|Year : 2021 | Volume
| Issue : 2 | Page : 53-58
Circadian rhythm of blood pressure: Implications for antihypertensive management
Barun Kumar1, Omna Chawla2, Manasi Bhattacharjee3, Anupam Singh4
1 Department of Cardiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of Physiology, Seema Dental College, Rishikesh, Uttarakhand, India
3 Department of Physiology, All India Institute of Medical Sciences, Guwahati, Assam, India
4 Department of Ophthalmology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
|Date of Submission||15-Jan-2021|
|Date of Acceptance||20-Jan-2021|
|Date of Web Publication||22-Mar-2021|
Dr. Omna Chawla
Department of Physiology, Seema Dental College, Rishikesh - 249 203, Uttarakhand
Source of Support: None, Conflict of Interest: None
Circadian rhythms synchronize human physiological changes with the day and night cycle. However, with the invention of artificial lighting, the consequences of disrupted rhythm also started showing in various areas of human health including vital parameters such as blood pressure. It is one of the strictly regulated variables in the cardiovascular system and thus understanding its variability is significant. The normal circadian variation in blood pressure is characterized by a 10%–20% reduction in the night recordings and the individuals with this decrease in the night-time blood pressure are termed “dippers,” a blunted decline in night-time blood pressure is seen in “nondippers.” Evidence suggests a relatively increased risk of cardiac and extracardiac morbidity in individuals with nondipping blood pressure patterns. The purpose of this review was to summarize the literature regarding various factors contributing to circadian variations in blood pressure and explore the role of chronotherapy in hypertension. We found that there is conflicting evidence to suggest the role of night time administration of antihypertensive drugs, but the understanding of these mechanisms can be utilized for strategic management of hypertension and suggests that if drugs are aligned with the circadian rhythm then may be useful in not only controlling hypertension but also improving cardiovascular outcomes.
Keywords: Blood pressure, chronotherapy, circadian rhythm, dippers, nondippers
|How to cite this article:|
Kumar B, Chawla O, Bhattacharjee M, Singh A. Circadian rhythm of blood pressure: Implications for antihypertensive management. Indian J Med Spec 2021;12:53-8
|How to cite this URL:|
Kumar B, Chawla O, Bhattacharjee M, Singh A. Circadian rhythm of blood pressure: Implications for antihypertensive management. Indian J Med Spec [serial online] 2021 [cited 2021 Apr 14];12:53-8. Available from: http://www.ijms.in/text.asp?2021/12/2/53/311697
| Introduction|| |
Blood pressure, one of the central parameters of homeostasis, is an important factor in clinical decision-making in various disease processes. The Austrian physician Samuel Ritter Von Basch invented the first sphygmomanometer in 1881. A user-friendly design was introduced with the contributions of Scipione Riva-Rocci in 1896 and Harvey Cushing in 1901. With the advancement in technology, the monitors which record ambulatory or home blood pressure have been demonstrated to be superior to the blood pressure recording in the health care setup for the diagnosis and clinical management of hypertension., This has led the researchers to realize that the phenomenon of 24-h variability shown by many other biological processes is also present in blood pressure. At the same time, critical concerns have been raised by many physicians and cardiologists regarding the clinical meaning as well as the impact of this phenomenon on their routine clinical practice.
Hypertension has been one of the critical and economically, expensive noncommunicable public health problems, which affects approximately 1.2 billion people worldwide. The American Heart Association reports that only about 64% of patients on antihypertensive medications may achieve adequate blood pressure control, therefore, indicating the need to adopt a better antihypertensive pharmacotherapeutic measure. There is some evidence that the modification of the timing of administration of antihypertensive drugs concerning the circadian rhythm may be beneficial, the so-called chronotherapy. This approach though has not currently been unequivocally accepted in clinical hypertension management. However, there is a need to evaluate the circadian variations in blood pressure physiology. This review attempts to discuss the pivotal role of circadian variation in the physiology of blood pressure and its potential significance in the management of hypertension.
| The Pattern of 24-h Blood Pressure Variation|| |
The important feature of mammalian lifestyles is the portion of the day when they actively perform activities associated with survival. Although other animals may have a different pattern human lifestyle is thought to follow a diurnal pattern which is characterized by activity period during daytime followed by sleep and rest at night. The continuous blood pressure monitoring in the people following a diurnal lifestyle reveals a typical variation pattern during the 24 h. The waking up period which is associated with upright posture, eating breakfast, and a basic level of activity shows a peak in blood pressure about 2–3 h after waking up as compared to night-time blood pressure levels. A secondary smaller surge in blood pressure can occur in the early evening, especially if they take an afternoon nap. The night-time blood pressure shows three types of variations, namely, dippers, nondippers, and reverse dippers. If the blood pressure at night is about 10%–20% lower than the daytime recordings, individuals are termed as “dippers,” whereas “nondippers” are those individuals who have a fall in blood pressure but the difference from the daytime recording is <10%. The third pattern is a paradoxical increase in the night-time blood pressure and this group of individuals is termed “reverse dippers.”,
The observed circadian variation in blood pressure during the 24 h can be attributed to several factors as elaborated in the subsequent section.
