Circadian rhythms in cardiac arrhythmias and opportunities for their chronotherapy

It is now well established that nearly all functions of the body, including those that influence the pharmacokinetics and pharmacodynamics of medications, exhibit significant 24-hour variation. The electrical properties of the heart as well as cardiac arrhythmias also vary as circadian rhythms, even though the suboptimal methods initially used for their investigation slowed their identification and thorough characterization. The application of continuous Holter monitoring of the electrical properties of the heart has revealed 24-hour variation in the occurrence of ventricular premature beats with the peak in events, in diurnally active persons, between 6 a.m. and noon. After the introduction of implantable cardioverter-defibrillators, ventricular tachycardia or fibrillation were also found to peak in the same period of the day. Even defibrillator energy requirements show circadian variation, thus supporting the need for a temporal awareness in the therapeutic approach to arrhythmias. Imbalanced autonomic tone, circulating levels of catecholamines, increased heart rate and blood pressure, all established determinants of cardiac arrhythmias, show circadian variations and underlie the genesis of the circadian pattern of cardiac arrhythmias. Arrhythmogenesis appears to be suppressed during nighttime sleep, and this can influence the evaluation of the efficacy of antiarrhythmic medications in relation to their administration time. Unfortunately, very few studies have been undertaken to assess the proper timing (chronotherapy) of antiarrhythmic medications as means to maximize efficacy and possibly reduce side effects. Further research in this field is warranted and could bring new insight and clinical advantage

Circadian variation of blood pressure: the basis for the chronotherapy of hypertension

Ambulatory blood pressure (BP) measurements present a close correlation with target organ damage and cardiovascular events, including myocardial infarction, stroke and cardiovascular mortality. With the use of this measurement technique, a significant circadian variation has been shown to characterize BP. This circadian BP variation, although affected by a variety of external factors, represents the influence of internal factors such as ethnicity, gender, autonomic nervous system tone, vasoactive hormones, and hematologic and renal variables. In most individuals, BP presents a morning increase, a small post-prandial valley, and a deeper descent during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced or even reversed. This cannot be determined by traditional clinical or home BP assessments. Subjects with a diminished nocturnal BP decline (non-dipper pattern) have a significantly worse prognosis than the ones with a normal dipper pattern. In particular, the non-dipper circadian BP pattern represents a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia and myocardial infarction. The normalization of the circadian BP pattern to a dipper profile is a novel therapeutic goal, and accumulating medical evidence suggests this can delay the progression towards the renal and cardiovascular pathology known to be a consequence of the non-dipper BP pattern. The features of the circadian BP profile have direct implications for improving the drug-delivery of antihypertensive therapies as well as the qualification of patients for medication trials and assessment

(Chronobiology of hypertension)

Chronobiological diagnosis and therapy of hypertensio

Role of sleep-wake cycle on blood pressure circadian rhythms and hypertension

Stages of different depth characterize the temporal organization of sleep. Each stage exerts an effect on blood pressure (BP) regulation and contributes to its 24-h variation. The main determinant of the circadian influences of sleep and wakefulness on BP is the daytime sympathetic and nighttime parasympathetic prevalence, but many other physiologic mechanisms known either to induce sleep or determine arousal may play an important role in the mediation of sleep influences on BP. Alteration of one or more of such mechanisms may be reflected in altered circadian BP rhythms. Sleep- and arousal-related mechanisms and phenomena that affect circadian BP rhythms include neurohumoral sleep factors (arginine vasopressin, vasoactive intestinal peptide, somatotropin, insulin, steroid hormones and metabolites, and serotonin among others) and waking factors (corticotropin-releasing factor, adrenocorticotropin, thyrotropin-releasing hormone, endogenous opioids, and prostaglandin (E(2))). Pathologic respiratory variations (sleep-disordered breathing) and insomnia are major causes of the sleep-related alteration of the circadian BP profile, including loss of the expected normal decline in BP by 10-20% from the daytime level. A great number of medical disorders can cause insomnia, but objective sleep studies have been performed only in a minority of them. Overall, the sleep-related pathophysiological mechanisms actually involved in causing altered circadian BP rhythms in different normotensive and hypertensive conditions are not completely understood. In any case, changes in the circadian BP rhythm are known to be strongly related to one's risk of cardiovascular morbidity and mortality, thus representing strong prognostic indicators worthy of further investigation

