Hfnef

Dr.DurgaPavan

HFnEF-CONCEPTS AND MANAGEMENT

Heart failure (HF) can be defined as the inability of the heart to provide sufficient forward output to meet the perfusion and oxygenation requirements of the tissues while maintaining normal filling pressures. There are two major mechanisms by which this can occur:

Systolic dysfunction, in which there is impaired cardiac contractile function.

Diastolic dysfunction, in which there is abnormal cardiac relaxation, stiffness or filling


Nearly half of patients with symptoms of heart failure are found to have a normal left ventricular (LV) ejection fraction.

This has variously been labelled as diastolic heart failure, heart failure with preserved LV function or heart failure with a normal ejection fraction (HFNEF).

The preferred term should be HFNEF because accumulative evidence suggests that the physiological abnormalities in these patients are not restricted to diastole only, and systolic function is not entirely ‘‘preserved’’ when measures other than the ejection fraction are used.


History Late seventies, the first studies appeared that

showed diastolic LV dysfunction to importantly contribute to HF in hypertrophic cardiomyopathy, aortic stenosis, and hypertensive heart disease.

First reports on HFPEF date back almost 30 years.

Pulmonary congestion was reported in a small group of elderly, mostly female African-American hypertensive patients with supranormal systolic pump function and evidence for diastolic dysfunction.


It is now well established that among patients with the clinical syndrome of heart failure (HF), approximately half have preserved systolic function, known most commonly as heart failure with preserved ejection fraction (HFpEF).

Although originally considered to be predominantly a syndrome that pathophysiologically involves abnormalities in diastolic function (relaxation and/or stiffness), ongoing investigation suggests that, although diastolic abnormalities may be present in many patients, other aspects of pathophysiology likely also contribute to symptoms


DefCurrent European Society of Cardiology

(ESC)/Heart Failure Association (HFA) recommendations requireSigns and/or symptoms of heart failure, An ejection fraction above 50% Either direct evidence of diastolic dysfunction

or indirect evidence


DebatesDHF vs HFPEF vs HFNEF (Terminology )One disease continuum vs. two distinct

disease entities


Diastolic LV dysfunction was not unique to diastolic HF but also was present in HF with systolic LV dysfunction, the term diastolic HF was largely abandoned and was replaced by the terms HF with preserved LVEF or HFNEF.

Preserved LVEF implies knowledge of a pre-existing LVEF, which is usually absent, and the exact range of a normal LVEF is hard to define.



PathophysiologyDiastolic LV dysfunctionSystolic LV dysfunction Impaired ventricular vascular couplingAbnormal exercise-induced and flow

mediated vasodilation,Chronotropic incompetence,Pulmonary arterial hypertension


Diastolic LV dysfunction


Diastolic MechanismsEarly rapid filling - 70% to 80% of LV filling

driven by the LA to LV pressure gradient Myocardial relaxation, LV diastolic stiffness, LV elastic recoil, LV contractile state, LA pressures, Pericardial constraint, LA stiffness, Pulmonary vein properties, Mitral orifice area


Diastasis LA and LV pressures are usually almost equal. It contributes < 5% of the LV filling, Its duration shortens with tachycardia


Atrial systole - 15% to 25% of LV diastolic fillingwithout raising the mean LA pressure. depends on

PR interval, Atrial inotropic state, Atrial preload, Atrial afterload, Autonomic tone, Heart rate.


Although diastolic function is complex, the most important components are LV relaxation and LV diastolic stiffness.


Left Ventricular Relaxation Active, energy-dependent process Begins during the ejection phase of systole , continues through isovolumic relaxation and

the rapid filling phase



Left Ventricular Relaxation and stiffnessDiastolic dysfunction is caused by one or

more of the following structural abnormalities:

HypertrophyFibrosisInfiltrative diseasesPericardial constrictionMyocardial edema


Left Ventricular Relaxation and stiffnessFunctional cellular abnormalities which is reversible and transient .

Causes of impaired myocyte relaxation include:Ischemia and/or hypoxiaCellular calcium overload and/or ATP

depletionCertain cardiovascular drugs, eg, digitalisThe hypertrophy process itself which alters

the contractile and metabolic phenotype


Cellular mechanisms of LV relaxation and stiffnessRole of calcium

For complete myocyte relaxation to occur, the cytosol must be largely cleared of calcium so that calcium dissociates from troponin C, and all tension-generating actin-myosin bonds must be lysed.

Increased intracellular calcium can directly impair diastolic relaxation by persistent activation of the actin-myosin cross-bridge interaction if calcium is not adequately cleared from the cytosol.



