(Circulation. 1995;91:2508-2509.)
© 1995 American Heart Association, Inc.
Articles |
Sympathetic Activity as the Cause of the Morning Increase in Cardiac Events
A Likely Culprit, but the Evidence Remains Circumstantial
From the Institute for Prevention of Cardiovascular Disease, Cardiovascular Division, Deaconess Hospital, Harvard Medical School, Boston, Mass.
Correspondence to James E. Muller, MD, Institute for Prevention of Cardiovascular Disease, Cardiovascular Division, Deaconess Hospital, Harvard Medical School, One Autumn St, Fifth Floor, Boston, MA 02215.
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The well-documented morning increase in myocardial infarction, sudden cardiac death, and other cardiovascular disorders provides a new opportunity to identify the causes of disease onset. In this issue of Circulation, Middlekauff and Sontz1 report on efforts to determine whether the sympathetic nervous system is responsible for the increase in disease onset in the morning. They have picked a prime candidate for a causal role, because (1) events associated with increased sympathetic discharge, such as heavy exertion, have been shown to trigger infarction onset2 ; (2) morning is a time associated with a transition from low to high sympathetic activity3 ; and (3) both observational and randomized studies have demonstrated elimination of the morning peak of disease onset in individuals receiving ß-adrenergic blocking agents.4 5
Middlekauff and Sontz directly measured firing rates of sympathetic nerves to skeletal muscle at rest and during stress in the morning and afternoon. The study was conducted in eight healthy subjects who had spent the previous night in the Clinical Research Center. The morning measurements (obtained between 6:30 and 8:30 AM) were compared with afternoon measurements (obtained between 2 and 4 PM). After basal levels were recorded, lower-body negative pressure was applied (to simulate the stress of assuming the upright posture), and a handgrip exercise was performed. The study convincingly demonstrates that, under these experimental conditions and in these supine subjects, there is no difference in basal or stressed sympathetic firing rate to skeletal muscles in morning versus afternoon testing.
Although this is a valuable study in an understudied area, it is important to note its limitations, most of which were addressed by the authors, and to initiate a full discussion of the manner in which sympathetic activity might account for disease onset.
A major limitation of the study as a means to explain the morning increase of cardiac events is that it addresses the difference between morning and afternoon stressors administered with subjects in the supine position at both times of day, whereas the morning peak of events results primarily from a difference in event rates between the hours of sleep, when subjects are supine, and the first 3 hours after awakening, when subjects are upright.5 The posture difference is important, because previous studies have shown that plasma norepinephrine levels increase by approximately 50% when subjects change from supine to upright posture, regardless of the time of day.6 In addition, resumption of the supine posture for 30 minutes, as was done in the present study, is sufficient to return plasma norepinephrine levels to the low values observed during nighttime sleep. Thus, the present study compared stressors in two similar catecholamine states (as documented by the similar basal norepinephrine levels in the morning and afternoon studies), whereas the events increase as patients move from the low-catecholamine state during supine sleep to the high-catecholamine state of upright activities.
As noted by the authors, there is a possibility that the sympathetic input to the heart might respond differently from that to skeletal muscle. In addition, it is possible that findings might be different in individuals at higher risk of disease onset, ie, those with endothelial dysfunction, angina, prior infarction, or congestive heart failure. Finally, the potential role of vagal withdrawal leading to sympathetic dominance is not addressed.7
Bearing in mind these methodological limitations, let us for purposes of discussion accept that the present study demonstrates that stressors applied in the morning after awakening elicit the same sympathetic response when applied in the afternoon. Indeed, such a conclusion is supported by a study by Jimenez et al8 who demonstrated that the hemodynamic and hemostatic responses to handgrip exercise did not differ in morning versus afternoon sessions, although basal fibrinolytic activity was lower in the morning. Also, Murray et al9 found that the rate of cardiac events was not significantly higher in a group of cardiac patients who performed rehabilitation exercises in the morning versus those exercising in the afternoon.
