Grant: Operating 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. Cardiovascular disease appears to follow a day-night rhythm as well. For example, heart attacks (myocardial infarction or MI) are more likely to occur in the morning than at night. Disturbing rhythms (e.g. shift work or sleep disorders) increases likelihood of heart disease and death. In preliminary studies we show remarkable variation in gene activity in the heart; 13% of heart genes display rhythmic expression over 24-hour diurnal cycles. Moreover, we show that disturbing rhythms worsens heart disease; damage subsides only when rhythm disruption ceases. Rhythm disturbance is a major health risk. We further demonstrate that timing treatments with body rhythms (chronotherapy) may improve outcome of patients with heart disease. However circadian control of cardiac remodeling is a major yet relatively unrecognized issue. We will now determine i) how rhythms and their disturbance contribute to cardiac dysfunction, ii) the molecular circadian mechanisms that affect the structure and function of the heart and how it remodels in disease, and iii) how timing of therapy with ACE inhibitors can improve outcome post-MI. This represents a fundamental new approach to understanding and treating heart disease. This novel strategy can ultimately benefit patients in clinical settings.