Intravenous AAV8 encoding Urocortin‐2 provides sustained augmentation of left ventricular function in heart failure mice (699.4)

Abstract

Urocortin 2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. Here we ask if a single intravenous injection of adeno-associated virus type 8 encoding murine UCn2 (AAV8.UCn2) might increase left ventricular (LV) function in mice with heart failure (HF). Myocardial infarction (MI, by coronary ligation) was used to induce HF, which was assessed by echocardiography 3w after MI. Mice with fractional area change (FAC) <30% received AAV8.UCn2 (5x 1011 gc, IV) or IV saline, and 5 weeks later echocardiography showed increased FAC in mice that received UCn2 gene transfer (HF: 11±1%, n=10; HF+UCn2: 19±3%, n=10; p=0.025). In vivo physiological studies showed increased rates of LV pressure development (LV +dP/dt) and decay (LV -dP/dt; Figures), indicating increased LV contractile and diastolic function. We conclude that a single IV of AAV8.UCn2 increases function of the failing heart. The simplicity of IV injection of a long-term expression vector encoding a gene with paracrine activity to increase cardiac function is a potentially attractive strategy for the treatment of heart failure.