Share this article on:

Triggers of Clinical Coronary Heart Disease

Siscovick, David S.

doi: 10.1097/01.ede.0000231372.34197.2a

From the Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA.

Correspondence: David Siscovick, Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA. E-mail:

In this issue of Epidemiology, Baylin et al1 suggest that drinking a cup of coffee has the potential to trigger an acute myocardial infarction (MI). Clinical observations and research on mechanisms of disease have long raised concerns that transient activation of the sympathetic nervous system might trigger MI and sudden cardiac arrest. Importantly, Baylin et al explore the transient increase in risk after coffee intake in the context of other factors that might alter susceptibility, which provides additional support for the hypothesis.

Where does this finding fit in the broader context of triggers of clinical coronary heart disease (CHD) and its prevention? CHD results from coronary atherosclerosis, a long-term process that begins early in life. Acute clinical events such as MI occur during the later stages of coronary atherosclerosis. Acute coronary events in turn lead to further damage to the heart, culminating in heart failure and life-threatening arrhythmia, the primary mechanisms of CHD death. There has been considerable progress in understanding coronary risk development, but the identification of triggers of acute events remains a challenge.

Using animal models, physiological studies have demonstrated the role of ischemia, exercise, and drug therapies as potential triggers of acute coronary events. Pathologic triggers include coronary atherosclerotic plaque rupture and erosions. Histologic characteristics of plaques such as inflammatory infiltrates and thin caps might also influence risk of rupture.2 Case series have raised concerns that drug therapies that activate the sympathetic nervous system might contribute to acute events. In addition, studies have considered factors that affect cardiac susceptibility to triggers, eg, prior MI, drug therapies, habitual physical activity, and dietary intake of long-chain n-3 polyunsaturated fatty acids.

Epidemiologic studies have suggested that the occurrence of MI and sudden cardiac arrest is not random in time; there is a peak of MI and cardiac arrest in the early morning hours, and beta-blocker therapy blunts this morning increase in risk.3,4 Epidemiologic studies also have identified several exposures associated with an acute, transient increase in the risk of MI and cardiac arrest, including acute bouts of exercise or physical exertion,5–7 sexual activity,8 marijuana use,9 anger,10 war,11 and air pollution.12 Taken together, these findings provide some support for the hypothesis that exposures that alter sympathetic activity have the potential to trigger acute CHD events.

Coffee consumption is another factor that alters sympathetic activity. Baylin et al test the hypothesis that coffee is associated with the onset of (nonfatal) MI, particularly in the presence of other factors that predispose to atherosclerotic coronary disease. Using a case–crossover design, the authors report that the risk of MI was transiently increased 1.5-fold during the 1-hour period after intake of coffee compared with risk at other times. When the hazard period was extended to 2 or 3 hours after a cup of coffee, there was no increase in risk, supporting 1 hour as the appropriate hazard period.

This report illustrates issues of design and analysis related to the identification of triggers. The authors focused on a common, transient exposure, namely the acute (recent) consumption of caffeinated coffee. The caffeine in coffee has acute physiological effects such as increases in sympathetic tone and the release of catecholamines,13 which have the potential to trigger an MI. The authors chose a hazard period based on the pharmacology (absorption and bioavailability in the blood) of caffeine.14 They estimated the time at risk from coffee and the time not at risk, using reports of habitual coffee consumption and assuming that relevant effects persist for 1 hour after a cup of coffee.

Importantly, the report presents evidence that other characteristics such as habitual coffee consumption, physical inactivity, and the presence of multiple risk factors may modify the transient coffee effect. Specifically, coffee intake may trigger the onset of MI only among persons who are susceptible to a transient increase in sympathetic activity. The transient increase in risk with coffee intake was lower with habitual coffee consumption; the transient increase was particularly large (4-fold) among occasional coffee drinkers (≤1 cup/d) and more modest (1.6-fold) among moderate coffee drinkers (2–3 cups/d). There was little evidence of a transient increase in risk (1.1-fold) among heavy coffee drinkers (>4 cups/d). It is possible that habitual coffee consumption results in tolerance that alters the acute physiological response to intake of coffee.

The transient increase in risk was not present among persons who engaged in habitual physical activity, possibly because habitual physical activity also influences the response to exposures that have the potential to activate the sympathetic nervous system.8 These latter observations are consistent with reports on the impact of habitual physical activity on the acute transient increase in risk of MI and cardiac arrest with acute bouts of exercise or physical exertion.5–7

There also was some evidence that the transient increase in risk might be higher among those with 3 or more risk factors, but the transient increase in risk was similar among those with and without other risk factors considered separately. The authors suggest that the presence of multiple coronary risk factors may influence the transient risk because of the association of multiple risk factors with the presence of vulnerable plaques. Whether other characteristics such as common genetic variation and differences in usual diet also influence the transient increase in risk is unknown.

