Is neurohormonal activation a major determinant of the response to ACE inhibition in left ventricular dysfunction and heart failure?

Correspondence to: Dr A Sigurdsson, Division of Cardiology, Department of Medicine, Ostra Hospital, 416 85 Gothenburg, Sweden. Chronic heart failure is characterised by varying degrees of symptoms and high mortality mainly from progressive myocardial failure and sudden death. Increased understanding of pathophysiological mechanisms has shown that heart failure is progressive and characterised by myocardial dysfunction and activation of complex adaptive and maladaptive processes. Moreover, a number of large clinical trials have shown that the progressive nature of and high mortality from the disorder may be affected by pharmacological interventions. The initial event in the clinical pathophysiology of heart failure is myocardial damage, which may be caused by many different mechanisms such as toxins, infections, and prolonged volume or pressure overload.' In Western societies the initial injury is most often an acute myocardial infarction, though the cause often remains unknown, as in idiopathic dilated cardiomyopathy. Clinical heart failure may develop immediately after the myocardial injury or after a period of asymptomatic left ventricular dysfunction. The pathophysiological events which follow an acute myocardial injury and ultimately lead to progressive heart failure are not exactly understood, although our knowledge of the complicated mechanisms involved in the development of left ventricular dilatation, hypertrophy, and dysfunction has recently increased.2 Activation of different neurohormonal systems as well as autocrine and paracrine mechanisms has an essential role in this process. Pharmacological treatment of chronic heart failure has traditionally been aimed at the underlying cardiac disease and at reducing symptoms such as dyspnoea and fluid retention. More recently, treatment has been targeted increasingly at delaying the progression of the disorder and at reducing mortality. Treatment with angiotensin converting enzyme (ACE) inhibitors can positively influence prognosis. Moreover, 1 adrenergic blockers can reduce mortality in patients with heart failure after myocardial infarction,6 and they seem to delay the progression of the disorder among patients with idiopathic dilated cardiomyopathy.7 ACE inhibitors have multiple mechanisms of action, which involve both haemodynamic and neurohormonal factors as well as autocrine and paracrine mechanisms. In this article we will review the importance of neurohormonal mechanisms for the efficacy of ACE inhibitors in the treatment of asymptomatic left ventricular dysfunction and chronic heart failure. Although doctors focus on treatment of patients with systolic dysfunction of the left ventricle, it is important to remember that, in some cases of heart failure, alterations in myocardial relaxation (diastolic dysfunction) may predominate.8 Although the initial event in the development of left ventricular dysfunction is structural damage to the myocardium, heart failure is not merely a disease of the heart. Patients with left ventricular dysfunction frequently have no symptoms of heart failure, probably because compensatory mechanisms enable maintenance of cardiac output and peripheral perfusion. These adaptive responses are the result of a complex interplay between myocardial, haemodynamic, and neurohormonal mechanisms which are activated almost immediately after the myocardial injury. Compensatory mechanisms may, however, become exhausted, and many patients ultimately develop symptoms of heart failure. At this stage, activation of the sympathetic nervous system and the renin-angiotensin system seems to be maladaptive and may cause further harm to the myocardium, leading to progression of the disorder.9 10 Furthermore, baroreflex responses are not able to limit the magnitude of activation of the vasoconstrictor hormones as baroreceptor function may be impaired." 12 Thus, sustained neurohormonal activation is partly maintained by altered baroreceptor function, which may reduce inhibitory signals to the vasomotor centre and thereby diminish the inhibition of sympathetic outflow. The time course of neurohormonal activation, from the onset of myocardial injury to the development of chronic heart failure, has never been studied in detail in the same population of patients. Several studies have, however, investigated neurohormonal activation in patients with acute myocardial infarction, asymptomatic left ventricular dysfunction, or chronic heart failure.