Molecular Clock Mechanisms and Circadian Rhythms Intrinsic to the Heart

Circadian rhythms are the external expression of an internal clock mechanism that measures daily time.1 Periodic environmental cues entrain or set the circadian clocks. The daily light-dark cycle represents the most dominant and potent entraining stimulus in mammals. An entrained clock coordinates physiological events to the 24-hour day. Normally, cardiovascular or hemodynamic parameters, such as heart rate and blood pressure, exhibit variations consistent with circadian rhythm. Additionally, several types of acute pathological cardiac events exhibit circadian or at least diurnal rhythm patterns. Specifically, the incidences of acute myocardial infarction, myocardial ischemia, out-of-hospital cardiac arrest, ventricular tachycardia, postmyocardial infarction, and sudden death in heart failure all vary according to the time of day.2–5 Also, diurnal rhythms can influence degree and form of cardiac hypertrophy and remodeling.6,7 For instance, the degree of nocturnal blood pressure elevation in patients with systemic hypertension correlates with the severity and concentricity of left ventricular hypertrophy.8,9 Investigators postulate that these circadian or diurnal variations depend on centrally mediated autonomic or neurohumoral activation. However, peak incidence for some acute events, such as sudden death, does not temporally correspond to the circadian sympathetic activation. Thus, alternative inputs or mechanisms for these rhythm patterns have been postulated. Regardless of the input, the intrinsic clock mechanism must respond and regulate some of the circadian rhythms within the heart itself.The intrinsic response elements for the putative external circadian inputs had not until recently been identified or characterized in the heart.10,11 Circadian rhythms are controlled by a transcriptional feedback system fluctuating as a function of the light-dark cycle. Molecular control of a circadian clock mechanism has been described in detail in the fruit fly.12 Similarities between the core clock mechanisms in fruit flies and mice occur with both exhibiting interlocking positive and negative transcriptional and translational …