingg and conventional capillary microscopy to study the human microcirculation, J Appl Physi-ol.ol. 2001:91:74-8.
11.. Mathura KR, Bouma GJ. Ince C. Abnormal microcirculation in brain tumours during surgery. Lancet.Lancet. 2001:358:1698-9-
12.. Spronk PE, Ince C, Gardien MJ, Mathura KR. Oudemans-van Straaten HM. Zandstra DF. Nitro-glycerinn in septic shock after intravascular volume resuscitation. Lancet. 2002:360:1395-6.
13-- Spronk PE, Zandstra DF, Ince C. Norepinephrine compromises intestinal microvascular per-fusion?? Intensive Care Med. 2004;30:173-4: author reply 175.
14.. Harris AG, Leiderer R, Peer F, Messmer K. Skeletal muscle microvascular and tissue injury af-terr varying durations of ischemia. Am J Physiol. 1996:271 :H2388-98.
15.. Bax JJ. Molhoek SG, van Erven L. Voogd PJ. Somer S. Boersma E. Steendijk P. Schalij MJ. Van derr Wall EE. Usefulness of myocardial tissue Doppler echocardiography to evaluate left ven-tricularr dyssynchrony before and after biventricular pacing in patients with idiopathic dilated cardiomyopathy.. Am J Cardiol 2003:91:94-7.
16.. Groner W, Winkelman JW. Harris AG, Ince C. Bouma GJ, Messmer K, Nadeau RG, Orthogonal polarizationn spectral imaging: a new method for study of the microcirculation. Nat Med. 1999:5:1209-12. .
17.. Linde C, Leclercq C, Rex S. Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, Deha-roo JC. Alonso C. Walker S, Braunschweig F, Bailleul C, Daubert JC. Long-term benefits of biven-tricularr pacing in congestive heart failure; results from the MUltisite STimulation in cardio-myopathyy (MUSTIC) study. J Am Coll Cardiol. 2002;40:111-8.
18.. Gorcsan J. 3rd, Kanzaki H. Bazaz R, Dohi K. Schwartzman D. Usefulness of echocardiography tissuee synchronization imaging to predict acute response to cardiac resynchronization thera-py.. Am ƒ Cardiol. 2004:93:1178-81.
19.. Blanc JJ. Etienne Y. Gilard M. Mansourati J, Munier S. Boschat J. Benditt DG. Lurie KG. Evalua-tionn of different ventricular pacing sites in patients with severe heart failure: results of an acutee hemodynamic study. Circulation. 1997:96:3273-7.
20.. Leclercq C. Cazeau S. Le Breton H, Ritter P. Mabo P. Gras D. Pavin D, Lazarus A, Daubert JC. Acutee hemodynamic effects of biventricular DDD pacing in patients with end-stage heart fail-ure.. J Am Coll Cardiol. 1998:32:1825-31-
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21.. Bittner HB, Diemel KD. Friedel N. Stengele B, Hetzer R. Skin microcirculation and laser Dop-plerr blood flow in patients supported by the Berlin heart biventricular assist device. Vasa. 1992:21:149-53--
22.. Wrobiewski H. Kastrup J, Norgaard T, Mortensen SA. Haunso S. Evidence of increased microv-ascularr resistance and arteriolar hyalinosis in skin in congestive heart failure secondary to id-iopathicc dilated cardiomyopathy. Am } Cardiol. 1992;69:769-74.
23.. Farquharson CA. Butler R, Hill A. Belch JJ. Struthers AD. Allopurinol improves endothelial dysfunctionn in chronic heart failure. Circulation. 2002:106:221-6.
24.. Andersson SE, Edvinsson ML. Edvinsson L. Cutaneous vascular reactivity is reduced in aging andd in heart failure; association with inflammation. Clin Sci [Lond). 2003:105:699-707.
25.. Levine B. Kalman J. Mayer L. Filïi t HM. Packer M. Elevated circulating levels of tumor necrosis factorr in severe chronic heart failure. N Eng! ƒ Med. 1990:323:236-41.
26.. Creteur J D8D, Sakr Y, Koch M. Vincent JL.. Determinant of sublingual PC02 in patients with septicc shock. Critical Care MEd. 2003:31 :A116:419.
27.. Farkas K KE. JaraiZ. Nemcsik f, Farsang C. Non-invasive assessment of microvascular endothe-liall function by laser doppler flowmetry in patients with essential hypertension. Atheroscle-rosis.rosis. 2004;173:97-102.
28.. Jaap AJ, Pym CA, Seamark C. Shore AC. Tooke JE. Microvascular function in type 2 (non-insu-lin-dependent)) diabetes; improved vasodilation after one year of good glycaemk control. Dia-betMed.betMed. 1995:12:1086-91.
157 7
Reversedd Remodelling of Dilated Leftt Sided Cardiomyopathy After
Upgradingg From WIR to WIR Biventricularr Pacing
Case-reportt and review of the literatur e
Aytenn Erol-Yilmaz MD. Raymond Tukkie MD PhD. Tim Schrama, Hans Romkes MD
andd Arthur Wilde MD PhD
EuropaceEuropace 2002: 4:445-449.
Abstract t
Aims s
Too show reversed remodelling of the left ventricle and left atrium after upgrading to
biventricularr pacing in a patient with worsening of heart failure due to WIR pacing.
Too review the literature concerning reversed remodelling after upgrading to biven-
tricularr pacing.
Methodss and results
Inn a 61-year-old man, with cardiomyopathy and worsening of heart failure and
mitrall insufficiency following conservative pacing after His-bundle ablation, upgrad-
ingg to biventricular pacing showed left sided reversed remodelling of the heart with
decreasee of mitral regurgitation in 6 months. The literature is reviewed with search
inn medline between 1966-2001,
Conclusions s
Thee occasionally observed progressive heart failure after RV pacing following His-
bundlee ablation can be reversed by upgrading to W1R biventricular pacing and
underr these circumstances upgrading to biventricular pacing should be considered.
160 0
Chapterr 9
Introductio n n
Promisingg results for the treatment of heart failure patients with cardiac dyssyn-
chronyy have been described with simultaneous right (RV1 and left ventricular (LV)
(biventricular)) pacing in order to obtain improved synchronisation of ventricular
contraction.1"100 The usual indication for biventricular pacing are patients with dilated
cardiomyopathyy without conventional pacing indications, broad QRS and severe
symptomss despite optimal drug therapy. This article describes to our knowledge for
thee first time reversed remodelling of the LV and left atrium after upgrading to
biventricularr pacing in a patient with worsening of heart failure due to WIR pacing.
Thee literature concerning remodelling of the heart due to pacing is discussed.
Casee Report
AA 61-year- old resting butcher was admitted to our hospital with progressive in-
creasee of mitral regurgitation (MR) after WIR-pacing of the right ventricle.
Inn 1978 he was treated because of endocarditis of the mitral valve with positive
bloodculturess (staphylococcus aureus). The chest radiograph documented mild
cardiomegalyy and mild mitral regurgitation was described. The ECG showed atrial
fibrillationn with high ventricular response, which was converted to sinus rhythm by
electricc cardioversion. Therapy with cardioquin and Coumadin was started. With
controll of sinus rhythm, he had minimal dyspnoe on effort, his heart size remarka-
blee decreased and the mitral regurgitation resolved, Between 1978 and 1983 the
patientt was free of atrial fibrillation. From 1983 to 1998 recurrent episodes of atrial
fibrillationn occurred with again increase of heartsize and increase in dyspnoe on
effort.. Several drugs were tested (including amiodarone) without success. Extensive
analysiss did not reveal a cause for the cardiomyopathy (heart catheterisation,
coronaryy angiography, gallium-scintigrafy, cardiac biopsy). We postulated that during
thiss period the increase in left ventricular enddiastolic diameter (LVEDD), from 59
too 69 mm, was due to tachycardiomyopathy (mean resting heart rate was > 100
beats/min).. In an attempt to stop the LV-dilatation and control ventricular rate. His-
bundlee ablation was performed with implantation of a WIR pacemaker in 1998
(Biotronicc actros SR. Biotronik GMBH. Berlin, Germany), The heart rates before and
afterr His-bundle ablation with RV pacing showed improvement. Unexpectedly
161 1
withinn a year after RV pacing. MR increased from moderate to severe (fig. 3. large jet
area,, considerable prevalvular acceleration, calculated regurgitant volume measured
withh Proximal Isovelocity Surface Area (PISA) 62 ml. and systolic flow reversal in the
leftt upper pulmonary vein) with increase in systolic pulmonary artery pressure to
400 mm Hg and decrease of LV ejection fraction to 29 % (table I). These findings
suggestt that WIR pacing of the right ventricle with resultant ventricular dyssyn-
chronyy had increased the MR. Therefore he was admitted to upgrade the pacemaker
systemm from WIR right ventricular to WIR (2V) biventricular. The old pacemaker
(Biotronicc Actros) was explanted and the right ventricular bipolar lead (Slimtime S)
disconnectedd from the pacemaker. A new pulsegenerator DDDR (Guidant Contak TR
1241)) with an accelerometer sensor was subcutaneously implanted. The atrial port
off the pulsegenerator was connected to the right ventricular electrode. The left
ventricularr port was connected to a new unipolar lead (Guidant Easytrak 4512).
whichh was placed in the posterolateral vein over the left ventricular free wall
throughh the coronary sinus (figure 1). The RV port of the pacemaker was sealed.
