Grant: Project Grant

Body processes in mammals cycle with a 24-hour day-night (circadian or diurnal) rhythm, which is controlled by molecular clocks in the brain and other tissues such as the heart. Our cardiovascular system appears to follow a day-night rhythm as well. For example, heart rate and blood pressure are highest during the day when we are awake and lowest at night during sleep. Heart disease also exhibits a rhythm, as heart attacks and sudden cardiac death are more likely to occur in the morning than at night. In earlier and preliminary studies we used murine heart disease models and showed that the circadian mechanism underlies time of day variations in the genes and proteins in the heart, cardiac structure and function, and pathophysiologic responses to disease. Several of our high impact murine experimental studies reveal clear translational potential for applying circadian biology to benefit treatment of heart disease. 1) Timing drug therapies to the body's physiologic and molecular rhythms can improve drug efficacy and benefit outcome of heart disease. 2) Minimizing circadian rhythm disruption in the first few days of critical illness can improve healing - this especially has implications for intensive care units and multi-bedded wards where daily rhythms are disturbed. Here we intend to pursue the insights gained from our most promising circadian rhythms research studies, and apply them to the treatment of clinically relevant myocardial ischemia-reperfusion (mI/R, heart attack). We will demonstrate efficacy and uncover the direct role of the circadian mechanisms in rodent mI/R models, followed by vital testing in our new pre-clinical centre with state-of-the-art imaging relevant to humans (echocardiography, cardiac magnetic resonance imaging). Reconsidering how we practice medicine, by translational application of circadian biology to clinical cardiology (and medicine in general), is a fundamental new approach to understanding and treating heart disease.