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Chronotherapeutic applications in cardiovascular conditions
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States of wakefulness and sleep have long inspired not only poets, artists and musicians to create beautiful metaphorical descriptions of these phases of cognition; they have fascinated cardiologists and other medical professionals as well.
In landmark research, Muller and colleagues reported a bi-modal distribution for MI, with predominance in the morning hours. Sympathovagal balance, a major determinant of circadian variation in BP and CV function, is integrally related to sleep-wake activity. It has been postulated that the observed increased risk for acute MI in the evening or nighttime in a sub-population of patients with LV dysfunction, diabetes and congestive HF may be related to increased sympathetic tone which leads to an abnormal continual elevation in BP throughout a 24-hour period. Many of these patients present with chronic kidney disease and may benefit from nighttime reductions in BP.
In a recent study by Minutolo et al dosing of antihypertensive agents according to principles of circadian variation led to restoration of a normal circadian pattern of CV hemodynamics and significantly decreased proteinuria in a group of individuals with chronic renal disease presenting as “non-dippers.” This study gives credence to the concept that chronotherapeutic dosing strategies lead to improved patient outcomes. There are more outcomes studies on the horizon evaluating the effects of dosing medications according to principles of circadian variation.
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Supraventricular and ventricular arrhythmias and occurrence of sudden cardiac death also manifest a bi-modal distribution in patterns of occurrence. Considering that atrial fibrillation is the most commonly occurring arrhythmia, assessment of heart rate variability and provision of adequate rate control for this population is important, particularly during these periods of risk. Beta-adrenergic receptor antagonists and aspirin have been shown to attenuate morning risk of cardiac events. Further study of chronotherapeutic applications with beta adrenergic antagonists and other rate controlling agents is warranted.
One of the major concerns with use of antiarrhythmic drugs is their proarrhythmic effect. Two clinical markers for predicting risk for proarrhythmia include the QT-interval and T-wave morphology. Considering that heart rate also demonstrates a circadian pattern of elevation and decline, establishment of a “range” of QTc measurements for a given individual during the course of a 24-hour period may give a better indication of whether or not certain times of the day represent vulnerable periods for proarrhythmia for that individual. Isolated random baseline readings may not reveal transient QTc prolongation during vulnerable periods. Such a range of QTc readings may help to determine if dose adjustment of antiarrhythmics is needed to maintain a safe and effective QTc, particularly during vulnerable periods, such as initiation or dosage escalation of therapy. Evening administration of beta-adrenergic antagonists may ensure adequate rate control and cardioprotection versus the early morning surges in sympathetic tone. As competitive antagonists of the adrenergic system, these agents dynamically control heart rate and sympathetic tone in response to increased sympathetic outflow.
Other rate controlling agents, such as calcium channel blockers, which also reduce sympathetic outflow, may be considered for evening administration as well. Further studies of response to such therapies may provide more information on beneficial effects on patient outcomes.
For more information:
- Hannah Cooke Ariel, PharmD, is an integrative medicine specialist and researcher for the Boston-based Natural Standard Research Collaboration.
- Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79:733-43.
- Minutolo R, Gabbai FB, Borrelli S, et al. Changing the timing of antihypertensive therapy to reduce nocturnal blood pressure in CKD: an 8-week uncontrolled trial. Am J Kidney Dis. 2007;50:908-17.
- Johnstone MT, Mittleman M, Tofler G, Muller JE. The pathophysiology of the onset of morning cardiovascular events. Am J Hypertens. 1996;9:22S-28S.