The suprachiasmatic nuclei and melatonin
The suprachiasmatic nuclei, a cluster of cells at the base of the anterior hypothalamus head the hierarchy of biological clocks, located in almost all the cells. The suprachiasmatic nuclei regulate these rhythms by various mechanisms involving humoral, endocrine, and neural signals. The intrinsic period (24 h and 11 min) of the peripheral and central oscillators differs to some extent from the exact 24 h of the earth's rhythm. Therefore, cyclic external time cues are essential to achieve synchronization or ”entrainment” in these oscillators. Light is the most important Zeitgeber (synchronizer) for entrainment. The photic information reaches the suprachiasmatic nuclei by the retinohypothalamic pathway which, in turn, regulates the secretion of melatonin hormone by the pineal gland. Melatonin has G-protein-coupled receptors present in the central nervous system and also in the central and peripheral vasculature. The mechanism of action of melatonin for the regulation of blood pressure is explained as a dual effect depending on the type of receptor activation. The MT1-receptor activation is responsible for vasoconstriction and the MT2-receptor causes vasodilation. The counteracting responses in vascular smooth muscle cells are concentration dependent. Melatonin potentiates smooth muscle contractions at lower concentrations, whereas, at higher concentrations, contractions are diminished. Therefore, at night when melatonin concentrations are high, there is a dip in blood pressure.
The antioxidant action of melatonin is receptor independent by activation of several enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. The role of melatonin is complex as other than these mechanisms, high melatonin levels also inhibit the sympathetic nervous system. Therefore, at night, the high melatonin levels contribute to physiological dipping in blood pressure. However, it has also been suggested that exposure to light at night suppresses its secretion and thus has the potential to reset the circadian clock., It is sometimes observed that melatonin secretions are low at night, though increased daytime production leads to nondipping blood pressure patterns. Thus, it does not seem unreasonable to suppose that long hours of artificial light exposure may be a reason for changes in melatonin levels and thus circadian rhythm disturbance of an important parameter like blood pressure.
Circadian rhythmicity of the autonomic nervous system
Cardiovascular homeostasis requires a well-modulated autonomic nervous system, which follows a circadian pattern as the sympathetic nervous system tone is known to dominate during the waking up period. During the initial hours of wakefulness, plasma noradrenaline, and adrenaline and urinary catecholamine concentrations are high, whereas the nonrapid eye movement sleep (NREM sleep) is marked by the dominance of parasympathetic tone with the lowest arterial blood pressure is recorded in deeper stages of NREM, especially in Stage N3. However, during rapid eye movement sleep (REM sleep), blood pressure shows a rise. This happens due to an increase in sympathetic outflow to the skeletal muscle causing vasoconstriction thus increase in venous return and thereby blood pressure surge during REM sleep. Arousal from any stage of sleep is likely to cause activation of the sympathetic nervous system, leading to raised catecholamine secretion, which results in increased heart rate and blood pressure. If frequent enough, these sympathetic surges may spill over onto the waking state, leading to increased diurnal sympathetic tone and thus clinical hypertension.
The core body temperature shows higher values when recorded in the late afternoon and early evening but shows a decline before the onset of sleep. These changes in body temperature are due to various physiologic mechanisms that bring about heat loss. The body heat loss is brought about by increased peripheral blood flow which occurs due to decreased sympathetic outflow. This night-time peripheral vasodilatation and resultant fluid shifts from the central compartments to the extracellular milieu results in a decrease of plasma volume during sleep and as a consequence, blood pressure. The situation reverses in the morning and during waking; thus, the peripheral blood flow is reduced, and peripheral resistance is increased. However, this pattern is also altered in hypertensive patients with modified nocturnal blood pressure dipping patterns.
