Circadian rhythmic and environmental determinants of 24-hour blood pressure regulation in normal and hypertensive conditions

The biology of human beings is not constant during the 24 hours, menstrual cycle, and year as inferred by the concept of homeostasis. Instead, most of life's functions vary predictably and often dramatically over these and other time periods. Circadian rhythms, in particular, are of great importance to clinical medicine in general (565) and to CV medicine in particular. In this chapter, we discussed in great detail the 24-hour patterns of BP, HR and other CV hemodynamics in normal and hypertensive states. These patterns arise from circadian rhythms in neuroendocrine and other functions plus day-night differences in physical activity, mental strain, and posture. In hypertensive patients at risk to CV events, the staging of the peak and trough of these critical circadian rhythms gives rise to an increased vulnerability to angina, myocardial infarct, sudden cardiac death, and stroke in the morning when environmental triggers of CV events tend to be most intense. Not only does the vulnerability to myocardial infarct vary during the 24 hours, but so does its clinical course (566). Symptom onset between 6.00h and noon is associated with greatest infarct size, whereas an onset time between midnight and 6.00h is associated with significantly lower risk of circulatory arrests from ventricular arrhythmias (567). Moreover, the circadian-time-dependent occurrence of myocardial infarction is likely to affect the success of thrombolysis, which has been shown to be less in patients who have a morning onset (568). Finally, the body’s biological time structure can also exert significant influence on the pharmacokinetics and effects of antihypertensive and other medications used to treat hypertensive and other CV conditions. This will be discussed in depth in another chapter of this volume. Nonetheless, the prominent circadian patterns in BP, myocardial oxygen demand, coagulation and CV events bring to fore the concept of chronotherapeutics — medications which proportion their concentration during the 24 hours in synchrony with day-night differences in the biological requirement for therapy. In the United States two verapamil chronotherapies are now approved by the Food and Drug Administration. One is approved for the treatment of angina pectoris and both are approved for the treatment of hypertension. These chronotherapies have been shown to be effective in attenuating the rapid rise of BP in morning and elevated level during daytime activity without inducing super-dipping of BP during sleep. Nonetheless, it is not yet known whether they afford primary protection against CV morbidity and morality in the long term. The answer to this question must await the completion of the CONVINCE trial that entails the comparison of conventional equal-interval, equal-dose, ß-blocker and diuretic therapy versus verapamil chronotherapy dosed once daily in the evening (569).