Amlodipine Monotherapy, Angiotensin-Converting Enzyme Inhibition, and Combination Therapy With Pacing-Induced Heart Failure

Amlodipine Monotherapy, Angiotensin-ConvertingEnzyme Inhibition, and Combination Therapy With

Pacing-Induced Heart FailureScott B. Kribbs, William M. Merritt, Mark J. Clair, R. Stephen Krombach, Ward V. Houck,

Michael G. Dodd, Rupak Mukherjee, Francis G. Spinale

Abstract—In patients with congestive heart failure (CHF) receiving therapy with angiotensin-converting enzyme (ACE)inhibition, institution of calcium channel antagonism with amlodipine provided favorable effects. The goal of the presentstudy was to define potential mechanisms for these effects by measuring left ventricular function, hemodynamics, andneurohormonal system activity in a model of CHF in which amlodipine treatment had been instituted either as amonotherapy or in combination with ACE inhibition. Thirty-two pigs were instrumented to allow measurement ofcardiac index, total systemic resistance index, and neurohormonal activity in the conscious state and assigned to one of fourgroups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n58), (2) amlodipine (1.5 mg z kg21 z d21) and pacing (n58), (3)ACE inhibition (fosinopril 1.0 mg/kg BID) and pacing (n58), and (4) amlodipine and ACE inhibition (1.0 mg z kg21 zd21 and 1.0 mg/kg BID, respectively) and pacing (n58). Measurements were obtained in the normal control state and afterthe completion of the treatment protocols. With rapid pacing, basal resting cardiac index was reduced compared withcontrol values (2.760.2 versus 4.760.1 L z min21 z m22, respectively, P,.05) and increased from rapid pacing–only valueswith either amlodipine or combination therapy (3.760.3 and 4.460.5 L z min21 z m22, respectively, P,.05). Basal restingtotal systemic resistance index was higher in the rapid pacing–only group compared with control values (27316263 versus1721653 dyne z s z cm25 z m2, respectively, P,.05), was reduced with either amlodipine treatment or ACE inhibition(21256226 and 23796222 dyne z s z cm25 z m2, respectively, P,.05), and was normalized with combination therapy.Plasma catecholamines, renin activity, and endothelin levels were increased threefold with rapid pacing. Amlodipine, eitheras a monotherapy or in combination with ACE inhibition, did not result in increased plasma catecholamines and reninactivity compared with the rapid pacing–only group. Furthermore, combination therapy reduced steady state norepi-nephrine and normalized epinephrine levels. The results of the present study demonstrated that monotherapy with eitheramlodipine or ACE inhibition provides beneficial effects in this pacing model of CHF. Combined amlodipine and ACEinhibition provided greater benefit with respect to vascular resistance properties and neurohormonal system activitycompared with either monotherapy. (Hypertension. 1998;31:755-765.)

Key Words: angiotensin-converting enzyme inhibition n amlodipine n heart failure n exercisen ventricular function, left

The development and progression of CHF is associated withsignificant morbidity and mortality.1–3 Current strategies in

the treatment of CHF include LV afterload reduction byvasodilation and/or neurohormonal modulation.4–8 For exam-ple, ACE inhibition has been clearly demonstrated to havebeneficial effects on LV function and survival in patients withdeveloping CHF.4,5 However, clinical trials with short-actingcalcium channel antagonists, which also effectively reducesystemic vascular resistance and thereby LV afterload, havereported deleterious effects in patients with CHF.7–13 Specifi-cally, treatment with the calcium channel antagonist nifedipinein patients with CHF was associated with a worsening ofsymptoms and heightened neurohormonal system activa-

tion.7,13 However, longer-acting compounds of the dihydro-pyridine subclass of calcium channel antagonists, such asamlodipine, have been shown to significantly reduce vascularresistance properties without apparent negative effects on LVmyocardial contractility and neurohormonal activity.14–18 In arecent clinical trial, chronic amlodipine therapy was associatedwith no adverse effects on morbidity and mortality in patientswith severe CHF and appeared to provide favorable effects inpatients with nonischemic etiologies.19 In this past report,however, patients were concomitantly treated with ACEinhibition therapy, and therefore the potential mechanism forthe effects of amlodipine therapy in CHF remains poorlyunderstood.20 Past studies have demonstrated the synergistic

Received August 18, 1997; first decision September 11, 1997; revision accepted October 28, 1997.From the Division of Cardiothoracic Surgery (S.B.K., W.M.M., M.J.C., R.S.K., W.V.H., R.M., F.G.S.), Medical University of South Carolina

(Charleston); and Pfizer Central Research (M.G.D.), Sandwich, UK.Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery and Physiology, Medical University of South Carolina, 171 Ashley Ave,

Charleston, SC 29425-2279.© 1998 American Heart Association, Inc.

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effects of combined amlodipine and ACE inhibition therapy inthe treatment of hypertension.21–24 However, whether and towhat extent combined amlodipine treatment and ACE inhi-bition provides interactive effects with the development ofCHF remain unexplored. Accordingly, the overall goal of thepresent study was to determine the effects of amlodipinetreatment, ACE inhibition, or combination therapy on LVfunction, hemodynamics, and regional blood flow patterns inthe normal state and after the development of CHF.

MethodsRationalePast reports from this laboratory and others have demonstrated thatchronic pacing tachycardia in animals causes progressive changes in LVgeometry and pump function and neurohormonal system activationconsistent with the clinical spectrum of CHF.25–32 Specifically, thedevelopment of pacing-induced CHF is associated with severe LV pumpfailure, heightened catecholamine levels, and increased vascular resistancein several circulatory beds.25–32 In addition, the pacing model of CHF hasbeen successfully used to examine specific systemic and neurohormonalchanges that occur during exercise with the development of CHF.27,29

Accordingly, in the present study, we used a pacing-induced model ofCHF to examine the potentially differential effects of amlodipine treat-ment, ACE inhibition, and combined treatment on LV pump function,systemic hemodynamics, and regional blood flow patterns both at rest andwith treadmill-induced exercise.

