Circadian rhythms and coronary artery disease

Circadian Rhythmsand Coronary Artery Disease MICHAEL

B.

ROCCO, MD, ELIZABETH G. NABEL, and ANDREW P. SELWYN, MD

Circadian variations have long been observed in several metabolic functions, many of which are directly or indirectly related to the cardiovascular systern and its pathophysiology. Recent reports linking circadian patterns to the development of symptomatic and asymptomatic myocardial ischemia, sudden

MD,

cardiac death and myocardial infarction raise important questions concerning the mechanisms of myocardial ischemic activity in patients with coronary artery disease, and they have implications for prognosis, therapy and further research. (Am J Cardiol 1987;59:13C-17C)

M

any biologic systems exhibit prominent and reproducible temporal- patterns, which, when they occur regularly over a %-hour period, are referred to as circadian rhythms. Many of these patterns, such as the neuroendocrine release of adrenocorticotropic hormone and thyroid stimulating hormone, are under internal control. However, exogenous factors, such as cyclic alterations in environmental stimuli, may influence the expression of daily rhythms. For example, the rest/activity cycle, which is influenced by changes in light and dark, temperature and social interactions, remains the most powerful modifier of biologic rhythms in humans. The presence of circadian rhythms in human health and illness has been alluded to since the time of Hippocrates. The existence of such rhythms was reported as early as 1845, when Davy recorded daily alterations in body-core temperature that were unrelated to environmental temperature activity.l However, it was not until the 1960s that a large variety of physiologic functions and biologic rhythms were described. Biologic variations have now been reported for several metabolic parameters, including urinary excretions of 17-keto steroids,2 levels of plasma cortisol3 urinary and plasma catecholamines and immunoreactive insulin.4 Likewise, temporal patterns are seen in the manifestations of many illnesses.5 For example, exacerbations of hay fever tend to occur in the early morning hours; symptoms of atopic dermatitis and

asthma tend to be worse at night. The development of fever upon exposure to viral or bacterial agents also demonstrates reproducible temporal rhythms. The bioavailability, disposition, pharmacokinetics and excretion of many drugs vary over %hour periods. Circadian variations in the effects of various compounds such as salicylates, indomethacin, histamine, acetylcholine, digoxin, lidocaine and others have been well documented. Many normal circadian patterns have important relations with cardiovascular function, both in health and in disease. Plasma cortisol reaches a peak at the time of awakening.3 Subsequently, there is an increase in plasma catecholamine levels during the later morning hours4 Heart rate and blood pressure are also known to increase during this same time periode6 Floras et al7 have further demonstrated that a major increase in blood pressure occurs abruptly at the time of awakening. Recent observations describe an increase in platelet aggregability8 and a decrease in fibrinolytic activitygJO in the early morning hours. Similar circadian patterns demonstrate a morning increase in cardiac output and ventricular contractility as measured by systolic time intervals, I1 All or a combination of these factors may alter the cardiovascular response at different times of the day and influence the development of clinical cardiac syndromes,

Circadian Rhythmsand CardiovascularDisease Clinicians have long observed that episodes of angina pectoris may be more frequent and precipitated by lower levels of work during the morning hours. Investigators 12.13have demonstrated that patients are more likely to develop angina, or ST-segment depression on treadmill tests, at lower thresholds in the morning than in the afternoon. Studied” in patients with

From the Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts. Address for reprints: Michael B. Rocco, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. 13c

14C

A SYMPOSIUM:

fihe ofA7y HRfqwnj

6I

THE CONCEPT

OF THE TOTAL

ISCHEMIC

BURDEN

7:43 628

833

845

940

951

3a8

110

92

96

92

92

122

A&e I

If0

8I

I 10

&I

I

I

I

I

-9 I1

2

4

6

8

10

Prinzmetal’s variant angina have demonstrated an increase in the frequency of attacks between 2 A.M. and 4 A.M. Yasue et all5 studied 13 patients with Prinzmetal’s variant angina who performed treadmill exercise tests in the early morning, between 5 A.M. and 8 A.M., and again in the afternoon, between 3 P.M. and 4 P.M. Attacks of angina associated with ST-segment elevations were induced in all 13 patients during the morning exercise but in only 2 of 13 patients during afternoon exercise, despite the fact that treadmill speed and duration of exercise were greater in the afternoon. Angiographic evaluation in similar patients demonstrated that epicardial coronary vessel caliber was smaller and had a greater dilating response to nitroglycerin in the morning than in the afternoon. Based on these and other studies, it has been suggested that temporal variations in vasomotor tone of the large coronary arteries, via (Yadrenergic-mediated vasoconstriction, partially explain the clinical variability in symptoms and exercise physiology in patients with variant angina.16J7 The recent use of calibrated ambulatory monitoring of the electrocardiogram has demonstrated that the

FIGURE 1. Results of a typical 24hour electrocardiographic recording session In a 74-year-old man wlth coronary artery dlsease. Seven episodes of lschemlc ST-segment depression occurred throughout the day, only one of which was associated with pain. Most episodes occurred within the first 3 hours after awakening. HR = heart rate; bpm = beats/ min.

