Chronobiology and Chronotherapeutics - Possible Strategy for Hypertension and Ischemic Heart Disease

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Abstract

A frequently asked question in clinical pathology is why must statin drugs be dosed in the evening rather than in the morning? The answer is that the liver manufactures more cholesterol in the evening than in morning. Thus, the efficacy of statins is remarkably diminished when the drugs are not dosed at the correct time.
Many biologic phenomena display cyclic variation or rhythmicity, operating according to a 'biologic timekeeper'. These biologic rhythms are observed as adaptive adjustments to cyclic environmental changes occurring over the course of the day, a month, or a season. Differences in physiology according to the time of day, time of month, time of year, or even the period in one's life encompass the discipline of chronobiology. The exposure of healthcare providers to the field of chronobiology has been limited.

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The endocrine system provides many examples illustrating chronobiology. It is the monthly alteration in hormones that initiates menses. The timing of puberty provides another example. Some components of the endocrine system follow a diurnal pattern of activity.

There are a number of hormones that are secreted in the morning, including cortisol, catecholamines, plasma renin, aldosterone, and angiotensin. In contrast, gastric acid, growth hormone, prolactin, melatonin, follicle-stimulating hormone, luteinizing hormone, and adreno-corticotrophic hormone (ACTH) peak in the evening or during sleep. There are consequences to the circadian changes in these hormones. For instance, the increase in catecholamines in the morning promotes platelet aggregation. This is especially important since fibrinogen also increases, and the body's own endogenous t-PA decreases, promoting a procoagulant state with increased blood viscosity.

Ambulatory blood pressure has provided insight into the change in blood pressure and heart rate throughout the day. The difference between normotensive and hypertensive patients is the level of blood pressure throughout the day. The peak blood pressure is between 6 am and noon.With activation of the sympathetic nervous system prior to awakening, blood pressure begins to increase. Heart rate also increases.

These changes in blood pressure parallel the morning activation in catecholamines, renin, and angiotensin. Activity and sleep influence the level of blood pressure throughout the day. Between midnight and 6 am, blood pressure is generally lowest. Individuals who work from midnight to 8 am have their lowest blood pressure during their sleep period. Patients with autonomic dysfunction have their lowest blood pressure during standing and highest blood pressure when supine.

Normally, blood pressure declines 10% to 20% from the activity period to the sleep period. Patients with less than a 10% reduction in daytime blood pressure are referred to as 'non-dippers'. Research suggests that a blunted nocturnal decline in blood pressure may be due to diminished sodium excretory capacity, alteration in the autonomic nervous system, or other factors. In addition, nondippers are more likely to have a secondary cause of hypertension. Endocrine causes include diabetes mellitus, pheochromocytoma, primary aldosteronism, licorice intoxication, Cushing's syndrome, and highdose corticosteroids.

Other causes include autonomic dysfunction, renal failure, obstructive sleep apnea, cardiac transplantation, pre-eclampsia and eclampsia. Target organ damage appears to be more common as a consequence.

Epidemiologic studies document that these individuals are at a greater risk of left ventricular hypertrophy, renal disease, and cardiovascular events. Another group is classified as 'extreme dippers' individuals whose blood pressure declines excessively (>20%) during sleep.These individuals appear to be at an increased risk of blindness (anterior ischemic optic neuropathy) and stroke. Unfortunately, the determination of non-dippers and extreme dippers is confounded by poor repeatability using ambulatory blood pressure monitoring. />/>/>/>/>/>/>/>/>/>/>/>

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