Heterogeneous transmural distribution of beta-adrenergic receptor subtypes in failing human hearts

Abstract

Background: Downregulation of myocardial beta-adrenergic receptor density does not occur in a spatially uniform distribution in patients with congestive heart failure. Rather, it results primarily from loss of receptors in the subendocardium. In patients with dilated cardiomyopathy, beta 1-receptors have been found to be downregulated selectively. These observations suggest that considerable transmural heterogeneity in the distribution of beta-adrenergic receptor subtypes exists in the failing human heart. The present study was designed to test this hypothesis.

Methods and results: We used quantitative autoradiography of radioligand binding sites to measure the distribution of beta-adrenergic receptor subtypes in transmural sections of left ventricular myocardium obtained from cardiac transplant patients with ischemic (n = 13) and idiopathic dilated (n = 12) cardiomyopathy and from 4 subjects with no history of cognitive heart failure. Analysis of radioligand binding isotherms revealed a significant reduction in total beta-adrenergic receptor density in hearts of patients with ischemic and idiopathic cardiomyopathy (20.3 +/- 1.9 and 18.2 +/- 2.0 fmol/mg protein, respectively, versus 40.0 +/- 11.4 in control subjects; P < .01 for both). Loss of the beta 1-subtype accounted for 86% of the total reduction in beta-receptor density in failing hearts. Despite the significant decreases in overall tissue receptor content, the densities of total beta-receptors and beta-receptor subtypes in subepicardial myocytes were equivalent in failing and control hearts. However, in contrast to control hearts, in which the transmural distribution of total and beta 1-receptors was uniform (endocardial: epicardial receptor density ratios, 0.97 +/- 0.14 and 1.0 +/- 0.2, respectively), hearts of patients with ischemic and idiopathic dilated cardiomyopathy had significantly lower total beta-receptor and beta 1-receptor densities in the subendocardium (ratios, 0.66 +/- 0.06 and 0.46 +/- 0.09 for total and beta 1-receptors, respectively, in ischemic cardiomyopathy and 0.60 +/- 0.08 and 0.52 +/- 0.11 in dilated cardiomyopathy; P < .001 for all values compared with a ratio of 1). Thus, beta 1: beta 2 receptor density ratios were markedly decreased in the subendocardium of ischemic and idiopathic dilated left ventricles compared with control hearts.

Conclusions: A significant transmural gradient in the density of myocardial beta 1-adrenergic receptors exists in the hearts of patients with ischemic and dilated cardiomyopathy, resulting in a markedly altered beta 1: beta 2 receptor density ratio in the subendocardium.