Beta-adrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy

Abstract Alterations in the myocardial receptor-G protein-adenylate cyclase (RGC) complex and cardiac adrenergic neurons in the failing human heart result in subsensitivity to β-adrenergic stimulation. Pharmacologic interventions such as β blockade may modify critical components of the RGC complex and partially restore the sensitivity of the β-adrenergic pathway. Among the receptors coupled to the stimulatory (G a ) protein are the β 1 and β 2 receptors. Because of differences in receptor population and agonist (i.e., norepinephrine) affinity, the β 1 -receptor is the predominate adrenergic subtype regulating contractility in the nonfailing myocardium. Down-regulation occurs in the myocardial β-receptor component of the RGC complex with mildto-moderate and severe left ventricular dysfunction. However, abnormalities of the RGC complex vary with the etiology of heart failure; β 1 -receptor down-regulation is greater in idiopathic dilated cardiomyopathy than in post-infarction cardiomyopathy, while β-receptor uncoupling is greater in post-infarction disease. In chronic heart failure, the adrenergic nervous system is activated in the heart and kidney. There is evidence that an increased cardiac norepinephrine concentration contributes to the decrease in β 1 -receptor density in heart failure. However, norepinephrine exposure is not the only factor responsible for regulating β-adrenergic receptors in heart failure. Chronic β blockade may improve hemodynamic and clinical response in patients with idiopathic dilated cardiomyopathy by protecting the myocardium from the cardiotoxic effects of increased catecholamines and by up-regulating the β 1 receptors. However, our investigation of the β-blocker metoprolol and the vasodilating β-blocker carvedilol showed a significant increase in ventricular ejection fraction with both drugs and a 46% increase in myocardial β-receptor density with metoprolol therapy but no change with carvedilol therapy or with placebo. It would appear that improvement in resting left ventricular function with β blockade can occur in the absence of β-receptor up-regulation.