The first objective of this study was to select an appropriate dosingstrategy for amlodipine treatment, ACE inhibition, and combinedamlodipine therapy and ACE inhibition. The amlodipine dosage inboth the monotherapy and combination therapy groups was selectedto produce plasma drug levels that have been previously reported tohave pharmacological activity against the vascular smooth muscleL-type calcium channel.15,33,34 For the ACE inhibition dose-determi-nation studies, the criterion for dose selection was to obtain a relativeinhibition of the Ang I pressor response while not producingsignificant differential effects on resting blood pressure. After theidentification of suitable dosing regimens, the second objective of thepresent study was to institute concomitant amlodipine treatment, ACEinhibition, or combination therapy with chronic rapid pacing. After21 days of concomitant treatment and pacing tachycardia, terminalstudies were performed in which LV function and geometry, neuro-hormonal profiles, and regional blood flow patterns were examined.For comparison purposes, age- and weight-matched pigs were usedthat underwent chronic pacing without treatment.

Dose-Selection StudiesNine Yorkshire pigs (20-kg males; Hambone Farms, Orangeburg, SC)were chronically instrumented to measure arterial blood pressure inthe conscious state. The pigs were anesthetized with isoflurane(3%/1.5 L per minute) and nitrous oxide/oxygen (50:50), intubatedwith a cuffed endotracheal tube, and ventilated at a flow rate of 22mL z kg21 z min21 and a respiratory rate of 15 min21. A leftthoracotomy was performed, and the thoracic aorta at the location ofthe hemiazygous crossover was exposed. A catheter connected to avascular access port (model GPV, 9F; Access Technologies) was placed

in the aorta and sutured in place. The access port was buried in asubcutaneous pocket over the thoracolumbar fascia. After a recoveryperiod of 7 to 10 days, the animal was returned to the laboratory foran initial Ang I and Ang II pressor response study. For these studies,the animals were sedated with diazepam (20 mg PO [Valium];Hoffmann-LaRoche) and placed in a custom-designed sling thatallowed the animal to rest comfortably. All studies were performedwith the animals in the conscious state without the additional use ofsedation. The vascular access port was entered with the use of a12-gauge Huber needle (Access Technologies), and basal, restingarterial pressure, and heart rate were recorded. Pressures from thefluid-filled aortic catheter were obtained using an externally calibratedtransducer (Statham P23ID; Gould). The ECG and pressure waveforms were recorded with a multichannel recorder (Hewlett Packard),as well as digitized on computer for subsequent analysis at a samplingfrequency of 100 Hz/channel (80486 processor; Zenith Data Systems).After these baseline measurements, an infusion of Ang I (10 mg; SigmaChemical) was administered, and hemodynamic measurements wererecorded for 5 minutes. After the Ang I pressor test and a 60-minutestabilization period in which hemodynamic indices returned to basalstate values, an Ang II (10 mg; Sigma) infusion was performed in anidentical fashion. The animals were allowed to recover from thepressor studies for 48 hours and then entered into the dose-determi-nation protocols.

Pigs were randomly assigned to receive either the calcium channelantagonist amlodipine (1.5 mg z kg21 z d21), the ACE inhibitorfosinopril (1.0 mg/kg BID), or combination therapy (1.5 mg z kg21 zd21 amlodipine and 1.0 mg/kg fosinopril BID) for 3 days, after whichthe Ang I and Ang II pressor- response studies were repeated. A 3-daydrug treatment interval was selected to achieve steady-state plasmadrug levels. With amlodipine, basal resting blood pressure was reducedcompared with control animals (8564 versus 10363 mm Hg, respec-tively, P,.05). The Ang I (P5.07) and Ang II pressor response wasreduced with amlodipine (Fig 1). The decreased pressor response withamlodipine likely reflected the decrease in vascular smooth muscletone and responsiveness.17 This dose of amlodipine resulted in plasmadrug levels of '18 to 30 ng/mL. With ACE inhibition, minimaleffects were observed on resting blood pressure (9560.3 versus10363 mm Hg, P5.16) and the Ang II pressor response (Fig 1).However, the response after Ang I pressor challenge was significantlyreduced (Fig 1). In preliminary dual-therapy dose-determinationstudies, combined treatment using both monotherapy doses resulted insignificant hypotension and reflex tachycardia. Accordingly, the dose

Figure 1. Percent change in mean arterial pressure after a sep-arate infusion (10 mg) of Ang I or Ang II in conscious pigs. Amlo-dipine (1.5 mg z kg21 z d21) resulted in a decreased Ang I(P5.07) and Ang II (P,.05) pressor response compared withcontrol values. ACE inhibition with fosinopril (1.0 mg/kg BID)caused a significant blunting of the Ang I pressor response(P,.05), with no effect on the Ang II pressor response. Com-bined amlodipine and ACE inhibition (1.0 mg z kg21 z d21 and 1.0mg/kg BID, respectively) reduced the Ang I pressor response(P,.05), whereas the Ang II pressor response remainedunchanged. These monotherapy and combination therapy dos-ing regimens were then administered concomitantly with chronicrapid pacing. ‡P,.05 vs corresponding control values.

Selected Abbreviations and Acronyms

ACE 5 angiotensin-converting enzymeAng I 5 angiotensin I

Ang II 5 angiotensin IICHF 5 congestive heart failure

CI 5 cardiac indexHPLC 5 high-performance liquid chromatography

LV 5 left ventricular, ventricleTSR 5 total systemic resistance index

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of amlodipine was reduced to 1.0 mg z kg21 z d21, and this newcombined dose (1.0 mg z kg21 z d21 amlodipine and 1.0 mg/kgfosinopril BID) was used in further studies. With combined treatment,basal resting blood pressure was reduced from control values (7462versus 10363 mm Hg, respectively, P,.05). Although the Ang IIpressor response remained unchanged, the response after Ang I pressorchallenge was significantly reduced (Fig 1). After the dose-selectionstudies, the effects of these monotherapy and combination therapyprotocols with chronic rapid pacing were examined.

Instrumentation and Experimental DesignThirty-two pigs were chronically instrumented to allow measurementof systemic hemodynamics and neurohormonal profiles in the con-scious state. The pigs were anesthetized and intubated as described.After a left thoracotomy was performed, a catheter connected to avascular access port was placed in the aorta as previously described.Additional catheters connected to vascular access ports were placed inthe pulmonary artery and left atrium in a similar fashion. The accessports were buried in a subcutaneous pocket over the thoracolumbarfascia. A 20-mm-flow probe (Transonics) was placed around thepulmonary artery immediately distal to the pulmonary artery catheter,and the electrical connection was exteriorized through the thoraco-lumbar fascia. A shielded stimulating electrode was sutured onto theleft atrium, connected to a modified programmable pacemaker (8329;Medtronic), and buried in a subcutaneous pocket. The thoracotomywas closed in layers, and the pleural space was evacuated of air. Aftera 14- to 21-day recovery from the surgical procedure, the animalswere returned to the laboratory for baseline studies.

