Circadian rhythm and environmental determinants of blood pressure regulation in normal and hypertensive conditions

This chapter first discusses the fundamental properties of biological rhythms and biological timekeeping. It provides an in-depth discussion of the role of circadian (24-h) rhythms in blood pressure regulation and day-night patterns in common cardiovascular diseases

Ambulatory blood pressure monitoring - Application to clinical medicine and antihypertension medication trials

The wide use of ABPM has resulted in greater appreciation of the circadian time structure of BP variability and its clinical relevance. It is now recognized that the day-night change in BP results from an interplay of circadian rhythms in neurohumoral mechanisms coupled with temporal patterns in physical activity and mental load. The composite effect and balance of these endogenous and exogenous cyclic phenomena give rise to elevated BP during diurnal activity and reduced BP during nighttime repose in both normotension and uncomplicated essential hypertension. The balance is frequently disturbed in complicated and secondary forms of hypertension causing gross alteration of the 24-hour BP profile. ABPM also reveals the efficiency of antihypertensive treatment throughout the 24 hours and as a function of drug administration time. The pharmacokinetics and/or pharmacodynamics of antihypertensive medications have been demonstrated to vary with ingestion time. Such time-dependencies arise from circadian rhythms in BP and underlying mechanisms. The effect of antihypertensive medications is not simply superimposed upon endogenous bioperiodicities. Rhythms in neurohumoral mechanisms of BP control may modulate treatment effect. Certain aspects of the shape of the 24-hour BP profile, such as the magnitude of the morning surge and nocturnal decrease, have been implicated as determinants of morbid and mortal cardiovascular events. One large clinical multicenter investigation, known as the CONVINCE (Controlled Onset Verapamil Investigation of Clinical Endpoints) trial, is aimed at assessing the impact (cardiovascular morbidity and mortality) of verapamil chronotherapy over standard diuretic or beta anatagonist treatment in hypertensive patients with at least one risk factor of coronary heart disease. ABPM will help ascertain to what extent depression of the morning surge in BP relates to reduction in cardiac morbidity and mortality in this as well as other such trials. In any event, the importance of ABPM and the indices derived from its application are just beginning to be appreciated and explored

Chronopharmacology and chronotherapy of cardiovascular medications: relevance to prevention and treatment of coronary heart disease

Biological functions and processes, including cardiovascular ones, exhibit significant circadian (24-hour) and other period rhythms. Ambulatory blood pressure assessment reveals marked circadian rhythms in blood pressure both in normotensive persons and hypertensive patients, whereas Holter monitoring substantiates day-night patterns in electrocardiographic events of patients with ischemic heart disease. The concept of homeostasis, that is, constancy of the milieu interne, which has dominated the teaching, research, and practice of medicine during the 20th century,is now being challenged by emerging concepts from the field of chronobiology-the science of biological rhythms. Epidemiologic studies document the heightened morning-time risk of angina, myocardial infarction, and stroke. Circadian rhythms in coronary tone and reactivity, plasma volume, blood pressure, heart rate, myocardial oxygen demand, blood coagulation, and neuroendocrine function plus day-night patterns in the nature and strength of environmental triggers all contribute to this morning vulnerability. Homeostatically devised pharmacotherapies, that is, medications formulated to ensure a near-constant drug concentration, may not be optimal to adequately control diseases that vary in risk and severity during the 24 hours. Moreover, circadian rhythms in the physiology of the gastrointestinal tract, vital organs, and body tissues may give rise to administration-time differences in the pharmacokinetics and effects of therapies. Thus the same medication consumed in the same dose under identical conditions in the evening and morning may not exhibit comparable pharmacokinetics and dynamics. New technology makes possible chronotherapy, that is, increase of the efficiency and safety of medications by proportioning their concentrations during the 24 hours in synchrony with biological rhythm determinants of disease. The chronotherapy of peptic ulcer disease achieved by the evening dosing of H-2-receptor antagonists and of asthma by the evening dosing of special drug delivery forms of theophylline and morning methylprednisolone administration has proven to be beneficial. Controlled-onset extended-release verapamil constitutes the first chronotherapy of essential hypertension and ischemic heart disease; once-a-day bedtime dosing results in a high drug concentration in the morning and afternoon and a reduced one overnight. Studies demonstrate effective 24-hour control of blood pressure, including the attenuation of its rapid rise in the morning, without induction of nighttime hypotension. Moreover, this formulation effectively controls angina, especially in the morning when the risk of ischemia is greatest. Determination of the role of verapamil chronotherapy in the primary prevention of cardiovascular morbidity and mortality awaits the results of the CONVINCE trial now in progress

