Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model

Abstract

Background: Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis.

Objective: To determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI.

Methods: Rats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI) . Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up.

Results: Treatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% ± 2.5% vs 43.3% ± 1.7% in control; P < .01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6% ± 2.6% vs 43.3% ± 1.7% in control; P < .01) and decreased VT inducibility (9.1% vs 68.4% in control; P < .05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction.

Conclusions: Treatment with an A2BAdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A2BAdoR antagonists may be a new target for the prevention of adverse remodeling after MI.

Keywords: 5′-N-ethylcarboxamidoadenosine; A(2B) adenosine receptor; A(2B)AdoR; ACEI; APD(80); CV; EF; Fibrosis; LV; MI; Myocardial infarction; NECA; Optical mapping; PCL; Remodeling; VT; Ventricular tachycardia; action potential duration at 80% repolarization; angiotensin-converting enzyme inhibitor; conduction velocity; ejection fraction; left ventricular; myocardial infarction; pacing cycle length; ventricular tachycardia.