(Circulation. 1995;91:2504-2507.)
© 1995 American Heart Association, Inc.
Articles |
Structural Basis for Heart Failure
Ventricular Remodeling and Its Pharmacological Inhibition
From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School (Minneapolis).
Correspondence to Jay N. Cohn, MD, Cardiovascular Division, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455.
Key Words: heart failure • clinical trials • editorials • pharmacology
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Introduction |
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 Top Introduction References |
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The syndrome of heart failure has traditionally been viewed as a functional disorder precipitated by impaired left ventricular pump performance. The classification into systolic and diastolic dysfunction has emphasized the functional distinction between abnormalities in contraction and relaxation. Recently, however, attention has been directed toward the possibility that the systolic dysfunction, which has been thought to be related to contractile failure, could be a consequence of a structural increase in ventricular chamber volume. This construct would revise the conventional view—contractile failure leads to chamber dilatation—with a more anatomic basis for heart failure: Chamber dilatation occurs as an early response that results in the reduced wall motion that is mandated to generate a normal stroke volume from a large ventricular end-diastolic volume. This structural alteration is not necessarily related to the underlying etiological cardiac pathology but rather represents an intrinsic morphological change that progresses over time in response to an initiating event. The term "remodeling" often is used to address these structural changes and may be best defined as a change in chamber volume and shape not related to a preload-mediated increase in sarcomere length.
In this issue of Circulation, Greenberg and his SOLVD
colleagues1 revisit the remodeling issue in chronic heart
failure with echocardiographic data collected in the long-term trial of
enalapril versus placebo in both symptomatic and asymptomatic patients
with left ventricular remodeling. Patients were selected for this study
on the basis of an ejection fraction of 
35%. At the time the study
was designed, this low ejection fraction was defined as systolic
dysfunction. The implication of that designation is that an impairment
of myocardial shortening was the primary abnormality. A more
contemporary hypothesis, based on the concept of left ventricular
remodeling, is that the low ejection fraction reflects in part a
primary increase in chamber volume that will obligatorily result in a
low ejection fraction in the absence of peripheral demand for a high
stroke volume. Therefore, it is perhaps appropriate to reexamine our
approach to classifying heart failure as systolic or diastolic
dysfunction on the basis of the ejection fraction. Perhaps remodeling,
not contractile dysfunction, is the key to the severity of depression
of ejection fraction.
One important concept supported by the SOLVD data is that remodeling is a progressive process even in a state of apparently stable heart failure. That this progressive remodeling process is not necessarily the result of further insult to the myocardium from ischemia, infarction, or infection is supported by animal model studies. In a canine model of localized left ventricular damage developed in our laboratory2 and applied by McDonald et al,3 a progressive pattern of remodeling could be demonstrated over the course of at least 1 year. Thus, although remodeling may be initiated at the time of a myocardial infarction and early intervention, as documented by SAVE,4 AIRE,5 and SMILE,6 can favorably affect remodeling and outcome, the process may continue at a slower but progressive rate over long periods of time. The SOLVD data also provide further evidence that angiotensin-converting enzyme (ACE) inhibitors can favorably influence that long-term progressive process.
The mechanism by which ACE inhibitors favorably influence the
remodeling process cannot be addressed in the SOLVD trial or in any
other large-scale trial. ACE inhibitors were initially introduced into
the heart failure regimen as vasodilators that could enhance function
of the failing left ventricle.7 At the time we first
proposed chronic vasodilator therapy,8 9 the concept
was
that improved ventricular emptying resulting from a lowered impedance
to ejection could produce a sustained improvement in hemodynamics and
in the symptoms of heart failure. Long-term structural improvement in
the heart might then be viewed as a bonus of the reduced ventricular
preload and afterload. The benefit of the use of hydralazine plus
isosorbide dinitrate on mortality in V-HeFT I10 was viewed
as the ultimate test of this load-reducing hypothesis. Subsequent
observations have forced reexamination of this overly simple view. In
V-HeFT I, an effective vasodilator, prazosin, failed to exert a
favorable long-term effect on ventricular structure or function or on
mortality.10 In our canine remodeling studies, an
1-blocker, terazosin, failed to inhibit
remodeling,11 whereas ACE
inhibitors11 12 and
nitrates13 did. Data on calcium antagonists as chronic
vasodilators in heart failure should soon be available. Consequently,
it may ultimately be necessary to dissociate load reduction from
antiremodeling effects of vasodilator drugs.
