Abstract 17106: Rapamycin Increases Infarct Size and is Detrimental During Acute Ischemia-Reperfusion
Background: The inflammatory response associated with myocardial ischemia and reperfusion has been shown to have both cardioprotective and damaging mechanisms. The effect of immunosuppression in this setting is unknown. We hypothesized that treatment with the immunosuppressant rapamycin prior to acute ischemia/reperfusion injury would be detrimental to cardiac function.
Methods/Results: Male Yorkshire swine (16-19 kg) received either no drug (controls) or were given 4mg of rapamycin daily. After two weeks of treatment, all animals underwent sternotomy and the mid-LAD was occluded for 60 minutes followed by 120 minutes of reperfusion. Left ventricular pressure-volume data was collected throughout the operation. The ischemic and infarct areas were measured by triphenyltetrazolium chloride staining. Rapamycin levels were significantly higher in the treated animals compared to controls. Animals pre-treated with Rapamycin had significantly lower cardiac output (p=0.016), stroke work (p=0.022), and maximum power (p=0.017) compared to controls. There was nearly a two fold increase in infarct size in the treated animals compared to controls with no significant difference in the size of the ischemic territories between groups. Protein expression of p-SP6, p-P70S6K, and p-4E-BP1 were all significantly higher in the rapamycin treated group (Table).
Conclusions: Pre-treatment with the immunosuppressant rapamycin, an inhibitor of mTOR, diminished cardiac function by several measures and increased infarct size after ischemia/reperfusion. Interestingly, the downstream substrates of mTOR were more highly expressed in the rapamycin treated animals. These results suggest that patients taking rapamycin, or carrying stents coated with rapamycin may not only be at higher risk for cardiac events but may also be predisposed to poorer outcomes after such events. The mechanism remains to be determined.
- © 2011 by American Heart Association, Inc.