After measurements under normal resting conditions and withexercise, the pacemakers were activated to 240 bpm for a period of 21days. It has been demonstrated in this laboratory that this rate andduration of chronic rapid atrial pacing reliably cause LV dilation andpump dysfunction.25,28,30,32 In the present study, the pigs were ran-domly assigned to one of four groups: (1) rapid atrial pacing (240 bpm)for 3 weeks (n58), (2) concomitant amlodipine and rapid pacing(n58), (3) concomitant ACE inhibition and rapid pacing (n58), and(4) concomitant ACE inhibition and amlodipine and rapid pacing(n58). The drug treatment protocols were begun at the initiation ofpacing and continued for the entire 21-day pacing protocol. Cardiacauscultation and electrocardiograms were performed frequently duringthe pacing protocol to ensure proper operation of the pacemaker andthe presence of 1:1 conduction. At the completion of the pacingprotocol, the animals were returned to the laboratory, and thepacemaker was deactivated. After a 1-hour stabilization period, restingand exercise data were collected again. After the final set of measure-ments, the animals were killed with an overdose of pentobarbital(1000 mg), and tissue was harvested. All animals were treated andcared for in accordance with the National Institutes of Health “Guidefor the Care and Use of Laboratory Animals” (National ResearchCouncil, Washington, 1996).

Measurements at Rest and With ExerciseOn the day of study, the animals were sedated with diazepam (20 mgPO) and placed in a custom-designed sling that allowed the animals torest comfortably. All experiments were performed with the animals inthe conscious state without additional use of sedation. An ECG wasestablished, and the pacemaker was deactivated (pacing groups only).After a 60-minute stabilization period, two-dimensional and M-modeechocardiographic studies (ATL Ultramark VI 2.25-MHz transducer)were used to image the LV from the right parasternal approach.25,28,32

LV fractional shortening was calculated as (end-diastolicdimension2end-systolic dimension)/end-diastolic dimension and ex-pressed as a percentage. The vascular access ports were entered withthe use of a 12-gauge Huber needle, and basal resting pressures andheart rate were recorded and digitized for subsequent computeranalysis, as previously described. The flow probe was connected to adigital flowmeter (T106; Transonics) as well as digitized to computerfor processing. With the digitized flow signal, stroke volume wascomputed on a beat-to-beat basis and averaged from a minimum of 25beats. Cardiac output and stroke volume were indexed to body surfacearea (m2) computed using the relation: body surface area59.9p(body

weightp1000)2/3p1024.35 Pulmonary vascular resistance index (dyne z sz cm25 z m2 ) was computed as [(mean pulmonary artery2left atrialpressure)/cardiac index]p80. A direct measurement of right atrialpressure was not available in this chronic preparation, and thereforetotal systemic resistance index (dyne z s z cm25 z m2 ) was computed as(mean aortic pressure)/cardiac index)p80. From the aortic catheter, 30mL of blood was drawn into chilled tubes containing EDTA (1.5mg/mL) and centrifuged (2000g, 10 minutes, 4°C). The plasma wasplaced in separate tubes, frozen in liquid nitrogen, and stored in280°C for subsequent measurements of neurohormonal profiles oramlodipine levels. Samples were also drawn from the pulmonaryartery and atrial catheters and immediately measured for oxygensaturation and hemoglobin content (CO-Oximeter; Instruments Lab-oratory). Oxygen content was calculated as the product of hemoglo-bin concentration and oxygen saturation, which was then multipliedby the constant 1.34 to obtain oxygen values in mL/dL. Systemicoxygen consumption (V̇O2 ) was computed as the difference in arterialand pulmonary artery oxygen content multiplied by cardiac index (indL z min21 z m22 ).

After collection of the hemodynamic data and blood samples, fluores-cent microspheres (33106; Molecular Probes) of specific emission spectrawere injected into the left atrium. A reference aortic sample waswithdrawn at a rate of 7 mL/min, which was initiated 5 seconds beforeinjection and continued for 120 seconds after injection. The pigs werethen placed in custom-designed vests that protected all connections. Theanimals were positioned in a modified treadmill containing balanced and

Figure 2. Echocardiographic measurements of LV end-diastolicdimension, fractional shortening, and peak wall stress in con-scious pigs under ambient resting conditions. After 21 days ofchronic rapid pacing, LV end-diastolic dimension increased,fractional shortening decreased, and LV peak wall stressincreased from control values in the rapid pacing–only groupand in all treatment groups. With either amlodipine monotherapyor combination therapy, LV end-diastolic dimension decreased,fractional shortening increased, and LV peak wall stressdecreased from rapid pacing–only values. With ACE inhibition,LV end-diastolic dimension was reduced from rapid pacing–only, amlodipine monotherapy, and combination therapy values.With either ACE inhibition or combination therapy, LV peak wallstress was reduced from amlodipine monotherapy values.pP,.05 vs control. 1P,.05 vs rapid pacing only. §P,.05 vsrapid pacing and amlodipine. ¶P,.05 vs rapid pacing and ACEinhibition.

Kribbs et al 757



calibrated pressure transducers. The pigs were exercised at a treadmillwork load of 3 mph at an 15-degree incline for a 10-minute interval. Inpreliminary studies from this laboratory, consistent with past reports,36 thistreadmill protocol resulted in a near-maximal heart rate for pigs. Duringthe last minute of exercise, hemodynamics and blood samples werecollected, and microspheres were delivered.