Other actions of ACE inhibitors certainly must be considered in the antiremodeling effect. Angiotensin II is identified by Greenberg et al1 as a putative mechanism stimulating hypertrophy and remodeling in the SOLVD patients, but other data suggest the possibility of alternate mechanisms of ACE inhibitor effect. In some experimental models, angiotensin II inhibition has been ineffective in blocking the remodeling process.11 14 15 In other studies, kinin activation resulting from ACE inhibition may play a critical role.12 16 17 The apparent left ventricular mass reduction reported in the SOLVD study is of particular interest. Whether this reduced mass can be attributed, as the authors suggest, to a decrease in wall stress or whether the ACE inhibitor has primarily affected myocyte growth and resulted in a reduction in chamber volume that caused the decrease in wall stress remains an elusive question. Unfortunately, echocardiographic estimates of myocardial mass in these remodeled and often asymmetrical ventricles may be sufficiently imprecise to leave unresolved the important question of the magnitude of the effect of the drug on mass. Future studies aimed at quantitating sequential changes in ventricular volume, mass, and wall stress should use a more precise method, such as magnetic resonance imaging.
The encouraging observations in this and other trials of therapeutic intervention in left ventricular remodeling must be tempered by a recognition that the magnitude of the benefit has been very modest. Even with the considerable sample size examined in SOLVD, the benefit on chamber volume was very small and of borderline statistical significance. A similarly small effect on left ventricular size of captopril administered for 1 year after an acute myocardial infarction was observed by Pfeffer et al18 and by Sutton et al in SAVE.19 In none of these studies did the use of an ACE inhibitor result in a mean reduction in left ventricular dilatation, but rather the drugs appeared to prevent the progressive increase in volume observed in the control groups. Can ACE inhibitors cause regression of remodeling or only an attenuation of the progressive process? Jugdutt et al20 showed a reduction in ventricular chamber size over 6 weeks in dogs whose treatment was initiated 48 hours after coronary ligation. McDonald et al21 demonstrated a significant reduction in chamber volume in a chronically remodeled canine ventricle treated for 3 months with captopril. In V-HeFT II,22 both enalapril and the combination of hydralazine and isosorbide dinitrate administered over 4 years produced a sustained small increase in ejection fraction not observed in the placebo group in V-HeFT I.10 This long-term increase in ejection fraction is certainly suggestive of a structural reduction in left ventricular end-diastolic volume. Such a volume reduction in response to enalapril also was observed in a smaller SOLVD substudy with radionuclide ventriculography or invasive left ventriculography.23 The differences observed in these studies could relate to differing methodologies, differing patient populations, or differing protocols. Nevertheless, at best the mean changes in ventricular volume attributed to the ACE inhibitor have been small. Furthermore, the reduction in mortality observed in all of these large-scale clinical trials in patients with left ventricular remodeling has been only modest, and the mortality rate in this population remains unacceptably high. Therefore, if there is a link between regression of remodeling and the favorable effect on outcome,19 24 neither effect has been satisfactorily prominent in these trials. Indeed, it is unlikely that all of the benefit from medical therapy in patients with left ventricular remodeling can be attributed to the antiremodeling effect of the therapy. In V-HeFT, the benefit of enalapril on survival could be attributed in part to a favorable effect on left ventricular ejection fraction,24 but the differential mortality benefit between enalapril and hydralazine plus isosorbide dinitrate suggested an additional mechanism probably related to neurohormonal inhibition.25 Thus, efforts to exert a more favorable effect on prognosis in heart failure will require attention to mechanisms in addition to the regression of left ventricular remodeling.
Another inference from the SOLVD study, and one common to all large, simple trials, is that mean changes in response to a therapy in a heterogeneous population should not be interpreted as the expected response to this therapy in selected patients. The trend in large-scale trials is to enter a diverse group of individuals who meet certain entrance criteria for the disease in question. In SOLVD, the entrance criterion of a low ejection fraction led to the inclusion of patients with a wide range of cardiac diseases, coexistent illnesses, and cotherapies. Mean changes in left ventricular volume and mass in this heterogeneous population may obscure profoundly favorable effects in some and adverse effects in others. In the patients included in the echocardiographic substudy, it is not possible to identify characteristics that might contribute to a more favorable antiremodeling effect of enalapril. Of perhaps more importance is the possibility of identifying responders early in the course of long-term therapy. If regression of remodeling or prevention of progression of remodeling is a therapeutic goal, then identifying an individual who is exhibiting a favorable response to the therapy as opposed to one whose ventricle has not responded should be of critical importance in selecting strategies for long-term management. The modest effect of enalapril observed in SOLVD suggests that we will be exploring other therapies or combinations of therapy to deal with nonresponders. An early marker for the failure to respond would be a valuable tool to improve the effectiveness and precision of our medical therapy.