Role of titin Giant elastic protein expressed in cardiomyocytes

in two main isoforms, N2B (stiffer spring) and N2BA (more compliant spring).

Titin functions as a bidirectional spring responsible for early diastolic LV recoil and late diastolic resistance to stretch.

Titin is compressed when the myocyte shortens during systole.

At the beginning of cell relaxation, when the actin-myosin crossbridges detach and active shortening tension begins to dissipate, the compressed titin forcefully expands and generates an intracellular "restoring force" that relengthens the sarcomere and myocyte


Isoform expression of titin differs in patients with SHF and DHF: in patients with SHF, titin isoform expression shifts towards the more compliant isoform, whereas in patients with DHF the shift is towards the less compliant isoform.

Isoform shifting may have an impact on diastolic function. shift to a larger isoform would predict a substantial decrease in passive myocardial stiffness.


N2BA:N2B - HFREF

N2BA:N2B - HFNEF


Systolic dysfunctionEjection fraction is an index of global

haemodynamic pump performance, insensitive to disturbances of ventricular muscle function.

A preserved ejection fraction often merely indicates that the radial (or circumferential) fibres of the ventricle have compensated for dysfunction of the longitudinal fibres.

Impaired longitudinal fibre function may be the single or most marked sign of cardiac dysfunction in HFpEF.


Patients with HFNEF have concentric LV remodeling with high LV mass/volume ratio in contrast to patients with HFREF, who have eccentric LV remodeling with low LV mass/volume ratio.

Signal transduction cascades driving myocardial remodeling differ in HFNEF and HFREF


ventriculo-vascular couplingVentricular and vascular stiffening increase with

ageing, hypertension, and diabetes, and are abnormally elevated in patients with HFpEF

Combined ventricular-arterial stiffening leads to greater blood pressure lability, by creating a ‘high gain’ system—with amplified blood pressure changes for any alteration in preload or afterload

Patients with HFpEF display attenuated exercise-mediated reductions in mean vascular resistance and arterial elastance, coupled with abnormalities in endothelial function and dynamic ventricular –arterial coupling



Chronotropic incompetenceChronotropic response during submaximal

and peak workload is impaired in HFpEF.

Autonomic dysfunctionBaroreflex sensitivity is reduced


cardiovascular reserve dysfunction


Pulmonary HTN

Both pre & post-capillary components


HFpEF may be conceived as a fundamental disorder of cardiovascular reserve function—Diastolic, Systolic, Chronotropic, Vascular.


Exaggerated hypertensive ageingMany of the abnormalities are noted with

normal ageing and are simply more markedly abnormal in HFpEF


DiagnosisSigns and/or symptoms of HF, Evidence of normal systolic LV function, Evidence of diastolic LV dysfunction or of

surrogate markers of diastolic LV dysfunction such as LV hypertrophy, LA enlargement, plasma levels of natriuretic peptides (NP)


C/F Framingham criteria


2 major criteriA OR 1 major criteriA plus 2 minor criteria

Diagnostic value of symptoms and signs

HFnEF-CONCEPTS AND MANAGEMENT Brunner-La Rocca [41] and Schweiz Me Forum2007;7(Suppl. 39):3–14 S

EVALUATION OF DIASTOLIC FUNCTION


DD INDICESMITRAL B BUMPIVRTMITRAL INFLOW – E, AMITRAL ANNULAR VELOCITIES- Mitral inflow propagation velocity -VP

Pulmonary Venous Doppler Flow into LA – SYSTOLIC (S), DIASTOLIC (D) , ATRIAL REVERSAL

(Ar),


Two-Dimensional EchocardiographyThe combination of Thickened left ventricular walls, Left atrial dilation, Absence of mitral valve disease Strong evidence of diastolic dysfunction and

elevated left ventricular diastolic pressure.


The normal rate of mitral valve closure after atrial systole is smooth and of brief duration.

Pts with increased LVEDP Onset of closure is premature Notch in between A and C Prolonged AC wave with a B bump

Sign is low sensitivity but high specificity for LVEDP(LAP) > 20 mmhg

Mitral B – bump


M-Mode Echocardiography


Mitral inflow patternsPulmonary vein flow

Doppler Evaluation of Diastolic Function


Transmitral Doppler Inflow

E velocity, A velocity, E/A deceleration time (DT) IVRT.


E -PEAK EARLY FILLING VELOCITY

A – PEAK FILLING VELOCITY DURING ATRIAL

SYS

E/A –LA-LV GRADIENT IN EARLY AND LATE

DIASTOLE.

DT –TIME INTERVAL FROM EARLY PEAK

INFLOW (E) TO CESSATION OF RAPID FILLING

PHASE.

