Acute myocardial infarction is among the most important predictors of perioperative short- and long-term morbidity and mortality in surgical patients. As our population ages, more high-risk cardiac patients will undergo surgery, and perioperative myocardial infarction is very likely to be an increasing problem. Current therapeutic interventions such as percutaneous coronary intervention in combination with anticoagulation and platelet inhibitors, however, may not be suitable in the perioperative setting due to the risk of bleeding from the surgical site. Therefore additional therapeutic approaches that would render the myocardium more resistant to ischemia and attenuate myocardial reperfusion injury are an intense area of investigation. Epidemiologic studies in humans indicate that susceptibility to ischemic myocardial tissue injury is time-of-the-day dependent, with more severe injury occurring in the early morning hours after a longer period without daylight. To address the possibility that light-exposure could function to attenuate ischemic myocardial injury, we pre-treated mice for different periods with intense light. Surprisingly, we observed a time-dependent reduction in myocardial infarct size and troponin I release following light treatment. A search for light inducible circadian rhythm proteins revealed a robust induction of cardiac Period 2 (Per2) protein levels upon intense light exposure. Proof-of-principle studies showed that light mediated cardio-protection or Per2 induction was abolished in mice lacking the Per2 protein or mice without the ability to sense light, respectively. Based on these findings, we hypothesize that intense light therapy provides robust cardio- protection by stabilizing cardiac Per2, thereby leading to concomitant cardio-protection from ischemia. To address this hypothesis, we designed three specific aims: 1. Define the dose, timing, and tissue specific source for light-elicited Per2 stabilization and cardio-protection, 2. Study molecular mechanisms of how light therapy functions to provide cardio-protection from ischemia and reperfusion, 3. Elucidate the influence of intense light therapy on the stabilization of PER2 protein in humans. The long-term goal of our studies is to introduce intense light therapy into the hospital to preven or treat myocardial injury in surgical patients, the most common cause of postoperative morbidity and mortality. We anticipate that successful completion of our Aims will allow us to initiate a clinical study on pre-operative intense light therapy in surgical patients towards the ed of the funding period.
Perioperative myocardial infarction is a major contributor to mortality in surgical patients. Observations that myocardial ischemia could be worse after longer periods without daylight pointed us towards intense light as therapeutic strategy in perioperative myocardial ischemia. In fact, a light dependent circadian rhythm protein was found as molecular basis for intense light elicited cardio-protection. By using murine studies on tissue specificity, drug based therapy and metabolism in vivo in combination with human studies, we hope to establish intense light therapy in surgical patients to prevent or treat myocardial infarction.
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