Biventricularr pacing was established by programming the pacemaker to the DDDR
modee with the shortest A-V stimulation interval (10 ms). Direct after biventricular
pacingg QRS duration was clearly shortened (0,18 too 0.14 sec. figure 2). After 6
monthss follow up, echocardiography revealed obvious signs of reverse remodelling.
namely:: reduction of LVEDD from 69 to 62 mm and left atrial diameter from 54 to
499 mm, improvement of LV ejection fraction to 34 %, the MR diminished from
severee to moderate (calculated regurgitant volume measured with PISA 19 ml) and
pulmonaryy arterial pressure normalised (22 mmHg). The patient experienced
markedd increase in his exercise tolerance: the NYHA functional class after biven-
tricularr pacing reduced from III to II similar to before WIR pacing .
162 2
Chapterr 9
Tablee 1. Echocardiography before and after upgade
Yearr LVEDD FS MR grade LA diam RVSP EF tmm11 \%D U-41 imm1 (mmHgl t'V
6Q Q
62 2
s s ns s nd d
23* *
21 1
nd d s s
ns s
4 4 ipisaa 63 ml)
2 2 ipisaa 19 ml)
nd d s s
nd d
54 4
49 9
nd d nd d nd d
40 0
22 2
nd d nd d nd d
29 9
32 2
s s s s s s
Presentt Case 19977 35 1998.. just before His-bundle 6Q 17 3 53 29 ablationn and RV pacing 2000.. just before upgrade to BV-pacing g 2001.. 6 months after upgrade too BV pacing
Studies s Miracle"" " C.PLauetal .2--Medtronicc Insync1
Companion.. Contak CD, Path-CIIF. Mustic. Ventak CHF and Vigor CHF = none of these parameters is described.11 ^ """""
Tablee 1. RV- right ventricle; BV = biventricular: LVEDD = left ventricular enddiastolic diameter: MR== mitral regurgitation: PISA = proximal isovelocity surface area: LA diam = left atrial diameter: RVSP== right ventricular systolic pressure: F S- fractional shortening: EF- nuclear LV ejection fraction:: * = reduced afterload due to severe MR: s = significant; n s- not significant; nd= not described. .
Figuree 1. Upper panel: Twelve EKG leads before His-bundlee ablation; Atrial fibrillation, ventricular response 80-110/min.,, left heart axis. ORS duration 0.10 sec. ST-segmentt abnormalities (digoxin). Middle panel: after Hisbundlee ablation: Wl pacing 70/min., left heart axis, left bundlee branch block pattern, QRS duration 0.18 sec Lower panel:: during biventricular pacing, marked reduction in the pacedd QRS duration from 0.18 to 0 14 sec.
163 3
Figuree 2. Anteroposterior (left panel) and left lateral (right panel) chest X-rays showing the ventricu-larr pacing leads. Note the posterior position of the left ventricular lead.
Figuree 3- Apical four-chamber view with severe MR during RV pacing (left panel) and moderate MR duringg biventricular pacing (right panel).
Discussion n
Thee beneficial effects of His ablation and pacemaker therapy (improvement of LV
ejectionn fraction, exercise tolerance. Quality of Lif e and fewer hospitalisations) are
welll documented.11" In this case, however with tachycardia-induced dilated
cardiomyopathy,, catheter ablation of the His-bundle and permanent RV pacing
becausee of drug refractory atrial fibrillation, resulted in a marked increase in MR.
Mitrall regurgitation develops in a small number of patients who have His bundle
ablation,, and this occurs immediately after right ventricular pacing is initiated.14
Thee mechanism whereby right ventricular pacing results in MR appears to be
164 4
Chapterr 9
complex.. It affects the competence of the mitral valve due to changes in timing of
activationn of the mitral valve apparatus and/ or due to altered tension generation of
thee papillary muscles. This results in loss of coaptation and an increase orifice area
inn systole.14,15
Thee altered sequence of activation associated with RV apex pacing results in altered
mechanicall stress vectors, heterogeneity of regional coronary blood flow, and
elevatedd tissue catecholamine levels. These changes induce remodelling of the
globall ventricular shape with progressive changes in left ventricular performance.11
15188 Although the whole mechanism of remodelling muscle fibres is not clear yet,
manyy (experimental) studies, show that asynchronous electrical activation plays a
centrall role.3"6 19 In a study of de Cock et al. chronic (up to 3 months) ventricular
pacingg caused about 30% decrease of wall mass in early activated regions but did not
changee wall mass in late activated regions.20 This indicates that chronic asynchro-
nouss activation induces asymmetrical structural adaptations which gives an abnor-
mall LV wall motion pattern, in particular the left ventricular lateral free wall
contractss late in systole while the septum exhibits paradoxical movement. Thus not
onlyy the synchrony between both ventricles is important but also the synchrony in
differentt parts of each ventricle is important. The LV remodelling will lead to higher
volumess and worsening of the MR due to dilatation of the mitral valve annulus. Van
derr Heyden et al. showed in retrospective analyses that especially patients with
highh left ventricular end-diastolic dimensions (64 6 mm in this study) and
moderatee MR {our patient: LVEDD 69 mm and MR grade III) before initiation of RV
pacingg are prone to this complication after AV node ablation.15
Sincee mid 1990s, there is increasing evidence that the synchrony of the ventricles
cann be restored by biventricular pacing.21 Pacemakers capable of simultaneous
stimulationn of both ventricles improve ventricular systolic and diastolic properties
byy a variety of mechanisms including restoration of ventricular contractile synchro-
ny,, resynchronisation of ventricular septal motion, pacing induced decreased
atrioventricularr valve regurgitation and pacing related increases in ventricular
diastolicc fillin g time,
Lauu et al were the first to demonstrate regression of LV remodelling by synchronous
biventricularr pacing in patients with advanced heart failure.22 In this study, there
wass a statistically nonsignificant decrease of LVEDD within 1 week. The fractional
shorteningg of the LV increased within 1 week and was significant after 1 month,
165 5
whichh is comparable with the results of the larger Medtronic Insync study.9 The
Miraclee study showed a significant decrease in LVDD with a significant increase in
thee LV ejection fraction within 6 months.24 The LV ejection fraction was significant
increasedd within 1 month in the study of Lau and within 3 months in the
Medtronicc Insync trial. In the other trials these parameters are not described (see
tablee 1). ' However these patients were all without previous pacing.
Nuöezz et al. recently described a similar case of progressive deterioration after His
ablationn and WI pacing due to severe MR. which was reversed by biventricular
pacing,, but this patient had a mildly hypertrophic well contracting LV Earlier
echocariographicc segmental shortening of the free LV wall resulted in improved
papillaryy muscle function and decrease in MR.29 Also in our case 6 months of
biventricularr pacing resulted in clear reverse remodelling of the deleterious effects
off RV pacing.
Althoughh we cannot exclude continuation of cardiomyopathy in the natural history
off the patient, the time sequence of deterioration clinically and echcardiographical-
lyy after His ablationn makes RV pacing the most likely aetiological factor.
Conclusions s
Thiss case illustrates that the right ventricular apex is not the optimal pacing site in
humanss especially in patients with pre-existent dilated cardiomyopathy and mitral
regurgitation.. The occasionally observed progressive heart failure after RV pacing
followingg His-bundle ablation can be reversed by upgrading to WIR biventricular
pacingg which should be considered for such patients.
Acknowledgement t
Thee authors thank R. }. de Winter MD. PhD, for his skilful support during
implantation. .
16b b
References s
Chapterr 9
1.. Saxon LA. Boehmer JP. Hummel J. et al. Biventricular pacing in patients with congestive heart failure;; two prospective randomised trials. Am J Cardiol I999;S3:120D-123D.
2.. McVeigh ER, Prinzen FW, Wyman BT. Tsitlik JE. Halperin RH, Hunter WC. Imaging synchro-nouss mechanical activation of the paced heart with tagged MRI. MRM 1998:39:507-513.
3-- Prinzen FW, Augustijn CH, Arts T. Delhaas T, Reneman RS. The time sequence of electrical andd mechanical activation during spontaneous beating and ectopic stimulation. Eur Heart J 1992;13:535-543. .
4.. Van Oosterhout MF. Prinzen FW. Arts T. et al. Asynchronous electrical activation induces asymmetricall hypertrophy of the left ventricular wall. Circulation 1998:98:588-595-
5-- Prinzen FW, Van oosterhout MF. Vanagt WY, Storm C, Reneman RS. Optimization of ventricu-larr function by improving the activation sequence during ventricular pacing. PACE 1998:21:2256-2260. .
6.. Prinzen FW. Cheriex EC. Delhaas T, et al. Asymmetric thickness of the left ventricular wall re-sultingg from asynchronous electric activation study in dogs with ventricular pacing and in pa-tientss with left bundle branch block. Am Heart J 1995:130:1045-1053.
7.. Mansourati J. Etienne Y. Gilard M. et al. Left ventricular-based pacing in patients with chronic heartt failure; comparison of acute hemodynamic benefits according to underlying heart dis-ease.. Eur J Heart fail 2000;2:195-199.
8.. Chanda J, Kuribayashi R, Abe T. Ventricular remodelling in dilated cardiomyopathy. Lancet 1997:350:1705. .