A WAVE DURATION- ALONG WITH Pva

REFLECTS LV FILLING PRESSURES


A=83CM/S

E/A=1.4E=123c

m/s HFnEF-CONCEPTS AND MANAGEMENT

1.E -PEAK EARLY FILLING VELOCITY

2. A – PEAK FILLING VELOCITY DURING

ATRIAL SYS

3.E/A –LA-LV GRADIENT IN EARLY AND

LATE DIASTOLE.

4.DT –TIME INTERVALFROM EARLY PEAK

INFLOW (E) TO CESSATION OF RAPID

FILLING PHASE.

INVERSLY PROPORTIONAL TO CHAMBER

STIFFNESS.

5. A WAVE DURATION-ALONG WITH Pva

REFLECTS LV FILLING PRESSURES

DT=148ms



Limitations :

A large number of factors can affect the transmitral flow including age, heart rate, heart rhythm, loading conditions, LV systolic function, atrial function, and mitral valve disease.

TM flow cannot be used in isolation to assess diastolic function.


Valsalva ManeuverValsalva maneuver decreases preload during

the strain phase, pseudonormal mitral inflow changes to a pattern of impaired relaxation.

Mitral E velocity decreases with a prolongation of DT, whereas the A velocity is unchanged or increases, such that the E/A ratio decreases.

A decrease of 50% in the E/A ratio is highly specific for increased LV filling pressures.


IVRT

Normal – 70-90 ms.


IVRT lengthens - impaired LV relaxation shortens - LV compliance is decreased and LV

filling pressures increase.

IVRT varies with HR, preload and ventricular fn.


Pulmonary Venous Doppler Flow

right upper pul vein > 0.5 cm into the pul

vein End-expiration Sweep speed of 50 to

100 mm/s Average of 3 values


Measurements of pulmonary venous waveforms include

Peak systolic (S) velocity- S1,S2 in bradycardiaPeak anterograde diastolic (D) velocity,The S/D ratio – stages of diastolic dysfunction.Systolic filling fraction (S TVI/[S TVI + D TVI])Peak Ar velocity late diastole ,Duration of the Ar increases with increasing filling

pressures(Ar – A ) most sensitive and earliest indicator

elevated LV filling pressures. = LVEDPHFnEF-CONCEPTS AND MANAGEMENT


S wave -54.3 cm/sec


D = 74.2cm/sec

S/D<1


Ar vel = 36cm/s


Ar=130msAr-A=130-106=24ms


Normal values-

Peak S wave velocity: 60 ± 15 cm/sec.

Peak D wave velocity: 40 ± 15 cm/sec.

Peak S / Peak D ratio: 1.3 – 1.5 ( ± 0.3).

Systolic fraction= 60 – 68 ±10%

Peak Ar wave velocity: -32 ± 10 cm/sec.

Ar duration: 137 ± 31 msec.

Ar – A : < 30 msec


An Ar velocity >35 cm/sec & a difference in duration ( Ar – A ) >30 msec, is higly predictive of a LVEDP > 15 mm Hg.

Major limitation is difficult to obtain and influence by rhythm distrubances


Color M-Mode

Vp - the slope of the first aliasing velocity during early filling, measured from the MV plane to 4 cm into the LV or the slope of the transition from no color to color.

mitral inflow propagation velocity

Normal Values: Vp>5O cm/s(< 45 is abnormal in adults)

PCWP = [5.27 x E/Vp] + 4.6 (in mmHg)

(5.27X 123/33.5)+4.6 = 23.5

E/Vp > 2.5 to predict PCWP >15 mm Hg.

E/Vp ratio for the prediction of LV filling pressures in

patients with normal Efs should be cautious . (Vp may

be normal in pts with normal EF)


AFFECTED BY-

LV GEOMETRY

CHAMBER VOL

REGIONAL DYSSYNCHRONY

SYS FUNCTION

NEVER IN ISLOATION


Tissue Doppler Imaging (e’)

•Apical 4 chamber view•Positioned at or 1 cm within the septal and lateral insertion sites of the mitral leaflets•Sweep speed of 50 to 100 mm/s •end-expiration•average of 3•For mean take both medial and lateral annulus sites


systolic (S), early diastolic(Ea, Em, E’, e’, and

late diastolic velocities(Aa,Am, A’, or a’).

e’/a’ , E/e’ , TE-e’ .

e' is determined by LV relaxation,

preload (minimally)

a’ is determined by LA systolic function and

LvEDP HFnEF-CONCEPTS AND MANAGEMENT

e’The velocity of mitral annular movement

during early diastole, designated as e′ or E′ velocity.

correlates well with invasive measures of the time constant of myocardial relaxation tau .

