Circadian rhythms have long been recognized to occur in many biologic phenomena, including secretion of hor,mones and activities of the autonomic nervous system. More recently, circadian rhythms have also been noted to occur in the incidences of certain cardiac and cerebrovascuiar events, including transient myocardiai ischemia, myocardiai infarction, sudden cardiac death, and stroke. The pathophysioiogy and the mechanisms underlying these variations are the focus of much investigation. The effects of different drug treatments on these circadian rhythms are also being studied. This information should enable better treatment strategies to be planned for patients who have either silent or symptomattc episodes of transient myocardial ischemia and potentially to prevent the occurrence of sudden, catastrophic cardiac events. (AM HEART J 1990; 120~726.)
Arshed A. Quyyumi,
For many years, circadian rhythms have been recognized in many biologic phenomena, including secretion of hormones and activities of the autonomic nervous system. Recently the incidences of certain cardiac and cerebrovascular events have also been demonstrated to vary with the time of day. This has kindled interest in identifying the factors responsible for these variations, because they may not only provide clues to the triggering mechanisms of sudden cardiac events, but they may also lead to the rationalization of therapies designed to influence these events. CIRCADIAN Transient
ischemia. With the advent of frequency-modulated ambulatory monitoring systems in the early 198Os, it became possible to record and reproduce ST segment changes in the ECG that occur during patients’ normal daily activities. Transient episodes of ST segment depression or elevation in patients who have coronary artery disease have been documented to be associated with independent measures of myocardial ischemia, such as perfusion defects during radioisotope imaging,l wall-motion abnormalities,2 and elevations of left ventricular end-diastolic pressure.3 Ambulatory monitoring in patients who have stable coronary artery disease has demonstrated that transient episodes of ST segment depression occur frequently in some patients during their normal daily life and that 70 % to 80 % of these From the Cardiology Bethesda. Reprint Branch, 410122233
Branch, Arshed Building
A. Quyyumi, 10, Room
MD, Senior Investigator, Cardiology 7B15, Bethesda, MD 20892.
episodes may be silent.4 When the distribution of these episodes was examined in a consecutive series of 74 patients who had varying severity of coronary artery disease, 4, 5 it was clear that there was an uneven distribution: most ischemic episodes occurred during the morning hours, beginning around 7 to 8 AM, reached a plateau until 1 PM, and gradually decreased thereafter, with perhaps a second, smaller peak occurring around 6 PM; the fewest episodes occurred at night (Fig. 1). 4l 5 Other studies have subsequently confirmed these findings. When Rocco et a1.6 studied the occurrence of ischemic episodes relative to the time of awakening in 24 patients, it was evident that the largest proportion of episodes (24%) occurred within the first 2 hours of waking. Myocardiai infarction. Muller et a1.7 demonstrated a circadian pattern of distribution of myocardial infarcts after data were analyzed from a group of patients in the Multicenter Investigation of Limitation of Infarct Size (MILIS) (Fig. 1). The distribution of episodes of infarction was assessed by analyzing the time of first appearance of creatine kinase in the plasma. Other subsequent studie&lo have confirmed the results of earlier investigations that had used the onset of chest pain as a marker of the time of onset of myocardial infarction.‘iji2 The distribution of myocardial infarctions during the day was very similar to the distribution of transient episodes of myocardial ischemia in other studies, with an estimated threefold increased risk of myocardial infarction occurring in the morning hours between 7 AM and noon compared with late evening. It appears that the morning peak in the occurrence of myocardial infarction is independent of the sever-
