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(Circulation. 1996;94:604-606.)
© 1996 American Heart Association, Inc.
Articles |
Is There a Role for Endothelin in the Natural History of Heart Failure?
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. E-mail cohnx001@maroon.tc.umn.edu.
Key Words: Editorials • endothelin • heart failure
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Introduction |
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A role for locally released and circulating peptides in the progressive syndrome of heart failure has been widely entertained because of the evidence for activation of a number of these hormonal systems in experimental and clinical studies and because a satisfactory explanation for the progressive cardiac and vascular functional abnormalities in heart failure has remained elusive. Endothelin (ET) is a particularly attractive candidate because it is released by the endothelium, which is thought to be functionally abnormal in heart failure,1 2 3 and because it is a potent vasoconstrictor and growth promoter.4 5 Since vasoconstriction and myocardial and vascular growth and remodeling may characterize the syndrome,6 7 8 excess endothelin release could serve an important role in the initiation or perpetuation of these processes.
Shimoyama and his associates9 report in this issue of Circulation that the nonspecific endothelin receptor (ETA and ETB) antagonist bosentan exerted a vasodilator effect in their canine model of chronic left ventricular dilation that resulted from repeated coronary embolization. Because this vasodilator effect was not demonstrable in normal dogs, the authors appropriately suggest that the endothelin system appears to be upregulated in their canine model. The very modest increases in circulating levels of ET-1 they report in this model may not be pertinent because the peptide may act largely as a local hormone. Indeed, the striking rise in circulating ET-1 levels after receptor blockade confirms the active synthetic pathway. They speculate from these data that endothelin blockade may be a useful form of therapy for heart failure.
Such observations have already been extended to patients with heart failure. Kiowski et al10 recently reported that bosentan produced a dose-dependent lowering of arterial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, and right atrial pressure in 24 subjects with dilated hearts related to an ischemic or nonischemic etiology. These authors10 reported a doubling of ET-1 levels after bosentan, whereas Shimoyama et al9 describe an eightfold increase from lower initial levels that raises the possibility of methodological differences in the measurement of blood levels. Not only is endothelin a "sticky" peptide that may adhere to tubing and glassware, but the antibody used in the assay may have variable cross-reactivity with the endothelin precursor big endothelin and with ET-2 and ET-3. Bosentan dose-response was not explored by Shimoyama et al. Nonetheless, they address the recurring theme of whether the circulating levels of a hormone can serve as a marker for a favorable effect of its inhibition. Kiowski et al10 observed a direct relationship between ET-1 levels and bosentan effect in their patients, which is similar to the early observations of plasma renin activity and the response to converting enzyme inhibition in hypertension and heart failure.11 12 The apparent long-term efficacy of ACE inhibition, however, appears not to be dependent on systemic evidence of renin stimulation, either because the local hormone system is independently active or because the long-term benefits are not directly related to suppression of an activated system. We must anticipate a similar possibility when chronic studies are undertaken with endothelin inhibitors.
When we first raised the possibility that vasodilator drugs might have a long-term favorable effect on left ventricular function and progressive morbidity in heart failure,13 we were wedded to a simple hemodynamic concept based on the observation that vasodilator drugs could correct the reduced cardiac output and increased left ventricular filling pressure that characterize the circulatory abnormality in heart failure. Because counterregulatory vasoconstrictor forces appeared to be activated, the rational therapeutic approach was to counteract these with vasodilator drugs or, better still, to identify a specific vasoconstrictor mechanism that could be blocked by pharmacological inhibition. The problem, of course, was that normalizing "hemodynamics" did not necessarily correct the structural changes that had led to cardiac dilation in the patient with chronic heart failure. Indeed, our early studies with sodium nitroprusside infusion suggested that the left ventricular end-diastolic dimension actually increased as the left ventricular end-diastolic pressure fell.14 We nonetheless raised the possibility that the impedance load imposed by the vasoconstriction could have contributed to the structural changes and that chronic vasodilator therapy could reverse the functional and structural abnormality of heart failure.15
The first Vasodilator–Heart Failure Trial (V-HeFT), which was designed to test that hypothesis, demonstrated that all vasodilator interventions are not equal. The 
-1 adrenergic receptor blocker prazosin, which should have directly counteracted the sympathetically mediated vasoconstriction, was ineffective on left ventricular structure, function, and mortality.16 In contrast, the nitrodilator isosorbide dinitrate, combined with the arterial dilator hydralazine, produced a favorable effect on left ventricular structure, function, and mortality.16 A similar benefit of ACE inhibitors was subsequently demonstrated in V-HeFT II17 and Studies of Left Ventricular Dysfunction (SOLVD).18 We now have persuasive evidence that nitrates and ACE inhibitors exert direct effects to inhibit structural alterations in the vasculature and left ventricle19 20 and that the role of hydralazine in the therapeutic regimen may be in part to inhibit nitrate tolerance.21 22 23 24
Shimoyama and colleagues9 focus exclusively on the acute hemodynamic response to the endothelin-receptor blocker. They seek an explanation for the absence of a fall in arterial pressure in response to this vasodilator intervention in their dogs. But the mystery of drug-specific variations in hemodynamic response to vasodilator drugs extends far beyond these new data with bosentan. When converting enzyme inhibitors were subjected to acute hemodynamic study, it became apparent that the blood pressure reduction with these drugs was more profound and the stroke volume and cardiac output increased significantly less than with the potent vasodilator sodium nitroprusside or the oral combination of isosorbide dinitrate and hydralazine.25 26 If the increase in cardiac output were simply a passive mechanical response to the fall in vascular resistance, why was there less output response to an ACE inhibitor and why did cardiac output rise without a blood pressure fall after bosentan? Although the authors9 entertain a differential inotropic effect, most studies in humans with nitroprusside and other vasodilator drugs do not demonstrate an increase in contractility but rather a decline in dP/dt as the preload falls.
