Abstract 63: A Novel Inotropic Gene Therapy Approach for Aging Induced Cardiac Dysfunction

Abstract

We have developed a novel approach to increase cardiac contractility without the deleterious effects of existing inotropes (beta agonists, Ca2+ sensitizers). Using the strengths of protein engineering, we have shown that cardiac function can be directly controlled and strongly influenced by manipulating the Ca2+ dependent switch in cardiac muscle, troponin C (TnC). Our smartly formulated construct, L48Q TnC, is a strong Ca2+ sensitizer. Although effective acutely, long-term inotropic support is detrimental. We transduced mice with AAV9 L48Q TnC at 3 months of age and serially performed echocardiography for 2 years. The current dogma would suggest that chronic Ca2+ sensitization with L48Q TnC should result in a hypertrophic cardiomyopathy and compromised function. Astonishingly, the L48Q TnC mice maintained ejection fraction unlike the progressive decline observed in the controlled, age-matched mice. Furthermore, L48Q TnC mice had an increased rate of survival. Considering cardiovascular disease is an elderly issue, we reasoned L48Q TnC would be beneficial in other age-related cardiovascular problems (i.e., hypertension and pressure-overload). We tested this in two models, transverse aortic constriction (TAC, pressure-overload) and angiotensin II infusion (AngII, hypertension). Consistent with the aging results, L48Q TnC mice displayed enhanced cardiac function (ejection fraction, contractility, relaxation), performance (VO 2max , distance run before exhaustion), less adverse remodeling, and enhanced survival. These studies provide a promising approach (i.e., inotropic support via L48Q TnC) that can be used therapeutically to enhance heart function in a variety of cardiomyopathies associated with aging.