ity of coronary artery disease and left ventricular function. When the occurrence of myocardial infarcts was studied relative to the time of awakening in the Worcester Heart Attack Study,lO it was observed that 26% of patients who had myocardial infarctions in the hospital experienced the onset of symptoms within the first 2 hours of awakening. However, evidence is also emerging that not all subgroups of patients who have myocardial infarctions show this preponderance of events during the morning hours. Hjalmarson et a1.8 have reported a lack of any peak in the incidence of myocardial infarction in patients who had had a previous infarct. These investigators have also demonstrated two almost-equal peaks in the morning and the late evening in patients older than 70 years, in smokers, in diabetic persons, and in women. Finally, only a late evening peak was present in patients who had non-Q wave myocardial infarction and in those who had congestive heart failure. Sudden cardiac death. Analysis of death certificates for the time of occurrence of out-of-hospital sudden cardiac deaths in Massachusetts in 1983 demonstrated the presence of a circadian pattern of distribution that was very similar to the patterns for transient myocardial ischemia and myocardial infarction (Fig. 1).13 This study also effectively addressed methodologic problems relating to the difficulty of determining the exact time of occurrence of unwitnessed deaths. A similar pattern of distribution of sudden cardiac death was also observed in the Framingham Heart Study,14 which demonstrated a 70% increased risk of sudden cardiac death between the hours of 7 and 9 AM relative to the average risk during all other periods of the day. Stroke. Determining the exact time of onset of strokes is a problem in some patients because of the presence of symptoms at the time of awakening. Despite these difficulties, there is a clear preponderance of occurrence of ischemic stroke in the morning hours, which is similar to the pattern observed for other cardiac events.15t I6 PATHOPHYSIOLOGY AND MECHANISMS OF CARDIAC EVENTS Transient myocardial ischemia. Traditionally, the
precipitation of transient myocardial ischemia in patients who have coronary artery disease has been explained by increased myocardial oxygen demand in a setting of reduced coronary blood flow. Episodes of myocardial ischemia that occurred with little or no preceding increase in heart rate and blood pressure were considered to be caused largely by sudden reductions in coronary blood flow, and episodes pre-
8% 6% 4% 2% 0% 0
Fig. 1. Circadian variation in transient myocardial ischemia,nonfatal myocardial infarction, and suddencardiac death. (Reproducedwith permissionfrom Mulcahy D, et al. Lancet 1988:2:755-g.
ceded by significant increases in heart rate and blood pressure were considered to be caused by increases in myocardial oxygen demand. However, it is now clear that most spontaneous episodes of myocardial ischemia result from a combination of increases in demand and reductions in supply because of vasomotor changes in the epicardial coronary arteries. For example, it has been clearly demonstrated that such diverse stimuli as exercise,17,18 cold,lg and increased flow20 lead to vasoconstriction or failure of dilation at the sites of atherosclerosis in coronary arteries but lead to vasodilation in apparently normal sections of the coronary tree. Similar changes can be produced by intracoronary administration of low doses of acetylcholine. This suggests that dysfunction of the endothelium in the atherosclerotic segments of the coronary vasculature leads to vasoconstriction in response to the same stimulus that produces vasodilation in nonatherosclerotic coronary 21 Studies of various vasoconstricarterial segments. tors, which were conducted in isolated preparations of human coronary arteries by Brown,22 have shown that vasoconstriction in segments of alreadynarrowed coronary arteries can lead to dramatic increases in resistance and thus to reductions in coronary blood flow, which would substantially reduce the ischemic threshold. Thus myocardial ischemia that occurs during exercise is largely the result of an increase in myocardial oxygen demand, although there may still be some “collapse” or vasoconstriction in atherosclerotic sections of coronary arteries. On the other hand, mental stress may precipitate ischemia, largely as a result of severe vasoconstriction in the coronary arteries, caus-
Quyyumi Heart Rate
Systolic Blood Pressure
8 10 12 14 16 18 20 22 24. 24-Hour day
8 10 12 14 16 18 20 22 24 24.Hour day
Fig. 2. Circadian variation in determinants of myocardial oxygendemand. (Adapted with permissionfrom Mulcahy D, et al. Lancet 1988;2:755-9;also adapted with permissionfrom Millar-Craig MW, et al. Lancet 1978:1:795-7:alsoadaoted from Tofler GH. et al. N Engl J Med 1987;316:1514-8by permissionof The New England Journal of Medicine.)