I &

frequency of symptomatic and asymptomatic episodes of ischemic ST-segment depression in patients with coronary artery disease is maximal in the early morning hours (Fig. 1).18Welg have demonstrated that the increase in myocardial ischemia in these patients is particularly enhanced in the first 1 to 3 hours after awakening. Although the number of episodes of myocardial ischemia that occurred during the morning hours was approximately twice the number of episodes that occurred during the evening hours, no significant differences were found in characteristics of the morning and evening ischemic episodes in terms of duration, maximal ST-segment depression, heart rate at onset of ST-segment depression or level of physical activity at the time of an event. However, when the threshold heart rate for the development of ischemic ST-segment depression was determined for each patient, patients were more likely to develop ischemia when their heart rate reached this threshold during the morning hours than when this level was attained during the evening hours [Fig. .z).~O Observations such as these may help explain why patients are more likely to

lschemic Episodes HR Range for Onset of ST+

FIGURE 2. The increased incidence of ST-segment depression in the morning as it relates to heart rate (HR) thresholds for developing ST-segment depression. Patients are more likely lo develop ST-segment depression when their heart rate threshold for ischemia is achieved in the morning rather than in the afternoon hours.

March 9.1987

CIRCADIAN RHYTHM OF CORONARY EVENTS

‘I2

3

6

9

12

3

6

9

THE AMERICAN

JOURNAL

OF CARDIOLOGY

Volume 59

15c

cardial infarction from the data base of the Multicenter Investigation of the Limitation of Infarct Size. This latter study is of particular note because it permitted objective determination of the time of onset of myocardial infarction based on the construction of CK-MB curves rather than on pain-estimated times of onset. A recent reviewz4 of more than 2,000 death certificates reported 387 sudden cardiac deaths occurring out of hospital in Massachusetts in 1983. Analysis revealed a prominent circadian rhythm of sudden cardiac death, with a primary peak between 7 A.M. and 11 A.M. This observation has been substantiated in a recent report from the Framingham Heart Study groupz5 utilizing much more precise records for determining the time and cause of death. Temporal differences in the occurrence of cardiac arrhythmias have also been reported. InvestigationsZ6 with &hour ambulatory monitoring have detected an increased frequency of atria1 and ventricular arrhythmias between 6 A.M. and 9 A.M. It is of interest that this rhythm resembles those observed for myocardial ischemia, myocardial infarction and sudden cardiac death.

CIRCADIAN RHYTHM OF CORONARY EVENTS

1

“0 P8 s 16

12

3

-------am-u

6

9

12

3

6

9

pm-

7h? of Dqy FIGURE 3. The 24-hour distribution of myocardial ischemia episodes detected by ambulatory monitoring, fop, is displayed along with the hourly patterns for onset of myocardial infarction, middle, and out-of-hospital cardiac death, bottom. The peak frequencies in all 3 pathologic conditions occur in the morning hours after awakening. STD = ST-segment depression. Top and middle panels are adapted with permission from N Engl J Med.2i Bottom panel is adapted with permission from Circulation.24

'12

6

9

12

3

6

9

Blood Pressure*

g:::; 500

have ischemia in the morning than in the evening hours. Circadian variations in the frequency of ischemic episodes in ambulatory patients is of particular interest because it parallels variations reported for the onset of myocardial infarction and death from cardiac causes (Fig. 3].21Many studies demonstrate a temporal distribution of myocardial infarction, with a peak in onset of pain between 6 A.M. and 12 ~~~~~~~~~~~ In one of the earliest studies of a large population, MasteP reported a peak incidence of myocardial infarction at 10 A.M.. In a study of over 1,200 patients reported by Stephens5 the onset of myocardial infarction, based on the commencement of symptoms, demonstrated a bimodal distribution, with a major peak around 9 A.M. and a secondary peak approximately 12 hours later. This is very similar to the recent report of Muller et aP detailing the circadian variation in the onset of myo-

3

Systok

’