Neurohormonal Profiles and Drug LevelsThe plasma samples were assayed for renin activity, endothelinconcentration, catecholamine levels, and amlodipine levels. Plasmarenin activity was determined by computing Ang I production usinga radioimmunoassay procedure (ARUP Laboratories). This assaysystem was associated with a maximum of a 2% coefficient ofvariation. For the endothelin assays, the plasma was first eluted over acation exchange column (C-18 Sep-Pak; Waters Associates) and thendried by vacuum-centrifugation. The samples were reconstituted in0.02 borate buffer, and a high-sensitivity radioimmunoassay wasperformed (RPA 545; Amersham Life Science Inc). The recoveryfrom the extraction procedure was 7565% based on plasma spikedstandards (4 to 20 fmol/mL). The interassay variation was 10% and theintra-assay variation was 9% for the endothelin radioimmunoassayprocedure. Plasma norepinephrine and epinephrine levels were mea-sured using HPLC and normalized to pg/mL of plasma; this assaysystem was associated with a ,4% coefficient of variation. Plasmalevels of amlodipine were determined through HPLC as describedpreviously.37

Regional Blood Flow MeasurementsAll of the tissues samples were fixed in 10% formaldehyde tofacilitate sectioning. The midregion of the LV free wall wasseparated into endocardial and epicardial layers weighing '3 geach. Samples of '3 to 5 g were also collected and prepared fromthe basal regions of the lung, kidney, latissimus dorsi, and gluteusmaximus. The tissue samples were carefully weighed and thendigested with the use of a potassium hydroxide solution asdescribed previously.38,39 The aortic reference samples were ex-tracted using an identical digest solution. The fluorescence of theextracted samples were then determined with spectrofluorimetry(Gilford Fluoro IV). The fluorescent microspheres used in thisstudy with respect to excitation/emission characteristics wereblue-green, 428/457 nm; orange, 534/550 nm; red, 580/594 nm;and scarlet, 650/674 nm. These fluorescent microspheres werechosen because a spectral scan that conformed to a gaussiandistribution could be obtained uniformly, minimal spectral cross-over occurred, and an equivalent sensitivity was provided.39 Re-gional blood flow computations were determined using the stan-dard formula Qm5(Ar3Am)/Qr, where Qm is the blood flow(mL/min), Ar is the fluorescence of the aortic reference samples, Am

is the fluorescence of the tissue sample, and Qr is the withdrawalrate of the reference sample. Final blood flow values werenormalized to sample weight and expressed as mL z min21 z g21.Coronary vascular resistance was determined as the mean aorticpressure divided by LV myocardial blood flow and expressed asdyne z s z cm25 z g.40

TABLE 1. Systemic Hemodynamics and LV Function With Pacing-Induced Heart Failure: Effects of Amlodipine, ACE Inhibition, orCombined Amlodipine and ACE Inhibition During the Progression of Heart Failure

Control Rapid Pacing¶Rapid Pacing and

Amlodipine**

Rest Exercise Rest Exercise Rest Exercise

Heart rate, bpm 11863 26365\ 15367* 21469*\ 13966* 21967*\

Respiratory rate, min21 3362 6462\ 5364* 8766*\ 5166* 7265†\

Pump function

Stroke index, mL/m2 41.361.7 39.561.4 18.061.5* 31.661.9*\ 28.162.3*† 35.062.9\

Cardiac index, L z min21 z m22 4.760.1 10.460.4\ 2.760.2* 6.960.4*\ 3.760.3*† 7.660.6*\

Pressure, mm Hg

Aorta 9962 10862\ 9062* 8762* 9464 8862*

Pulmonary artery 1861 2761\ 3564* 3863* 3361* 3662*

Left atrium 1161 1061 2863* 2662* 2262*† 1863*†

Resistance index, dyne z s z cm25 z m2

Pulmonary 126613 134615 235673* 147632\ 251643* 189634*

Total systemic 1721653 883639\ 27316263* 1031684\ 21256226*† 971673\

Neurohormone

Norepinephrine, pg/mL 136611 881698\ 6986171* 337761406*\ 427689* 17186180*†\

Epinephrine, pg/mL 82619 226627\ 252647* 6196242*\ 259641* 426665*†\

Renin activity, ng z mL21 z h21 4.360.4 9.261.1\ 32.4610.1* 30.267.6* 13.563.5*† 22.664.9*

Endothelin, fmol/mL 3.160.2 3.760.2\ 10.261.0* 11.461.9* 6.861.0*† 6.661.1*†

Sample size, n 32 32 8 8 8 8

Values are mean6SEM.*P,.05 vs control.†P,.05 vs rapid pacing only.‡P,0.05 vs rapid pacing and amlodipine.§P,.05 vs rapid pacing and ACE inhibition.\P,.05 vs resting state.¶Rapid pacing: 21 days of chronic rapid pacing at 240 bpm.**Rapid pacing and amlodipine: 1.5 mg/kg amlodipine SID.††Rapid pacing and ACE inhibition: 1 mg/kg fosinopril BID.‡‡Rapid pacing and amlodipine/ACE inhibition: 1 mg/kg amlodipine SID and 1 mg/kg fosinopril BID.




Data AnalysisIndexes of LV function, systemic hemodynamics, and regional bloodflow were compared among the treatment groups using ANOVA forrepeated measures. If the ANOVA revealed significant differences,pairwise tests of individual group mean values were compared usingtwo-tailed Bonferroni probabilities. For comparisons of neurohor-monal profiles, the Student-Newman-Keuls test was used. All statis-tical procedures were performed using BMDP statistical software.Results are presented as mean6SEM, and values of P,.05 wereconsidered to be statistically significant.

ResultsAfter 3 weeks of chronic rapid pacing, all pigs in the untreatedgroup demonstrated clinical symptoms consistent with CHF,including tachypnea and the development of ascites andperipheral edema during the last week of rapid pacing. In thepigs that underwent either amlodipine monotherapy, ACEinhibition monotherapy, or combination therapy, these clinicalsymptoms of CHF were not as readily apparent. In theconcomitant amlodipine and rapid pacing group, plasma am-lodipine levels were 2566 ng/mL, and in the combinationamlodipine and ACE inhibition group, plasma amlodipinelevels were 2263 ng/mL.

LV Function With Chronic Rapid Pacing: Effectsof Monotherapy and Combination Therapy

Resting StateLV size and function were assessed by echocardiography underbasal resting conditions in the rapid pacing–only group and allthree treatment groups (Fig 2). In the rapid pacing–onlygroup, LV end-diastolic dimension increased, fractional short-ening decreased, and LV peak wall stress increased compared

with the control state. In the amlodipine monotherapy group,LV end-diastolic dimension decreased, fractional shorteningincreased, and LV peak wall stress decreased, compared withrapid pacing only values. In the ACE inhibition group, LVend-diastolic dimension and LV peak wall stress decreasedfrom rapid pacing only values. In the combination therapygroup, LV end-diastolic dimension decreased, fractional short-ening increased, and LV peak wall stress decreased from rapidpacing only values. In the ACE inhibition group, LV end-di-astolic dimension was reduced from either amlodipine mono-therapy or combination therapy values. In the ACE inhibitionand combination therapy groups, LV peak wall stress wasreduced from amlodipine monotherapy values.

