Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A(3) adenosine receptors

An increased expression of adenosine receptors is a promising target for gene therapy aimed at protecting the myocardium against ischemic damage, but may alter cardiac electrophysiology. We therefore studied the effects of heart-directed overexpression of A(3) adenosine receptors (A(3)ARs) at different gene doses on sinus and atrio-ventricular (AV) nodal function in mice. Mice with heart-specific overexpression of A(3)AR at high (A(3)(high)) or low (A(3)(low)) levels and their wild-type littermates were studied. Telemetric electrocardiogram (ECG) recordings in adult freely moving A(3)(high) mice showed profound sinus bradycardia resulting in either ventricular escape rhythms or an incessant bradycardia-tachycardia syndrome (minimal heart rate A(3)(high) 217+/-25*; WT 406+/-21 beats/min, all values as mean+/-S.E.M., n=7 per genotype, *p