9-- Gras D, Mao P. Tang T, et al. Multisite pacing as a supplemental treatment of congestive heart failure:: preliminary results of the Medtronic Inc. Insync study. PACE 1998:21:2249-2255-
10.. Daubert JC. Ritter P. Lebreton H. et al. Permanent left ventricular pacing with transvenous leadss inserted into the coronary veins. PACE 1998:21:9-245-
11.. Brown CS. Mill s RM. Conti JB, Curtis AB. Clinical Improvement after atrioventricular nodal ab-lationn for atrial fibrillation does not correlate with improved ejection fraction. Am J Cardiol. 1997:80:1090-1091--
12.. McComb JM. Gribbin GY. Effect of pacing mode on morbidity and mortality: update of clinical pacingg trials. Am J Cardiol 1999:83:211D-213D.
13-- Leclerq C. Victor F. Alonso C. et al. Comparitive effects of permanent biventricular pacing for refractoryy heart failure in patients with stable sinus rhythm or chronic atrial fibrillation. Am J Cardioll 2000:85:1154-1156.
14.. Twidale N. Manda V. Holliday RT, et al. Mitral regurgitation after atrioventricular node cathe-terr ablation for atrial fibrillation and heart failure; Acute hemodynamic features. Am Heart ] 1999:138:1166-1175--
15.. Vanderheyden M, Goethals M, Anguera I, et al. Hemodynamic deterioration following radiof-requencyy ablation of the atrioventricular conduction system. PACE 1997:20:2422-28.
16.. Mera F, Delurgio DB. Patterson RE. Merlino JD, Wade ME, Leon AR. A comparison of ventricu-larr function duringhigh right ventricular function during high right ventricular septal and apicall pacing after His-bundle ablation for refractory atrial fibrillation. PACE 1999:22:1234-1239. .
17.. Rosado A. Lamas GA. left ventricular remodelling clinical significance and therapy. Basic Res Cardioll 1997:92:66-68.
18.. Moe GW. Armstrong P. Pacing-induced heart failure a model to study the mechanism of dis-easee progression and novel therapy in heart failure. Cardiovasc Res 1999;42:591-599-
19-- Vioral G. Florea. Left ventricular remodelling: the chicken and an egg story of structure and function.. Int J Cardiol 1999:71:207-208.
20.. Cock CC, Meyer A, Kamp O. Visser CA. Hemodynamic benefits of right ventricular out-flowtractt pacing: comparison with right ventricular apex pacing. PACE 1998:21:536-541.
21.. Bakker PF. Meiburg H. de Jonge. Beneficial effects of biventricular pacing in congestive heart failuree (abstract). PACE 1994:17:820.
22.. Lau CP. Cheuj-man Y Chau E, et al. Reversal of left ventricular remodeling by synchronous biventricularr pacing in heart. PACE 2000:23:1722-1725.
167 7
23.. Cazeau S. Leclerq C. Lavergne T, et al. Effects of multisite biventricular pacing in patients withh heart failure and intraventricular conduction delay. N Engl } Med 2001:344:873-880.
24.. Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and effi-cacyy of cardiac resynchronisation therapy in patients with advanced heart failure: the multi-centerr Insync randomized clinical evaluation (MIRACLE). J Card Fail 2000:6:369-380.
25.. Bristow MR. Feldman AM. Saxon LA. Heart failure manamgment using implantable devices forr ventricular resynchronisation: comparison of medical therapy, pacing, and defibrillation inn chronic heart failure (COMPANION) trial. ) Card Fail 2000:6:276-285.
26.. Auricchio A, Stellbrink C. Sack S, et al. The pacing therapies for congestive heart failure (PATH-CHF)study:: rationale, design, and endpoints of a prospective randomized multicenter study.. Am J Cardiol 1999;83:I30D-135D.
27.. Ferrari R, CRT a new dimension in the treatment of heart failure: Landmark trials. Up- to-date onn cardiac resynchronization therapy (editorial), HF- Contdxkt 2001:1:8015.
28.. Up- to-date on cardiac resynchronization therapy. HF- Cpnt(Vkt 2001:1:8015-8022. 29.. Nunez A, Alberta MT. Cosio FG et al. Severe mitral regurgitation with right ventricular pacing
succesfullyy treated with left ventricular pacing. Pacing Clin Electrophysiol 2002:25:226-30.
168 8
Summaryy and conclusions
Chapterr 10
Thee purpose of this thesis was to evaluate the effect of manual adjustment of rate
adaptivee pacemakers on exercise physiology and quality of lif e and to study some
neww aspects of cardiac resynchronization therapy. The first part of the thesis
(Chapterr 2 to 6) concerned studies in pacemaker patients on the effect of individual
optimizationn of pacemaker sensors on exercise physiology and quality of life. The
secondd part of the thesis (Chapter 7 to 9) described the effect of cardiac resynchro-
nizationn therapy on cardiac function, the neurohumoral system and microcircula-
tionn in patients with heart failure.
Partt I Studies on pacemaker sensors
Automaticc functions are increasing in rate response pacemakers. Whether we can
relyy on these automatic functions in daily practice is limited described. We there-
foree reviewed in chapter 2 the various types of sensors used in current pacemakers
andd tried to answer the question whether manual rate response optimization
improvess patient outcome and is still necessary given the existing automaticity in
ratee response pacemakers.
Inn chapter 3 heart rate curves of healthy individuals (HI) from different age catego-
riess are described during the chronotropic assessment exercise protocol (CAEP) and
6-- minute hall walk test (6-HWT). Heart rate (HR) at rest. HR at 1 minute of exercise,
timee to peak HR. maximal achieved HR. HR at 1,3 and 10 minutes recovery period,
exercisee duration, and METS or achieved distance (meters) were measured. The
achievedd HR at one minute of exercise was significantly higher and the time to peak
HRR significantly shorter during 6-HWT compared to CAEP, although the achieved
maximall HR was comparable. There were no gender differences in HI randomized to
6-HWTT and minimal gender differences in HI randomized to CAEP. The predicted
maximall HR according to the Astrand formula (220-age) was not significantly
differentt compared to the achieved maximal HR in both tests. Thus, the Astrand
formulaa (220-age) can still be used for prediction of the maximal HR. The HR rate
profiless described in this chapter can be used to further optimize of the pacemaker
sensors.. The 6-HWT is preferable for pacemaker sensor optimization.
Chapterr 4 described the influence of individual optimization of sensors on quality
off life (QOU and exercise tolerance in a randomized, single blind study in patients
withh WIR. DDDR or AAIR pacemakers. Patients with > 75% pacing were randomized
173 3
too optimized sensor settings (OSS) or default sensor setting (DSS). Standardized
optimizationn was performed using three different exercise tests. QOL question-
nairess (QOL-q: Hacettepe. Karolinska and RAND-36) were used for evaluation of the
sensorr optimization. One month before and after optimization, exercise capacity
usingg CAEP and the three OOL-q were assessed. We showed that one month after
sensorr optimization the achieved maximal HR and METS were significantly higher
inn OSS compared to DSS. Highest HR and METS were achieved in patients with
pacemakerss with accessible sensor algorithms. In patients with automatic slope
settings,, exercise capacity did not improve after sensor optimization. Surprisingly.
QOLL did not improve in OSS compared to DSS.
Inn chapter 5 we investigated whether variation in HR during exercise affects the flow
velocityy in the middle cerebral artery and cardiac output. We therefore evaluated in
patientss with complete heart block and rate responsive pacemakers, the effect of DSS
andd OSS on blood pressure, stroke volume and mean flow velocity in the middle
cerebrall artery during graded ergometry cycling. For both OSS and DSS there was no
significantt increase in flow velocity in the middle cerebral artery during exercise.
Strokee volume and cardiac output increased minimal with OSS compared to DSS.
Wee directly compared the chronotropic function of the peak endocardial accelera-
tionn (PEA) sensor to the activity sensor in chapter 6. Patients with > 75% pacemaker
drivenn HR and a PEA sensor and HC underwent a CAEP exercise test. The pacemak-
erss were programmed in the default setting and WIR mode, with adjustment of the
upperr sensor rate as an age related maximum value (220-age). The activity sensor
wass externally strapped on the thorax. We showed that the PEA sensor functions
hypochonotropicc during exercise programmed as a single sensor system. Although
bothh groups had normal left ventricular functions, the exercise capacity of pacemak
err patients was significantly lower than in HC. It is therefore preferable to combine
thee PEA sensor with an activity-based sensor in a dual sensor system.
174 4
Chapterr 10
Partt II Studies on biventricular pacing
Too examine whether cardiac resynchronization therapy (CRT) induces favourable
changess in the neurohumoral system, we measured in chapter 7 in patients with
heartt failure, myocardial 123I-metaiodobenzylguanidine (123I-MIBG) uptake indices and
brainn natriuretic peptide (BNP) before and after 6 months of CRT. Furthermore, NYHA
classificationn and echocardiographic indices were assessed. Six months of CRT
resultedd in 1) significant improvement in NYHA classification, 2) reduction in QRS
width,, LV end- diastolic diameter, LV end systolic diameter, septal to lateral delay and
mitrall regurgitation, 3) improvement of delayed !23I-MIBG heart/mediastinal ratios
andd decrease of 123I-MIBG washout and A) decreased BNP levels. From these data we
concludedd that CRT induces favorable changes in the neurohumoral system.
