Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response.

TLDR

The study used radiolabeled (-)[125I]iodocyanopindolol to identify β‑adrenergic receptors in high‑yield membrane preparations from right ventricular biopsies and performed graded dobutamine and calcium gluconate infusions in patients stratified by left ventricular ejection fraction to assess receptor function. Binding studies showed specific, high‑affinity β‑adrenergic receptors in biopsy membranes, but patients with mild‑moderate and severe heart failure had 38.2 % and 57.7 % reductions in receptor density without changes in affinity, and severe dysfunction was associated with a marked loss of dobutamine‑induced contractile response while calcium responses remained intact, indicating that β‑adrenergic down‑regulation begins early in heart failure and correlates with impaired β‑agonist contractility.

Abstract

We developed methods for identifying beta-adrenergic receptors in human right ventricular endomyocardial biopsy tissue with the radioligand (-)[125I]iodocyanopindolol (ICYP). Specific ICYP binding in a crude, high-yield membrane preparation derived from endomyocardial biopsy tissue was high (specificity greater than 90%), of high affinity (KD around 20 pM), saturable and stereospecific for the (-) vs the (+) isomer of isoproterenol. Subjects with mild-moderate and severe biventricular dysfunction had respective decreases in beta-adrenergic receptor density of 38.2% and 57.7% when normalization methods were averaged, with no significant differences in ICYP dissociation constant. A subgroup of subjects was subdivided by left ventricular ejection fraction (LVEF) into those with mild cardiac dysfunction (LVEF less than 0.50 greater than 0.40) and severe heart failure (LVEF less than 0.20) and given graded sequential infusions of dobutamine and calcium gluconate. Those with severe cardiac dysfunction had marked impairment of the dobutamine dP/dt and stroke work index response, whereas these responses to calcium did not differ in the two groups. These data indicate that in the intact human heart endomyocardial biopsy may be used for direct analysis of beta-adrenergic receptors, heart failure-associated myocardial beta-adrenergic down-regulation begins with mild-moderate ventricular dysfunction, reduction in myocardial beta-receptor density is related to degree of heart failure, and beta-receptor down-regulation is associated with pharmacologically specific impairment of the beta-agonist-mediated contractile response.