All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- Title: Chronotherapeutics and Its Role in the Treatment of Hypertension and Cardiovascular Disease Authors: Domenic A. Sica, MD; William White, MD Source; J Clin Hypertens 2(4):279-286, 2000 INTRODUCTION How circadian rhythms align results in a peaking of cardiovascular event rates in the morning hours shortly after awakening. Doctors are usually unfamiliar with chronobiology and chronotherapeutics. We focus on the chronobiology of heart disease. We will also comment on giving drugs according to a specific timing. It may indeed matter when a patient takes a given drug to make it work properly. Humans greatly vary in their circadian rhythms. These rhythms play a part in how a disease affects a person. BLOOD PRESSURE AND HEART RATE CYCLES Through clinical trials and studies, it has become known that the levels of disease activity have a pattern linked to the body's internal clock, set to circadian (day-night or awake-sleep cycles), monthly, or seasonal rhythms. These rhythms are important to cardiology because they affect high blood pressure, heart attack, and stroke. it has been shown that many heart "events" strike in the early morning hours and may be linked with awakening. In most people with high blood pressure, there is definite rise in blood pressure upon awakening that is called the morning or "A.M." surge. Systolic blood pressure rises about 3 mm Hg per hour for the first 4 to 6 hours after waking. Diastolic pressure goes up about 2 mm Hg per hour. In most such patients, blood pressure goes down starting in mid-afternoon, and reaching its lowest point between midnight and 3:00 AM. Regardless of blood pressure, it and heart rate vary according to both mental and physical activity levels. Night-time blood pressure and pulse rate change with changing nervous system activity. Typically, nervous system activity slows while asleep, with changes governed by posture and sleep, with norepinephrine level regulated more by posture. Epinephrine level is lower during sleep and begins to increase with morning awakening. Norepinephrine level does not increase much until an upright position is added. Under certain circumstances the morning peak in heart attack risk or sudden cardiac death may reflect exaggerated organ response to norepinephrine. ILLNESS CHANGES RHYTHMS In a healthy person, circadian rhythm is not much of a factor. The 24 hour low-to-high change in blod pressure usually amounts to 15 to 25 mm Hg. In high blood pressure patients, the strength of the rhythm may change. In some cases, the rhythm itself may be destroyed. The circadian rhythm may be reversed in some illnesses that change blood pressure. The term "dippers" describes patients whose nigh-time pressure drops at least 10% below their daytime pressure. "Nondippers" are patients in whom night-time declines in blood pressure no longer happen. A nondipping pattern of circadian blood pressure changes is clinically important. Recent studies suggest that these patients may have increased risk for heart-related events. Illness which causes high blood pressure can change the circadian rhythm. However, little is known about what causes rhythm changes in those who have high blood pressure not caused by a distinct disease. The elderly and black people are at more risk to be nondippers. Patients who are salt sensitive are more likely to be nondippers. HEART ATTACK Acute heart attacks are 3 times more frequent in the morning than in the late evening. In the TIMI II trial, 34% of events happened between 6 in the morning and noon. Certain groups in the study had even higher rates of morning heart attack. These groups were: 1) those who did not take a beta-blocker within the previous 24 hours; 2) those who had no chest pain in the preceding 48 hours; 3) those who had their heart attack on a weekday. It has also been reported that SCD (sudden cardiac death) and TIA (mini-strokes) happen more often in the morning. Holter monitoring has shown that TIA occurs more often in the first 4 to 6 hours after waking. This may be due to various causes. Triggers for morning events may include the increase in physical and mental activity during awakening, release of stimulant chemicals in the body, and increases in the blood level of cortisol, which together may increase stress on the heart. Increases in blood "thickness," blood vessel narrowing, and amount of blood in the body in the early morning hours may reduce the heart's oxygen supply. In a person with semi-blocked arteries, early morning activity might cause some of the blockage to break loose from the blood vessel wall, causing a stroke (blood clot) or heart attack. ARRHYTHMIA Heart arrhythmias also follow a circadian rhythm. However, because arrhythmias are unpredictable, little has been documented. Early studies using repeated Holter monitoring to study the timing of PVCs (too-fast, weak heart beats) revealed that most occurred between 6 A.M. and noon. In one study, 68 patients who came to