Of Mice and Men

Abstract

Circadian rhythms in humans significantly influence cardiovascular biology. The well-known early morning peak of adverse cardiovascular events, such as acute myocardial infarction and sudden cardiac death, are highly correlated with circadian changes in coagulation factors, platelet activation,1 and endothelial function2 that act to increase susceptibility to thrombosis in the morning. See Research Commentary, p e110 Cardiovascular circadian regulation is hierarchical. Specialized neurons in the suprachiasmatic nucleus entrained by sunlight produce 24-hour cycles of physiological signals that include changes in core body temperature and glucocorticoid production that act in combination with direct neural input to synchronize peripheral clock programs in the heart. Autonomously functioning clocks in cardiac myocytes in turn regulate circadian gene expression through complex transcription–translation feedback loops involving multiple core clock genes that may influence up to 10% of the transcriptome. As a result, cyclic changes in protein expression in cardiomyocytes may exert broad effects on myocardial metabolism and energetics. The ability to change substrate utilization in the setting of myocardial ischemia to a more oxygen-efficient strategy may confer myocardial protection and reduce infarct size. Because many of the modulators of glucose and free fatty acid metabolism are controlled by cardiomyocyte clock programs, the tolerance to ischemia in humans may demonstrate a circadian-dependent variability, as recently demonstrated by Durgan et al3 in a closed-chest mouse infarction model. By performing 45-minute coronary occlusions in the mouse at different time points during a 24-hour cycle (12-hour light/12-hour dark), they were able to demonstrate that infarct size resulting from a coronary occlusion applied at the time of the light to dark transition (zeitgeber time, [ZT]12) was 3.5 times greater than if the same coronary occlusion was applied 12 hours earlier (ZT0) at the onset of light. At 1 month, hearts that had undergone coronary occlusion at ZT0 had improved …