Ethics and methods for biological rhythm research on animals and human beings

This article updates the ethical standards and methods for the conduct of high-quality animal and human biological rhythm research, which should be especially useful for new investigators of the rhythms of life. The editors of Chronobiology International adhere to and endorse the Code of Conduct and Best Practice Guidelines of the Committee On Publication Ethics (COPE), which encourages communication of such updates at regular intervals in the journal. The journal accepts papers representing original work, no part of which was previously submitted for publication elsewhere, except as brief abstracts, as well as in-depth reviews. The majority of research papers published in Chronobiology International entails animal and human investigations. The editors and readers of the journal expect authors of submitted manuscripts to have made an important contribution to the research of biological rhythms and related phenomena using ethical methods/procedures and unbiased, accurate, and honest reporting of findings. Authors of scientific papers are required to declare all potential conflicts of interest. The journal and its editors endorse compliance of investigators to the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council, relating to the conduct of ethical research on laboratory and other animals, and the principles of the Declaration of Helsinki of the World Medical Association, relating to the conduct of ethical research on human beings. The peer review of manuscripts by Chronobiology International thus includes judgment as to whether or not the protocols and methods conform to ethical standards. Authors are expected to show mastery of the basic methods and procedures of biological rhythm research and proper statistical assessment of data, including the appropriate application of time series data analyses, as briefly reviewed in this article. The journal editors strive to consistently achieve high standards for the research of original and review papers reported in Chronobiology International, and current examples of expectations are presented herein

Ethical and methodological standards for laboratory and medical biological rhythm research

The main objectives of this article are to update the ethical standards for the conduct of human and animal biological rhythm research and recommend essential elements for quality chronobiological research information, which should be especially useful for new investigators of the rhythms of life. A secondary objective is to provide for those with an interest in the results of chronobiology investigations, but who might be unfamiliar with the field, an introduction to the basic methods and standards of biological rhythm research and time series data analysis. The journal and its editors endorse compliance of all investigators to the principles of the Declaration of Helsinki of the World Medical Association, which relate to the conduct of ethical research on human beings, and the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council, which relate to the conduct of ethical research on laboratory and other animals. The editors and the readers of the journal expect the authors of submitted manuscripts to have adhered to the ethical standards dictated by local, national, and international laws and regulations in the conduct of investigations and to be unbiased and accurate in reporting never-before-published research findings. Authors of scientific papers are required to disclose all potential conflicts of interest, particularly when the research is funded in part or in full by the medical and pharmaceutical industry, when the authors are stock-holders of the company that manufactures or markets the products under study, or when the authors are a recent or current paid consultant to the involved company. It is the responsibility of the authors of submitted manuscripts to clearly present sufficient detail about the synchronizer schedule of the studied subjects (i.e., the sleep-wake schedule, ambient light-dark cycle, intensity and spectrum of ambient light exposure, seasons when the research was conducted, shift schedule in studies involving shift work, and menstrual cycle stage in studies involving young women). Rhythm analysis of time series data should be performed with the perspective that rhythms of different periods might be superimposed upon the observed temporal pattern of interest. A variety of different and complementary statistical procedures can be used for rhythm detection. Fitting a mathematical model to the time series data provides a better and more objective analysis of time series data than simple data inspection and narrative description, and if rhythmicity is documented by objective methods, its characterization is required by relevant parameters such as the rhythm's period (tau), MESOR (time series average), amplitude (range of temporal variation), acrophase (time of peak value), and bathyphase (time of trough value). However, the assumptions underlying the time series modeling must be satisfied and applicable in each case, especially the assumption of sinusoidality in the case of cosinor analysis, before it can be accepted as appropriate. An important aspect of the peer review of manuscripts submitted to Chronobiology International entails judgment of the conformity of research protocols and methods to the standards described in this article

Ambulatory blood pressure monitoring: basis for improving detection, evaluation, treatment, and prevention of target organ damage of arterial hypertension