Althoughh it is known that CRT in heart failure patients improves systemic circula-
tion,, its acute effects on microcirculation are as yet unknown and improvement of
thee macrocirculation does not necessarily result in improvement of the microcircu-
lation.. Chapter 8 describes the sub-lingual microcirculatory changes in heart failure
patientss due to CRT and right ventricular pacing by use of orthogonal polarization
spectrall (OPS) imaging. Six months of CRT resulted in a reduction in NTHA class and
echocardiographicc reverse remodeling. Acute microcirculatory changes were as-
sessedd by functional capillary density (FCD) and capillary velocity (CV) after previ-
ouss six months of CRT. FCD and CV were measured sublingual after pacing 15
minutess in one of three pacing modalities (no pacing, RV only pacing, and biven-
tricularr pacing with a sensed AV interval of 100-120 msec). FCD was significantly
higherr in healthy controls compared to heart failure patients with right ventricular
pacingg and no pacing. CRT significantly increased FCD in heart failure patients
comparedd to right ventricular pacing and no pacing. CV was normal in all patients
withh or without pacing.
Inn chapter 9 we described in one of the first case reports, reversed remodeling of
thee left ventricle and left atrium after upgrading to biventricular pacing in a patient
withh worsening of mitral regurgitation and heart failure due to WIR pacing after His
bundlee ablation and reviewed the literature concerning reversed remodeling after
upgradingg to biventricular pacing.
175 5
Interpretation ss and conclusions
Thee studies concerning individual optimization of pacemaker sensors on exercise
physiologyy and quality of lif e that are described in this thesis lead to the following
conclusions: :
1.. The majority of pacemaker sensors remain at the original programmed settings of
thee manufacturer, although there is evidence that individually adjustment of
pacemakerr sensors improves exercise capacity and quality of life.
2.. Automatic features can be helpful in reducing the time needed to perform a
follow-upp of pacemakers, however individually adjustment of pacing sensors is
stilll necessary.
3.. The development of a sensor system that can simulate ideal sinus rhythm behav-
iorr remains a challenge for scientists and manufacturers.
4.. International guidelines are needed to standardize pacemaker sensor optimiza-
tionn in all chronotropic incompetent patients,
5.. Individual optimization of rate response pacemakers improves exercise capacity
andd increases maximum HR. although OOL remained unchanged.
6.. Accessible pacemaker sensor algorithms are mandatory for individual optimization.
7.. Pacemaker sensor optimization increased stroke volume and cardiac output
minimallyy during exercise and had no measurable effect on flow velocity in the
middlee cerebral artery.
8.. The PEA sensor functions hypochonotropic during exercise programmed as a
singlee sensor system.
Inn conclusion, individual optimization of pacemaker sensors is necessary. Therefore
accessiblee pacemaker sensor algorithms and clear international guidelines are of
utmostt importance. Combination of a physiologic and an activity based sensor in dual
sensorr systems mimics the sinus node behavior better than a single sensor system.
Thee conclusions of the second part of the thesis concerning the effects of cardiac
resynchronizationn therapy on cardiac function, neurohumoral system and microcir-
culationn in patients with heart failure are:
1.. CRT induces favorable changes in the neurohumoral system in patients with
176 6
Chapterr 10
heartt failure (BNP levels decreased, delayed 123I-MIB G heart/mediastinal ratios
improvedd and 123I-MIB G washout decreased), parallel to significant functional
improvementt and echocardiographic reverse remodeling.
2.. In CRT responders. CRT improves sub-lingual microcirculation in heart failure
patientss as assessed by OPS imaging.
3-- The occasionally observed progressive mitral regurgitation and heart failure after
rightt ventricular pacing following His-bundle ablation can be reversed by upgrad-
ingg to WIR biventricular pacing and in these circumstances upgrading should be
considered. .
Inn conclusion, cardiac resynchronization therapy improves the macrocirculation. the
microcirculationn and induces favorable changes in the neurohumoral system in
patientss with heart failure, Reversed remodeling of the left ventricle can be
achievedd with long- term CRT.
Recommendationss and futur e directions
Parti i
Ourr results might have a number of implications for the clinician. Today, most pacemak-
erss are programmed in the default setting of the manufacturer. We recommend individ-
uall optimization in all chronotropic incompetent patients. After the implantation of a
pacemaker,, carefully follow- up of the patients is needed. The function of the pacemak-
err sensors has to be evaluated and optimized using an exercise test. We feel that in-
hospitall exercise tests are artificial, especially the treadmill and bicycle tests. We
recommendd therefore the use of e.g. a hall walk test with stair climbing, which resem-
bless closer daily lif e activities than other in- hospital tests. Ideally, the sensor function
shouldd be measured directly during daily living activities with for example holter
registration.. In addition, investigating the effects of programming sequence (e.g. first
thresholdd adjustment followed by slope adjustment) of rate response parameters is very
important,, although time consuming and strenuous for the patients. Development of
toolss for home monitoring of the separate rate response parameters can be helpful to
gainn more insight in this issue.
177 7
Thee achieved rate profile during treadmill exercise testing resulting from dual sensor
pacingg (with complementary properties) is improved over single sensor pacing
becausee sensor combination provides improvement in speed, proportionality, sensi-
tivit yy and specificity. As consequence, we recommend to use dual sensor systems with
aa combination of an accelerometer and a physiologic sensor (minute ventilation, QT,
peakk endocardial acceleration) in chronotropic incompetent patients.
Inn our study described in chapter four. OOL-q remained unchanged after one month
off individual optimization of rate response pacemakers. An explanation for the
failuree to improve OOL after sensor optimization could be the relatively good
baselinee functional capacity, because patients with relative preserved functional
capacityy at enrollment show the lowest improvement in health related issues.
Anotherr reason could be the partly inadequate questioning of specific pacemaker
patientt related symptoms with the used OOL-q in this study. Therefore, we advise
too use the Aquarel OOL-O. which is a recently developed pacemaker patient specific
OOL-qq and we feel that future research to improve QOL-q related to pacemaker
patientss has still several challenges. Insight in the interpretation of the OOL-q
scoress in relation with classical used clinical parameters such as NYHA classification
iss important.
Partt II
Furthermore,, the automaticity in rate response pacemakers is increasing tremen-
dously.. Although, automaticity can reduce pacemaker follow- up time, accessible
pacemakerss remain needed for individually adjustment of the rate response param-
eters.. Whether automatic adjustment is better than manual adjustment should be
investigatedd in randomized trials.
Thee results of our studies concerning the effects of CRT on neurohumoral system
andd microcirculatory changes form a step forward in the unraveling of the working
mechanismss of CRT in heart failure patients. To get more insight in this issue we
suggestt to replicate these studies in both responders and non-responders to CRT. It
wouldd be of interest to know whether microrocirculatory changes at implant could
predictt beneficial response to CRT and whether CRT induces beneficial long-term
microcirculatoryy changes. In addition, nowadays patients are selected for CRT
mainlyy on electrocardiographic criteria. The standard EKG is less reliable in the
178 8
Chapterr 10
characterizationn of the extent of dyssynchrony. since even patients with normal QRS
durationn on EKG can have marked dyssynchrony, while 20-30% of patients with wide
QRSS complexes do not respond to CRT. We therefore recommend to select patients
usingg advanced tissue-doppler imaging techniques, because this technique is likely
too improve the response rate to CRT.
Furthermore,, the deleterious effects of right ventricular pacing (RV) are now well
documented.. Considering the large magnitude of the deleterious effects of RV
pacingg we strongly suggest' to go away of the RV' or to minimize RV pacing using
algorithmss such as search hysteresis and mode switching. We think that left ven-
tricularr pacing using the coronary sinus is a more physiologic pacing site also for
conservativee pacing indications (sick sinus syndrome, AV-block) as for the modern
pacingg indications (resynchronization therapy) in patients with already reduced left
ventricularr function and/or mitral valve insufficency. More studies are needed to
identifyy patients who are at high risk for deterioration with RV pacing. Improving
thee technique for pacemaker lead implantation in the coronary sinus (to reduce lead
implantt time) wil l widen the indication for left ventricular pacing.
Finally,, extrapolating from recent developments, J Warren Harthorne (professor in
medicinee Massachusetts General Hospital, Boston, USA, writer of the book 'the future
off cardiac pacing), has suggested, that the future wil l give us "implantable computers
thatt wil l serve as an electronic service center" able to communicate with various
organn systems " to rouse flagging performance of heart, cerebral, respiratory,
gastrointestinal,, genitourinary, and musculoskeletal function" Electrostimulation has
evolvedd so far since its beginning that this description does not seem entirely outside
thee realm of the possible.
179 9
Samenvattingg en conclusies
182 2
Chapcerr I ]
Hett doel van dit proefschrift was om de effecten van manuele optimalisatie van
frequentie-adapterendee pacemakers op inspanningsfysiologie en kwaliteit van leven
tee onderzoeken en bepaalde nieuwe aspecten van cardiale resynchronisatietherapie
tee bestuderen. Het eerste deel van dit proefschrift (hoofdstuk 2 tot en met 6)
behandeltt studies in pacemakerpatiënten naar het effect van individuele optimali-
satiee van pacemakersensoren op inspanningsfysiologie en kwaliteit van leven. Het
tweedee gedeelte van dit proefschrift (hoofdstuk 7 tot en met 9) beschrijft de effect-
enn van de cardiale resynchronisatietherapie op de hartfunctie. het neurohumorale
systeemm en de microcirculatie in patiënten met hartfalen,
Deell I Studies met pacemakersensoren
Automatischee functies nemen toe in frequentie-adapterende pacemakers. Of we in
dee dagelijkse praktijk kunnen rekenen op deze automatische functies is beperkt
beschreven.. In hoofdstuk 2 worden de verschillende typen sensoren die gebruikt
wordenn in huidige pacemakers beschreven en werd geprobeerd om de vraag te
beantwoordenn of manuele optimalisatie van frequentie-adapterende pacemakers
resulteertt in klinische verbetering van patiënten en ook wordt de vraag beantwoord
off het nog steeds noodzakelijk is. gezien de bestaande automaticitieit in frequentie
adaptievee pacemakers.