ing reduction of coronary blood flow in a setting of relatively smell increase in myocardial oxygen demand as measured by increases in heart rate and
blood pressure.23 Mechanisms underlying circadian variation. Understanding of these basic principles has led to the investigation of factors that may be responsible for the circadian variation in the occurrence of transient ischemic episodes. Heart rate,* blood pressure,24s 25 and probably contractility (measured indirectly as plasma epinephrine leve126), all determinants of myocardial oxygen demand, peak in early morning hours between 7 AM and noon (Fig. 2). These changes parallel the circadian distribution of transient ischemic episodes. Factors that may directly or indirectly lead to increases in vasoconstrictor tone also have a circadian variation. Thus plasma norepinephrine leve126 and plasma renin activity,27 both powerful vasoconstrictor influences, are increased during the morning hours (Fig. 3). Platelet aggregability26 is higher in the morning (Fig. 4). It has been hypothesized that aggregation of platelets over atherosclerotic plaques can result in an increase in local release of vasoconstrictor factors such as thromboxane and can cause vasoconstriction. The increase in plasma cortisol levels that also occurs in the morning hours has a synergistic effect on the action of catecholamines on the vasculature.28 The circadian changes in humoral and neural vasoconstrictor factors were demonstrated to have an impact on the coronary and peripheral vasculature of patients who have stable coronary artery disease.2g Patients who had coronary artery disease were shown
to have a circadian variation in ischemic threshold: it was easier to precipitate ischemia during treadmill exercise in the morning and at night than at other times of the day. A similar circadian variation in vascular resistance in the forearm was also demonstrated, which suggests that there is a circadian variation in both coronary and peripheral vascular resistance. It is also pertinent to separate the variation in physiologic parameters into those that truly have an endogenous circadian variation and those that are determined mainly by awakening and assumption of an upright posture. The latter are likely to be more important in causing the preponderance of transient ischemic episodes and myocardial infarcts that have been shown to be determined largely by wake-up time.6 Thus, changes in plasma cortisol level appear to have a true endogenous circadian variation, whereas the increase in platelet aggregability occurs only after the assumption of upright posture.30 Other factors, such as heart rate, blood pressure, plasma norepinephrine level, and plasma renin activity, have an underlying endogenous circadian variation that is exaggerated by awakening and exercise. Myocardial infarction. It is now accepted that myocardial infarction occurs as a result of thrombus formation over a ruptured or fissured atherosclerotic plaque. 31-33 Moreover, several studies have now shown that in more than two thirds of all cases, the thrombosis leading to myocardial infarction is likely to occur at the site of a mild atherosclerotic lesion, of less than 60% stenosis, than at the site of the most severe lesion.34-36 However, the most severe lesion is
z350 $300 .$ 250 “n 200 2 El50 $100 I
1 * PC.05
6, 8 10 12 14 16 18 20 22 24 24-Hour day
Fig. 3. Circadian variation in determinants of myocardial blood flow. (Adapted from Tofler GH, et al. N Engl J Med 1987;316:1514-8by permissionof The New England Journal of Medicine; also adapted from Gordon RD, et al. J Clin Invest 1966;45:1587-92by copyright permissionof the American Society for Clinical Investigation.)