Figure 3. The absolute change from resting values for plasmanorepinephrine, epinephrine, renin activity, and endothelin withtreadmill exercise. The relative rise in plasma norepinephrinewas increased from the control state in the rapid pacing–only,amlodipine monotherapy, and combination therapy groups. Witheither amlodipine or ACE inhibition monotherapy, the relativerise in plasma norepinephrine was reduced from rapid pacing–only. In the rapid pacing–only group, the relative rise in plasmaepinephrine was increased from the control state. In all treat-ment groups, the relative change in plasma epinephrine wasreduced from the rapid pacing–only group. With ACE inhibition,the relative change in plasma epinephrine was blunted. In therapid pacing–only group, the relative change in plasma reninactivity was reduced. In all treatment groups, the relative rise inplasma renin activity was increased above that of the rapid pac-ing–only group. With monotherapy treatment, the relativechange in plasma endothelin with exercise was blunted. In thecombination therapy group, the relative change in plasma endo-thelin was reduced from control, rapid pacing–only, and ACEinhibition groups. pP,.05 vs control. 1P,.05 vs rapid pacingonly. §P,.05 vs rapid pacing and amlodipine. ¶P,.05 vs rapidpacing and ACE inhibition.

TABLE 1. Continued

Rapid Pacing and ACEInhibition††

Rapid Pacing andAmlodipine/ACE Inhibition‡‡

Rest Exercise Rest Exercise

146610* 22766*\ 13965* 235614*†\

3963*†‡ 6464†\ 3863†‡ 6768†\

20.062.1*‡ 29.261.5*‡\ 31.863.4*†§ 35.961.7†§

2.860.2*‡ 6.660.4*\ 4.460.5†§ 8.460.6*†§\

8065*†‡ 7464*†‡ 7663*†‡ 8263*

2963*† 2962†‡ 3062*† 3763*§\

2163*† 1262†‡\ 1861*† 1663*†

282656* 226646* 240651* 228641*

23796222*† 911659\ 15066170†‡§ 809655†\

5996138* 17966277*†\ 273648*†§ 25586732*\

247655* 240649†‡ 153638‡ 346668†\

14.962.5*† 20.364.3* 19.561.7*† 25.765.1*

7.661.7*† 7.761.3*† 7.661.5*† 6.461.2*†

8 8 8 8

Kribbs et al 759



Hemodynamic indices measured in the resting awakestate for the rapid pacing– only group and all three treatmentgroups are summarized in Table 1. Ambient resting heartrate was increased by '30% in all rapid pacing groupscompared with the control state. Stroke volume index wasreduced from control values in the rapid pacing– only groupand in all treatment groups. In the amlodipine monotherapyand combination therapy groups, stroke volume index wasincreased from rapid pacing– only values. Cardiac index wasreduced from the control state in the rapid pacing– only andmonotherapy treatment groups. With either amlodipinemonotherapy or combination therapy, cardiac index wasincreased from rapid pacing– only values. Moreover, withcombination therapy, cardiac index was not significantlydifferent from control values (P5.11). Resting aortic pres-sure was decreased from control values in the rapid pacing–only group. In the ACE inhibition and combination therapygroups, aortic pressure was reduced from control, rapidpacing– only, and amlodipine monotherapy values. Pulmo-nary vascular resistance index was increased in all rapidpacing groups compared with the control state. In themonotherapy and combination therapy groups, total sys-temic resistance index was reduced from rapid pacing– onlyvalues. Further, total systemic resistance index was reducedin the combination therapy group to a greater degree thanmonotherapy values.

Treadmill ExerciseChanges in LV pump function and hemodynamics withtreadmill-induced exercise are summarized in Table 1. In all

groups, respiratory rate significantly increased with tread-mill exercise compared with resting values. In the normalcontrol state, heart rate increased by more than twofoldfrom resting values. In all rapid pacing groups, heart rateincreased significantly with exercise from resting values butremained lower than that achieved in the normal controlstate. Stroke volume index remained unchanged fromresting values with treadmill exercise in the normal controlstate, but cardiac index increased by more than twofold. Inthe rapid pacing– only group and both monotherapy treat-ment groups, treadmill exercise resulted in a significantincrease in stroke volume index and cardiac index fromresting values. In the combination therapy group, cardiacindex significantly increased with exercise and were higherthan corresponding rapid pacing– only and ACE inhibitionvalues. Pulmonary vascular resistance index fell in the rapidpacing– only group with treadmill exercise but remainedelevated from control values in all the treatment groups.Total systemic resistance index decreased in all groups withtreadmill exercise. Total systemic resistance index wasreduced in the combination therapy group compared withrapid pacing– only values. In the normal control state,systemic oxygen consumption (V̇O2) increased by more thanfourfold with treadmill-induced exercise (19969 versus862655 mL of O2 z min21 z m22, P,.05). In the rapidpacing group, V̇O2 was reduced from control values both atrest and with treadmill exercise (165611 versus 602634 mLof O2 z min21 z m22, P,.05). In all three treatment groups,basal resting V̇O2 was similar to the normal control state.

TABLE 2. Blood Flow With Pacing-Induced Heart Failure: Effects of Amlodipine, ACE Inhibition, or Combined Amlodipine andACE Inhibition During the Progression of Heart Failure

Control Rapid Pacing¶Rapid Pacing and

Amlodipine**

Rest Exercise Rest Exercise Rest Exercise

LV myocardium, mL z min21 z g21

Endocardial flow 2.06613 8.6560.51\ 1.5260.16* 5.4560.56*\ 1.7960.10 6.7560.36*†\

Epicardial flow 1.66611 7.46641\ 1.2160.11* 3.6360.28*\ 1.6660.09† 6.0360.43*†\

Average myocardial flow 1.8660.12 8.0560.45\ 1.3760.13* 5.0960.64*\ 1.7360.09† 6.396*0.37*†\