However, we do not believe that equivalent effects of postawakening and afternoon stress eliminate increased sympathetic activity as a cause of the morning increase in events. As noted above, the morning increase is primarily an increase from the hours of sleep, and neither the present study nor the studies of Murray et al9 and Jimenez et al8 address the sleep-wake transition.
Thus, we differ with the authors' conclusion that their "findings challenge the concept that higher morning sympathetic nerve activity underlies the circadian pattern of cardiac risk." Even if we accept the findings of the present study, there are several possible mechanisms through which a morning surge in sympathetic activity could cause an increased incidence of morning events. For instance, sympathetic surges may be more frequent in the morning than at other times of the day. In addition, it is possible that coronary atherosclerotic plaques become vulnerable to producing disruption and thrombosis randomly over a 24-hour period and that the morning surge of sympathetic activity simply harvests those ripe to produce disease. Finally, there may be some as yet undetected interaction between sympathetic surges and a truly endogenous process, such as plasma cortisol variation.
The results of the present study do not appear to support the hypothesis stated in the discussion that the sympathetic nervous system's contribution to morning events might be mediated via an increased morning sensitivity to catecholamines. Equivalent levels of norepinephrine and sympathetic nerve activity were associated with equivalent levels of arterial pressure response in morning versus afternoon comparisons during supine posture, appearing to argue against increased sensitivity of at least the pressor response to sympathetic stimuli under these conditions.
A valuable next step might be to apply the superb methods of the present report to the study of individuals with coronary artery disease and define precisely the sympathetic changes that occur in the transition from supine sleep to the start of the activities of the day in the upright posture—that is, to focus on the transition and the individuals in whom the events are more likely to occur. Such studies could perhaps clarify the role of the sympathetic nervous system in cardiovascular disease onset and explain the enigma of why ß-adrenergic blocking agents are so effective in preventing the process of plaque disruption and thrombosis and sudden cardiac death.
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References |
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TopIntroductionReferences |
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1. Middlekauff HR, Sontz EM. Morning sympathetic nerve activity is not increased in humans: implications for mechanisms underlying the circadian pattern of cardiac risk. Circulation. 1995;91:2549-2555.
2.
Mittleman MA, Maclure M, Tofler GH, Sherwood JB,
Goldberg RJ, Muller JE, for the Determinants of Myocardial Infarction
Onset Study Investigators. Triggering of acute myocardial
infarction by heavy physical exertion: protection against triggering by
regular exertion. N Engl J Med. 1993;329:1677-1683.
3. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-1518. [Abstract]
4. Peters RW, Muller JE, Goldstein S, Byington R, Friedman L. Propranolol and the morning increase in the frequency of sudden cardiac death (the BHAT study). Am J Cardiol. 1989;63:1518-1520. [Medline] [Order article via Infotrieve]
5. Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors, and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994;23:809-813. [Abstract]
6. Winther K, Hillegass W, Tofler GH, Jimenez A, Brezinski DA, Schafer AI, Loscalzo J, Williams GH, Muller JE. Effects on platelet aggregation and fibrinolytic activity during upright posture and exercise in healthy men. Am J Cardiol. 1992;70:1051-1055. [Medline] [Order article via Infotrieve]
7. Verrier RL, Dickerson LW. Central nervous system and behavioral factors in vagal control of cardiac arrhythmogenesis. In: Levy MN, Schwartz PJ, eds. Vagal Control of the Heart. Mt Kisco, NY: Futura Publishing Co; 1994:557-577.
8. Jimenez AH, Tofler GH, Chen X, Stubbs ME, Solomon HS, Muller JE. Effects of nadolol on hemodynamic and hemostatic responses to potential mental and physical triggers of myocardial infarction in subjects with mild systemic hypertension. Am J Cardiol. 1993;72:47-52. [Medline] [Order article via Infotrieve]
9.
Murray PH, Herrington DM, Pettus CW, Miller HS,
Cantwell JD, Little WC. Should patients with heart disease
exercise in the morning or afternoon? Arch Intern
Med. 1993;153:833-836.
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