clearly the cause of transient myocardial
ischemia. Thus, despite the parallel circadian distribution of myocardial infarction and transient myocardial ischemia, the pathophysiologic processes and the location of the responsible lesions in the coronary tree for these two events are often different. Triggers of myocardial infarction. Factors that contribute to thrombus formation are more prevalent in the morning hours (Fig. 4). Platelet aggregability increases after arousal and the assumption of the upright posture. 3o Blood fibrinolytic activity is lowest in the morning,37$ 38 largely because of a low blood activity of tissue plasminogen activator and a high activity of plasminogen activator inhibitor. Also, blood viscosity is highest during the morning hours.3g A scenario can be constructed in which the sharp increase in blood pressure and heart rate in the morning, against a background of increased vasoconstrictor tone, may so dramatically increase the shear forces across atherosclerotic plaques that a “vulnerable” plaque ruptures. The prothrombotic condition prevailing during the morning hours allows propagation of the thrombus that forms at the site of the ruptured plaque and leads to myocardial infarction. If the myocardial infarction is large or is accompanied by a sustained ventricular arrhythmia, sudden cardiac death will occur. However, later in the day, when blood pressure is generally lower, the likelihood of precipitating the rupture of a plaque is also lower. Even if a plaque ruptures, the propagation of a thrombus may be impeded by the relative increase in blood fibrinolytic
activity, and the situation may not progress to myocardial infarction. Investigators now hypothesize that physical or mental stress may often precipitate changes in blood pressure, heart rate, and vasoconstrictor tone, which, singly or together, may cause a vulnerable atherosclerotic plaque to rupture.40 Little is known at the present time about factors that make plaques more vulnerable to rupture, about the specific factors that cause plaques to rupture, and about how vulnerable plaques could be identified. Nevertheless, it is apparent that it is not usually the severely narrowed lesions that are vulnerable but rather the mildly stenosed areas in the coronary artery tree that often lead to myocardial infarction. Sudden cardiac death. Davies and Thomas32T 33studied 100 consecutive patients with coronary artery disease who died suddenly (within 6 hours of onset of symptoms). They found occlusive thrombosis in 74% and plaque fissuring or rupture in 21% . These investigators proposed that in the latter group, the thrombus that had formed over the ruptured plaque may have lysed in the intervening period. Thus, even though sudden death is ultimately an arrhythmic event, the precipitating factor seems most often to be plaque rupture. Therefore, it is likely that the triggers of most cases of sudden cardiac death are similar to the triggers of myocardial infarction. Another speculation is that some patients may die suddenly as a result of sustained ventricular arrhythmia precipitated by an episode of silent ischemia, which makes the myocardium more vulnerable to an arrhythmic event.41 However, most patients who die suddenly
Platelet Aggregability (Tofler et al)
September IWO Heart Journal
“1 7 1200
40 e 30 3 2 20 .!2 = 10 0
8 10 12 14 16 18 20 22 24 24.Hour day
8 IO 12 14 16 18 20 22 24 24.Hour day
Fig. 4. Circadian variation in thrombogenic factors (PAI, Plasminogenactivator inhibitor.) (Adapted
from Muller JE, et al. N Engl J Med 1985;313:1315-22 by permissionof The New England Journal of Medicine; also adapted from Tofler GH, et al. N Engl J Med 1987;316:1514-8by permissionof The New England Journal of Medicine; alsoadapted from RosingDR, et al. Circ Res1970;237:171-84by permission of the American Heart Association, Inc.; alsoadapted with permissionfrom Andreotti F, et al, Am J Cardiol 1988;62:635-7;alsoadapted from Ehrly AM, and Jung G. Biorheology 1973;10:577-83with permission of Pergamon Press,Inc.)
