Heterogeneous Transmural Distribution of β-Adrenergic Receptor Subtypes in Failing Human Hearts

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Abstract

Background.

Downregulation of myocardial β-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, β1-receptors have been found to be downregulated selectively. These observations suggest that considerable transmural heterogeneity in the distribution of β-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 β-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 congestive heart failure. Analysis of radioligand binding isotherms revealed a significant reduction in total β-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 β1-subtype accounted for 86% of the total reduction in β-receptor density in failing hearts. Despite the significant decreases in overall tissue receptor content, the densities of total β1-receptors and β-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 β1-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 β-receptor and β1-receptor densities in the subendocardium (ratios, 0.66±0.06 and 0.46±0.09 for total and β1-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, β1: β2 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 β1-adrenergic receptors exists in the hearts of patients with ischemic and dilated cardiomyopathy, resulting in a markedly altered β1: β2 receptor density ratio in the subendocardium. (Circulation.1993;88:2501–2509.)

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