Adenylyl Cyclase Gene Transfer Increases Cardiac Function in Murine Cardiomyopathy

Abstract

Background Cardiac expression of Gαq results in heart failure (HF), and crossing Gαq mice and mice with cardiac expression of adenylyl cyclase VI (ACVI) prevents HF. However, this does not indicate that ACVI is useful to treat HF for two reasons: 1) HF was prevented, not treated; 2) transgenic lines express high levels of the gene in all cardiac myocytes—impossible to replicate in clinical settings. Here we ask whether intracoronary delivery of an adenovirus encoding ACVI (Ad.ACVI) would increase LV function in Gαq mice with active HF. Methods and Results Before treatment, Gαq mice showed reduced fractional area change (echocardiography) (Gαq: 25±12%; Con: 42±12%; n=8 both groups; p<0.012), increased LV end-diastolic dimension (Gαq: 4.2±0.1 mm; Con: 3.2±0.4 mm; n=8 both groups; p<0.0001) and exercise duration was reduced (Gαq: 399±23 s, n=5; Con: 509±68 s, n=7; p<0.007). Gαq mice then received 2.5x1010 vp of Ad.ACVI (n=10) or Ad.EGFP (enhanced green fluorescent protein, n=10) via intracoronary gene delivery in a blinded study; 14d later LV dP/dt in response to dobutamine (1–30 μmol/l) was measured in isolated perfused hearts. Gαq mice that received Ad.ACVI showed increased LV +dP/dt and –dP/dt compared to Gαq mice that received Ad.EGFP (p<0.0001) (Figure). Basal heart rates in the ex-vivo setting were similar (Ad.ACVI: 234±33 bpm; Ad.EGFP: 218±55 bpm; n=10 both groups; p=0.44). Figure 1Open in figure viewerPowerPoint Conclusion Intracoronary delivery of ACVI increases cardiac function in mice with heart failure. This research was supported by NHLBI Minority Research Supplement.