12

I

I

I

3

6

9

I

12

I

3

I

6

I

9

Heart Rote *

FIGURE 4. The same distribution of myocardial ischemic episodes, top, is displayed along with the diurnal patterns of blood pressure, middle, and heart rate, boffom. Morning increases in heart rate and blood pressure coincide with increased frequency of ischemic activity. STD = ST-segment depression. Adapted with permission from Lancet.6

16C

A SYMPOSIUM:

THE CONCEPT

OF THE TOTAL

AM Circadian Patterns

ISCHEMIC

BURDEN

Supply / Demand Ratio

t Activity

INCREASED

t Cotecholamines t Cortisol t Platelet Aggregability ? t Vasular Receptor Sensitivity FIGURE 5. Hypothetical causes of morning increases in the incidence of coronary events. The interactlon of external (increased physical activity and environmental stimuli) and internal (increased sympathetic cardiac activity, platelet aggregabillty and, possibly, altered sensitivity of vascular receptors to constrictor stimuli) circadian rhythms may adversely Influence the myocardial supply and demand ratlo and result in an increased incidence of coronary events in the morning hours after awakenlng. (See text.) HR = heart rate; BP = blood pressure.

PossibleMechanismof Increased Morninglschemia Temporal patterns of cardiac disease may well be influenced by many of the exogenous and endogenous periodic rhythms observed in humans. A variety of external factors, such as physical effort and emotional stimuli over a .%-hour time span, may interact to produce enhanced ischemic disease activity in the morning. However, circadian rhythmicity in endogenous cardiovascular functions must also be considered. As previously cited, circadian rhythms have now been demonstrated for systolic and diastolic blood pressures 6,7heart rate,6 plasma catecholamine levels4 cortiso13and myocardial contractility.l* Intrinsic morning increases in plasma catecholamine levels may result in increased heart rate, blood pressure and ventricular contractility, all of which contribute to increased myocardial oxygen demand (Fig. 4). External stimuli associated with time of rising may further enhance sympathetic cardiac activity and its subsequent effects on myocardial oxygen demand and oxygen uptake. Morning increases in coronary tone, possibly due to an increase in the level of circulating catecholamines or altered morning sensitivity of vascular receptors, may result in altered or diminished coronary blood flow. In vitro studies of cultured smooth muscle cells have shown that overnight exposure to hydrocortisone results in a marked increase in the density of al-adrenergic receptors (W.S. Colucci, personal communication). Morning peaks in the level of plasma cortisol may increase the sensitivity of epicardial vessels to vasoconstrictor stimuli. Heightened platelet aggregabilitys and a decrease in the function of the fibrinolytic systemgJOmay result in a hypercoagulable state, thrombosis and further impedance of coronary blood flow. A relative imbalance in myocardial oxygen demand and supply due to the interaction of these factors may be more prominent in the early morning hours than at other times of the day, thus resulting in lower morning thresholds for the development of myocardial ischemia (Fig. 5). Clearly, further studies are needed to

determine the possible influence of these various rhythms on the clinical expression of ischemic heart disease.

Conclusionsand ClinicalImplications Twenty-four hour rhythms in the normal and pathophysiologic function of the cardiovascular system, now well described, may result from cyclic variations in the external environment or endogenous biologic functions. These observations have important therapeutic implications for patients with coronary artery disease: A better understanding of the factors that influence ischemic disease activity may lead to better control of myocardial ischemia and a decrease in cardiac morbidity and mortality. The marked increase in ischemic activity soon after awakening is of potential concern, because frequently used medical regimens may not provide patients with adequate protection at times when they are at greatest risk of developing ischemia. Descriptions of the association between increased frequency of myocardia1 ischemia and serious coronary events are drawn from observations of daily life, not from testing in the hospital. The patterns exhibited suggest that ischemic disease activity is a dynamic process influenced by the cyclic rhythms and activities of daily life. In efforts to find new treatment strategies for myocardial ischemia, there is a need to focus on these patterns of real-life events.

References 1. Davy J. On the temperature of man. Philos Tram R Sot Lond 1845;319-333. 2. Reinberg A, Smolensky MH. Introduction of chronobiology. In: Reinberg A, Smolensky MH, eds. Biological Rhythms and Medicine: Cellular. Metabolic, Physiopothologic, and Pharmacologic Aspects. New York: Springer-Verlag, 1984%22. 3. Weitzman ED, Fukushima D, Nogeire C, Roffwarg H. Gallagher TF, Hellman L. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. 1 Clin Endocrinol Metab 1971;33:14-22. 4. Turton MB, Deegan T. Circadian variations of plasma catecholamine, cortisol and immunoreactive insulin concentrations in supine subjects. Clin Chim Acta 1974;55:389-397. 5. Smolensky MH. Aspects of human chronopathology. In: Reinberg A, SmoIensky MH, eds. Biological Rhythms and Medicine: Cellular, Metabolic. Physiopathologic. and Pharmacologic Aspects. New York: Springer-Verlag. 1983:131-209.