In healthy young individuals, septal e′ is >10 cm/s and lateral e′ >15 cm/s at rest.


E/e’ , Normal-5-10 cm/secPredicts lv filling pressure- LAP - PCWP


E/e’Limitations

Different cardiac cyclesAge,preload,sys functionProsthetic valvesAnnular rings ---- DECREASE e’Annular calcificationSevere primary MR – increase e’ so, IVRT/E-e’

used


IVRT/Te −E′

The ratio of IVRT/Te′−E was inversely related to mean wedge pressure (and LA pressure) in patients with high filling pressures.

The concept was evaluated in patients with mitral disease and atrial fibrillation.

The major limitation to this method is the need to measure 3 time intervals from different cardiac cycles.

IVRT/TE-e’ <2 indicates increased LAP.


QRS TO e’

458msHFnEF-CONCEPTS AND MANAGEMENT

T e’-E =

21

E/e’

> 158 –15

< 8

LVEDP > 12

LVEDP N Normal LV FMitral valve

diease

IVRT/ TE-e’ < 2

YesNo

TISSUE DOPPLER ANNULAR DIASTOLIC VELOCITIES



QRS TO E

479msHFnEF-CONCEPTS AND MANAGEMENT

Stages of DHF



Diastolic Stress Test

E/e ´ ratio remains unchanged or is reduced-NORMAL E/e´ratio increases - impaired myocardial relaxation

Exercise is usually performed using a supine bicycle protocol,


In patients with diastolic heart failure, LA pressure is increased, leading to an increase in mitral E velocity, whereas annular e′ velocity remains reduced given the limited preload effect on e′.

On the other hand, in the absence of cardiac disease, e′ increases to a similar extent to the increase in mitral E velocity, and the normal E/e′ ratio essentially is unchanged with exercise.


Twisting and untwisting Twisting and untwisting of the LV are important aspects of cardiac

mechanics and function.

The apical portion of the LV normally twists counterclockwise and

the basal segment twists clockwise during systole, storing potential

energy.

The LV untwists immediately after systolic contraction,

contributing to generating an intraventricular pressure gradient.

LV torsion is the summation of the apical and the basal twisting.

measure twist using TDI and STE from short-axis images of the LV

These studies showed that torsion and circumferential strain are

normal in patients with diastolic heart failure whereas longitudinal

and radial deformation are reduced.HFnEF-CONCEPTS AND MANAGEMENT

MRIAcquire images in any selected plane or along

any selected axis. This makes CMR the gold standard for LV volume, LA volume, and LV mass measurements.

MR can provide a whole range of LV filling parameters which are identical or nearly identical to those obtained with echocardiography.

CMR constitutes not only a valid alternative to echocardiography but could also be the first-choice technique if small changes in LA or LV volumes and in LV mass are expected.

Several morphological and functional parameters such as tissue characterization or LV diastolic untwisting can only be assessed by CMR


NPNPs may be much less useful in this condition:

Increased wall stress is the stimulus for NP production and release from the cardiomyocyte, but, according to La-Place’s law, wall stress may be normal in a non-dilated, hypertrophied ventricle.

Under these circumstances, NPs may mainly originate from the atria, explaining the common finding of only marginally elevated BNP or NT-proBNP levels despite highly symptomatic patients.

NPs rise sharply once atrial fibrillation occurs, further underpinning the poor diagnostic value of these markers.


Cardiac catheterizationSimultaneous right & left heart

catheterization can be useful in total hemodynamic assessment including elevated LV pressures & CO.

Coronary angiography will help us to diagnose significant CAD.




Diagnostic guidelines


When comparing these 4 sets of diagnostic guidelines, it becomes evident that the mere presence of signs or symptoms of HF and a normal LVEF never sufficed to firmly establish the diagnosis of HFNEF, which always required additional evidence of diastolic LV dysfunction, LA size, or LV mass.



Natural HistoryMortality - Allcause mortality for HFnlEF is

similar to that of HF with a reduced EF.HF patients with normal EF more often died

of noncardiovascular causes, whereas deaths due to coronary disease were less frequent.


Framingham Heart Study, for patients with HFNEF the annual mortality was 8.7% compared with 3% in matched controls and for SHF was 18.9% compared with a 4.1% in age- and sexmatched controls over 6.2 years.


Management Two objectives

Treat the presenting syndrome of HF— Relieve resting or exercise-associated venous

congestion and Eliminate precipitating factors.

