Interaction of exercise and simvastatin on myocardial ischemia-reperfusion (I/R) injury and post-ischemic cardiac function
Simvastatin is one of the statins, which are a class of drugs originally developed to fight cardiovascular disease by lowering cholesterol. However, it is now clear that they have effects independent of cholesterol. For example, statin therapy, like exercise, induces adaptations within the heart that protect it against I/R injury. Patients are frequently advised to undergo a combination treatment of statins and chronic exercise, although little is known about how this combination treatment affects cardioprotective adaptations. Both treatments appear to exert their cardioprotective effects through different mechanisms, therefore it appears plausible that combining the two treatments would provide added cardioprotection than either treatment alone. Purpose: To investigate the effects of a combination treatment of statins and exercise upon parameters of post-ischemic myocardial function and damage. Methods: Female Sprague-Dawley rats (6 months of age) were separated into 4 groups for a period of 4 weeks: Sedentary (S, n=10), sedentary plus 10 mg simvastatin (Zocor®)/kg body wt/ day (SD, n=9), exercise (R, n=9), and exercise plus simvastatin (RD, n=9). R and RD were exercised identically on a treadmill for 5 days/week at an intensity of about 70% VO2max and for a duration that was gradually increased to 60 min/day. Twenty-four hrs following the last exercise bout, isolated perfused working hearts were subjected to 30 min of global ischemia followed by 30 min of normoxic reperfusion. Coronary effluents were used to determine lactate dehydrogenase (LDH) leakage and prostaglandin generation. Results: Cardiac function was similar in all groups prior to ischemia. Post I/R recovery of cardiac function in S was 17.6 [greater than or equal to]6.6% of pre-ischemic cardiac output times systolic pressure. Recovery was significantly higher in SD (37.7[greater than or equal to]7.7%) and R (40.1[greater than or equal to]7.8%) and tended to be highest in RD (49.7[greater than or equal to]7.1%). SD had significantly higher pre-ischemic coronary flow per g heart weight (CF/g) than all other groups. At 10 min post-ischemia, simvastatin treatment significantly increased CF/g compared to S (p<0.05). Exercise had an effect on increasing post-ischemic myocardial efficiency and RD had significantly higher post-ischemic myocardial efficiency vs. S (p<0.05). Compared to S, LDH leakage during reperfusion was dramatically decreased in SD, R and RD by approximately similar amounts. Simvastatin treatment doubled the basal production of protective prostaglandins, whereas exercise did not significantly alter their production and combining both treatments yielded a lower prostaglandin release than simvastatin treatment. SD had s significantly higher basal prostaglandin release than R (p<0.05). Conclusion: Although the combination treatment of simvastatin and exercise did not result in a statistically significant addition in cardioprotection compared to either treatment alone, there was a trend for improved parameters of post-ischemic cardiac function and damage upon combining both treatments compared to each treatment alone. Specifically, the prostaglandin, CF/g and efficiency data suggest that exercise and statininduced cardioprotection against I/R injury appears to occur by different mechanisms and combining the two treatments may provide greater protection than either alone.