March 9.1987

6. Millar-Craig MW, Bishop CN. Raftery EB. Circadian variation of bloodpressure. Lancet 1978;1:795-797. 7. Floras IS. Jones IV, Johnston ]A, Brooks DE, Hassan MO, Sleight P. Arousal and the circadian rhythm of blood pressure. Clin Sci Mol Med 1978;55: 395s-397s. 8. Tofler CH, Czeisler CA, Rutherford 1. Williams GH, Muller JE. Increased platelet aggregability after arising from sleep (abstr]. [ACC 1986;7:suppl A:116A. 9. Rosing DR. Brakman P, Redwood DR. Goldstein RE, Beiser GD, Astrup T. Epstein SE. Blood fibrinolytic activity in man. Diurnal variation and the response to varying intensities of exercise. Circ Res 1970;27:171-184. 10. Petralito A, Mangiafico RA, Gibino S. Cuffari MA, Miano MF, Fiore CE. Daily modifications of plasma fibrinogen. platelets, aggregation, Howell’s time, PTT. TT and antithrombin III in normal subjects and in patients with vascular disease. Chronobiologia 1982:9:195-201. 11. Wertheimer L, Hasse” AZ, Delman A]. The 24-hour (circadian) rhythm of the cardiovascular system (abstr). Clin Res 1972;20:404. 12. Henkels U, Blumchen G. Ebner F. Zur problematick vane belastungsprufungen in abhangigkeit van der tageszeit bei patienten mit koronarinsuffizienz. Herz Kreisal 1977;9:343-347. 13. Yasue H. Omote S. Takizawa A. Nagao M. Miwa K. Kato H. Tanaka S. Akiyama F. Pathogenesis and treatment of angina pectoris at rest as seen from its response to various drugs. Jpn Circ r 1978;42:1-10. 14. Karoiwa A. Symptomatology ofvariont angina. rpn Circ J 1978;42:459-476. 15. Yasue H. Omote S, Takizawa 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: 938-948. 16. Yasue H. Touyama M. Shimamoto M. Kato H, Tanaka S, Akiyama F. Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation 1974;50:534-539. 17. Yasue H, Touyama M, Kato H. Tanaka S. Akiyama F. Prinzmetal’s variant

THE AMERICAN

JOURNAL

OF CARDIOLOGY

Volume 59

17c

form of angina as a manifestation of alpha-adrenergic receptor-mediated coronary artery spasm: documentation by coronary arteriography. Am Heart J 1976;91:148-155. 18. Deanfield IE. Selwyn AP. Chierchia S. Maseri A, Ribeiro P, Krikler S, Morgan M. Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;2:

753-758. 19. Rocco MB, Barry 1. Campbell S, Nabel E, Cook EF, Goldman L. Selwyn AP. Circadian variation of transient myocardial ischemia in potients with coronary artery disease. Circulation 1987;75:395-400. 20. Rocco MB, Barry 1. Campbell S, Nabel EG, Selwyn AP. Morning surge I” myocardial ischemia is due to differences in myocardial supply (abstr]. Clin Res 1986;34:339A. 21. Muller LE. Stone PH, Turi ZG. Rutherford ID. Czeisler CA, Parker C. Poole WK. Passamani E, Roberts R. Robertson T, Sobel BE, Willerson IT. Braunwald E. MILIS Study Group. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-1322. 22. Master AM. The role of effort and occupation [including physicians) in coronary occlusion. IAMA 1960;174:942-948. 23. Regional Office of Europe. World Health Organization. Myocardial infarction community registers: results of a WHO international collaborative study coordinated by the regional office for Europe. Public Health in Europe, no. 5, Copenhagen, 1976;1-232. 24. Muller )E. Ludmer PL. Willich SN, Tofler GH, Aylmer G, Klangos I, Stone PH. Circadian variation in the frequency of sudden cardiac death. Circulation 1987;75:131-138. 25. Willich S. Rocco M, Tofler G. Stone P, Muller J, Levy D. Circadian frequency distribution of sudden cardiac death: the Framingham Heart Study [abstr]. Circulation 1986;74:suppl 11:21X 26. Brisse 8, Bender F, Gradaus D. Giilker H, Schwippe G, Bramann H, Kuhs H. Circadian changes of heart rate and arrhythmias (abstr). Chronobiologia 1979;6:81.