This is a special issue of Chronobiology International dedicated to the clinical implications of a "time-aware" approach to the diagnosis, treatment, and target-organ-damage prevention of arterial hypertension based on ambulatory blood pressure (BP) monitoring. After the introductory editorial call for a routine use of all the precious information provided by the technique --not just part of it and only in special situations like most current guidelines still recommend-- the circadian epidemiology of cardiovascular diseases is presented, and the circadian patterns of BP are analyzed in relation to their underlying pathophysiological mechanisms. Then, the best methodology of ambulatory BP monitoring, possibly combined with actigraphy, is discussed in relation to its clinical application in hypertensive patients. The prognostic value of ambulatory BP monitoring and its use as an essential tool for the diagnosis of hypertension and the evaluation of treatment efficacy are analyzed in detail. Specific articles are dedicated to the diagnostic, therapeutic, and prognostic issues of ambulatory BP monitoring in different types of both pseudo and true hypertension (sustained, nocturnal, masked, and so on), in relation to aging, gender differences, pregnancy, and in subgroups of patients affected by diabetes mellitus, chronic kidney disease, and resistant hypertension

Ethics, standards, and procedures of animal and human chronobiology research

The majority of research papers published in Chronobiology International report the findings of investigations conducted on laboratory animals and human beings. The editors and the readers of the journal expect the authors of submitted manuscripts to have made an important contribution to biological rhythm and related research through the ethical conduct of investigations and unbiased and accurate reporting of findings. Authors of scientific papers are required to disclose any potential conflict of interest. The journal accepts only papers that are original work, no part of which has been submitted for publication elsewhere, except as brief abstracts. The journal and its editors endorse the compliance of investigators to the principles of the Declaration of Helsinki of the World Medical Association, which relate to the conduct of ethical research on human beings, and the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council, which relate to the conduct of ethical research on laboratory and other animals. The peer review of manuscripts by Chronobiology International thus includes judgment as to whether or not the investigative methods conform to the standards of good research practice. This article updates the ethical policies, standards, and procedures for manuscripts submitted to Chronobiology International that involve human and animal biological rhythm research, both from the perspective of the criteria of quality chronobiology investigation and from the perspective of humane and ethical research on human beings and animals

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

Ethical principles and standards for the conduct of human and animal biological rhythm research

Most research papers published in Chronobiology International report the findings of investigations conducted on laboratory animals and human beings. The Journal, its editors and the publication committee endorse the compliance of investigators to the principles of the Declaration of Helsinki of the World Medical Association relating to the conduct of ethical research on human beings and the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council relating to the conduct of ethical research on laboratory and other animals. Chronobiology International requires that submitted manuscripts reporting the findings of human and animal research conform to the respective policy and mandates of the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals. The peer review of manuscripts will thus include judgment of whether or not the involved research methods conform to the standards of good research practice. This article outlines the basic expectations for the methods of human and animal biological rhythm research, both from the perspective of the fundamental criteria necessary for quality chronobiology investigation and from the perspective of humane and ethical research on human beings and animals

Relevance of chronobiology to the research and clinical practice of neurorehabilitation

The major goals of this article relative to neurorehabilitation are to stimulate new research into (1) the chronobiology of neurologic conditions and their therapy as a means of improving patient management and outcomes, and (2) work schedules to enhance well-being and productivity of involved health care workers. Chronobiology has been little investigated for its relevance to neurorehabilitation; nonetheless, findings of patient investigations involving a broad spectrum of other medical conditions suggest the field is likely to play a strong role in improving the management and therapy for patients with neurologic deficits. The mood, motivation, tolerance for, and therapeutic benefit of cognitive and physical retraining all can vary in a predictable manner during the 24 hour as a result of the staging of the multitude of rhythms that comprise the CTS. Primary and secondary neurologic deficits may disrupt the CTS, manifesting as altered sleep-wake cycling, melancholy/depression, and extreme fatigue/poor stamina, which may be unknowingly worsened by unnatural, inappropriate, and illogical LAN coupled with poorly lit daytime ambient conditions of patient housing. The CTS also has been shown to influence the PK and PD of most classes of medications. Thus, poorly chosen times to administer medications, both for neurologic and coexisting acute and chronic medical conditions, can compromise the extent of desired outcomes, magnify adverse effects, and perhaps interfere with neurorehabilitation. Brain trauma itself may result in disruption of the CTS, which may interfere with the success of physical and cognitive retraining programs. In certain circumstances, patients can benefit from resynchronization of their CTS, either by use of properly timed bright-light therapy or physiologic melatonin dosing at optimal circadian times, resulting in better tolerance to and effects of interventions. The work schedule of health care personnel may also be disruptive to their CTS. Day-work schedules that commence too early in the morning or rotating and night shift work arrangements can result in undue fatigue with risk of less than optimal work performance and patient management. Relevant investigations of circadian rhythm are warranted to improve both patient outcomes and the working-time arrangements and welfare of neurorehabilitation employees