Abstract 3876: Diurnal Variation in Myocardial Ischemia/Reperfusion Tolerance: Mediation by the Circadian Clock within the Cardiomyocyte
Diurnal variations in cardiovascular physiology (e.g. blood pressure and heart rate) and pathophysiology (e.g. myocardial infarction (MI)) exist. For example, humans exhibit a marked increase in MI frequency during the early hours of the morning. However, MIs that occur during the evening are more likely to result in subsequent heart failure (i.e. decreased tolerance). These phenomena have largely been attributed to rhythms in neurohumoral factors. Recent studies suggest a role for intracellular circadian clocks in modulating cardiovascular function. We therefore hypothesized that the cardiomyocyte circadian clock regulates tolerance of the heart to ischemia/reperfusion (I/R). Wild-type (WT) and cardiomyocyte-specific clock mutant (CCM) mice were subjected to 45 minutes of ischemia (through left anterior descending coronary artery occlusion) followed by 24 hours of reperfusion. The closed chest model was utilized to minimize acute influences of an immune response. Animals were housed in a 12hr: 12hr light:dark cycle, and I/R and sham interventions were performed either at the dark-to-light transition (ZT0) or the light-to-dark transition (ZT12). Similar to clinical observations, echocardiographic assessment of cardiac function revealed a significant reduction in ejection fraction and fractional shortening following I/R at ZT0, but not at ZT12 (Table⇓). Release of cardiac troponin I and induction of myocardial BNP were also greatest in WT mice subjected to I/R at ZT0, versus ZT12. These diurnal variations in I/R tolerance, as assessed at functional, humoral, and transcriptional levels, were completely absent in CCM hearts. Diurnal variations in infarct size were also observed in WT, but not CCM, hearts. Surprisingly, infarct size was greater when I/R occurred at ZT12 versus ZT0. Taken together, these observations expose a marked diurnal variation in myocardial I/R tolerance, which is mediated by the circadian clock within the cardiomyocyte.