One neglected hemodynamic factor that may contribute to the output and pressure response to vasodilator agents is their action on the conduit arteries. An important contributor to the stroke-volume increase in response to nitroprusside is its effect on arterial compliance. In the large arteries, an increase in compliance allows a greater storage of stroke volume in the conduit arteries at a lower or unchanged pressure during systole. This stored blood is released during diastole to augment diastolic forward flow and even to increase diastolic pressure in the face of vasodilation. Thus, the increased arterial compliance reduces impedance to left ventricular ejection and results in a larger stroke volume, often with a lower systolic pressure and higher diastolic pressure, and an unchanged mean pressure. The authors of the present paper9 did not provide systolic and diastolic pressures to allow for more critical analysis of the hemodynamic effect of the drug.
Another important influence of arterial compliance is on oscillatory or reflected waves.27 The heart failure state in humans is characterized by a decrease in compliance of the more distal arterial segments that influence reflections.28 If these reflections return to the root of the aorta during late systole, as they may do in aging and in many disease states,27 29 impedance to left ventricular ejection may be augmented by a pressure wave that is not detected in the periphery. The nitrodilators, through exertion of a relaxing effect on both proximal and distal arterial segments, may produce a profound blunting of these late systolic pressure waves. The site of the arterial pressure measurement is critical to identify these reflections, and it is not clear whether Shimoyama et al9 used measurements in the root of the aorta or in the femoral artery.
The most logical source of endogenous vasoactive substances that control large conduit and small artery compliance is the endothelium directly in contact with the underlying vascular smooth muscle. Constitutive release of nitric oxide likely plays a role in the maintenance of compliance of the normal arterial bed.30 Constitutive or induced release of endothelin may well serve as the counteracting vasoconstrictor in the usual "yin/yang" biological regulatory organization. Because these potent endogenous substances control growth as well as tone,31 they provide the potential of the whole panoply of vascular functional and structural alterations associated with heart failure and other disease states. Furthermore, endothelin and nitric oxide also have the potential to influence functional and structural processes in the myocardium.32 33 Thus, for assessment of the potential cardiovascular effects of endothelin and nitric oxide, arterial structure or compliance and cardiac structure measurements may be more sensitive and revealing than pressure measurements.
The therapeutic potential for endothelin antagonists in heart failure, therefore, may not be dependent on their short-term hemodynamic effects. The long-term benefit of ACE inhibitors and the nitrate-hydralazine combination on mortality in heart failure probably is related to their ability to inhibit or regress the structural remodeling process in the left ventricle. The failure of the -1 adrenoceptor antagonists prazosin and terazosin to alter mortality or the natural history of ventricular remodeling in the dog34 or in humans35 indicates that not all vasodilators share these structural properties in this syndrome. It may be a tissue growth-inhibiting property of effective vasodilators that accounts for their favorable long-term effects. Such an action of another potent class of vasodilators, the calcium antagonists, has been sought in two recent trials,36 37 with inconclusive results. Since endothelin is known to have potent mitogenic effects,5 31 chronic blockade of this peptide might prove to be clinically effective. Whether this blockade should involve ETA or ETB receptors remains to be determined. Furthermore, we should guard against repeating the error of ACE inhibitor development: to study the chronic efficacy of a single dose without establishing the mechanistic dose-response efficacy that could guide clinical management. Even now, we do not know the proper dose of an ACE inhibitor to produce the desired pharmacological effect for optimal long-term efficacy in heart failure. Furthermore, we should be alert to the possibility that bosentan will prove not to be selective enough to test the role of endothelin in heart failure satisfactorily. And the possibility of an adverse effect of endothelin inhibition on neural growth and development is not to be disregarded.38 We can anticipate the development of an inhibitor of the enzymatic conversion of big endothelin to the active forms of endothelin, which should provide us with an alternate pharmacological means to inhibit the system.39 We await appropriately designed long-term studies.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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