(Circulation. 1997;95:1752-1754.)
© 1997 American Heart Association, Inc.
Articles |
Reversing Congestive Heart Failure With Endothelin Receptor Antagonists
the Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo (Japan) (Y.Y.), and Health Service Center, University of Tokyo (T.Y.).
Correspondence to Yoshio Yazaki, MD, PhD, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo,7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Key Words: Editorials • congestive heart failure • endothelin
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Introduction |
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Eight years have passed since endothelin-1 (ET-1) was isolated from the supernatant of cultured porcine endothelial cells.1 In addition to exerting potent and prolonged vasoconstrictor effects on both venous and arterial smooth muscle cells, ET-1 has a diverse set of biological activities (such as positive inotropic2 and chronotropic3 effects on cardiac myocytes, proliferative effects on various cells,4 and stimulation of hormone release and modulation of central nervous activities5 ). Moreover, it has recently been elucidated that the mice homozygous for ET-1 null mutation represent not only cardiovascular malformations but also morphological abnormalities of the pharyngeal arch–derived craniofacial tissues and organs,6 7 indicating that ET-1 is essential to normal embryonic development. To date, ET-1 is known to be the sole vasoactive peptide that is involved in normal morphogenesis. Furthermore, a recent in vitro study has confirmed the involvement of ET-1 as an autocrine factor in pressure overload–induced cardiac hypertrophy.8
Many studies have found that the ET-1 level is increased in the plasma of symptomatic congestive heart failure (CHF) patients,9 10 11 12 13 14 and the concentrations increase as the severity of CHF increases. Namely, the elevation of circulating ET-1 levels in CHF has been shown to be negatively correlated with left ventricular ejection fraction (LVEF) and cardiac index and positively correlated with New York Heart Association functional class, left ventricular (LV) end-diastolic volume index,15 left atrial pressure,16 and extent of pulmonary hypertension.10 Moreover, plasma ET-1 levels in the subacute phase after myocardial infarction provide prognostic information independent of clinical and biochemical variables including patient age, previous treatment for systemic hypertension, presence of clinical heart failure, and the levels of plasma atrial natriuretic factor that is an established neurohumoral prognostic marker of CHF.17 Plasma levels of big ET-1, which is inactive until it is converted, have also been shown to predict mortality in patients with moderate and severe CHF better than hemodynamic variables (such as LVEF and atrial natriuretic factor levels).18 Furthermore, measurement of ET-1 concentrations has been shown to be a useful and noninvasive approach for evaluating the clinical response to drug therapy in CHF patients. Krum et al19 have reported that the change in ET-1 levels in CHF patients receiving a ß-blocker vasodilator (carvedilol) is an independent, sensitive, and noninvasive marker of changes in disease status after drug therapy.
It has been reported that plasma levels of ET-1 but not other neurohumoral vasoconstrictor factors (such as norepinephrine and vasopressin) measured during exercise were inversely correlated with maximum oxygen consumption in patients with CHF.20 This finding suggests that among such vasoconstrictors, ET-1 is the strongest contributor to exercise intolerance, implying the possibility that ET receptor antagonists may be useful for the treatment of CHF. Kiowski et al21 have recently studied the acute favorable effects of the combined ETA/ETB receptor antagonist bosentan on the hemodynamics of CHF patients. They administered either placebo or bosentan (100 mg followed after 60 minutes by 200 mg) intravenously to 24 patients with NYHA functional class III CHF and high plasma concentrations of ET-1. Compared with placebo, bosentan not only reduced cardiovascular hemodynamic parameters (systemic blood pressure, pulmonary arterial pressure, right atrial pressure, pulmonary artery wedge pressure, systemic vascular resistance, and pulmonary vascular resistance) but also increased the cardiac index by 
14%. Heart rate did not change, and plasma concentrations of angiotensin II (Ang II) and norepinephrine were unaltered. Moreover, in this issue of Circulation, Spinale et al22 present a study that examines the effectiveness of chronic blockade of the ETA receptor. The authors not only investigated global LV function but also isolated myocyte function in rabbits in the following three groups: chronic rapid ventricular pacing (RVP), RVP and concomitant administration of the ETA receptor antagonist PD156707, and sham controls. Treatment with PD156707 for 3 weeks improved LV fractional shortening that was decreased after RVP and reduced the dimension of the end-diastolic LV enlarged after RVP. These improvements were not accompanied by a significant decrease in systemic blood pressure. Furthermore, isolated myocyte shortening velocity declined after RVP was normalized by the chronic blockade of the ETA receptor, and the reduced inotropic responsiveness of myocytes to ET-1 as well as extracellular calcium ion and ß-receptor stimulation returned to the control levels with PD156707. Therefore, the authors provide the first evidence of the beneficial effects of chronic blockade of the ETA receptor on LV function at cellular levels as well as hemodynamic levels. The authors pointed out some possible mechanisms: treatment with the ETA receptor antagonist (1) reduced the LV afterload that caused the decrease in oxygen demand of cardiomyocytes, (2) increased myocardial blood flow, (3) increased oxygenation capacity after decreased pulmonary vascular resistance, (4) decreased heart rate leading to the reduced consumption of oxygen, (5) inactivated neurohumoral systems, and (6) improved the contractility of cardiac myocytes that was probably induced by the maintenance of calcium ion homeostatic processes, increased production of cAMP, and overexpression of sarcolemmal ETA receptors.
