Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A3 adenosine receptors

Abstract

Objective: 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 A3 adenosine receptors (A3ARs) at different gene doses on sinus and atrio-ventricular (AV) nodal function in mice. Methods and results: Mice with heart-specific overexpression of A3AR at high (A3high) or low (A3low) levels and their wild-type littermates were studied. Telemetric electrocardiogram (ECG) recordings in adult freely moving A3high mice showed profound sinus bradycardia resulting in either ventricular escape rhythms or an incessant bradycardia–tachycardia syndrome (minimal heart rate A3high 217±25*; WT 406±21 beats/min, all values as mean±S.E.M., n=7 per genotype, *p<0.05). Exercise attenuated bradycardia in A3high mice (maximal heart rate A3high 650±13*; WT 796±13 beats/min) and first-degree AV nodal block was present (PQ interval A3high 36±4*; WT 23±5 ms). Isolated hearts showed complete heart block (10/17 A3high* vs. 1/17 WT). Atrial bradycardia and AV block were already present 3 weeks after birth. Doppler echocardiography revealed atrial dysfunction and progressive atrial enlargement that was moderate at 3 and 8 weeks, and progressed at 12 and 21 weeks of age (all p<0.05 vs. WT). Atrial contractility and sarcoendoplasmic Ca2+ ATPase (SERCA) 2a protein expression were reduced in isolated left A3high atria at the age of 14 weeks. Fibrosis was present in left A3high atria at 14 weeks, but not at 5 weeks of age. A3low mice had first-degree AV block without arrhythmias or structural changes. Conclusions: Heart-directed overexpression of A3AR resulted in gene dose-dependent AV block and pronounced sinus nodal dysfunction in vivo. Profound bradycardia heralded atrial and ventricular dilatation, dysfunction, and fibrosis. In contrast to A1 adenosine receptors (A1AR), the effects of A3AR overexpression were attenuated during exercise. This may have implications for the physiology of sinus nodal regulation and for therapeutic attempts to increase the expression of adenosine receptors.