FOCUS: Heart Failure

BRIEF REVIEWPacing-Induced Heart Failure:Past Lessons and Future ProspectsFrancis G. Spinale, MD, PhD, Medical University of South Carolina, Charleston, SouthCarolina

Historical Background

I n the early part of this century, it became apparent thattachyarrhythmias, such as chronic tachycardia, maycontribute to the development and progression of car-

diac enlargement and congestive heart failure (CHF) (1).These reports provided the basis for the hypothesis thattachycardia is an etiologic factor for CHF. It was not until1962 when Whipple et al. (2) clearly demonstrated thatchronic tachycardia directly caused CHF. Using a modifiedexternal pacemaker, these investigators induced chronictachycardia in dogs and documented changes in systemichemodynamics consistent with the physiological profile ofCHF (2). Over this past decade, the model of pacing tachy-cardia has been used with greater frequency in order todetermine mechanisms underlying the left ventricular (LV)pump dysfunction that occurs in the setting of CHF. In areport by a National Institute of Health Task Force onResearch in Heart Failure (3), it was recommended that thepacing model of CHF be studied intensively since this modelmay “be particularly promising to our understanding ofhuman heart failure.”

The purpose of this review is to present a brief perspectiveon the pertinent issues surrounding chronic pacing tachy-cardia with respect to the strengths and limitations of thisapproach as a model for CHF. More detailed reviews regard-ing the pathophysiology of pacing tachycardia–inducedCHF have been prepared previously (4,5).

The Animal Model of Pacing Tachycardia

The initial studies using the animal model of pacing-inducedtachycardia were focused on simulating specific tachyar-rhythmias, such as that of Wolff-Parkinson-White syn-drome. In these initial studies, large animal models wereused in order to serially follow changes in LV geometry andfunction not only during the progression of pacing-inducedCHF but also following termination of the pacing tachycar-dia. These early reports demonstrated that pacing tachycar-dia caused severe LV dilation and pump dysfunction. Thesestudies also demonstrated that LV systolic function returnedtoward normal with termination of rapid pacing. However,results from these animal studies also demonstrated that

termination of the pacing stimulus following the develop-ment of CHF did not result in a complete normalization ofLV geometry and structure. Thus, these animal studies ofpacing-induced tachycardia provided the fundamental in-formation necessary to warrant more aggressive treatment orablation of tachyarrhythmias in patients presenting withsymptoms of LV systolic dysfunction. Furthermore, thesestudies added to the body of evidence that suggested thatchronic tachycardia may be an independent causal factor forCHF, as well as a frequently unrecognized clinical etiologyfor this disease process.

Although the model of chronic pacing has improved theunderstanding of tachycardia-mediated CHF, this model hasevolved into a commonly used substrate for mechanisticstudies regarding the pathogenesis of the CHF process.Specifically, chronic rapid pacing in large animal models,such as pigs, dogs and sheep, have been used in whichchronic atrial or ventricular pacing is induced at rates of210–250 bpm for 3–4 weeks. Large animal species havebeen used for these studies due to their lower intrinsic heartrates, compared with smaller animals, and the ability forinvestigators to use imaging modalities commonly used inclinical practice, such as ventriculography, radionuclidestudies and echocardiography. However, pacing-inducedCHF can be successfully induced in smaller animal species(6).

A confounding factor, and perhaps one of the significantlimitations of this model, is the variability between labora-tories with respect to the site chosen for the pacing stimulus,the pacing rate and the duration. It is well known thatventricular pacing can produce a heterogenous activationsequence that in turn will acutely influence LV myocardialcontractility and ejection performance. Differences in thetime to LV failure have been reported in which rapid pacingwas induced from the atrium or the ventricle. In the author’slaboratory, rapid atrial pacing at 240 bpm in pigs results inreliable atrioventricular nodal conduction, preserved ven-tricular activation patterns and a homogeneous LV myocar-dial contraction. In addition to the site of the pacing stimu-lus, some laboratories alter the pacing rate and the durationover the course of the study period. These dissimilar meth-odological approaches can often be overlooked and result indifficulties when interpreting the results from different lab-oratories or across species.

Pacing-Induced CHF: Similarities to the ClinicalPhenotype of CHF

The three features of pacing-induced CHF that have partic-ular clinical relevance are: 1) significantly impaired LV func-tion accompanied by hemodynamic profiles consistent withCHF; 2) neurohormonal system activation and defects inreceptor transduction pathways and 3) myocyte contractile

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dysfunction with alterations in excitation-contraction cou-pling processes (4,5).