The distinction often made between compensatory or adaptive remodeling and decompensatory or maladaptive remodeling remains somewhat ethereal. Although it was at one time believed that an increase in chamber volume reflected an increase in sarcomere length on the basis of the Frank-Starling mechanism to enhance contractile performance, the volume increase observed in remodeling clearly is structural and not functional.11 A mass increase to augment wall thickness in response to a pressure load to normalize wall stress is an entirely appropriate response in hypertension and aortic stenosis. Similarly, an increase in mass would be an obligatory response if mitral regurgitation demanded a stroke volume larger than could be delivered from a normal chamber end-diastolic volume. The increase in chamber radius in this situation would mandate wall thickening to moderate stress. On the other hand, if the dilatation results from new sarcomeres being generated in series to lengthen the normal myocyte remote from a regionally dysfunctional area, then avoidance of that hypertrophic response might be beneficial. Otherwise, the lengthening myocyte will result in a larger, remodeled chamber with an increased radius of curvature that could increase myocardial oxygen consumption,26 impair subendocardial blood flow,3 generate abnormal myocardial bioenergetics,27 and increase the risk of ventricular arrhythmias.28
After an acute myocardial infarction involving only a portion of the left ventricle, and one in which global systolic performance is adequate in the early stages of infarct recovery, progressive remodeling of the noninfarcted myocardium may play no compensatory role and the process of dilatation and hypertrophy may be maladaptive from the start. Remodeling of the ventricle therefore cannot be viewed as a stereotypical process, but the mechanism and physiological rationale for its occurrence should be understood before a determination can be made as to whether its inhibition should be sought early or at some stage after a compensatory phase has been accomplished. In acute myocardial infarction, the data may already be available. Prevention of remodeling by early administration of an ACE inhibitor apparently has a long-term favorable effect even if the mass and volume increases that might otherwise have occurred are prevented.4 5 6 The benefit may be modest enough, however, that it is difficult to demonstrate efficacy when a population unselected for the likelihood of subsequent remodeling is treated aggressively.29
Our expanding insight into the natural history and mechanisms of ventricular remodeling has provided persuasive evidence that the process is modifiable. Despite the evidence for the effectiveness of ACE inhibitors, it is clear that more potent and perhaps more highly selective interventions must be developed. Further knowledge about the molecular, neurohormonal, bioenergetic, and mechanical contributors to this process is necessary if we are to develop more effective and better targeted therapies. The importance of this search cannot be overestimated, because success could mean prevention of the heart failure syndrome, which is one of the most prevalent, costly, and lethal diseases in Western society.
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References |
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TopIntroductionReferences |
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M. Zaugg, W. Xu, E. Lucchinetti, S. A. Shafiq, N. Z. Jamali, and M. A. Q. Siddiqui {beta}-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes Circulation, July 18, 2000; 102(3): 344 - 350. [Abstract] [Full Text] [PDF]
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A. Goette, T. Staack, C. Rocken, M. Arndt, J. C. Geller, C. Huth, S. Ansorge, H. U. Klein, and U. Lendeckel Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1669 - 1677. [Abstract] [Full Text] [PDF]
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G. S. Francis Heart failure J. Am. Coll. Cardiol., April 1, 2000; 35(5_Suppl_B): 6B - 9B. [PDF]
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E Roig, F Perez-Villa, M Morales, W Jimenez, J Orus, M Heras, and G Sanz Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure Eur. Heart J., January 1, 2000; 21(1): 53 - 57. [Abstract] [PDF]
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P. Madeddu, C. Emanueli, R. Maestri, M. B. Salis, A. Minasi, M. C. Capogrossi, and G. Olivetti Angiotensin II Type 1 Receptor Blockade Prevents Cardiac Remodeling in Bradykinin B2 Receptor Knockout Mice Hypertension, January 1, 2000; 35(1): 391 - 396. [Abstract] [Full Text] [PDF]
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 L. M. Ruilope Is it wise to combine an ACE inhibitor and an angiotensin receptor antagonist? Nephrol. Dial. Transplant., December 1, 1999; 14(12): 2855 - 2856. [Full Text] [PDF]