Coronary vascular resistance (3103 dyne z s z

cm25 z g)46506243 1191680\ 56566748* 15396196\ 44476311† 1126671†\

Blood flow to regional beds, mL z min21 z g21

Lung 0.960.1 2.964\ 0.260.1* 0.860.3*\ 0.560.1*† 2.160.6†\

Kidney 4.960.3 7.860.5\ 2.660.5* 5.761.2*\ 2.160.3* 5.360.8*\

Latissimus dorsi 0.3760.02 1.7460.17\ 0.4160.17 0.6660.12* 0.4560.12 0.6860.16*

Gluteus maximus 0.3760.02 1.7760.17\ 0.3960.15 0.8560.21*\ 0.4560.11 0.7560.18*

Sample size, n 32 32 8 8 8 8

Values are mean6SEM.*P,.05 vs control.†P,.05 vs rapid pacing only.‡P,.05 vs rapid pacing and amlodipine.§P,.05 vs rapid pacing and ACE inhibition.\P,.05 vs resting state.¶Rapid pacing: 21 days of chronic rapid pacing at 240 bpm.**Rapid pacing and amlodipine: 1.5 mg/kg amlodipine per day.††Rapid pacing and ACE inhibition: 1 mg/kg BID fosinopril.‡‡Rapid pacing and amlodipine/ACE Inhibition: 1 mg/kg per day amlodipine and 1 mg/kg BID fosinopril.




However, with treadmill exercise, V̇O2 was equivalent torapid pacing– only values.

Neurohormonal Activity: Effects of Monotherapyand Combination Therapy

Resting StatePlasma neurohormonal profiles in the normal control state andin the rapid pacing groups are summarized in Table 1. Underbasal resting conditions, plasma norepinephrine increased fromcontrol values in all rapid pacing groups. With combinationtherapy, plasma norepinephrine was reduced from rapid pac-ing–only and ACE inhibition values. In the rapid pacing–onlyand monotherapy treatment groups, plasma epinephrine waselevated from the control state. In contrast, with combinationtherapy, plasma epinephrine was similar to control values(P5.14). In all rapid pacing groups, plasma renin activity andendothelin levels were increased from control values. Plasmarenin activity and endothelin levels were reduced from rapidpacing–only values in all treatment groups.

Treadmill ExerciseThe effects of treadmill exercise on plasma neurohormones aresummarized in Table 1. In general, with treadmill exercise,plasma catecholamines were increased from the resting state inall groups. In the monotherapy treatment groups, plasmanorepinephrine was reduced from rapid pacing–only values. Inall treatment groups, plasma epinephrine was reduced fromrapid pacing–only values. With treadmill exercise, plasmarenin activity and endothelin levels remained elevated fromnormal control values in all rapid pacing groups. The relativechange in neurohormonal activity from resting values withtreadmill exercise is summarized in Fig 3. With either amlo-dipine monotherapy or ACE inhibition, the relative rise inplasma norepinephrine was reduced from rapid pacing–onlyvalues. In all treatment groups, the relative change in plasmaepinephrine was reduced from the rapid pacing–only group,whereas the relative rise in plasma renin activity was increasedabove rapid pacing values. With combination therapy, the

relative change in endothelin was reduced from control, rapidpacing–only, and ACE inhibition values.

Regional Blood Flow: Effects of Monotherapyand Combination Therapy

Resting StateRegional blood flow values to specific circulatory beds in thenormal control state and in all rapid pacing groups aresummarized in Table 2. Under ambient resting conditions, LVmyocardial blood flow was reduced in the rapid pacing–onlygroup compared with normal control values. With amlodipinemonotherapy, LV myocardial blood flow was normalized,whereas in the ACE inhibition and combination therapygroups, LV myocardial blood flow values remained reducedfrom the normal control state. Coronary vascular resistance wasincreased in the rapid pacing–only group compared withcontrol values, but in all treatment groups, coronary vascularresistance was normalized. Pulmonary parenchymal flow wasreduced by .50% from normal control values in the rapidpacing group. In all treatment groups, pulmonary parenchymalblood flow was increased from rapid pacing–only values.Renal blood flow was reduced from the normal control state inall rapid pacing groups and was not influenced by drugtreatment. Representative resting skeletal muscle blood flow,as determined by blood flow to the latissimus dorsi and gluteusmaximus, was unchanged from normal control values in allrapid pacing groups.

Treadmill ExerciseChanges in regional blood flow distribution after treadmillexercise in the normal control state and in all rapid pacinggroups are summarized in Table 2. LV myocardial blood flowincreased by more than fourfold in the normal control statewith treadmill exercise. In the rapid pacing group, LV myo-cardial blood flow increased with exercise but was 37% lowerthan normal control values. LV myocardial blood flow re-mained reduced from control values in all treatment groups.With amlodipine monotherapy, LV myocardial flow wasincreased from rapid pacing–only values. Coronary vascularresistance was reduced with treadmill exercise but remainedincreased from control values in either the ACE inhibition orcombination therapy groups. With amlodipine monotherapy,coronary vascular resistance was reduced from rapid pacing–only values. Pulmonary parenchymal flow increased by three-fold in the normal control state with treadmill exercise and wassignificantly blunted in the rapid pacing group. In the amlo-dipine monotherapy and combination therapy groups, pulmo-nary parenchymal flow was normalized to normal control statevalues. Renal blood flow increased by .50% in the normalcontrol state with exercise. In all rapid pacing groups, renalblood flow remained reduced from normal control values.Skeletal muscle blood flow increased by more than fivefold inthe control state and was significantly reduced in all of the rapidpacing groups.

DiscussionACE inhibition has been demonstrated to provide beneficialeffects on LV function and survival in patients with developingCHF.4,5 However, clinical trials with short-acting calcium

