The winter's tale—and toll
Article Outline
In 1985, Muller et al1—using the MILIS database—described what many clinicians had seen but not observed; namely, a circadian variation in the onset of acute myocardial infarction, with an increased frequency in the morning hours, and a secondary peak in the late afternoon. Shortly thereafter, they2, 3 and others4 extended the observation to patients with life-threatening ventricular arrhythmias and victims of sudden cardiac death. Subsequent population-based studies5, 6 reported weekly and seasonal variations in these cardiac events, as well. Two related questions were apparent. First, what were the mechanisms and interactions underlying the circadian (daily), circaseptan (weekly), and circannual (seasonal) variations? Second, to what degree was the sudden death observation secondary to associated myocardial ischemia and/or infarction? Englund et al7 provided a partial answer to the latter when they found similar circadian patterns of life-threatening ventricular arrhythmias in patients with ischemic and nonischemic heart disease with implanted cardioverter defibrillators (ICDs). An article in this issue of the Journal, by Müller et al,8 further addresses the same questions by examining the annual distribution of ventricular tachycardia and ventricular fibrillation—also documented by ICDs—in 233 patients, about one-third of whom did not have ischemic heart disease. Their central observation is that a seasonal variation, with a winter peak, occurs both in patients with and without ischemic heart disease.
Time-related influences, be they circadian or seasonal, are but 2 potential “triggers” for acute cardiac events in susceptible individuals. It is likely that there are many potential triggers, as summarized by Servoss and Muller,9, 10 especially when underlying ischemic heart disease is present. Examples include activity shortly after awakening, heavy physical exertion, anger and mental stress, chemicals such as cocaine, and even environmental factors, such as airborne particulate matter. The role and importance of each proposed trigger (and their interaction) may be different with different underlying heart diseases and at different stages of the heart disease. It has been proposed9 that currently identifiable triggers can plausibly be ascribed a contributory role in at least 20% of patients experiencing acute cardiac events. The fact that significant numbers of acute events occur throughout the 24-hour period (and that large data bases are required to confirm the circadian relationship) attests to the number and complexity of factors that can contribute to their onset.
For Muller et al in 1985,1 the tool used to prove the circadian variation of acute myocardial infarction was a large clinical data base, yielding, for the first time, objective, quantifiable data about the onset of acute myocardial infarction in about a thousand patients (in fact, the circadian relationship had been proposed 2 decades before, but not confirmed). For Müller et al,8 the ICD, with its retrievable data, was the tool used to objectively determine seasonal relationships of life-threatening ventricular arrhythmias. The use of the ICD for studies like the current one are limited by the numbers of patients, and it is yet not clear the degree to which observations from the select groups with these devices can be extended to broader groups of patients.
Most of the prior reports of seasonal variation have described patients with known coronary heart disease, or have relied upon population-based death certification data for patients who died suddenly. Most, but not all,11 have demonstrated a significant winter increase in cardiac death, especially in the northern hemisphere during the months of December and January. Although there is a clear correlation of temperature with cardiac death rates in most of these studies, similar seasonal variations have been reported in countries with widely varying climates,12 and in some regions with temperate environments where there are no winter temperature extremes.6 Indeed, the winter increase in cardiovascular death is present in Los Angeles, where the seasonal temperature range is limited, and in Kuwait, where—though in the northern hemisphere—winter is the most comfortable season, with average January temperature of 18°C.12 It has been proposed12 that the effect of climate may be related more to relative changes than to absolute temperature. And there is more to winter than cold weather. Behavioral changes, such as types and amount of physical activity and eating and drinking habits, as well as emotional stresses and travel accompany seasonal changes in many areas. Indeed, in more than one study6, 13 there has been a clustering of events within the winter season that was independent of temperature, and perhaps “holidays-related.” But while emotional, dietary, and alcohol effects may play a role in holiday-season cardiac events, a study by Scherlag et al14 suggests other factors are also involved. They reported that in an experimental model of myocardial infarction in the dog, the incidence of sudden death (as well as inducible sustained ventricular tachycardia in surviving dogs) was increased in winter months. In this model, neither holiday-related behavorial, emotional, or dietary changes were plausible explanations.
In Australia and New Zealand, a winter increase in cardiac event rates has been reported,15 although the seasons are reversed compared to the Northern Hemisphere.
A reasonable conclusion of the available studies is that while temperature may be a contributor to seasonal differences in cardiovascular death rates—particularly when temperatures are extreme and in patients with underlying ischemic heart disease—it does not solely explain the winter increase.
What then are alternative or possible contributing mechanisms for the seasonal differences? For the circadian variation of acute myocardial infarction and associated ventricular arrhythmias, a number of potential contributors have been proposed.9 It is well established that catecholamine blood levels, coronary resistance and blood flow, platelet aggregability, and intrinsic plasminogen activator activity exhibit circadian rhythms. Each of these, acting alone or in concert could contribute to ischemia, or in a patient with a vulnerable coronary plaque, could further promote plaque instability and thrombosis. Some of these effects may be amplified when physical activity is undertaken in the hours just after awakening; and it does appear that it is activity shortly after awakening, rather than the absolute hour of the day, that is important. The morning surge in catecholamine levels is most commonly proposed as a key mediator of the increase in cardiac events, and perhaps more so in patients without ischemic heart disease10 where the coagulation and coronary blood flow changes are unlikely contributors. Some electrophysiologic parameters, including ventricular refractoriness, also demonstrate time-of-day variability.16 There is maximal shortening of the measured ventricular refractory period in the morning, and a diurnal pattern for QTc has been described, as well as maximal variability of the QTc in the morning hours,17 perhaps reflecting autonomic instability during this period.
The circadian rhythms are largely controlled via the suprachiasmatic nucleus, located above the optic chiasm, in the hypothalamus.18 This structure regulates a number of cyclic physiologic functions, including body temperature and some hormonal levels. It is influenced both by neural input and by light. Its function may extend beyond that of the body's central day/night clock, roughly with a 24-hour cycle. Indeed, it is possible that entrainment of the circadian clock by the day-length (photoperiod) may contribute to a circannual rhythm as well.12 The short days of winter—independent of temperature—could thereby affect hormonal, electrophysiologic, and hemodynamic changes that could play a role in susceptible individuals in precipitating cardiovascular events, including ventricular arrhythmias and sudden death. These would act either as a trigger or by altering the local physiologic environment such that another potential trigger becomes active. Were this the case, is it possible that “treatment” with light, in a manner analogous to that proposed19 for seasonal affective disorder, might exert a mitigating influence? Such a proposal remains, of course, pure speculation, as it was in 1999, when it was originally proposed by us.20 Indeed, the relative roles and effective means of control of the putative mediators of circadian variation of acute myocardial infarction and sudden cardiac death have not been fully established either. Continued research toward a clearer understanding of the mechanisms and reversibility of cardiovascular triggers could lead to novel treatments and means of prevention. For the circadian, circaseptan, and circannual influences, perhaps the time is right.
References
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PII: S0002-8703(03)00425-3
doi:10.1016/S0002-8703(03)00425-3
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