seem to have plaque rupture or fissuring, so the latter mechanism, if it occurs, probably accounts for few sudden cardiac deaths. OTHER SYNDROMES
The pattern of circadian variation in patients who have variant angina is significantly different from that of patients who have stable coronary artery disease. In variant angina there appears to be a very early morning peak (between 5 and 6 AM) in both painful and silent episodes of &hernia. This is a time when ischemia occurs least frequently in patients who have stable coronary artery disease.42* 43Patients who have non-Q wave myocardial infarction do not appear to have a morning peak in incidence.44 EFFECTS OF TREATMENT ON CIRCADIAN IN CARDIOVASCULAR DISEASE
The impact of conventional medical therapy on circadian patterns in myocardial ischemic syndromes has been investigated in several studies. ,&Adrenergic blockade. P-Blockers not only reduce the frequency of occurrence of both symptomatic and silent myocardial ischemia,5p 45 but they also blunt the morning increase in episodes of transient myo-
cardial ischemiaa5f 46 This has been demonstrated in studies of atenolo15 and metoprolol,46 and it probably applies to most of the ,&adrenergic-blocking agents that do not have intrinsic sympathomimetic activity when they are administered to have a 24-hour effect. Analysis of the MILIS data base revealed that patients who were on P-blocker therapy at the time of myocardial infarction did not have a morning peak in the incidence of myocardial infarction.7 This finding has now been confirmed for myocardial infarction with the data base from the Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) Study.g Also, the results of the Beta Blocker Heart Attack Trial (BHAT)47 showed that there was an estimated 44% reduction in the incidence of sudden cardiac death during the morning hours in the P-blockertreated group. Although @-blockers have been proved to be effective in reducing the incidence of recurrent myocardial infarction and death in patients after myocardial infarction, 4814g it is unclear whether &blockade also has a primary preventive effect in reducing the incidence of myocardial infarction or sudden cardiac death in patients with coronary artery disease who have not had a previous myocardial infarction. Some studies in patients who have
hypertension have also demonstrated a salutary effect of @-blocker therapy in reducing the morbidity and mortality associated with cardiovascular events. In the Metoprolol Atherosclerosis Prevention in Hypertension Study (MAPHY),50 a significant reduction in the mortality associated with coronary artery disease was observed in patients treated with the &blocker. Another case-control study in patients who had hypertension also suggested that &blockers may reduce the incidence of myocardial infarction by 38% .51 Calcium channel blockers. Monotherapy with currently available calcium channel blockers has a variable effect on transient myocardial ischemia. Veraparnil, which is effective in lowering heart rate and blood pressure, significantly reduces both transient silent and symptomatic myocardial ischemia, but its effect on the circadian rhythmicity of episodes is unknown.52 On the other hand, nifedipine does not lower heart rate, and, when used as monotherapy, it is less effective in reducing the frequency of transient myocardial ischemia and has little impact on the circadian distribution of the episodes.5! 33Diltiazem has been demonstrated to reduce the frequency of silent and symptomatic episodes of myocardial ischemia in some studies, but it appears to be less effective than P-blockers,53 and appears to not completely abolish the morning increase in episodes. Analysis of the data base from the ISAM study, in which a subgroup of patients received calcium channel blockers at the time of myocardial infarction, revealed the persistence of a morning peak in the incidence of myocardial infarctions.s Whether all calcium channel blockers are equally ineffective in changing the pattern of frequency of myocardial infarction needs to be determined. Analysis of 28 trials in which calcium channel blockers were administered after acute myocardial infarction or episodes of unstable angina showed no reduction in the risk of initial or recurrent myocardial infarction or death.54 Nitrates. No data are available on the impact of nitrate therapy on the circadian changes in ischemic episodes, myocardial infarction, or sudden death. Nitrates may be effective to counteract the vasoconstrictor changes that are prevalent in the morning hours. In a study of patients who had variant angina, Yasue et al.55 demonstrated that coronary arteries were narrower in the morning than in the evening and that this vasoconstriction was responsive to therapy with nitroglycerin. With the current vogue for intermittent use of nitrate therapy to avoid the tolerance that develops with continuous therapy, attention should be given to the impact of therapy on the morning peak of episodes of ischemia when patients are advised to have a nitrate-free interval during