Chronotherapy of hypertension

This chapter addresses the chronotherapy of hypertension. Chronotherapeutics is the purposeful timing of medications, whether or not they utilize special drug-release technology, to proportion their serum and tissue concentrations in synchrony with known circadian rhythms in disease processes and symptoms as a means of enhancing beneficial outcomes and/or attenuating or averting adverse effects (Smolensky and Haus, 2001). The concept of chronotherapeutics, although relatively new to hypertension and cardiovascular medicine, was first introduced and proven worthy in clinical medicine in the 1960s; the morning alternate-day corticosteroid tablet dosing schedule was introduced as a convenient means of minimizing the adverse effects of such anti-inflammatory medications as prednisone and methylprednisolone (Harter et al., 1963; Reinberg, 1989). The chronotherapy of hypertension takes into account the clinically relevant features of the 24h pattern of blood pressure (BP), e.g., the accelerated morning rise at the commencement of diurnal activity and the extent of decline during nighttime sleep, plus potential administration-time (circadian rhythm) determinants of the pharmacokinetics and dynamics of individual antihypertensive medications. Herein, we focus on the chronotherapy of hypertension; however, as necessary background we first present the major concepts and mechanisms of biological timekeeping

Biological rhythms, medication safety, and women's health

Biological processes and functions in women are well organized in time, as evidenced by the expression of ultradian (high frequency), circadian ( approximately 24-hour), circamensual ( approximately monthly), and circannual ( approximately yearly) rhythms and by the changes that occur with menarche, reproduction, and menopause. Attributes of women's circamensual structure have been explored in depth, particularly with regard to fertility/infertility and birth control. However, the role of 24-hour and other rhythms in health, disease, and treatment has been little studied. The symptom intensity of a variety of chronic medical conditions is rhythmic, as is the risk of severe events, such as stroke and myocardial infarct (MI). Improving the safety, efficacy, and preventive qualities of medications requires the understanding of how rhythms impact drug pharmacokinetics and pharmacodynamics. The therapeutic and adverse effects of prescription and nonprescription medications widely used by women can vary markedly with the (circadian) time of administration. Circadian rhythm-dependent differences in the safety of medications are particularly relevant to pregnant women; laboratory animal studies show that the fetal toxicity of various treatments varies not only with developmental stage but also with circadian time. Rhythm-dependent differences in the actions of medications are also of great importance to perimenopausal and postmenopausal women, who are advised to ingest prescribed pharmacotherapy for osteopenia and osteoporosis in the morning to minimize the risk of adverse effects and, as a consequence, may elect to take other medications at times not recommended in the instructions for their use. Medication trials must be comprehensive and representative of women and men of different life stages, ethnicities, and likely times (morning vs. evening) of drug use

Chronotherapy of hypertension: administration-time-dependent effects of treatment on the circadian pattern of blood pressure

Some specific features of the 24-hour blood pressure (BP) pattern are linked to the progressive injury of target tissues and the triggering of cardiac and cerebrovascular events. Thus, there is growing interest in how to best tailor the treatment of hypertensive patients according to the circadian BP pattern of each individual. Significant administration-time differences in the kinetics (i.e., chronokinetics) plus beneficial and adverse effects (i.e., chronodynamics) of antihypertensive medications are well known. Thus, bedtime dosing with nifedipine GITS is more effective than morning dosing, while also significantly reducing adverse effects. The dose-response curve, therapeutic coverage, and efficacy of doxazosin GITS are all markedly dependent on the circadian time of drug administration. Moreover, valsartan administration at bedtime, as opposed to upon wakening, results in an improved diurnal/nocturnal BP ratio, increased percentage of controlled patients, and significant reduction in urinary albumin excretion in hypertensive patients. Chronotherapy provides a means of individualizing the treatment of hypertension according to the circadian BP profile of each patient, and constitutes a new option to optimize BP control and to reduce the risk of cardiovascular disease (myocardial infarction and stroke) and of end-organ injury of the blood vessels and tissue of the heart, brain, kidney, eye, and other organs