Correspondence
Sympathetic-Nerve Activity during Sleep
N Engl J Med 1993; 328:1850-1851June 24, 1993
- Article
To the Editor:
Somers et al. (Feb. 4 issue)1 found that rapid-eye-movement (REM) sleep is associated with profound sympathetic activation in normal subjects. Because sleep cycles change with aging, the hemodynamic and sympathetic changes found during REM sleep in these subjects, whose mean age was 25 years, cannot be extrapolated to explain ischemic events that occur in much older patients. If such sleep-related changes were also found in older people, this might help clarify the higher-than-expected incidence of myocardial infarction and stroke in the morning hours. There is, however, a more likely explanation for this phenomenon. The ischemia may have begun at some unknown time during sleep but could not be diagnosed until the patient awakened. Hence, ischemic cardiovascular events may yet be random occurrences. The increased incidence of events in the morning may only seem real because of the foreshortened period available for diagnosis.
1 ReferencesMartin Terplan, M.D.
California Pacific Medical Center, San Francisco, CA 941151
Somers VK ,Dyken ME ,Mark AL ,Abboud FM . Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993;328:303-307
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To the Editor:
Somers et al. suggest that a particular event occurring during REM sleep, profound sympathetic activation, may trigger adverse myocardial events hours later. If such an extrapolation is deemed reasonable -- and to me it is not -- then we are also entitled to assume that any other event or altered activity that is hours remote from the time of clinical ischemia is also potentially culpable. For example, the finding that heart rate did not increase as much during REM sleep as did sympathetic outflow suggests that cardiac parasympathetic activity is increased, as the authors acknowledge. Other evidence1 suggests a cholinergic rather than an adrenergic component of spasm. There are peaks and troughs for a wide array of circadian variables during various stages of sleep. Any one of these variables may be implicated in coronary dynamics. Of greatest interest would be variables that change most around the time of a myocardial event.
1 ReferencesStanley Kalsner, Ph.D.
City University of New York Medical School, New York, NY 100311
Kalsner S . Cholinergic constriction in the general circulation and its role in coronary artery spasm. Circ Res 1989;65:237-257
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To the Editor:
In the light of the findings by Somers et al., would it be advisable for patients who take long-acting beta-blocker drugs once a day to take their tablets before going to bed?
C.J.M. Cockx, M.D.
Ballast Nedam Groep, Riyadh 11432, Saudi ArabiaAuthor/Editor Response
The authors reply:
To the Editor: Dr. Kalsner takes issue with the hypothesis that sympathetic and hemodynamic changes during REM sleep may initiate a coronary thrombosis that presents clinically hours later. Intravascular thrombus formation is related to multiple factors, including vessel tone, platelet adhesiveness, blood flow, clot propagation, and the balance between thrombotic and fibrinolytic states. The time from the onset of thrombus formation to the eventual myocardial infarction may vary. Studies in animals show marked cyclic flow variations in stenosed coronary arteries with endothelial damage1. Unstable angina in humans is associated with partially occlusive thrombi2 and may persist for hours to days before progressing to infarction. A substantial number of acute myocardial infarctions occur within a few hours of severe physical exertion3. In the review he cites, Dr. Kalsner himself provides some support for our hypothesis when he states that, “Contrary to popular belief, the majority (59%) of myocardial infarctions occur in patients while sleeping or resting and only a few percent take place during heavy physical exertion”4. This suggests either that rest is more likely to trigger an infarction (which is unlikely) or, alternatively, that the presentation of infarction may be “remote” from the triggering event, in keeping with our speculation. To put it simplistically, if we limited our interest to the variables that change most around the time of a myocardial event, we would not recognize the influence of factors such as cholesterol, hypertension, smoking, and family history.
Dr. Kalsner's hypothesis about cholinergic coronary spasm is reasonable; it too deserves consideration, especially in view of the role of endothelium in mediating coronary vasodilation and that of endothelial dysfunction in coronary atherosclerosis, diabetes, and hypertension.
Dr. Terplan raises the important question of age and its influence on sleep. We hope to be able to provide a definitive answer soon. Elderly people experience the loss of slow-wave sleep (stages 3 and 4)5. The percentage of REM sleep remains essentially unchanged. It would be remarkable if physiologic responses to REM sleep diminished dramatically in older people. The oldest subject in our study (36 years old) had the most profound sympathetic activation during REM sleep. Other changes with aging include insomnia and sleep apnea, which may also have implications for neural circulatory control.
Dr. Terplan proposes that the initiation of ischemia during sleep may be a random event. Perhaps, but studies we cited suggest otherwise. REM sleep induces a reduction in blood flow in stenosed coronary arteries in animals6. In humans awakening with nocturnal angina, 32 of 39 episodes of chest pain with electrocardiographic changes occurred during REM sleep7. REM sleep has been associated with chest pain and electrocardiographic changes characteristic of angiographically demonstrated coronary spasm8.
When beta-blockade is indicated for ischemia, it would seem important to ensure adequate 24-hour beta-blockade. Beta-blockers blunt the morning increase in myocardial infarction3. In individual patients in whom pharmacokinetics do not permit 24-hour beta-blockade despite adequate dosage, a twice-daily beta-blocker may be indicated, especially in patients with angina or silent ischemia during sleep.
8 ReferencesVirend K. Somers, M.D., D.Phil.
Mark E. Dyken, M.D.
Francois M. Abboud, M.D.
University of Iowa College of Medicine, Iowa City, IA 522421
Folts JD ,Crowell EB Jr ,Rowe GG . Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 1976;54:365-370
Web of Science | Medline2
Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemic cardiac pain at rest: results of the Thrombolysis in Myocardial Ischemia (TIMI IIIA) Trial
Web of Science | Medline3
Pasternak RC, Braunwald E, Sobel BE. Acute myocardial infarction. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. 4th ed. Vol. 2. Philadelphia: W.B. Saunders, 1992:1200-91.
4
Kalsner S . Cholinergic constriction in the general circulation and its role in coronary artery spasm. Circ Res 1989;65:237-257
Web of Science | Medline5
Bliwise DL. Normal aging. In: Kryger MH, Roth TC, DeMert WC, eds. Principles and practice of sleep medicine. Philadelphia: W.B. Saunders, 1989.
6
Kirby DA ,Venier RL . Differential effects of sleep stage on coronary hemodynamic function during stenosis. Physiol Behav 1989;45:1017-1020
CrossRef | Web of Science | Medline7
Nowlin JB ,Troyer WG Jr ,Collins WS , et al. The association of nocturnal angina pectoris with dreaming. Ann Intern Med 1965;63:1040-1046
Web of Science | Medline8
King MJ ,Zir LM ,Kaltman AJ ,Fox AC . Variant angina associated with angiographically demonstrated coronary artery spasm and REM sleep. Am J Med Sci 1973;265:419-422
CrossRef | Web of Science | Medline
