Vascular tone in heart failure: the neuroendocrine-therapeutic interface.

264 Br Heart J 1991;66:264-7 REVIEW Vascular tone in heart failure: the neuroendocrine-therapeutic interface John G F Cleland, Celia M Oakley Impaired cardiac function is of course the primary problem in heart failure, but it is also the stimulus to activation of several integrated neuroendocrine systems. Activation of these neuroendocrine systems at first seems to have important beneficial effects for the failing circulation-maintaining cardiac output, blood pressure, blood flow to essential organs, and the glomerular filtration rate. Prolonged or extreme neuroendocrine activation, however, may prove deleterious. The advent of effective diuretics had a tremendous impact on the management of patients with heart failure. Then, in the absence of a cure for the primary problem, thoughts returned to agents that either increased the force of myocardial contraction (inotropic agents) or reduced the load on the failing heart (vasodilator agents). Both modes of treatment have proved effective in improving haemodynamic function in the short term. Neither therapeutic intervention has yet been established as having beneficial effects for long term treatment of heart failure. A fourth group of agents was added to the treatment of heart failure in the 1980s. The angiotensin converting enzyme (ACE) inhibitors have showed not only their ability to improve symptoms and exercise performance, but also to reduce mortality and possibly slow the rate of decline in ventricular function. In the 1990s their use is certainly going to increase. These agents are more than just another group of vasodilator agents. Their effects on neuroendocrine activity seem to be integral to their success. A review of the interaction between neuroendocrine variables and vasodilator therapy is timely. Department of Medicine (Clinical Cardiology), Royal Postgraduate Medical School, Hammersmith Hospital, London G F Cleland C M Oakley J Correspondence to Dr John G F Cleland, Department of Medicine, Clinical Cardiology Unit, Hammersmith Hospital, Du Cane Road, London W12 ONN. Historical perspectives Before the 1940s theories on the nature of the circulatory disorder in heart failure abounded, but the means of treating the condition were limited. The advent of cardiac catheterisation, of methods of measuring regional blood flow, and, finally, of non-invasive measures of cardiovascular function has contributed to better understanding of the interplay between the failing heart and the abnormal circulation that it still supports. The introduction of mercurial diuretics in the 1920s, thiazides in the 1950s, and loop diuretics in the 1960s all made substantial contributions to the alleviation of symptoms while leading indirectly to some deleterious haemodynamic and neuroendocrine effects. The relation between cardiac output and venous pressure in heart failure was described at the Hammersmith Hospital in the 1940s, and Wood recognised that increased systemic vasoconstriction was one of the hallmarks of heart failure.'2 These ideas were brought together by Braunwald in the 1960s, who integrated the concepts of altered pre-load, after-load, and myocardial contractility and promoted the theoretical rationale for vasodilator therapy for heart failure.3 However, the concept of reducing vascular tone in the treatment of heart failure is much older. Osler (1892) used nitroglycerine4 and Savill (1936) suggested sympathectomy5 as a treatment for intractable heart failure. These ideas gained substance in the 1950s, with the use of ganglion blocking agents6 and nitrates.7 Since then, nitrates have achieved a lasting place in the management of pulmonary oedema. The use of phentolamine in the 1970s ushered in the "modern" era of vasodilator therapy.8 However, despite all the theoretical considerations, until the appearance of ACE inhibitors in the 1980s, vasodilator agents achieved no firm practical role in the management of chronic heart failure. Neuroendocrine consequences of heart failure The circulation responds both to changes in volume and to changes in pressure. Those reflexes which depend on pressure receptors (that is, carotid, aortic arch, and renal) seem to work fairly normally in heart failure,910 with reduction in arterial wall tension activating the sympathetic nervous and renin-angiotensinaldosterone systems. Though such reflexes may be slightly blunted they work in a directionally normal sense. In contrast, volume dependent reflexes (that is, of the atria and great veins) seem to be markedly blunted or directionally abnormal. The diuresis that can be elicited by atrial distention is reduced. Although atrial natriuretic peptide is increased" its renal effects are considerably reduced in heart failure. Plasma concentrations of arginine vasopressin, which would normally be suppressed during atrial distention, are increased. Animal models of heart failure suggest that initial activation of the sympathetic nervous Vascular tone in heart failure: the neuroendocrine-therapeutic interface and renin-angiotensin systems results in fluid retention and vasoconstriction.'2 If the primary myocardial insult is not too severe, fluid retension causes blood volume expansion with a restoration of arterial pressure, and as this occurs activation of the neuroendocrine systems wanes. This is consistent with observations in patients developing heart failure after myocardial infarction.'3 However, if the cardiac insult is severe enough haemodynamic equilibrium cannot be achieved. This may manifest itself in several ways; cardiogenic shock will result from an excessive fall in stroke output or pulmonary oedema from an excessive rise in left atrial pressure. Most patients with chronic heart failure are already receiving diuretics which prevent the patient from equilibrium; haemodynamic attaining therefore activation of vasoconstrictor neuroendocrine systems is maintained. Diuretics, by reversing fluid retention, reveal the underlying activation of the reninangiotensin system. High plasma concentrations of renin, angiotensin II, noradrenaline, and atrial natriuretic peptide are also important and indicate a poor prognosis.4 15 High concentrations of catecholamine and angiotensin II6 may be directly cardiotoxic as well as adding to a downward spiral of increasing vascular resistance, neuroendocrine activation, and function. haemodynamic deteriorating However, it is not certain whether neuroendocrine activation itself makes a contribution to increasing mortality or is just a marker of severity. The demonstration that normal concentrations of plasma renin with high sympathetic activity may be exchanged for the converse by diuretics'7 illustrates the absence of any simple relation between neuroendocrine activation and prognosis. "Conventional" vasodilators Despite many trials on vasodilators there is little evidence that they are effective in improving symptoms and exercise performance in chronic heart failure. "20 Although the comb (...truncated)