An acute coffee effect among light drinkers may help explain several epidemiologic observations, including the J-shaped dose–response relation of MI risk reported with coffee consumption overall, the differences in findings from case–control and cohort studies (given that the former focus on recent exposure), and the peak MI risk noted in the morning.15,16

Given the widespread consumption of coffee, these findings need to be put into perspective. The transient increase in risk associated with coffee seems to be limited to a susceptible subset of the population. Even among the most susceptible people (the occasional and light coffee drinkers), the transient 4-fold increase in MI risk in the hour after coffee intake will result in only a small increase in the absolute risk of MI given the low absolute risk of MI per hour.

As noted here, there are other exposures that can transiently influence risk, and these exposures might have occurred during the hour after a cup of coffee. The authors examined the possibility of confounding by coincident sexual activity and physical activity (reported within 1 hour of MI), cigarette smoking (through restriction), and time of day. They conclude that bias due to these factors was not likely, although bias due to other unknown and unmeasured transient risk factors could not be ruled out.

How generalizable are findings from this study conducted in Costa Rica? Although the amount of coffee consumed in Costa Rica is not unusual, there may be major differences between Costa Rica and other countries in other factors such as the dietary consumption of saturated fatty acids from tropical oils. Effect modification could occur with differences in lifestyle, health status, or medical therapies. Thus, differences in these potential effect modifiers would need to be explored fully before assuming that the hazard would be similar in other settings.

Baylin et al are to be commended for taking into account the limitations of case–crossover studies (eg, recall bias, definition of hazard period, choice of reference period, bias due to other transient exposures, and effect modification by other factors). This article provides a useful example of how to examine the transient risk of MI associated with a potential trigger and how to explore factors that potentially modify that risk.

The identification of triggers of acute CHD events has implications for clinical care and public health. The avoidance of potential triggers (particularly when the transient risks outweigh any health benefits) offers an approach to disease prevention. Attention to factors that modify the effects of triggers such as habitual physical activity and drug therapies may also reduce risk. More generally, research on triggers may help to define more fully the complex interrelationships between chronic and acute exposures and their effects on cardiac risk.

Back to Top | Article Outline


DAVID SISCOVICK is Professor of Medicine and Epidemiology, Codirector of the Cardiovascular Health Research Unit, and Director of the Cardiovascular Epidemiology Training Program at the University of Washington. His research interests have focused on cardiovascular disease with a special interest in reducing mortality from out-of-hospital cardiac arrest. His research on cardiac arrest during vigorous exercise, now published over 20 years ago, put into perspective the transient cardiac risks and benefits of vigorous exercise.

Back to Top | Article Outline


2. Virmani R, Burke AP, Farb A, et al. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47(suppl):C13–18.
3. Muller JE. Circadian variation and triggering of acute coronary events. Am Heart J. 1999;137:S1–S8.
4. Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313:1315–1322.
6. Siscovick DS, Weiss NS, Fletcher RH, et al. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med. 1984;311:874–877.
7. Albert CM, Mittleman MA, Chae CU, et al. Triggering of sudden death from cardiac causes by virgorous exertion. N Engl J Med. 2000;343:1355–1361.
8. Muller JE, Mittleman A, Maclure M, et al. Triggering myocardial infarction by sexual activity. Low absolute risk and prevention by regular physical exertion. Determinants of Myocardial Infarction Onset Study Investigators. JAMA. 1996;275:1405–1409.
11. Kark JD, Goldman S, Epstein L. Iraqi missile attacks on Israel. The association of mortality with a life-threatening stressor. JAMA. 1995;273:1221.
13. Nurminen ML, Niittynen L, Korpela R, et al. Coffee, caffeine and blood pressure: a critical review. Eur J Clin Nutr. 1999;53:831–839.
14. Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol. 1983;24:93–98.
15. Greenland S. A meta-analysis of coffee, myocardial infarction, and coronary death. Epidemiology. 1993;4:366–374.
16. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. The J-shaped effect of coffee consumption on the risk of developing acute coronary syndromes: the CARDIO2000 case–control study. J Nutr. 2003;133:3228–3232.
© 2006 Lippincott Williams & Wilkins, Inc.