the hospital with tachycardia, onset of symptoms such as palpitations, near-fainting and fainting were interviewed. Ventricular tachycardia was found to happen the most at 9 in the morning. Recently, precise study of ventricular arrhythmia frequency became possible due to ICDs (iplanted cardio- defibrillators). These devices permit a precise time recording for arrhythmia. All but one of these studies showed that most tachycardia or fibrillation happened between 6 A.M. and noon. the one study by Wood et al showed peak arrhythmia between noon and 7 in the evening. These studies clearly show that arrhythmia happens far less often during sleep. This is called "sleep suppression." Sleep suppression is defined as more than a 50% reduction in night-time PVCs compared to daytime numbers. STROKE Stroke also happens most frequently in the first several hours after waking. In one large study of 1167 patients, strokes happened more often between 10 A.M. and noon than at any other 2-hour interval. Stroke onset decreased steadily during the rest of the day and early evening, with stroke least likely in the late evening, before midnight. Another large study by Gallerani studied the timing of strokes in 926 people. All types - cerebral infarction, TIA, and cerebral hemorrhage - peaked in frequency between 6 A.M. and noon. Studies of stroke from hemorrhage show events peaking in the late morning hours. Nakamura analyzed circadian blood pressure pattern in 76 patients who had suffered a prior cerebrovascular event. It was found that "dippers" (those with more than 10 mm Hg drop in average arterial pressure during sleep) TAKING a high blood pressure-controlling drug had MORE cerebrovascular events than "dippers" NOT taking such drugs OR all "nondippers." This raises the concern that reducing night-time blood pressure too much may make high blood pressure patients with atherosclerosis prone to having ischemic events in the brain. CHRONOTHERAPEUTICS FOR HEART DISEASE The main objective of chronotherapy for heart disease would be to deliver needed drugs in higher concentrations during the time they are needed the most (early morning after-waking period) ; and at reduced drug levels when the need is less (during the middle of the sleep cycle). There are no in-depth studies showing us the way in this matter yet. In one study, an ACE inhibitor was dosed either in the early morning or at bedtime in 18 patients with moderately high blood pressure. Palatini et al showed that night-time dosing resulted in a greater effect on night-time pressure than morning dosing. There was no difference in daytime pressure between the 2 groups. Measurement of ACE activity showed that night-time dosing caused a more even, lasting reduction in blood levels of ACE. In contrast to the ACE inhibitor study, studies with the beta-blocker atenolol, and the calcium channel blockers nifedipine and amlodipine, showed no different effects on pressure when dosed in the morning versus evening. Like many such studies, too few patients were studied to draw strong conclusions. It is obvious, though, that drug class, formulation, and size of dose have a large influence on the effect seen. TIME-TAILORED DRUGS One chronotherapeutic drug for high blood pressure and angina has now been marketed. Verapamil is now in a delivery system that delays release after taking the pill for 4 to 5 hours, and then has an extended release for 18 hours. Taken at bedtime, this gives higher drug levels between 4 A.M. and noon, when both pressure and heart rate rise. This type of therapy may be important since studies have shown that cardiovascular events often happen in the early morning hours. Chronotherapy links the effects of a disease to time, and the timing of drug delivery. Future research will show whether timing of drug delivery affects outcomes. SUMMARY Drug therapy which more precisely controls blood pressure and pulse rate according to circadian patterns may give benefit to patients. Chronotherapeutics is the delivery of drugs in levels that match the body's chnaging needs at certain times of day or night. Since studies have shown that heart-related events occur most often in the morning - varying with the 24 hour circadian rhythm - this concept may be important. The first chronotherapeutic drug for blood pressure control and angina has now been marketed : COER-verapamil. Patients with high blood pressure and angina are better covered in the early morning hours when need appears to be the greatest with this new drug formula. TIMING OF EVENTS IN HEART DISEASE Angina Chest pain more common during early A.M. Heart attack Happens most often in early A.M. Sudden cardiac death Ventricular tachycardia happens most often in early A.M. Stroke Happens most often in early A.M. ILLNESSES CAUSING REDUCTION IN NIGHT-TIME DECLINE OF BLOOD PRESSURE Diabetes with neuropathy or nephropathy Kidney failure with dialysis Cushing's syndrome Cyclosporine and high-dose steroid drugs Severe systolic high blood pressure in the elderly