It is known that adenosine reduces myocardial injury when given at reperfusion. We previously gathered indications that adenosine may beneficially affect left ventricular (LV) remodelling. However, the long-term effects of adenosine on cardiac repair after myocardial infarction have not been addressed.Methods
18 adult male Wistar rats were subjected to acute myocardial infarction by permanent ligation of the left anterior descending coronary artery and were divided in 3 groups (n=6 each): control (vehicle), 2-chloroadenosine (CADO, stable analogue of adenosine) and CADO with the nonselective antagonist of adenosine receptors 8-sulfophenyltheophilline (8-SPT). Drugs were administered intraperitoneally twice daily for 2 months, starting 7 days after induction of myocardial infarction. 6 additional rats were sham-operated. Cardiac function was evaluated at 48 hours, 1 month and 2 months by 18F-Fluorodeoxyglucose positron emission tomography.Results
1-month after ligation, all rats displayed cardiac dilatation as attested by increased LV volumes and stroke volume. Dilatation was amplified after 2 months, and LV ejection fraction was impaired (41% for LAD-occluded rats vs 57% for sham-operated rats, P < 0.001). Treatment with CADO preserved cardiac function, as attested by increased EF during the 2-months follow-up period ( + 22% for CADO-treated rats vs -7% for LAD-occluded rats, P=0.03), and decreased LV volumes. Fibrosis (assessed by Masson trichrome staining) was decreased and angiogenesis (CD31 staining) was increased in the border zone of hearts from CADO-treated animals. Segmental contractility in remote, infarct and border zones was assessed through mean values of myocardial thickening. Myocardial thickening was decreased in non-infarcted segments of LAD-occluded rats, except after CADO treatment ( + 40% for CADO-treated rats vs -12% for LAD-occluded rats, P < 0.05). Cardiomyocytes proliferation (PCNA staining), which was stimulated after ligation, was unaltered by CADO treatment. All the beneficial effects of CADO were abolished by blockade of adenosine receptors with 8-SPT.Conclusion
Chronic administration of a stable analog of adenosine preserves cardiac function after acute myocardial infarction. The mechanisms involve decreased fibrosis, increased revascularization and preservation of contractility. Therefore, our results suggest that adenosine may be useful to stimulate cardiac repair and limit the development of heart failure after myocardial infarction.