Abstract 10784: Blockade of the Late Na Current Accelerates Electrical Recovery and Restore Diastolic Function in the Aging Heart
Cardiovascular disorders in the elderly are partly associated with impaired diastolic function, a condition characterized by elevated filling pressures to maintain left ventricular (LV) volumes and cardiac output. In this study, we raised the possibility that alterations of the electrical properties of the old heart underlie defects in myocardial relaxation and distensibility, contributing to dysfunctional diastolic performance. Thus, physiological determinations in vivo, in papillary muscle preparations, and in isolated LV myocytes were conducted in young (3 months) and old (30 months) mice. Mitral inflow examination by Doppler echocardiography indicated that old animals present reduced E wave (LV passive filling) and increased A wave (active filling), with respect to young mice. Additionally, old animals displayed higher LV end diastolic pressure (LVEDP) and steeper slope of the LVEDP-Volume relationship. These findings are consistent with defective LV compliance and diastolic dysfunction in old mice. The QT interval of the ECG was significantly prolonged in old animals, indicating that aging delays the electrical recovery of the myocardium. Slower repolarization of epicardial monophasic action potentials (AP) in old hearts ex-vivo, and longer APs in old myocytes by patch-clamp, suggested that the electrical defect of the senescent heart originated from changes in trasmembrane ionic fluxes. In old myocytes, the late Na current (INaL) was upregulated and its blockade with mexiletine, shortened by 44% the intermediate repolarization phases of the AP. Importantly, administration of mexiletine in old mice reduced the QT interval by 25%, restoring ventricular electrical recovery. In respect to non-treated, INaL inhibition in old mice increased E wave (+12%) and E:A ratio (+19%), together with an attenuation of LVEDP and steepness of the LVEDP-Volume relationship. This intervention did not alter systolic parameters. Similarly, by isometrically twitching LV trabeculae, the elevated diastolic tension at maximal length of contraction in old mice was reduced by 30% with INaL blockade. Thus, restoration of the electrical recovery in the old myocardium results in amelioration of LV filling dynamics and normalization of diastolic function.
- © 2012 by American Heart Association, Inc.