Journal
HEART RHYTHM
Volume 11, Issue 1, Pages 101-109Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2013.10.023
Keywords
Myocardial infarction; Fibrosis; Optical mapping; Remodeling; Ventricular tachycardia
Categories
Funding
- Gilead Sciences, Inc.
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BACKGROUND Remodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A(2B) adenosine receptor (A(2B)AdoR) has been implicated in promoting fibrosis. OBJECTIVE To determine the effects of GS-6201, a potent antagonist of the A(2B)AdoR, 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 A(2B)AdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A(2B)AdoR antagonists may be a new target for the prevention of adverse remodeling after MI.
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