In vivo effects of cardiomyocyte-specific β-1 blockade on afterload- and frequency-dependent cardiac performance.

Abstract

Pharmacologic β-blockade is a well-established therapy for reducing adverse effects from sympathetic overactivity in cardiovascular diseases, such as heart failure. Despite decades of research efforts, in vivo cardiac functional studies using genetic animal models remain scant. We generated a mouse model of cardiomyocyte-specific deletion (cKO) of β-1 adrenergic receptor (ADRB1), the primary subtype expressed in cardiac myocytes, and demonstrated the role of ADRB1 in the maintenance of cardiac function at baseline and during exposure to increase in cardiac afterload by transient aortic occlusion and increasing heart rates (HRs) via atrial pacing. cKO hearts showed mildly depressed baseline left ventricular (LV) function, including slower HR, decreased contractility (dP/dt max/IP), and prolonged relaxation (Tau) in both sexes. Exposure to increased LV afterload depressed LV function in either genotype similarly; however, the functional recovery following the removal of the afterload was severely impaired in cKO hearts, whereas cardiac function was immediately normalized in wild-type (WT) hearts. When HR was altered from 400 to 700 beats/min, cKO hearts were deficient in HR-dependent improvement of cardiac contractility and relaxation, known as positive force-frequency relationship, that was evident in WT hearts. Enhanced phosphorylation of phospholamban by the HR increase was markedly blunted in cKO myocardium versus wild types, whereas CaMKII phosphorylation was comparable between the genotypes, suggesting the critical involvement of PKA. These results provide the first experimental evidence for the role of ADRB1 in cardiomyocytes for maintaining cardiac function at baseline and during acute stress, providing a clinical perspective relating to the management of patients on β-blockers.NEW & NOTEWORTHY Although the benefits of β-1 adrenergic receptor (ADRB1) blockade to cardiovascular disease are established, in vivo role for cardiomyocyte ADRB1 remains undetermined. Generating cardiomyocyte-specific ADRB1 knockout mice, we show that ADRB1 is pivotal to cardiac functional recovery from afterload elevation and heart rate-dependent functional enhancement as well as baseline performance. Our findings highlight the importance of cardiomyocyte ADRB1 in cardiac stress adaptability, which is of clinical importance in the management of patients on β-blockers.