Hoofdstukk 3 beschrijft hartfrequentieprofielen van gezonde proefpersonen in
verschillendee leeftijdscategorieën gedurende de treadmill test. het zogenaamde
chronotropicc assessment exercise protocol (CAEP) en de 6-minute Hall walk test (6-
HWT.. de 6 minuten looptest). Hart frequentie (HF) gedurende rust. HF na de eerste
minuutt van de inspanning, tijd tot maximale HF. maximaal behaalde HF. HF na 1. 3
enn 10 minuten van de herstelfase van de inspanning, inspanningsduur. inspanning-
scapaciteitt (metabolic equivalent, MET) en behaalde afstand (meters) zijn gemeten.
Dee bereikte HF na 1 minuut van de inspanning was significant hoger en de tijd tot
maximalee HF was significant korter tijdens de 6-HWT vergeleken met de CAEP,
alhoewell de bereikte maximale HF vergelijkbaar was in beide inspanningstesten.
Err waren geen geslachtgebonden verschillen tussen gezonde proefpersonen die
gerandomiseerdd waren naar de 6-HWT en minimale geslachtsgebonden verschillen
tussenn gezonde proefpersonen gerandomiseerd naar de CAEP. De voorspelde
183 3
maximalee HF volgens de bekende Astrand formule (220-leeftijd) was niet significant
verschillendd vergeleken met de behaalde maximale HF in beide inspanningstesten.
Hieruitt kunnen we concluderen dat de Astrand formule (220-leeftijd) nog steeds
gebruiktt kan worden om de maximale HF te voorspellen. De hartslagprofielen
beschrevenn in dit hoofdstuk kunnen als leidraad gebruikt worden voor de optimali-
satiee van de pacemakersensoren. De 6-HWT heeft de voorkeur om als leidraad
gebruiktt te worden voor de pacemaker sensor optimalisatie.
Hoofdstukk 4 beschrijft de invloed van individuele optimalisatie van sensoren op de
kwaliteitt van leven en inspanningstolerantie in een gerandomiseerde, single-
blindedd studie in patiënten waarvan de pacemakers geprogrammeerd zijn in WIR,
DDIRR of AAIR mode. Patiënten met > 75% pacing zijn gerandomiseerd naar optimale
sensorr setting (OSS) of default sensor setting (DSS). Gestandaardiseerde optimalisatie
iss uitgevoerd met behulp van drie verschillende inspanningstesten. Drie verschillende
kwaliteitt van leven vragenlijsten (Hacettepe. Karolinska, RAND-36) zijn gebruikt voor
dee evaluatie van de sensoroptimalisatie. Een maand voor-en-na optimalisatie is de
inspanningscapaciteitt tijdens CAEP bepaald en zijn de drie kwaliteit van leven vragen
afgenomen.. Aangetoond werd dat 1 maand na sensoroptimalisatie de behaalde
maximalee HF en METS significant hoger waren in de OSS vergeleken met de DSS,
Hoogstee HF en METS waren behaald in patiënten met pacemakers met toegankelijke
herprogrammeerbaree sensor algoritmen voor manuele afstelling- Bij patiënten
waarvann de pacemakersensor een automatische slope setting hadden, was de inspan-
ningscapaciteitt niet verbeterd na sensoroptimalisatie. Opvallend was dat sensoropti-
malisatiee de kwaliteit van leven niet verbeterde.
Inn hoofdstuk 5 werd onderzocht of de optimalisatie van de HF tijdens inspanning
dee snelheid van bloeddoorstroming in de arteria cerebri media en de cardiac output
beïnvloedt.. Om deze vraag te beantwoorden werd in patiënten met derde graads AV-
blockk en frequentie-adapterende pacemakers het effect van DSS en OSS op bloed-
druk,, slagvolume, en gemiddelde bloedstroomsnelheid in de arteria cerebri media
tijdenss fietsergometrie bepaald. De bloedstroomsnelheid in de arteria cerebri media
tijdenss inspanning nam niet toe.
Slagvolumee en cardiac output namen minimaal toe in OSS vergeleken met DSS.
Inn hoofdstuk 6 werd de chronotrope functie van de piek endocardiale acceleratie
tPEA)) sensor direct vergeleken met de activiteitssensor. Patiënten die > 75% pace-
makerr gestuurde HF hadden met een PEA sensor en gezonde proefpersonen hebben
184 4
Chapterr 11
dee CAEP inspanningstest ondergaan. De pacemakers waren geprogrammeerd in de
defaultt setting en de WIR mode met uitzondering van de maximale HF (upper
sensorr rate). De maximale HF werd aan de hand van de leeftijd (220-leeftijd) gepro-
grammeerd.. De activiteitssensor werd uitwendig op de thorax geplakt. Aangetoond
werdd dat de PEA sensor geprogrammeerd als single sensor systeem hypochonotroop
functioneertt gedurende inspanning. Ondanks dat de patiënten een normale linker
ventrikell functie hadden, was de inspanningscapaciteit van pacemakerpatiënten
significantt lager dan die van de gezonde proefpersonen. Het is daarom aan te
bevelenn om de PEA sensor te combineren met een activiteit gebaseerde sensor in
eenn zogenaamde dual sensor systeem.
Deell II Studies met biventriculai r pacing
Omm te onderzoeken of cardiale resynchronisatietherapie (CRT) gunstige neurohu-
morall en structurele veranderingen induceert, werd in hoofdstuk 7 bij patiënten
mett hartfalen voor-en-na 6 maanden CRT, de myocardiale 123I-metaiodobenzylguani-
dinee (123I-M1BG) opname het brain natriuretic peptide (BNP), de New York Heart
Associationn (NYHA) klasse en echocardiografische parameters bepaald. Zes maanden
CRTT resulteerde in 1) significante verbetering van de NYHA klasse, 2) reductie van
QRSS duur, linker ventrikel einddiastolische diameter, linker ventrikel eindsysto-
lischee diameter; vermindering van het septale tot laterale linkerventrikel activatie
verschill en vermindering van mitralisklepinsufficiëntie, 3) verbetering van de
delayedd 123I-MIBG hart/mediastinale ratio en afname van 123I-MIBG washout en 4)
afnamee van de BNP spiegel. Vanuit deze data werd geconcludeerd dat CRT gunstige
veranderingenn induceert in het neurohumorale systeem.
Alhoewell het bekend is dat CRT in hartfalen patiënten systemische circulatie
verbetert,, is het directe effect op microcirculatie nog niet bekend. Verder betekent
eenn verbetering van macrocirculatie niet noodzakelijkerwijs eveneens verbetering
vann microcirculatie. Hoofdstuk 8 beschrijft de sub-linguale microcirculatoire
veranderingenn in hartfalen patiënten door CRT en rechter ventrikel pacing met
orthogonall polarization spectral (OPS) imaging. Zes maanden CRT resulteerde in
reductiee van NYHA klasse en echocardiografische reverse remodeling. Na zes
maandenn CRT werden acute microcirculatoire veranderingen onderzocht middels
185 5
hett meten van de functionele capillaire densiteit (FCD) en capillaire stroomsnelheid
(capillaryy velocity, CV). Na pacing in een van de drie pacing modaliteiten ( niet
pacen.. rechter ventrikel pacing, en biventriculair pacing met een gesensde AV
intervall van 100-120 msec). De FCD was significant hoger in gezonde proefpersonen
vergelekenn met hartfalen patiënten met rechter ventrikel pacing en hartfalen
patiëntenn met eigen ritme. CRT verhoogde significant de FCD in hartfalen patiënten
vergelekenn met rechterventrikel pacing en het eigen hartritme. De CV was normaal
inn alle patiënten ongeacht wel of geen pacing. Hoofdstuk 9 beschrijft een van de
eerstee case reports waarbij reversed remodeling aangetoond wordt van de linker
ventrikell en linker atrium na upgrading tot biventriculair pacing in een patiënt met
verslechteringg van mitralisklepinsufficientie en hartfalen veroorzaakt door WIR
pacingg en His bundel ablatie. Tevens wordt in dit hoofdstuk de literatuur betref-
fendee reversed remodeling na upgrading tot biventriculair pacing beschreven.
Interpretatie ss en conclusies
Dee studies welke in dit proefschrift zijn beschreven betreffende het effect van
individuelee optimalisatie van pacemaker sensoren op inspanningsfysiologie en
kwaliteitt van leven, leiden tot de volgende conclusies:
1.. De meeste pacemaker sensoren blijven geprogrammeerd in de nominale setting
vann de fabrikant, ondanks dat er bewijs is dat individuele afstelling van pacemak-
ersensorenn de inspanningscapaciteit verbetert.
2.. Automatische pacemaker functies kunnen de tijd die nodig is bij de poliklinische
follow-upp van pacemakerpatiënten reduceren, desalniettemin is individuele
afstellingg van pacemakersensoren nog steeds noodzakelijk.
