Transmural heterogeneity of norepinephrine uptake in failing human hearts

Abstract

Objectives. The aim of this study was to determine whether regional heterogeneity in myocardial sympathetic neural function measured by the uptake of norepinephrine could account for the spatial heterogeneity of beta-adrencrgic receptor down-regulation that occurs in the failing human heart.Background. Myocardial beta-adrenergic receptor density and function are diminished in patients with chronic heart failure. Down-regulation occurs predominantly in the subendocardium, suggesting that local rather than systemic alterations in sympathetic neural function may be responsible. Although some studies have implicated hypofunction of cardiac sympathetic nerves with defective norepinephrine uptake, others suggest increased cardiac sympathetic nerve activity with unimpaired uptake.Methods. We measured norepinephrine uptake by incubating transmural slices of the left ventricle from 19 patients who had chronic heart failure and three nonfailing control hearts with [3H]norepinephrine with or without desipramine, a neuronal uptake blocker. The density of uptake sites was measured in subepicardial and subendocardial myocyte regions with light microscopic autoradiography.Results. Although the amount of [3H]norepinephrine uptake varied considerably in failing ventricles, uptake was directly proportional (r = 0.46, p < 0.05) to beta1-adrenergic receptor density measured in additional slices with radioligand binding assays. In addition, marked transmural heterogeneity in [3H] norepinephrine uptake was consistently observed in failing ventricles. Uptake in subendocardial myocyte regions was significantly less than in subepicardial regions (mean [±SDj subepicardial/subendocardial uptake ratio 4.7 ± 4.8, p < 0.01). The extent of transmural heterogeneity in norepinephrine uptake was similar in patients with idiopathic and ischemic cardiomyopathy. In contrast, nonfailing hearts exhibited more uniform transmural [3H]norepinephrine uptake (subepicardial/ subendocardial uptake ratio 1.8 ± 1.2, p = NS).Conclusions. Specific [3H]norepinephrine accumulation is approximately fivefold lower in subendocardial regions of failing left ventricles than in subepicardial regions. These findings support the hypothesis that a subendocardial defect in norepinephrine uptake may chronically elevate local interstitial catecholamine levels and thereby down-regulate beta-adrenergic receptors in a spatially heterogeneous distribution.