Cardiovascular circadian rhythms
the night. In patients who use monotherapy with nitrates, it may be important to administer sublingual nitroglycerin along with the transdermal nitrate preparation on awakening, to prevent a period of inadequate medication at the time when ischemic activity is likely to be highest. However, this therapeutic strategy remains to be tested in large clinical trials. Aspirin. Although two studies have shown persistence of the morning increase in incidence of myocardial infarction in patients who received aspirin therapy at the time of infarction,56T 57the Physicians’ Health Study was able to compare the incidence of nonfatal myocardial infarction in an aspirin-treated group and an untreated control group.57 Despite the persistence of an apparent morning peak in the aspirin-treated group, there was a 47% reduction in the overall incidence of myocardial infarction in the treated group compared with the control group.58 Most of the reduction in the incidence of myocardial infarction in the aspirin-treated group appeared to occur in the morning hours. Thus, if aspirin is acting mainly through its antiplatelet effects, then the fact that most of its beneficial effect appears to occur in the morning strongly supports the role of platelet aggregation in the triggering of myocardial infarction. Comment. &Blockers have been shown to abolish the morning peak in the incidence of transient myocardial ischemia and myocardial infarction, whereas aspirin, which has no effect on transient ischemia, also reduces the incidence of myocardial infarction during the morning hours. How other drugs affect these phenomena remains to be seen. Whether the effects of aspirin and P-blockers on the occurrence of myocardial infarction are synergistic needs to be studied. The effects of these two different agents on the frequency and prevalence of myocardial infarction provide important clues to the triggering mechanisms of myocardial infarction and sudden cardiac death. Recognition of circadian patterns in cardiovascular diseases will no doubt prove to be important in planning treatment strategies for patients with coronary artery disease who have either silent or symptomatic transient ischemia and to prevent the occurrence of sudden, catastrophic cardiac events. REFERENCES
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September 1990 Haart Journal
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angina: double blind comparison of beta blocker, calcium antagonist and nitrate. Br Heart J 1987;57:505-11. Imperi GA, Lambert CR, Coy K, Lopez L, Pepine CJ, Shepard C. Effects of titrated beta blockade (metoprolol) on silent myocardial ischemia in ambulatory patients with coronary artery disease. Am J Cardiol 1987;60:519-24. Peters RW, Muller JE, Goldstein S, Byington R, Friedman LM, and BHAT Study Group. Propranolol and the circadian variation in the frequency of sudden cardiac death: the BHAT experience [Abstract]. Circulation 1988;76(suppl IV):IV-364. Norweeian Multicenter Studv Groun. Timolol-induced reduction in-mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-7. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71. Wikstrand J, Warnold I, Olsson G, et al. Primary prevention with metoprolol in patients with hypertension: mortality results from the MAPHY study. JAMA 1988;259:1976-82. Psaty BM, Koepsell TD, LoGario JP, Wagner EH, Invi TS. fiBlockers and primary prevention of coronary heart disease in patients with high blood pressure. JAMA 1989;281:2087-94. Subramanian B, Bowles MJ, Davies AB, Raftery EB. Combined therapy with verapamil and propranolol in chronic stable angina. Am J Cardiol 1982;49:125-32.
Cardiovascular circadian rhythms
53. Stone PH, Gibson RS, Glasser SP, DeWood MA, et al. Comparison of diltiazem, nifedipine and propranolol in the therapy of silent ischemia. Circulation 1989;8O(suppl II):II-1064. 54. Held PH. Yusuf S. Furbere CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:1187-92. 55. Yasue H, Omote S, Takiiwa A, Nagao M, Miwa K, Tanaka S. Circadian variation of exercise capacity in patients with Prinzmetal’s variant angina: role of exercise-induced coronary arterial spasm. Circulation 1979;59:938-48. 56. Willich SN, Collins R, Peto R, Linderer T, Schroder R, and the ISIS-2 Study Group. Increased morning incidence of myocardial infarction: experience in the ISIS-2 trial [Abstract]. Circulation 1989;8O(suppl II):II-133. 57. Ridker PM, Manson JE, Hennekens GH. Circadian variation of myocardial infarction in a randomized trial of aspirin among U.S. male physicians [Abstract]. Circulation 1989;8O(suppl II):II-1378. 58. The Steering Committee for the Physicians’ Health Study Research Group. Preliminary Report: findings from the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1988;318:262-4.