3.. De ontwikkeling van sensorsystemen die de ideale sinusknoop functie kunnen
simulerenn blijf t een uitdaging voor wetenschappers en fabrikanten.
4.. Internationale richtlijnen die aangeven hoe individuele optimalisatie van pace-
makersensorenn uitgevoerd dient worden zijn noodzakelijk voor het standaardis-
erenn van pacemaker sensoroptimalisatie in chronotroop incompetente patiënten.
5-- Individuele optimalisatie van frequentie adapterende pacemakers verbetert de
inspanningscapaciteitt en verhoogt de maximale HF. alhoewel de kwaliteit van
levenn onveranderd blijft .
186 6
Chapterr 1 1
6.. Toegankelijke pacemaker sensor algoritmen voor manuele afstelling zijn belangri-
jkk voor individuele optimalisatie,
7.. Pacemaker sensor optimalisatie verhoogt minimaal het slagvolume en de cardiac
ouputt gedurende de inspanning en heeft geen meetbaar effect op de bloeddoor-
stromingssnelheidd in de arteria cerebri media.
8.. De PEA sensor functioneert indien geprogrammeerd als single sensor systeem
hypochonotroopp gedurende de inspanning.
Concluderend,, individuele optimalisatie van pacemaker sensoren blijf t vooralsnog
noodzakelijk,, waarbij, toegankelijke pacemaker sensor algoritmen voor manuele
afstellingg en duidelijke eenduidige richtlijnen voor de dagelijkse praktijk van groot
belangg zijn. Combinatie van een fysiologische en een activiteit gerelateerde sensor
inn een 'dual sensor systeem' benadert de sinusknoopfunctie beter dan een 'single
sensorr systeem.'
Dee conclusies van het tweede deel van dit proefschrift betreffende de effecten van
cardialee resynchronisatie therapie op de hartfunctie. het neurohumorale systeem en
dee microcirculatie in patiënten met hartfalen zijn als volgt:
1.. CRT induceert gunstige veranderingen in het neurohumorale systeem in patiënt-
enn met hartfalen (daling van BNP. de delayed 123I-MIBG hart/mediastinale ratio
warenn verbeterd en de 123I-MIBG washout nam af), parallel aan functionele
verbeteringg en echocardiografische reverse remodeling.
2.. In CRT responders verbetert CRT bij patiënten met hartfalen de sub-linguale
microcirculatiee (gemeten met OPS imaging).
3.. Het incidenteel voorkomen van progressieve mitralisklepinsufficiëntie en
hartfalenn bij patiënten met rechter ventrikel pacing en His-bundel ablatie kan
doorr upgrading tot een WIR biventriculair pacing systeem aanzienlijk geredu-
ceerdd worden. Indien een dergelijke casus zich voordoet dient upgrading overwo-
genn te worden.
Concluderend,, cardiale resynchronisatie therapie verbetert de macrocirculatie de
microcirculatiee en induceert gunstige veranderingen in het neurohumorale systeem
bijj hartfalen patiënten. Reversed remodelering van de linker ventrikel kan bereikt
wordenn met lange termijn CRT
187 7
Aanbevelingenn en toekomstperspectieven
Deell l
Onzee resultaten kunnen een aantal implicaties hebben voor de clinicus in de
dagelijksee praktijk. Tegenwoordig staan nog een groot aantal pacemakers in de
nominalee setting van de fabrikant. We bevelen bij alle patiënten met chronotrope
incompetentiee individuele optimalisatie van de sensor aan. Na de pacemaker
implantatiee is zorgvuldige poliklinische follow-up van de patiënten noodzakelijk
ookk ten aanzien van de pacemakersensor. Het functioneren van de pacemaker
sensorenn dient geëvalueerd en geoptimaliseerd te worden aan de hand van een
inspanningstest.. We vinden dat de huidige inspanningstesten (met name de testen
opp de loopband en de fietst) een artificieel karakter hebben. We bevelen het gebruik
vann de zogenaamde hall walk test aan. liefst gecombineerd met traplopen, daar de
halll walk test wat betreft het type inspanning het meeste lijk t op de dagelijkse
activiteitenn thuis.
Idealiterr zou de sensor functie direct gemeten moeten worden in de thuissituatie
doorr bijvoorbeeld het gebruik van holterregistratie.
Daarbijj is het onderzoeken naar het effect van de volgorde van de afstelling van
frequentie-adapterendee parameters (de threshold, de slope) erg belangrijk, ondanks
datt het tijdrovend is en vermoeiend kan zijn voor de patiënten. Ontwikkeling van
techniekenn om de frequentie-adapterende parameters separaat thuis te monitoren
kunnenn behulpzaam zijn bij het verkrijgen van meer inzicht daarin.
Dee bereikte HF profielen gedurende inspanning op de loopband van dual sensor
systemenn (met complementaire eigenschappen) is beter in vergelijking met die van
singlee sensor systemen, doordat het combineren van sensoren verbetering geeft in
snelheid,, proportionaliteit, sensitiviteit en specificiteit. Daarom raden we aan om
inn chronotroop incompetente patiënten dual sensor systemen te gebruiken.
Dee automaticiteit in frequentie-adapterende pacemakers neemt enorm toe. On-
dankss dat automatisch gestuurde functies in een pacemaker voor een tijdreductie
kann zorgen tijdens poliklinische controles van de patiënten, zijn de pacemakers die
toegankelijkk zijn voor manuele afstelling van frequentie adapterende parameters erg
belangrijk.. Of automatische individuele afstelling van frequentie adapterende
parameterss beter is dan manuele afstelling zou in de toekomst onderzocht moeten
wordenn met gerandomiseerde trials.
188 8
Chapterr 11
Inn de studie beschreven in hoofdstuk vier, bleef de kwaliteit van leven Quality of
life.. QOL) onveranderd 1 maand na individuele optimalisatie van frequentie adapt-
erendee pacemakers. Een mogelijke verklaring voor het niet verbeteren van QOL na
sensorr optimalisatie zou de reeds goede functionele capaciteit (verkregen na de
pacemakerr implantatie) ats uitgangswaarde kunnen zijn. gezien de patiënten met de
relatieff goede functionele capaciteit bij de inclusie nauwelijks verbetering laten zien
inn gezondheidsgerelateerde uitkomsten. Een andere mogelijke verklaring zou de
inadequatee ondervraging van pacemaker patiënt specifieke symptomen kunnen zijn
mett de gebruikte QOL vragen in deze studie. Daarom adviseren we het gebruik van
dee Aquarel QOL vragenlijst, welke recent specifiek is ontwikkeld voor de pacemaker
patiënt.. Desalniettemin denken we dat het nog steeds uitdagend is om onderzoek
tee doen naar mogelijkheden ter verbetering van pacemaker patiënt gerelateerde
QOLL vragen. Verkrijgen van inzicht in de interpretatie van de QOL scores in relatie
mett de inmiddels gangbare parameters zoals de NYHA klasse is erg belangrijk.
Deell II
Dee studies betreffende de effecten van CRT op het neurohumorale systeem en de
microcirculatoiree veranderingen vormen een voorwaartse stap bij de ontrafeling van
dee gunstige werkingsmechanismen van CRT in patiënten met hartfalen. Om meer
inzichtt te verkrijgen in deze materie stellen we voor om in de toekomst studies naar
dee effecten van CRT op het neurohumorale systeem en de microcirculatoire verand-
eringenn te herhalen in zowel responders als non-responders van CRT. Het is belangr-
ijkk om te achterhalen of de eventuele microcirculatoire veranderingen door de CRT
bijj de implantatie een voorspellende waarde hebben voor de selectie van patiënten
welkee baat zullen hebben van CRT en of CRT ook op lange termijn gunstige microcir-
culatioree veranderingen zou kunnen induceren. Daarbij is het zo dat tegenwoordig
patiëntenn grotendeels geselecteerd worden op grond van echocardiografische
criteria.. Het standaard ECG is minder betrouwbaar in het bepalen van de uitgebreid-
heidd van de dissynchronie van het hart, daar patiënten met normale QRS duur op
hett ECG aanzienlijke echocardiografische dissynchronie kunnen hebben, terwijl 20-
30%% van de patiënten met verbrede QRS complexen niet verbeteren na CRT. Om
dezee redenen raden we aan om bij de patiëntenselectie gebruik te maken van
189 9
geavanceerdee tissue-doppler echocardiografie, aangezien daarmee de kans op De
nadeligee effecten van rechter ventrikel (RV) pacing zijn uitgebreid beschreven in de
literatuur.. Beschouwende de nadelige effecten van RV pacing willen we ten sterkste
aanbevelenn 'om de RV te verlaten' of algoritmen te gebruiken ter bevordering van
minimalee RV pacing zoals search hysteresis and mode switching van AAI naar DDD.
Wee denken dat linker ventrikel pacing via de sinus coronarius een fysiologisch
gezienn betere pacing site is zowel voor de conservatieve pacing indicaties (sick sinus
syndrome,, AV-Block) dan voor de moderne pacing indicaties (resynchronisatie
therapie)) in patiënten met afgenomen linker ventrikel functie en/of mitralisklepin-
sufficientie.. Meer onderzoek is nodig naar de identificatie van patiënten met een
hoogg risico voor deterioratie door RV pacing. Verbeteringen in de technieken voor
pacemakerr lead implantatie via de sinus coronarius zullen de indicaties voor linker
ventrikell pacing verruimen.