The circadian rhythmicity of the renin-angiotensin-aldosterone system
The RAAS system of kidneys has a major role in the maintenance of fluid and electrolyte homeostasis, and therefore in the long-term regulation of blood pressure. The major determinants of renal regulation of blood pressure are glomerular filtration rate, renal blood flow, and the excretion of electrolytes (for example, sodium and potassium) and they also exhibit circadian rhythmicity.,
The renal sodium excretion aims at maintaining the sodium balance thus if sodium was retained during the day the nocturnal blood pressure is adjusted to a higher level, resulting in a nondipper pattern. Therefore, it is obvious that the hypertensive patients will be prone to retain sodium to a degree, affecting the blood pressure.
The role of Vitamin D in the RAAS system is also relevant. The Ludwigshafen Risk and Cardiovascular Health study revealed that the Vitamin D levels in serum were solely and inversely associated with renin and angiotensinogen II concentrations, suggesting the significant role of Vitamin D as an endocrine regulator of electrolytes, plasma volume, and blood pressure. As Vitamin D is influenced by the 24-h cycle of ultraviolet light exposure, it can be considered an important environmental regulator of blood pressure level and 24-h pattern adjustments.,
It is evident therefore that the factors responsible for the observed circadian rhythm in blood pressure may be deranged in hypertensive patients. Therefore, it is important to understand the circumstances under which there may be desynchronization of circadian rhythm, leading to an aberration in the physiological rhythmicity of blood pressure.
Circadian rhythm desynchronization
It has been known for long that there is continuous entrainment of the endogenously generated Circadian rhythm and if this “entrainment” (synchronization) with the environment fails it brings about various alterations in physiological phenomena. With the discovery of electricity, the wakefulness or sleep of the normal individual depends on professional or personal commitments and therefore interferes with the natural clock of the body. The desynchronized system ultimately leads to a decline in the quality of life and various pathological states. This has been observed in certain situations such as jet lag and shift work. The symptoms of the disturbed physiological state due to jetlag depends on the distance, the direction, and the time of departure. As the traveler crosses the different time zones, the longer it will take him to adjust to the new time patterns; in this regard, it may be noted that practice is not likely to help. Therefore, the crossing of different time zones uncouples the various cellular rhythms from the day-night cycle and each other. The normal circadian network is disturbed and leads to systemic adaptations that entrain the cardiovascular system to operate at a raised blood pressure modifying the equilibrium and increases the probability of hypertension.,
Clinical implications of circadian blood pressure alterations and its desynchronization
Pharmacological management of hypertension includes several classes of antihypertensive medications such as angiotensin II receptor blockers, diuretics, calcium channel blockers, α-and β-adrenoceptor antagonists, angiotensin-converting enzyme inhibitors, and others. These medications differ in their sites/mechanisms of action, but the main mechanisms regulating the blood pressure are circadian phase dependent. The most popular treatment strategy of the antihypertensive drug(s) is the once-daily administration (usually in morning hours), which has probably been adopted to improve patient adherence and compliance. This, however, usually leads to peak drug concentrations within 60–90 min which likely coincides with the timing of blood pressure measurement in the physician's office. Therefore, when blood pressure is measured in the clinic, the antihypertensive effect is likely to be at its peak.
However, as the early morning increase in blood pressure will occur before most of the drugs are absorbed, these patients will be protected against blood pressure surge only if the medication has a duration of action of at least 24 h. Evidence suggests that the management of hypertension may be more effective if it matches the patient's circadian state though presently the patients are usually instructed to take medications as per convenience or in the morning. Thus comes the role of ambulatory blood pressure monitoring which measures a patient's BP throughout 24 h and is believed to be more reflective of clinical outcomes than single time measurements. Moreover, the pattern changes during day or night are not detected in the traditional office-based measurements. Therefore, home blood pressure monitoring may be the most important first step toward a perfect 24-h blood pressure control. The understanding of physiological rhythm and their alteration will help improve the medical management of hypertension about both medication efficacy and tolerability. Administration of antihypertensive agents in the evening or at bedtime may result in better control of night-time blood pressure than the usual morning dosing, without loss of efficacy of diurnal and 24-h mean blood pressure reduction. Roush et al. in their review have even pointed out that the prognostic value of systolic daytime pressures was less than the night-time blood pressures in terms of cardiovascular and all-cause mortality outcomes in hypertensive subjects. In the last several years, some researchers have tried to assess the concept of chronotherapy in the clinical management of hypertension and various clinical cardiovascular implications.