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D. L. Mann Mechanisms and Models in Heart Failure : A Combinatorial Approach Circulation, August 31, 1999; 100(9): 999 - 1008. [Full Text] [PDF]
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M. A. Acker Dynamic cardiomyoplasty: at the crossroads Ann. Thorac. Surg., August 1, 1999; 68(2): 750 - 755. [Abstract] [Full Text] [PDF]
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K. Onishi, M. Ohno, W. C. Little, and C.-P. Cheng Endogenous Endothelin-1 Depresses Left Ventricular Systolic and Diastolic Performance in Congestive Heart Failure J. Pharmacol. Exp. Ther., March 1, 1999; 288(3): 1214 - 1222. [Abstract] [Full Text]
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G. S. Francis Heart failure J. Am. Coll. Cardiol., February 1, 1999; 33(2): 291 - 294. [Full Text] [PDF]
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P. E. McEwan, G. A. Gray, L. Sherry, D. J. Webb, and C. J. Kenyon Differential Effects of Angiotensin II on Cardiac Cell Proliferation and Intramyocardial Perivascular Fibrosis In Vivo Circulation, December 15, 1998; 98(24): 2765 - 2773. [Abstract] [Full Text] [PDF]
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Z. Popovic, M. Miric, S. Gradinac, A. N. Neskovic, L. Jovovic, L. Vuk, M. Bojic, and A. D. Popovic Effects of partial left ventriculectomy on left ventricular performance in patients with nonischemic dilated cardiomyopathy J. Am. Coll. Cardiol., December 1, 1998; 32(7): 1801 - 1808. [Abstract] [Full Text] [PDF]
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 H. MAL, A. LEVY, T. LAPERCHE, C. SLEIMAN, J. L. STIEVENART, A. COHEN-SOLAL, O. BRUGIERE, G. LESECHE, G. JEBRAK, and M. FOURNIER Limitations of Radionuclide Angiographic Assessment of Left Ventricular Systolic Function before Lung Transplantation Am. J. Respir. Crit. Care Med., November 1, 1998; 158(5): 1396 - 1402. [Abstract] [Full Text] [PDF]
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L. F. P. Moreira, N. A. G. Stolf, E. A. Bocchi, F. Bacal, M. C. P. Giorgi, J. R. Parga, and A. D. Jatene Partial left ventriculectomy with mitral valve preservation in the treatment of patients with dilated cardiomyopathy J. Thorac. Cardiovasc. Surg., April 1, 1998; 115(4): 800 - 807. [Abstract] [Full Text] [PDF]
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M. Gheorghiade and R. O. Bonow Chronic Heart Failure in the United States : A Manifestation of Coronary Artery Disease Circulation, January 27, 1998; 97(3): 282 - 289. [Full Text] [PDF]
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 J. T. Sullebarger, P. M. D'Ambra, L. C. Clark, L. Thanikarry, and H. L. Fontanet Effect of Digoxin on Ventricular Remodeling and Responsiveness of {beta}-Adrenoceptors in Chronic Volume Overload Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1998; 3(4): 281 - 290. [Abstract] [PDF]
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L. Bolognese, G. Cerisano, P. Buonamici, A. Santini, G. M. Santoro, D. Antoniucci, and P. F. Fazzini Influence of Infarct-Zone Viability on Left Ventricular Remodeling After Acute Myocardial Infarction Circulation, November 18, 1997; 96(10): 3353 - 3359. [Abstract] [Full Text]
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R. J MacFadyen, C. S Barr, and A. D Struthers Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients Cardiovasc Res, July 1, 1997; 35(1): 30 - 34. [Abstract] [Full Text] [PDF]
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 R. S. Vasan, M. G. Larson, E. J. Benjamin, J. C. Evans, and D. Levy Left Ventricular Dilatation and the Risk of Congestive Heart Failure in People without Myocardial Infarction N. Engl. J. Med., May 8, 1997; 336(19): 1350 - 1355. [Abstract] [Full Text] [PDF]
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M. Guazzi, G. Marenzi, M. Alimento, M. Contini, and P. Agostoni Improvement of Alveolar–Capillary Membrane Diffusing Capacity With Enalapril in Chronic Heart Failure and Counteracting Effect of Aspirin Circulation, April 1, 1997; 95(7): 1930 - 1936. [Abstract] [Full Text]
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E. J. Eichhorn and M. R. Bristow Medical Therapy Can Improve the Biological Properties of the Chronically Failing Heart: A New Era in the Treatment of Heart Failure Circulation, November 1, 1996; 94(9): 2285 - 2296. [Abstract] [Full Text]
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J. N. Cohn The Management of Chronic Heart Failure N. Engl. J. Med., August 15, 1996; 335(7): 490 - 498. [Full Text] [PDF]
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J. N. Cohn Is There a Role for Endothelin in the Natural History of Heart Failure? Circulation, August 15, 1996; 94(4): 604 - 606. [Full Text]
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 X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
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