Extrapolerendd vanuit recente ontwikkelingen heeft J. Warren Harthoren (professor
inn de geneeskunde, Massachusetts General Hospital, Boston,USA, schrijver van het
boekk 'the future of cardiac pacing') gesuggereerd dat de toekomst ons 'implanteer-
baree computers zal geven die kunnen dienen als elektronische service centers' die
inn staat zijn om met verschillende organen te communiceren, die in staat zullen
zijnn om het cardiale, cerebrale, respiratoire, gastro-intestinale, uro-genitale en
muskulo-skeletalee functioneren weer te geven, Elektrostimulatie is sinds zijn
beginjarenn dusdanig ontwikkeld dat deze beschrijving niet onmogelijk lijkt .
190 0
Dankwoord d
194 4
Dankwoord d
Allenn die een bijdrage hebben geleverd bij de totstandkoming van dit proefschrift
wi ll ik hierbij bedanken.
Allereerstt wil ik alle patiënten en gezonde vrijwilligers, die meegedaan hebben aan
dee verschillende studies bedanken voor hun medewerking, geduld en vertrouwen in
klinischh wetenschappelijk onderzoek.
Dee volgende personen wil ik in het bijzonder bedanken.
Dr.Dr. R. Tukkie, Beste Raymond, mijn co-promotor. Je enthousiasme over de verschil-
lendee onderzoeksmogelijkheden en de daarop aansluitende rondleiding over de
afdelingg cardiologie en het halve AMC maakte bij mij tijdens onze eerste kennis-
makingg een dusdanig positieve indruk dat ik terplekke meteen besloot om te
beginnenn aan dit promotietraject. Ik heb je in de afgelopen 4 jaar leren kennen als
eenn erg betrokken, stabiele, en gemotiveerde begeleider, Je wist mij altijd goed te
stimulerenn door mij meteen, van het begin af aan, overal bij te betrekken, Ik mocht
meteenn mee naar de NASPE en naar allerlei cursussen waardoor ik in de gelegen-
heidd kwam om de 'pacing wereld' snel te leren kennen. Je bijzondere manier van
evaluerenn van de lopende onderzoeken, kritisch maar altijd met een positieve
benaderingg en je heldere open visie hebben mij altijd gemotiveerd. Daarnaast gaf je
ookk ruimte voor het bediscussiëren van nieuwe ideeën.
Bestee Raymond ook wil ik je bedanken voor je menselijk inlevingsvermogen, het
mooistee kraam-cadeau kreeg ik van jou. Je stelde zelf voor om 1 dag in de week
thuiss te werken waardoor ik mijn zoontje vaker zag. Je betrokkenheid bij je eigen
familiee bleek uit je leuke verhalen over je vrouw Lena en je zoontjes Marijn en
Wietse.. Daarnaast waren er natuurlijk de gezellige kerstborrels met de ep-leden bij
jouu thuis met echte cadeautjes onder de kerstboom voor iedereen. Ik ben je zeer
dankbaarr voor de manier waarop je mij al die jaren fantastisch hebt begeleid. Ik
hoopp je in de toekomst nog vaak te zien en op de hoogte te blijven van zowel je
werkzaamhedenn als de ontwikkelingen binnen je gezin.
Prof.Prof. Dr. AAM. Wilde, mijn promotor. Beste Arthur, door je heldere kritische blik
hebb je een grote bijdrage geleverd aan de voltooiing van de manuscripten. Ook als je
hett erg druk had werden de manuscripten in korte tijd nagekeken (binnen 1 dag
terug)) waardoor het mogelijk was om de manuscripten tijdig op te sturen. Ik heb
onzee besprekingen, die kort maar krachtig waren, altijd als erg stimulerend en
195 5
prettigg ervaren. Ik wil je bedanken voor het in mij gestelde vertrouwen.
Dee overig leden van de promotiecommissie, prof. dr. Ir.C. Ince. prof. dr. J. H Raves-
loot.loot. prof. dr .ir. J.M. T. de Bakker, prof. dr. M.J. Schalij, prof dr. N.M. van Hemel en
dr.dr. N. Sulke, dank ik voor de bereidheid plaats te willen nemen in de commissie ter
beoordelingg van mijn proefschrift.
Prof.Prof. dr. N. Sulke. I'm grateful for your willingness to participate in the evaluation
committeee of my thesis and to attend its defense here in Amsterdam.
Prof.Prof. dr. K.I. Lie. Beste professor Lie. ik ben u zeer erkentelijk dat u samen met Dr,
A.A. V. la Rivière mij de mogelijkheid heeft geboden om mijn opleiding tot cardioloog
inn het AMC te volgen. Dr. R.B.A. van den Brink dank ik voor het getoonde begrip in
mijnn gezinssituatie, ondersteuning en toestemming om te mogen beginnen met
mijnn vooropleiding dichtbij huis in Den Bosch.
ProfProf dr. J.G.P. Tijssen. Beste Jan, bedankt voor je hulp bij de randomisatie van de
STAPP en de POCASS studie.
ProfProf dr. J.J. Piek. Beste Jan, elk jaar was er minstens een keer sprake van een even-
tuelee verhuizing naar de cubicals van onderzoekers die geen onderzoek deden wat
directt verbonden was aan de cathkamers. Officieel hoorde ik daar ook bij maar
dankzijj jou mocht ik toch op B2 blijven. Jan. dankjewel.
DeDe pacemaker technici
TimTim Schrama. Beste Tim. je was een onmisbare spil voor mij de afgelopen vier jaren.
Jee had altijd tijd voor me. Ik heb veel van je geleerd maar ook veel met je gelachen
onderr een lekker bakje koffie in de meest luxuese pacemakerkamer die ik ken. Ik
benn blij dat je mijn paranymf wil zijn.
WandenaWandena Ramsoekh. Beste Wandena bedankt voor je actieve inzet bij de inclusie van
dee STAP studie en je vrolijkheid (ik heb je nog nooit chagrijnig meegemaakt).
MaritMarit Pfeiffer. Beste Marit, bedankt voor de samenwerking in de SOFA trial
Dee cardiologen wil ik bedanken voor het verlenen van toestemming voor de inclusie
vann patiënten in de verschillende studies. Martin Meesterman en de verpleegkundi-
genn op de cathkamer (Paul Soedarso), de dagverpleging (Truus Verboom. Trudy
]Qo o
Dankwoord d
Stapelkamp),Stapelkamp), en de research [ïndeke Radder) wil ik bedanken voor de gezelligheid
enn het meedoen als gezonde proefpersoon of zoeken daarvan.
HenkHenk de Weert (huisartsgeneeskunde), dr. Schïingeman (oogheelkunde)wil ik
bedankenn voor de inclusie van gezonde vrijwilligers.
DeDe echolaboranten {Irma, Rianne. Denise en Jim) wil ik bedanken voor hun bereid-
heidd van het maken van echo's bij de verschillende onderzoeken.
DeDe ECG laboranten op de polikliniek wil ik bedanken voor hun flexibiliteit bij het
plannenn van patiënten.
Drs.Drs. B.J Verberne, beste Hein het was me een waar genoegen om samen met jou het
artikell over de CRT en MIBG te schrijven. Je was altijd bereid om het artikel op-
nieuww te bespreken en als het stukje weer eens niet was geaccepteerd was je altijd
bereidd om een peptalk te geven. Maar je had gelijk in 'we moeten de bladen een
voorr een afwerken' nu is het toch nog in een goed blad terechtgekomen.
DeDe secretaressen Regina. Anita, Mary Ellen, Monique, en Gerdie wil ik bedanken
voorr hun interesse en meer dan secretariële steun.
Drs.Drs. M. Kortz. Beste Michael, door jou hulp bij de inclusie kwamen ruim eenderde van
dee patiënten van de STAP studie vanuit het Flevoziekenhuis. Bedankt voor je inzet.
Drs.Drs. de Boo. Beste Job. je gastvrijheid en die van de functielaboranten op de afdeling
cardiologiee van het Oosterschelde ziekenhuis bij de uitvoering van het onderzoek
naarr de PEA sensor heeft tot een publicatie in PACE geleid. Bedankt.
KarlaKarla Mulder wil ik bedanken voor de grote bijdrage die ze geleverd heeft door alle
databasess te bouwen voor mijn studies. Lieve Karla met het Acces software program-
maa dat je hebt gebouwd om hartslagen te kunnen samplen vanuit het Polar pro-
grammaa heeft mij heel veel werk uit handen genomen.
LieveLieve Margriet, ik heb veel lol met je gehad toen we samen naast de vroegere
koffiekamerr met Sianos woonden en regelmatig Fokke op bezoek hadden. Al die
verhalenn over je bijzondere vrienden zal me bij blijven.
197 7
Inn het onderzoeksstraatje van B2 richting de koffie kamer kwam ik regelmatig mijn
lotgenotenn tegen; de senior onderzoekers van de kloppende spier {Steven Cham-
uleau,uleau, Martijn Meeuwissen, Michiel Voskuil, Radha Bolangsing, Niels van Royen) en
dee rechter kamer {Anoek van Alem, Gijs Nollen, Igor Tïilevski) julli e zijn altijd een
groott voorbeeld voor me geweest. De overig (ex)-gangbewoners {Fons Windhausen,
MareMare van der Zee. Bektas Atasever, Bart-Jan Verhoeff, Alexander Hirsch, Pieter Bot,
PeterPeter Engel friet, Lilian Meiboom en Tomas Oosterhof), wil ik bedanken voor de
gezelligee dagelijkse, gezamenlijke lunch.
