Key result
Cardiac gene therapy with AAV9-PDE2A limited adverse left ventricle remodeling, dysfunction, and ventricular arrhythmias induced by chronic catecholamine exposure in mice.
Why the study?
It remained unknown whether acute elevation of PDE2 is efficient to prevent maladaptive remodeling and arrhythmia in heart failure.
Does AAV9-PDE2A gene therapy prevent maladaptive remodeling and arrhythmias in mouse models of catecholamine-induced heart failure?
Does AAV9-PDE2A gene therapy prevent maladaptive remodeling and arrhythmias in mouse models of catecholamine-induced heart failure?
Cardiac gene therapy with PDE2A prevents catecholamine-induced left ventricular remodeling, dysfunction, and arrhythmias in a preclinical mouse model, suggesting a potential novel therapeutic target for heart failure.
PDE2A gene therapy merits testing in larger models; leaves open its therapeutic potential in human heart failure.
BACKGROUND Constitutive cardiac PDE2 activation was shown to protect against contractile dysfunction and arrhythmia in heart failure (HF). However, it remains unknown whether an acute elevation of PDE2 is efficient to prevent maladaptive remodeling and arrhythmia. In this study we tested whether increasing acutely PDE2A activity in preclinical models of HF using cardiac PDE2 gene transfer could be of therapeutic value. METHODS AND RESULTS C57BL/6 male mice were injected with serotype 9 adeno-associated viruses (AAV9) encoding for PDE2A, or luciferase (LUC). Cardiac function assessed by echocardiography unveiled neither structural change nor dysfunction consecutive to PDE2A overexpression while AAV9 inoculation led to a ≈10-fold rise of PDE2A protein levels. Two weeks after AAV9 injections, mice were implanted with osmotic minipumps delivering NaCl or isoproterenol (Iso) (60 mg/kg/day) or Iso and phenylephrine (Iso+Phe, 30 mg/kg/day each) for 2 weeks. In LUC mice, chronic infusion with Iso increased left ventricular (LV) weight over body weight ratio, promoted fibrosis and decreased ejection fraction, but animals overexpressing PDE2A were protected towards these deleterious effects. Similarly, concomitant treatment with Iso+Phe promoted LV contractile dysfunction, fibrosis and apoptosis in LUC mice, while PDE2A overexpression limited these adverse outcomes. Furthermore, inotropic responses to Iso of ventricular cardiomyocytes isolated from Iso+Phe-LUC mice loaded with 1 µmol/L Fura-2AM and stimulated at 1 Hz to record calcium transients and sarcomere shortening were dampened. Chronic treatment with catecholamines favoured spontaneous calcium waves upon β-AR stimulation at the cellular level and promoted susceptibility to ventricular arrhythmias in vivo evoked by catheter-mediated ventricular pacing after Iso and atropine injection. However, these adverse effects were blunted by the cardiac gene therapy with PDE2A. CONCLUSION Gene therapy with PDE2A limits cardiac adverse left ventricle remodeling and dysfunction induced by catecholamines as well as ventricular arrhythmias, providing evidence that acutely increasing PDE2A activity could prevent progression towards HF.
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Kamel et al. (2023) studied Heart failure. AAV9-PDE2A gene therapy vs. AAV9-LUC (luciferase) was evaluated on Left ventricular remodeling, dysfunction, and ventricular arrhythmias. Cardiac gene therapy with AAV9-PDE2A limited adverse left ventricle remodeling, dysfunction, and ventricular arrhythmias induced by chronic catecholamine exposure in mice.
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