Cardiac gene therapy with type 2 phosphodiesterase (PDE2) in experimental heart failure: Complementary or alternative to β–blockers?

Abstract

Chronic activation of the β-adrenergic (β-AR) pathway induces cardiac remodeling and worsens outcome in heart failure (HF). β-blockers counteract β-AR pathway membranous activation and reduce mortality and morbidity in HF. Various cyclic nucleotide phosphodiesterases (PDEs) finely tune β-AR responses by degrading and compartmentalizing cAMP. Recent results suggest that cardiac PDE overexpression protects against maladaptive remodeling induced by chronic catecholamines infusion in mice. To determine if a cardiac PDE gene therapy would treat HF induced by pressure overload in mice, alone or in combination with β-blockers. HF was induced by transverse aortic constriction (TAC) and mice were injected with adeno-associated virus (AAV9 to allow preferential cardiac expression, 10^12 viral particles per mice) encoding PDE2A or the Luciferase (Luc) as a control for cardiac overexpression 1 week after surgery. Metoprolol (Meto) or NaCl were administered via osmotic minipumps at 2 weeks post-surgery during 4 weeks. Four groups were compared: TAC-Luc-NaCl, TAC-PDE2A-NaCl, TAC-Luc-Meto, TAC-PDE2A-Meto. Cardiac function was monitored by serial echocardiography and physical capacity tested by treadmill exhaustion test. Following euthanasia, hearts were harvested for histological and molecular analysis. In a pilot study, healthy mice were treated with Meto (30 mg/kg/day, n = 4) or NaCl ( n = 2). Meto decreases phospholamban phosphorylation, as well as heart rate (−18%) and ejection fraction (−17%). Following this validation, TAC mice with aortic gradient > 60 mmHg were randomized. Both PDE2A-AAV9 injection and Meto were well tolerated. On-going experiments should be completed by July. Preliminary results indicate that cardiac PDE2A gene therapy is well tolerated in mice with HF induced by pressure overload.