Abstract 16444: Aging on Cardiovascular Functional and Structural Responses: Does the Presence of β3-Adrenergic Receptors Have a Role?

Background: Aging has a remarkable effect on the heart and arterial system. Although cardiovascular functional responses to aging have not been fully investigated, recent evidence suggests that cardiovascular reserve function in advanced aged without cardiovascular disease is limited by suboptimal left ventricular (LV)–arterial coupling (LVAC) due to an age-associated augmentation of vascular afterload and reduced myocardial contractility due, in part, to a diminished effectiveness of adrenergic modulation. We have shown previously that aging up-regulates cardiac β 3 -adrenergic receptor (AR) which leads to β 3 -AR-mediated negative modulation on cardiac function, LVAC and effective β-AR signaling. We tested the hypothesis that aging-caused impaired LVAC, LV dysfunction and desensitization of β-AR signaling may be attenuated or prevented in β 3 -AR knockout (β 3 KO) aged mice. Methods: We evaluated the effects of aging on LV and vascular functional responses in 10 wild-type (WT) and 10 β 3 KO age-matched mice divided into 2 young (Y) (6 mo) and 2 aged (A) (28-32 mo) groups (5/group). Results: Compared with YWT, in AWT, there were no significant differences in heart rate, LV end-systolic pressure (P ES ), stoke volume (AWT: 27.2 vs YWT: 29.4 μl) and ejection fraction (60 vs 65%), but LV end-diastolic volume (V), P ED , the time constant of LV relaxation (τ, 9.9 vs 5.9 ms), arterial elastance of E A all increased. Importantly, compared with other groups, only in AWT, the early diastolic portion of LV P-V loop was shifted upward and rightward with decreased the peak rate of mitral flow. The P ES -V ES relation was also shifted to the right with reduced slopes of P ES -V ES (E ES ) (3.1 vs 3.9 mmHg/μl). LVAC was impaired with significantly decreased E ES /E A (0.8 vs1.2) and 32% reduction of LV mechanical efficiency (SW/PVA). In addition, in AWT, LV response to dobutamine (DOB, 5 μg/kg/min, iv) had a significantly lesser increase in E ES and less decrease in τ. Compared with YWT, both Yβ 3 KO and Aβ 3 KO mice had similar basal and DOB infusion-stimulated LV and vascular functional responses. Conclusions: β 3 KO prevents aging-caused impaired LVAC, LV dysfunction and desensitization of β-AR signaling. Thus, β 3 -AR inhibition may be considered as a potential molecular target in cardiac aging.