Dee onderzoekers van F3 en F4. Lieve Arno. wij blijven elkaar achtervolgen, eerst was
jee mijn mentor in Nijmegen en inmiddels zijn we collega's in Amsterdam. Mathijs
BoekholdBoekhold en Niek Bijsterveld bedankt voor julli e hulp bij het invriezen van de
neurohormonen. .
Lievee Nancy ik vond het altijd een heerlijke rust moment om met jou bij Antoinne
Petitt te"koffiëen" en bij te praten.
Lievee Gerlind. Je was een belangrijke steun en toeverlaat de afgelopen jaren op mijn
werk.. Ik vond het erg prettig dat ik iemand had waar ik echt alles aan kwij t kon en
diee ook echt luisterde. Met de gezellige bijklets momenten met jou onder een kopje
koffie,, koekjes met een wandelingetje in het AMC kon ik mijn gedachten goed
"resetten."" Ik zal deze momenten erg missen. Bedankt dat je mijn paranymf wil zijn.
Mij nn kamergenoten {Jacobijne, Saskia en Lea).
Lievee Jacobijne, Door jou aanwezigheid werd ik dagelijks op de hoogte gehouden
vann mijn horoskoop en zat ik nooit zonder drank. Lieve Saskia, ik hoefde maar een
engelss of nederlands woord te roepen en ji j wist het wel te vertalen. Mij n blindheid
voorr de lidwoorden de en het kon ik dankzij jou aanwezigheid ook goed vermom-
men.. Lieve Lea, je kennis over de statisitiek en over het algemeen over de comput-
erss vond ik erg waardevol bij het schrijven van de artikelen. Naast de inhoudelijke
supportt heb ik ook veel met julli e kunnen lachen met name tijdens onze 'evaluati-
emomentenn van deze en gene'. Ladies, ik zal julli e straks zeker missen.
FamilieFamilie Krouwel, lieve Aartje en jan dankzij julli e kon ik dagelijks met een gerust
hartt doorwerken. Bedankt voor julli e leuke opvang van Emre.
1QS S
Dankwoord d
LieveLieve pap, jij hebt de moedige stap gezet om naar Nederland te emigreren omm onze familie een beter bestaan te geven. Dat is je gelukt, alleen heb je err zelf te kort van kunnen genieten. Ik weet zeker dat je toch ergens meekijktt en erg trots op ons bent.
LieveLieve mam, canim annecigim. Je bent de sterkste vrouw in mijn leven. Dee wijze levenslessen heb ik van jou geleerd en niet op de schoolbanken. Jee hebt in je eentje ons opgevoed en je leven opgeofferd voor ons. Ik ben jee daar zeer dankbaar voor.
Lieve,Lieve, zus en broers canim ablacigim Sultan, canim abilerim Ersin ve EkremEkrem ve canim kardesim BattaL Jullie zijn mij erg dierbaar. Een voor een hebb ik al die jaren erg veel steun van julli e gehad op alle fronten mijn dankk daarvoor is moeilijk in woorden uit te drukken.
Dee andere leden van de familie mijn neefjes en nichtjes, de kleine sterren vann onze familie (Ethem, Zühal. Meva, Esra. Muhamed, Ekrem, Sükriye. Safa)Safa) en de aangetrouwde familie (Ömer, Selma, Ümran, Mehtap) bedankt voorr de gezelligheid.
Mij nn schoonouders Mehmeten Sebahat Erolwil ik bedanken voor de hartelijkheidd waarmee ze ons altijd ontvangen met de heerlijke uitgebreidee diners. De andere leden van mijn schoonfamilie (Suat, Burcu, Seray,Seray, Selcuk, Hasibe, Fuat, Fatih, Meral) wil ik tevens bedanken voor de gezelligee family meetings.
Lievee Sedat je bent voor mij en mijn idealen verhuisd, je hebt je eigen opleidingsplaatss verplaatst en bent daardoor later begonnen met je opleiding. . Jee was er altijd voor mij en Emre, zeker op de momenten dat ik door wilde werkenn om mijn deadlines te halen of weer vast zat in de file. Lieve schat, ikk hoop nu het proefschrift af is ook meer tijd voor jou te hebben.
Mij nn lieve schattige bambi. Emre, jij bent het mooiste wat mij ooit is overkomen.. Annen seni c,ok seviyor. Ja, mama zal elke dag al je teentjes eenn voor een blijven kussen. Dankzij de ontspannende momenten met jou hebb ik de files en de drukte van alle dag overleefd. Ik zal er altijd voor je zijn. .
199 9
Curriculu mm Vitae
Aytenn Erol-Yilmaz werd geboren op 15 april 1971 te Cicekdagi (Turkije). Na het
behalenn van de HAVO diploma aan de Notre Dame Des Anges in Ubbergen, stu-
deerdee zij eerst een jaar HBOV aan de hoge school van Nijmegen en volgde daarnaast
avondd VWO voor de vakken natuurkunde en scheikunde. Vervolgens studeerde ze
geneeskundee aan de Katholieke Universiteit van Nijmegen. De doctoraalfase werd
behaaldd in 1995 en eind 1997 werd door haar cum laude het artsexamen behaald.
Tijdenss haar studie heeft ze gewerkt als student -assistent bij de vakgroep
Anatomiee & Embryologie en als gids van het museum anatomicum.
Haarr interesse voor de cardiologie werd al vroeg gewekt tijdens klinische stages in
19944 en 1995 op de afdeling cardiologie aan de Hacettepe University (Ankara,
Turkije)) bij prof. dr. S. Kes en prof. dr. A. Oto.
Daarnaast,, heeft ze wetenschappelijk onderzoek gedaan naar acute en late
complicatiess bij percutane transluminal coronaire angioplastiek bij drs. Meursing,
dr.. Aengevaeren en prof. dr. F.W.A. Verheugt (afdeling cardiologie Canisius Wil-
helminaa Ziekenhuis en UMC St Radboud te Nijmegen).
Naa het behalen van de artsexamen heeft ze klinische ervaring opgedaan op de
afdelingg cardiologie van CWZ, UMC St Radboud te Nijmegen en UMC Utrecht bij
prof.. dr. Robles de Medina,
Vanaff begin 2001 is zij werkzaam op de afdeling cardiologie van het Academisch
Medischh Centrum (AMC) in het kader van haar promotie-onderzoek onder
begeleidingg van dr. R. Tukkie en prof, dr. A.A.M. Wilde. Daar heeft zij zich de afgelo-
penn jaren verdiept in pacemakersensor optimalisatie en cardiale resynchronisatie
therapie.. In 2004 schreef ze een LOI cursus over pacemakersensoren voor
pacemakertechnicii en ontving zij de Finapres Medical System travel fellowship
awardd gezamenlijk uitgereikt door de European Federation of Autonomie Societies
enn American Autonomy Society.
Vanaff 1 april 2005 start zij met haar opleiding tot cardioloog te beginnen met de
vooropleidingg interne geneeskunde aan het Bosch Medisch Centrum (opleider:
dr.. P.M. Netten). De opleiding tot cardioloog zal worden afgerond op de afdeling
cardiologiee van het AMC (opleider: dr. R.B.A. van den Brink).
Aytenn Erol-Yilmaz is getrouwd met Sedat Erol en heeft een zoontje Emre van
tweee jaar.
200 0
Stellingen n
1.. Ondanks verbetering van inspanningscapaciteit en verhoging van de maximale
hartfrequentiee resulteert individuele optimalisatie van frequentie-adapterende
pacemakerss niet tot verbetering van de kwaliteit van leven (dit proefschrift).
2.2. Pacemaker sensor optimalisatie leidt tot minimale toename in het slagvolume
enn de cardiac output gedurende de inspanning zonder verandering in de bloed-
doorstromingssnelheidd in de arteria cerebri media (dit proefschrift).
3.. Toegankelijke pacemaker sensor algoritmen voor manuele afstelling zijn erg
belangrijkk voor individuele optimalisatie (dit proefschrift).
4.. De piek endocardiale acceleratie (PEA) sensor functioneert indien geprogram-
meerdd als single sensor systeem hypochronotroop gedurende de inspanning
(ditt proefschrift),
5.. Zes maanden cardiale resynchronisatietherapie leidt tot gunstige veranderingen
inn het neurohumorale systeem (dit proefschrift)-
6.. Cardiale resynchronisatietherapie verbetert de sub-linguale microcirculatie (dit
proefschrift). .
7.7. Als we wisten wat we deden dan heette het geen onderzoek (Albert Einstein)
S.. Emancipatie van de vrouw betekent het waarborgen van de keuzevrijheid van
dee vrouw met behoud van vrouwelijke kenmerken en niet het verkrijgen van
dezee vrijheid dankzij het overnemen van mannelijk gedrag.
9.. De enige ware gids is de wetenschap (M. K. Atatürk)
10.. De toetredingscriteria voor het uiteindelijke lidmaatschap van Turkije bij de
Europesee Unie is net zo veranderlijk als het weer in Nederland.
11.. Het is een morele plicht van de mens om optimistisch te zijn (Sir Karl Popper,
filosoof). .
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