The specific effects of pacing CHF with respect to LVfunction, neurohormonal receptor systems and cellular andmolecular processes have been the focus of a number ofstudies published over the past several years, and spacelimitations prevent providing these citations in this review.Briefly, pacing-induced CHF is accompanied by increasedLV end-diastolic volumes and afterload. The increased LVafterload is due to inherent changes in LV geometry that inturn results in increased LV wall stress, as well as systemicvasoconstriction resulting from compensatory neurohor-monal system activation. With respect to neurohormonalreceptor pathways, increased circulating catecholamines oc-cur with pacing CHF and are accompanied by diminishedb-receptor density and a blunted response to b-receptoractivation. Other neurohormonal systems that are activatedduring the development of pacing CHF include the renin-angiotensin system and the endothelin receptor pathways.The development of pacing CHF is accompanied by cleardefects in myocyte contractility and a diminished or absentresponse to a number of agonists and intracellular mediatorsthat under normal conditions improve contractile perfor-mance. Thus, the reduction in LV pump function that occurswith pacing CHF is multifactorial and includes alterations inLV loading conditions and geometry, as well as intrinsicdefects in myocyte contractility and key receptor transduc-tion pathways.

The rapid pacing model provides a fairly uncomplicatedmeans by which to relate defects in molecular and cellularsystems that occur with the development of severe CHF toLV contractility and ejection performance. Moreover, whencare is taken with respect to the pacing site and rate, chronicpacing-induced tachycardia in animals causes well defined,predictable and progressive LV dilation, contractile dysfunc-tion and neurohormonal activation (4,7–9). Thus, it is pos-sible to perform serial studies in this animal model of CHF,as well as to design therapeutic interventions that are tar-geted against a specific enzyme system or receptor transduc-tion pathway. For example, the pacing CHF model has beensuccessfully used to examine the effects of modulating therenin-angiotensin pathway, as well as the endothelin recep-tor system (6–8). Thus, the rapid pacing model may provideimportant pre-clinical information on potential therapeuticstrategies for CHF with respect to the effects upon LV func-tion, systemic and neurohormonal systems and contractileperformance.

Although this rapid pacing model may serve as a usefultool for the elucidation of the mechanisms of CHF, it mustbe recognized that any animal model will not fully representthe complex clinical spectrum of CHF. Specifically, chronicrapid pacing causes LV dilation and dysfunction that issimilar to that of clinical dilated cardiomyopathy. However,

the changes in LV myocardial structure that occur withchronic pacing are not similar to clinical forms of CHF dueto chronic ischemia or hypertensive disease. Thus, extrapo-lation of the findings from this model of CHF to clinicalforms of CHF should be done with caution.

Future Prospects for the Pacing CHF Model

There are several important directions of research in whichthe pacing model of CHF may have particular relevance.These avenues of CHF research include LV myocardial re-modeling, bioactive peptide signaling pathways and myo-cyte contractility and viability.

The progression of the CHF process is often accompaniedby increased LV myocardial wall stress that can in turnpromote further dilation and reduced pump function.Taken together, these observations would suggest that sig-nificant myocardial remodeling occurs within the LV freewall during the progression to severe CHF. In the author’slaboratory, rapid atrial pacing has been used in pigs as ameans for identifying early and contributory events respon-sible for the LV remodeling that occurs with severe CHF(4,9). In these studies, it was identified that an early eventwith pacing CHF was a loss in the integrity of the myocardialcollagen matrix that coincided with LV chamber dilationand wall thinning. The myocardial fibrillar collagen weaveensures structural integrity of adjoining myocytes and pro-vides the means by which myocyte shortening is translatedinto overall LV pump function. The matrix metalloprotein-ases (MMPs) selectively degrade extracellular proteins, suchas the fibrillar collagens, and have been implicated to di-rectly contribute to tissue remodeling in a number of patho-logical processes. At the author’s laboratory, it was recentlyidentified that increased MMP activity occurs with pacingCHF and is temporally related to the changes in LV geometryand function (9). Thus, the pacing model may serve as auseful tool to identify enzymatic pathways that contribute tothe LV remodeling process with CHF and develop noveltherapeutic strategies to inhibit this process.

In patients with CHF, a consistent observation is theactivation of neurohormonal pathways and the elaborationof bioactive molecules. However, whether and to what de-gree the expression of these bioactive substances are primarycontributory factors toward the progression of the CHFprocess, or simply secondary effects are difficult to determinein clinical studies. The pacing model of CHF may be avaluable tool in more carefully elucidating the effects ofchronic activation of specific receptor transduction path-ways. The pacing model has been used with success previ-ously to identify defects in b-adrenergic transduction anddownstream defects in this important sarcolemmal receptorsystem (4,8). For example, this model provided importedinsight into the basis for b-receptor uncoupling and differentpatterns of adenylate cyclase expression with CHF. This