CHF is a clinical syndrome characterized by marked activation of neurohumoral mediators (such as the sympathetic nervous system and the renin-angiotensin system) to compensate for impaired cardiac performance. Long-term therapy with short-acting calcium channel blockers (such as nifedipine and diltiazem) has increased the risk of worsening CHF,23 24 whereas amlodipine, a long-acting calcium channel blocker, has not increased cardiovascular mortality in patients with severe CHF.25 The adverse reaction has possibly been attributed to the propensity of the drugs not to activate endogenous neurohormonal systems.26 In keeping with this idea, ACE inhibitors that effectively reduce mortality in CHF subjects27 28 29 have been shown to induce endogenous neurohormonal inhibition.30 In the study by Spinale et al,22 the chronic ETA receptor antagonist alone increased plasma norepinephrine and renin activity, but RVP plus an ETA receptor antagonist had no effect on these values compared with RVP alone. These results suggest that like ACE inhibitors, ETA receptor antagonists effectively decrease mortality in patients with CHF. Additional long-term effects of ETA receptor antagonists on mortality as well as LV function and neurohumoral mediators remain to be clarified.
Aging alters endothelial cells, which may play a vital role in vascular tone regulation. Marin31 has shown that vasocontractions induced by some constrictor agents (such as 5-hydroxytryptamine, histamine, high potassium, and Ang II) are barely affected by aging and that contractile responses elicited by calcium channel agonists is increased in senescence. However, the contraction elicited by ET is usually reduced with aging, suggesting that ET plays a minor role in the regulation of vascular tone in the elderly. The data support that third-generation calcium channel blockers (such as amlodipine)25 or ACE inhibitors may be more efficacious in the treatment of CHF, especially in older patients. This problem should be addressed in prospective clinical trials.
It has been shown that ET-1–overexpressing transgenic mice do not develop hypertension32 and that blood pressure in ET-1 +/- heterozygous mice is slightly elevated, contrary to expectation,6 suggesting the presence of unknown mechanisms modifying the vasoconstrictor activity of ET-1. Additionally, Wei and colleagues15 have indicated that plasma ET-1 levels are increased only in patients with moderate or severe CHF. This is due to the fact that increased circulating ET-1 was a late phenomenon in human CHF, and the levels were correlated with functional class and LV dysfunction only in moderately and severely symptomatic CHF. It also remains to be elucidated whether the ET receptor antagonist is an efficacious remedy for asymptomatic LV dysfunction or mild CHF.
A recent study indicates an important role for Ang II in the activation of ET in cultured cardiomyocytes.33 Clavell et al34 have also shown, using chronic thoracic inferior vena caval constriction in conscious dogs, that chronic ACE inhibition with low-dose enalapril abolishes the increases in circulating and tissue ET as well as plasma Ang II concentrations, suggesting that ACE inhibitors by themselves are sufficient for the treatment of CHF. In contrast, Townend and colleagues35 have demonstrated that quinapril or captopril for 16 weeks had no effect on plasma ET levels in patients with CHF, and Teerlink et al36 have shown that bosentan has an additive vasodilating effect when given with the ACE inhibitor cilazapril, compared with either cilazapril or bosentan alone, in conscious CHF rats. Exclusive of this additive effect, the specific action of ET-1 has been known. Ono et al37 have recently shown that ET-1 decreases cAMP accumulation and activates muscarine potassium current, leading to the inhibition of L-type calcium channels in the heart of guinea pigs. This negative modulatory action was increased when the heart was excited by sympathetic stimulation. Therefore, this combination therapy is worth considering for future applications.
Another area that remains to be explored is the selectivity of ET receptors. Both ETA and ETB receptors are involved in the vasoconstrictor action of ET-1 in human blood vessels,38 and Miyauchi et al39 have shown that the ET-1 binding site density of cardiac membranes in the CHF rats is significantly higher than that in the control rats. However, the functional significance of ETA and ETB receptors in the setting of CHF remains unknown. It has recently been indicated that an intracoronary infusion of the ETB receptor agonist sarafotoxin reduces coronary blood flow by 31% and increases coronary vascular resistance by 53% in an experimental canine model of CHF and that the vasoconstrictor action is stronger than that of ET-1.40 These results suggest an increase in vasoconstrictor sensitivity through the ETB receptor but not through the ETA receptor in CHF. On the contrary, vasoconstriction after a bolus injection of ET-1 has been reported to be blunted in mesenteric arteries of rats with CHF.41 The authors have concluded that the altered pressor response is due to the functional downregulation of the ETA receptor–mediated response. For clinical purposes, it remains to be elucidated whether ETA receptor antagonists, ETB receptor antagonists, or combined ETA/ETB receptor antagonists are most useful for treating CHF.
In summary, ET plays an important role in maintaining blood pressure and blood flow in the setting of CHF. Like the renin-angiotensin system, the ET system in CHF compensates for decreased LV function. However, increased ET induces vasoconstriction, leading to an increased overload on the heart, and the overloaded heart deteriorates LV function. This vicious circle results in irreversible heart failure. It has been confirmed that measurement of circulating ET levels is useful for diagnosis and prognostic evaluation of CHF. Therefore, the ET system is an attractive target for therapeutic intervention in CHF. The favorable effects of concomitant treatment with ET receptor antagonists on reduced LV function and increased mortality in CHF patients are being elucidated in clinical and experimental studies. The development of orally active ET receptor antagonists is essential for the long-term clinical application,42 and it is possible that they provide a new option for the treatment of CHF.
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Acknowledgments |
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This study was supported by a Grant-in-Aid for Scientific Research, Developmental Scientific Research, and Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture, Japan. We are indebted to Mary Mosley for the critical reading of the manuscript.
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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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