TABLE 2. Continued

Rapid Pacing and ACEInhibition††

Rapid Pacing andAmlodipine/ACE Inhibition‡‡

Rest Exercise Rest Exercise

1.6960.24 4.4860.48*‡\ 1.2560.08*‡ 4.9360.51*‡\

1.2060.09*‡ 3.5260.39*‡\ 1.2160.08*‡ 4.3860.50*‡\

1.4460.16* 4.0060.41*‡\ 1.2360.08*‡ 4.6560.49*‡\

47456496 15766144*‡\ 49476358 14796105*‡\

0.660.1*† 1.460.2*\ 0.560.1*† 2.560.7†\

2.960.4* 4.760.8*\ 2.260.2* 4.165*\

0.4560.11 1.006.14*\ 0.3860.04 1.0360.38*\

0.4660.11 0.8960.12*\ 0.3160.05 0.796.09*\

8 8 8 8

Kribbs et al 761



channel antagonists in patients with CHF have reporteddeleterious effects, including heightened neurohormonal sys-tem activity.7–13 Therefore, the therapeutic potential of calciumchannel antagonists in the setting of developing CHF remainscontroversial. In a recent clinical trial, the longer-actingcalcium channel antagonist amlodipine was associated with noadverse effects on morbidity and mortality in patients withsevere CHF and appeared to provide beneficial effects inpatients with nonischemic etiologies.19 In this past report,however, amlodipine was administered in the background ofACE inhibition therapy.19 Therefore, combination therapywith amlodipine and ACE inhibition may provide additiveand/or interactive effects with developing CHF. This issue wasaddressed in the present study, which examined LV pumpfunction, hemodynamics, neurohormonal profiles, and re-gional blood flow distribution in an animal model of pacing-induced CHF. The unique and significant findings from thepresent study were twofold. First, in the resting state, indexesof LV function were improved from rapid pacing–only valueswith either amlodipine monotherapy or combination therapy.Furthermore, in the resting state, combination therapy nor-malized cardiac index and reduced total systemic resistanceindex to a greater degree than either amlodipine monotherapyor ACE inhibition alone. However, with treadmill exercise,LV pump performance was not improved with any treatmentmodality. Second, in the resting state, combination therapyreduced plasma norepinephrine by 50% from rapid pacing–only and ACE inhibition groups and epinephrine by '40%from rapid pacing–only and amlodipine monotherapy valuesand significantly blunted the relative rise in plasma epinephrineand endothelin with treadmill exercise. These results suggestthat combination therapy with amlodipine and ACE inhibitionwith developing CHF reduced vascular resistive propertieswithout an exacerbation of neurohormonal system activity.

LV Function and Systemic HemodynamicsPast studies have demonstrated that monotherapy with eitheramlodipine or ACE inhibition during the development ofCHF provided beneficial effects on LV function and hemody-namics.4,5,41 Specifically, ACE inhibition has been shown toimprove LV function and survival in patients with developingCHF.4,5 Furthermore, Weinberg et al41 demonstrated thatchronic administration of amlodipine normalized LV end-di-astolic pressure in a model of LV hypertrophy. Consistent withpast reports,25–32 chronic rapid pacing caused LV dilation andpump dysfunction. In the present study, concomitant amlo-dipine monotherapy, ACE inhibition, or combination therapyinstituted during chronic rapid pacing reduced the degree ofLV dilation. With either amlodipine monotherapy or combi-nation therapy, indexes of LV pump function were improvedin the basal resting state compared with pacing CHF values. Toour knowledge, this was the first study to examine the directeffects of combined amlodipine and ACE inhibition therapywith the development of a CHF process. With combinationtherapy instituted during chronic rapid pacing, cardiac indexwas normalized. Under resting conditions, mean aortic pres-sure was not different from control values in the amlodipinemonotherapy group, whereas in the ACE inhibition andcombination treatment groups, mean aortic pressure was re-

duced from both control and rapid pacing–only values. In thecombination treatment group, mean aortic pressure was similarto ACE inhibition values, but total systemic resistance indexwas reduced to a greater degree compared with either mono-therapy value. Thus, likely contributory mechanisms for theimproved cardiac index with combination therapy in thismodel of CHF include decreased LV afterload as demonstratedby decreased peak wall stress and reduced total systemicresistance index.

Neurohormonal System ActivityIn the present study, the development of pacing-induced CHFwas associated with an approximately threefold increase inplasma catecholamines, renin activity, and endothelin levels.Past studies have demonstrated that the use of short-actingcalcium channel antagonists in the setting of CHF was associ-ated with heightened neurohormonal activity as demonstratedby increased plasma catecholamines and renin activity.10,13 Inthe present study and in contrast to these past reports, chronicamlodipine as either a monotherapy or in combination withACE inhibition did not result in increased plasma catechol-amines and renin activity. Furthermore, in the resting state,combination therapy reduced plasma norepinephrine fromrapid pacing–only values and normalized plasma epinephrinelevels. With either amlodipine monotherapy, ACE inhibition,or combination therapy plasma renin activity was decreasedfrom rapid pacing–only values. However, with treadmillexercise, the relative change in plasma renin activity wasincreased from rapid pacing–only values; likely reflecting aglobal reduction in renal perfusion pressure. With treadmillexercise, the relative change in plasma norepinephrine washigher in the combination therapy group that may have beensecondary to sympathetic activation due to a reduction in thetotal systemic resistance index. However, this issue remainsspeculative and warrants further investigation. With the devel-opment of pacing-induced CHF, plasma levels of the potentvasoactive peptide endothelin were significantly elevated.With either amlodipine monotherapy, ACE inhibition, orcombination therapy, plasma endothelin levels were reducedfrom pacing CHF values; both at rest and with treadmillexercise. Interestingly, with treadmill exercise, the relative risein plasma endothelin appeared to be blunted to a greater degreewith combination therapy compared with either monotherapytreatment. In patients with CHF, increased levels of plasmaendothelin have been correlated with the degree of LVdysfunction and have been demonstrated to influence pulmo-nary and systemic vascular resistance.42–44 Kiowski et al43

reported that acute administration of an endothelin receptorantagonist reduced systemic and pulmonary vascular resistancein patients with CHF. Therefore, the relative reduction inplasma endothelin levels with either amlodipine monotherapyor combination therapy likely contributed to the reduced totalsystemic resistive properties in this model of CHF. The directmechanistic relationship between endothelin levels, vascularresistance, and amlodipine therapy with the development ofCHF warrants further investigation. Nevertheless, an impor-tant finding of the present study was that amlodipine treat-ment, either as a monotherapy or in combination with ACE




inhibition, was not associated with significant neurohormonalactivation in this model of CHF.

