Chronobiology and chronotherapy of ischemic heart disease

The occurrence of the clinical manifestations of ischemic heart disease (IHD)--myocardial ischemia and angina pectoris, acute myocardial infarction, and sudden cardiac death--is unevenly distributed during the 24 h with greater than expected events during the initial hours of the daily activity span and in the late afternoon or early evening. Such temporal patterns result from circadian rhythms in pathophysiological mechanisms plus cyclic environmental stressors that trigger ischemic events. Both the pharmacokinetics (PK) and pharmacodynamics (PD) of many, though not all, anti-ischemic oral nitrate, calcium channel blocker, and beta-adrenoceptor antagonist medications have been shown to be influenced by the circadian time of their administration. The requirement for preventive and therapeutic interventions varies predictably during the 24 h, and thus therapeutic strategies should also be tailored accordingly to optimize outcomes. During the past decade, two first generation calcium channel blocker chronotherapies have been developed, trialed, and marketed in North America for the improved treatment of IHD. Nonetheless, there has been relatively little investigation of the administration-time (circadian rhythm) dependencies of the PK and PD of conventional anti-ischemic medications, and there has been little progress in the development of new generation IHD chronotherapies. Available epidemiologic, pharmacologic, and clinico-therapeutic evidence demonstrates how the chronobiologic approach to IHD can contribute new insight and opportunities to improve drug design and drug delivery to enhance therapeutic outcomes.