Reverse the factors responsible for diastolic dysfunction or other perturbations that lead to HFnlEF



Age 60 yearsCurrent HF symptoms

LVEF 0.45

NYHA Class III/IV

Echo (LVH, LAE)

ECG (LVH, LBBB)

CXR congestion

I-PRESERVE

NYHA class II - IV

CHF hosp. 6 months

Key Exclusions: SBP >160 mm Hg; prior EF <40%; ACS or stroke ≤ 3m, hypertrophic or restrictive CM, pericardial or valvular disease, significant pulmonary disease, creatinine >2.5, Hb <11


Months from Randomization

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No. at RiskIrbesartanPlacebo

HR (95% CI) = 0.95 (0.86-1.05)Log-rank p=0.35 Placebo

Irbesartan


Hong Kong Diastolic Heart Failure study Diuretics, Diuretics + Irbesartan, or

Diuretics + Ramipril were used. At the end of one year Irbesartan & Ramipril

groups were better than diuretics alone in reducing BNP & improving LV systolic & diastolic function.

Although quality of life & SBP & DBP were similar in all 3 groups








DiureticsMainstay of symptomatic treatment.Loop diuretics are preferred as they are more

potent compared with thiazides.Diuretics should be initiated at lower doses

and gradually up-titrated to maintenance doses.

However, patients with HFNEF are typically very sensitive to relatively small changes in blood volume and care must be taken to avoid hypotension.


Statins

Possible Mechanisms• Beneficial effects of statins in patients with

coronary artery disease, diabetes and impaired renal function which are common in patients with diastolic HF.

• Beneficial effects on LV hypertrophy and fibrosis.• Mild antihypertensive effect of statins.• Beneficial effect on endothelial function and

regression of aortic atherosclerosis.• Protective effect on LV remodeling.• Antiinflammatory and antioxidant effects.


Recently CORONA trial reported neutral outcome of statin therapy in the HFrEF patients of the.


Spirinolactone TOPCAT Aldosterone in Diastolic HF (ALDO-DHF)

the role of spironolactone versus placebo is being studied to elucidate if an anti-fibrotic intervention strategy is adequate to improve the outcome in HFNEF.

Long-term aldosterone receptor blockade with spironolactone improved diastolic function but did not affect clinical symptoms or exercise capacity.


DecompensationTriggers

Uncontrolled hypertensionIncreased salt and water intake and/or

retentionTachyarrhythmiasIschemiaChronic kidney diseaseAnemiaChronic lung diseaseInfection


ACC/AHA Heart Failure Guidelines HFNEF

Recommendation Class

Control systolic and diastolic hypertension I

Ventricular rate control in patients with atrial fibrillation I

Diuretics to control congestion and edema I

Coronary revascularization is reasonable in patients with symptomatic coronary artery disease

IIa

Restoration and maintenance of sinus rhythm in patients with atrial fibrillation might be useful to improve symptoms

IIb

Beta-blocking agents, ACE inhibitors, AT II receptor blockers, or calcium antagonists might be effective to minimize symptoms

IIb

The use of digitalis is not established IIb

Hunt et al. ACC/AHA Practice Guidelines JACC 2005;46:1-82HFnEF-CONCEPTS AND MANAGEMENT

HFSA Guidelines


Novel therapiesNovel strategies should try to interfere with

HFNEF-specific myocardial signal transduction pathways, which account for Prominent cardiomyocyte hypertrophy, Down-regulation of MMPs, Up-regulation of TIMPs, Hypophosphorylation of stiff titin isoforms, Substrate shifts from glucose to free fatty

acids.


Novel therapiesCyclic GMP Modulator

Reduce ventricular –vascular stiffening,Antagonize maladaptive chamber

remodelling,Improve endothelial function,Reduce pulmonary vascular resistance,Enhance renal responsiveness to NP.


Sildenafil

Patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.


Rho-kinase inhibitors such as fasudil and Y-27632 have vasorelaxation properties and have demonstrated the ability to blunt progression of hypertrophic remodelling in animal models of HF.

Alagebrium chloride (ALT-711) is a novel compound that breaks glucose cross-links and improves ventricular and arterial compliance in animals.

Acute modification of titin PKG phosphorylation sites may dynamically modulate titin stiffness.

The anti-anginal drug ranolazine blocks inward sodium Current, thereby reducing intracellular calcium, and it has also been suggested as a potential treatment for HFpEF,although human HFpEF data are currently unavailable.


HFNEF syndrome is a heterogenous entity with high prevalence and mortality rates almost as high as that of systolic HF.

It is a relatively common cause of HF in the elderly and has a variety of causes and pathophysiological mechanisms.

Despite improvements in its understanding, many questions remain and, as yet, there are no treatments of any proven benefit. Ongoing trials are underway.


Education

Hfnef