Regional Blood Flow DistributionConsistent with past reports,28,45 the present results demon-strated that the development of pacing-induced CHF wasassociated with a significant reduction in myocardial bloodflow at rest. This reduction in myocardial blood flow occurredin the absence of a physical obstruction to flow and thereforewas likely due to changes in vascular resistive properties in thecoronary vasculature. It has been reported previously that inpatients with nonischemic cardiomyopathy, abnormalities inmyocardial oxygen delivery/demand exist.46 Thus, althoughremaining speculative, the global reduction in LV myocardialblood flow may be a contributory factor toward the diminishedLV performance with pacing-induced CHF. In the presentstudy, amlodipine monotherapy normalized resting myocardialblood flow. With either ACE inhibition or combinationtherapy, LV myocardial blood flow was similar to pacing CHFvalues. However, in the ACE inhibition and combinationtherapy groups, aortic pressure was reduced despite normalizedcoronary vascular resistance. These results suggest that thepersistent reduction in LV myocardial blood flow with eitherACE inhibition or combination therapy was likely due to asignificant reduction in coronary driving pressure. To morecarefully examine LV myocardial blood flow under a physio-logical stress, measurements were also performed during tread-mill exercise. In the rapid pacing–only and concomitanttreatment groups, relative LV myocardial blood flow wasincreased with treadmill exercise but remained lower thancontrol values. A blunted response to endothelium-mediatedvasodilation as well as to adenosine has been reported with thedevelopment of CHF.28,47 In addition, it has been suggestedthat the diminished coronary flow reserve with pacing-inducedCHF may be due to increased LV myocardial wall stress duringdiastole.45 Thus, in the present study, the persistent reductionin LV myocardial blood flow, regardless of treatment modality,was likely due to additional vasoconstrictive and hemodynamicinfluences.

With the development of pacing-induced CHF, pulmonaryparenchymal flow was significantly reduced both at rest andwith treadmill-induced exercise. In all treatment groups, rest-ing pulmonary parenchymal flow was increased from pacingCHF values. Tsutamoto et al44 demonstrated that in patientswith severe CHF, endothelin spillover in the pulmonarycircuit occurred and correlated to the degree of pulmonaryvascular resistance. Thus, with either amlodipine mono-therapy, ACE inhibition, or combination therapy, a likelycontributory mechanism for increased resting pulmonary pa-renchymal flow was decreased circulating endothelin levels.With treadmill exercise, pulmonary parenchymal flow wasnormalized with either amlodipine monotherapy or combina-tion therapy but not with ACE inhibition. Roy et al48

demonstrated that Ang II–mediated vasoconstriction was de-creased in the pulmonary vasculature with pacing CHF. Thus,the effectiveness of ACE inhibition in reducing pulmonaryvascular resistance may be diminished with the development ofCHF. Although increased from rapid pacing values, restingpulmonary parenchymal blood flow remained reduced from

control values in all treatment groups. Thus, in the presentstudy, inherent defects in the vasodilatory properties of thebronchial smooth muscle may have occurred with pacingCHF, which in turn contributed to persistent defects inbronchial flow regardless of treatment modality. With thedevelopment of pacing CHF, renal blood flow was reducedfrom normal control values; both at rest and with exercise.Concomitant treatment with either amlodipine monotherapy,ACE inhibition, or combination therapy did not improve renalblood flow at rest or with exercise. Nevertheless, thesetreatment regimens did not compromise renal blood flow.With treadmill exercise, skeletal muscle blood flow was re-duced with pacing CHF. This observation is consistent withpast experimental and clinical reports in which abnormalities inskeletal muscle perfusion were noted during exercise.27,49,50

Chronic treatment with amlodipine monotherapy, ACE inhi-bition, or combination therapy did not increase skeletal muscleblood flow from CHF values during exercise. With exercise,significant vascular smooth muscle vasodilation occurs primar-ily due to the local release of a number of metabolites,51 and thevascular response to these local metabolites has been reportedto be abnormal with CHF.52,53 These abnormalities in localvasodilatory responses at the level of the muscle vasculaturelikely superseded any potential beneficial effects of concomi-tant amlodipine monotherapy, ACE inhibition, or combina-tion treatment.

Study Limitations and SummaryThe present project used a model of chronic rapid pacing thatproduced changes in LV functional and neurohormonal char-acteristics that appeared similar to that of the clinical spectrumof CHF.25–32 This model of CHF provided an opportunity toexamine the effects of pharmacological interventions in theabsence of confounding influences that may be encountered inclinical studies. However, it must be recognized that anyanimal model will not fully represent the complex clinicalspectrum of CHF. Specifically, the changes in LV myocardialstructure that occur with pacing-induced CHF are not similarto clinical forms of CHF due to chronic ischemia or hyper-tensive disease. Thus, extrapolation of the findings of thisproject to clinical forms of CHF should be done with caution.In the present study, the ACE-inhibition dose was selectedbased on attenuating the Ang I pressor response while notproducing a significant hypotensive effect. Thus, whetherhigher doses of ACE inhibition and amlodipine, either as amonotherapy or in combination, may influence hemodynamicand neurohormonal profiles with the development of CHFwas not addressed with the present experimental design. Theselimitations notwithstanding, the present study demonstratedthat with CHF, combined amlodipine and ACE inhibitioneffectively improved indexes of LV pump function and vascu-lar resistive properties without an exacerbation of neurohor-monal system activity. In a past clinical study of patients withsevere CHF undergoing ACE inhibition treatment, the insti-tution of concomitant amlodipine therapy was not associatedwith increased hemodynamic compromise or mortality butrather may have provided favorable effects in a subset ofpatients.19 The results of the present study demonstrated thatmonotherapy with either amlodipine or ACE inhibition pro-

Kribbs et al 763



vides beneficial effects in this pacing model of CHF. Com-bined amlodipine and ACE inhibition provided greater benefitwith respect to vascular resistance properties and neurohor-monal system activity compared with either monotherapy.

AcknowledgmentsThis work was supported by National Institutes of Health grantR01-HL-56603, a Grant-in-Aid from the American Heart Associa-tion, and a Basic Research Grant from Pfizer Inc. Dr Kribbs is aMedical Student Research Fellow of the American Heart Association.Dr Spinale is an Established Investigator of the American HeartAssociation. The authors wish to express their appreciation to JenniferHendrick, Mark Little, and Douglas Kugley for their excellenttechnical and administrative assistance in this project.

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Kribbs et al 765



Michael G. Dodd, Rupak Mukherjee and Francis G. SpinaleScott B. Kribbs, William M. Merritt, Mark J. Clair, R. Stephen Krombach, Ward V. Houck,

Therapy With Pacing-Induced Heart FailureAmlodipine Monotherapy, Angiotensin-Converting Enzyme Inhibition, and Combination

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 1998 American Heart Association, Inc. All rights reserved.

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Amlodipine Monotherapy, Angiotensin-Converting Enzyme Inhibition, and Combination Therapy With Pacing-Induced Heart Failure