The drugs that reduce the RAAS system activity such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have shown improvements with bedtime dosing and also normalize the nondipping profile. Diuretics and the long-acting calcium channel blockers may also be preferred as evening dosing as they help reinstate an abnormal nocturnal dipping to the normal dipping pattern in the hypertensive patient., β-adrenoceptor-mediated control of blood pressure is prominent principally during daytime hours and is of minor significance during the night and the early morning hours. In a randomized control trial, a single dose of amlodipine had a longer half-life with the night-time dose schedule as compared to the daytime administration, and similar observations were seen with perindopril suggesting the role of circadian rhythms in pharmacokinetic properties of antihypertensive drugs depending on the time of administration. In an open-labeled trial of chronic kidney disease patients, it was reported that a greater proportion of patients who were taking antihypertensives drugs at bedtime had better control of blood pressure compared to those ingesting medications upon awakening. In an interventional case–control study on refractory arterial hypertension patients, it was observed that changing the timing of antihypertensive drugs to evening significantly improved blood pressure control. These observations have brought the focus on the relevance of underlying circadian mechanisms in the antihypertensive treatment.
The authors of The Heart Outcomes Prevention Evaluation (HOPE) study suggested a favorable effect of evening dosing of ramipril as the antihypertensive therapy. The Ambulatory Blood Pressure Monitoring in the Prediction of Cardiovascular Events and Effects of Chronotherapy (MAPEC) study randomized the patients to a morning or night-time tablets over 5 years and showed that an adequate control in nocturnal blood pressure was associated with a substantial reduction in the relative risk of cardiovascular events, especially in those with diabetes, night-time hypertension, and chronic kidney disease. The Hygia Chronotherapy randomized trial showed that bedtime dosing of antihypertensive medications decreased cardiac mortality.
These findings correlate well with the fact that hypertension may result from disturbances associated with circadian variations of blood pressure and should get the due emphasis before considering the management of blood pressure alterations in health and disease.
But at the same time, there are studies to suggest that there is no effect on ambulatory blood pressure levels including morning, night-time, or 24-h control. The Hellenic-Anglo Research into Morning or Night Antihypertensive Drug Delivery (HARMONY) enrolled hypertensive patients for a cross over trial and randomized them to morning or evening drug administration for 12 weeks. After the results of cross-over data for 95 patients, it was observed that there was no difference in systolic blood pressure nor clinically significant blood pressure control.
Interestingly, the trials such as MAPEC, Hygia Chronotherapy, or HOPE trial who showed the benefits of night-time administration of antihypertensive drug therapy were not designed to study the issue of night-time dosing. However, along with blood pressure changes, it is also significant to evaluate whether night-time dosing of blood pressure medications improves other health outcomes in terms of morbidity or mortality related to hypertension. At the same time, it may be useful to demonstrate that these results are reproducible in other patient populations before night-time administration of antihypertensive drug therapy is adopted more widely in clinical practice.
Thus, though researchers are well aware of the circadian pattern of blood pressure, there seems to be a lack of consensus about designating the time of antihypertensive medications. The only means to derive any conclusion is through trials that incorporate 24-h continuous monitoring where blood pressure is analyzed with a focus on the relationship between the actual clock time of every measurement, treatment times, and due regard to the rest/activity cycle of the individual patient. The careless fixing of clock-hour intervals, instead of actual awakening/bedtimes may not represent actual chronotherapy. The report on therapeutic outcomes in terms of changes in other cardiovascular outcomes also is important. There are some important trials in progress such as the Treatment in Morning versus Evening (TIME) study and BedMed trial conducted by the University of Alberta. The BedMed trial will measure the outcomes of patients taking blood pressure medication, depending on the time of day they take their prescription with the belief that the timing of medicine has a significant influence on its effectiveness.
It is believed that the TIME study would represent the most cost-effective advancement in the treatment strategy of hypertension if the study shows definite benefits of dosing antihypertensive medication in alignment with the circadian rhythms.
The antihypertensive dosing prescription shows a significant variability; thus in this context, the decision on changing the timing of drug administration should be left to the judgment of the clinician and applied separately to meet the circadian rhythms.
| Conclusions|| |
Circadian rhythms have influenced various homeostatic parameters including the blood pressure with the day and night cycle. Physicians are trained to diagnose and treat, but the timing of drug administration is rarely considered. As briefly reviewed, several mechanisms are involved in the regulation and 24-h variations of blood pressure. However, there are conflicting data to support the effectiveness of chronotherapy for managing hypertension. As of now, the drug intake time of antihypertensive medication is determined by several factors such as the convenience of the patient, concurrence with the administration of other medications to improve compliance, and timing to minimize untoward effects of these medications. However, at the same time, one can point that if there are no other compelling reasons, the nocturnal dosing of the antihypertensive medications may be chosen so that their adequate concentrations are available and possibly help to decrease the early morning blood pressure surge.
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Conflicts of interest
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