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pacing model has also been useful in identifying potentiallydifferent mechanisms of action between angiotensin-con-verting enzyme (ACE) inhibition and selective blockade ofthe Ang AT1 receptor in the setting of developing CHF (7,8).Specifically, LV dilation and myocyte contractile dysfunc-tion was ameliorated to a greater degree with ACE inhibitionwhen compared with treatment with a pharmacologicallyequivalent dose of an Ang AT1 receptor antagonist. Com-bined ACE inhibition and Ang AT1 receptor blockade pro-vided additional protective effects when compared witheither treatment alone. These results suggested that an im-portant contributory mechanism for the effects of ACE inhi-bition is the potentiation of bradykinin and the productionof nitric oxide (NO). A recent study has clearly demon-strated a relationship between a reduction in myocardial NOproduction and alterations in myocardial metabolism withpacing CHF (10). Thus, it is likely that this model will bevaluable in elucidating the mechanistic basis and conse-quences of altered NO production with CHF. The potentbioactive peptide endothelin has been shown to influence anumber of processes relevant to the CHF process that in-cludes systemic and regional circulatory systems and myo-cardial contractility. Chronic pacing causes a time-depen-dent release of endothelin into the systemic circulation andis temporally related to the onset of LV pump dysfunctionand defects in myocyte contractility (5,6). The institution ofendothelin-receptor blockade during the progression of thepacing CHF process can ameliorate, to some degree, thedegree of LV pump failure and myocyte contractile dysfunc-tion (6). These findings would suggest that increased endo-thelin levels may exacerbate or hasten the CHF process, andthe pacing model may prove useful in testing this hypothe-sis.

With endstage CHF, defects in myocyte Ca12 homeo-static mechanisms have been identified, and some of thesedefects have been shown to occur with pacing CHF. Forexample, reduced expression of sarcoplasmic reticulumCa12 ATP-ase has been reported with pacing CHF (8).Recent studies have suggested that a contributory factor forthe LV remodeling process with certain forms of CHF ismyocyte loss due to programmed cell death or apoptosis.Initial results have suggested that the pacing model of CHFmay be accompanied by a loss of viable myocytes due toapoptosis. Thus, the pacing model may prove useful inidentifying intracellular pathways that compromise myocytecontractility and viability in the setting of severe CHF.

Conclusion

A recently performed search of the Medline database (Na-tional Library of Medicine) revealed approximately 550publications that have used this animal model of pacingCHF. Thus, it is likely that the rapid pacing model willremain in the research armamentarium regarding the patho-

genesis of CHF. With careful attention to the inherent limi-tations of the chronic pacing model, this model will likelyprove useful in identifying novel therapeutic targets for thetreatment of CHF.

The author must first acknowledge the significant research contributionsperformed by hundreds of investigators regarding the pacing model andwishes that all of them could have been referenced in this brief perspectivepaper. The results of studies outlined in this review were supported in partby the American Heart Association and National Institutes of Health grantsHL-56603, HL-59165, HL-57952. FGS is an Established Investigator of theAmerican Heart Association.

REFERENCES

1. Brill JC. Auricular fibrillation with congestive heart failure and no otherevidence of heart disease. Am Heart J 1937;13:175–82.

2. Whipple GH, Sheffield LT, Woodman EG, Thoephilis C, Friedman S.Reversible congestive heart failure due to rapid stimulation of the normalheart. Proc N Engl Cardiovasc Soc 1961–2;20:39–40.

3. Lenfant, C. Report of the task force on research in heart failure.Circulation 1994;90:1118–23.

4. Spinale FG. Left ventricular systolic function with chronic tachycardia.In: Pathophysiology of tachycardia-induced heart failure. Spinale FG, ed.Armonk, NY: Futura Publishing, 1996:235.

5. Elsner D, Riegger GAJ. Experimental heart failure produced by rapidventricular pacing in the dog. J Card Fail 1995;1:229–47.

6. Spinale FG, Walker JD, Mukherjee R, Iannini JP, Keever AT, GallagherKP. Concomitant endothelin receptor subtype A blockade during theprogression of congestive heart failure in rabbits has direct and beneficialeffects on left ventricular and myocyte function. Circulation 1997;95:1918–29.

7. Spinale FG, de Gasparo M, Whitebread S, et al. Modulation of therenin-angiotensin pathway through enzyme inhibition and specific re-ceptor blockade in pacing induced heart failure. I. Effects on leftventricular performance and neurohormonal systems. Circulation1997;96:2385–96.

8. Spinale FG, Mukherjee R, Iannini JP, et al. Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptorblockade in pacing induced heart failure. II. Effects on myocyte contractileprocesses. Circulation 1997;96:2397–406.

9. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, HebbarL. Time-dependent changes in matrix metalloproteinase activity and ex-pression during the progression of congestive heart failure: Relation toventricular and myocyte function. Circ Res 1998;82:482–95.

10. Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X, Hintze TH.Reduced nitric oxide production and altered myocardial metabolism dur-ing the decompensation of pacing-induced heart failure in the consciousdog. Circ Res 1998;83:969–79.

Address correspondence and reprint requests to Francis G. Spinale, MD, PhD,Cardiothoracic Surgery, Room 625, Strom Thurmond Research Building, 770MUSC Complex, Medical University of South Carolina, 114 Doughty Street,Charleston, SC 29425.

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