This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tofler, G. H. Articles by Muller, J. E. Search for Related Content PubMed PubMed Citation Articles by Tofler, G. H. Articles by Muller, J. E. Related Collections Behavioral/psychosocial - treatment Cardiovascular Pharmacology Compliance/Adherence Pathophysiology Risk Factors Arterial thrombosis Acute coronary syndromes

(Circulation. 2006;114:1863-1872.)
© 2006 American Heart Association, Inc.

Contemporary Reviews in Cardiovascular Medicine

Triggering of Acute Cardiovascular Disease and Potential Preventive Strategies

Geoffrey H. Tofler, MB, MD; James E. Muller, MD

From the Royal North Shore Hospital (G.H.T.), Sydney, Australia, and Massachusetts General Hospital (J.E.M.), Boston, Mass.

Correspondence to Geoffrey H. Tofler, Cardiology Department, Royal North Shore Hospital, Sydney, Australia. E-mail gtofler{at}nsccahs.health.nsw.gov.au

Key Words: myocardial infarction • plaque • risk factors • stress • thrombosis • circadian rhythm

	Introduction

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
The last 2 decades have seen major advances in understanding of the mechanism of onset and treatment of acute coronary syndromes. It has become accepted that acute myocardial infarction (MI), sudden cardiac death, and stroke can be triggered by stressors such as heavy physical exertion and severe emotional stress; the clinical implications that can be derived from the findings of triggering remain uncertain, however.

The triggering studies were stimulated by observations of a circadian variation and morning peak in MI, sudden cardiac death, and stroke that indicated that events did not occur randomly.¹ In a 1989 review in Circulation,¹ we stated that although the primary value of recognizing the circadian variation of acute coronary events was the emphasis that could be placed on pharmacological protection during the morning hours, the main significance was the support it provided for the broader concept that the onset of coronary thrombosis at any time of the day is frequently triggered by activities of the patient.

The aim of the present review is to update current knowledge about triggering of acute cardiovascular disease (CVD), place it in the context of advances in understanding of the mechanisms of onset, and suggest a 5-faceted strategy to protect against the pathophysiological effects of triggering. The rationale for such a strategy is discussed, with areas for further research highlighted.

	Long-Term Risk Factor Management

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
The treatment of hyperlipidemia and hypertension illustrates long-term risk factor management, in which an individual may take a daily lipid-lowering or antihypertensive agent for several years to reduce the risk of MI. Although the relative risk reduction with treatment may be 30%, the absolute risk reduction varies considerably, depending on the overall risk profile of a particular individual. For instance, in a moderately high-risk person with a 10% to 15% 5-year CVD event rate, a 30% risk reduction from 5 years of daily antihypertensive or lipid-lowering therapy translates into 4 CVD events prevented per 100 such subjects treated. The chance that a CVD event will be prevented in such an individual over a single day is 1 in 45 000. Thus, the absolute benefit from the preventive therapy on a specific day is very low, yet daily therapy is the standard of care.

Long-term daily therapy is used in part because atherosclerosis has been regarded as slowly progressive. Because it is not possible to predict when an MI will occur, it is logical to provide daily prevention therapy over long periods of time. Furthermore, the major randomized studies have been conducted with long-term daily therapy, and the discipline of taking daily therapy is considered to improve patient compliance. As opposed to a gradual progression of stenoses, however, CVD events frequently occur abruptly after plaque rupture and thrombosis.² In addition, plaque injury and nonocclusive thrombosis may lead to healing and a stepwise increase in stenosis.³ Concurrent with progress in understanding the determinants of plaque vulnerability to rupture,^4,5 triggering activities have been identified, such as heavy physical exertion, severe emotional stress, and respiratory infection, that can precipitate MI, sudden death, stroke, and acute left ventricular dysfunction.^6–12 The triggering data raise the possibility that a strategy directed against the short-term risk posed by triggering activities could complement a long-term risk factor reduction approach. Prevention of CVD at times of increased risk due to a trigger can be designated as triggered acute risk prevention (TARP) and can be considered analogous to the way a protective tarpaulin (often abbreviated as tarp) can be placed when rain is imminent.

	Terminology

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
The following terms are important to an understanding of short-term risk:

(1) Trigger: An activity that produces short-term physiological changes that may lead directly to onset of acute CVD.⁴

(2) Acute risk factor: A short-term physiological change, such as a surge in arterial pressure or heart rate, an increase in coagulability, or vasoconstriction, that follows a trigger and may result in disease onset.⁴

(3) Hazard period: The time interval after trigger initiation associated with an increased risk of disease onset because of the trigger. The onset and offset times of the hazard period, which could also be designated a "vulnerable period," may be sharply defined, as in heavy exertion, or less well defined, as with respiratory infection. The duration of the hazard period may also vary, eg from <1 hour during heavy physical exertion to weeks or months with bereavement.

(4) Triggered acute risk prevention (TARP): Cardiovascular risk reduction that focuses on the short-term increase in risk associated with a trigger.

	Evidence for Triggering of Acute CVD

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
Evidence for triggering has been summarized previously^4,13 and is based on the following points. First, MI results from plaque rupture or erosion and thrombosis.² Second, thrombotic occlusion frequently occurs at coronary artery sites that do not have severe stenosis before the acute plaque rupture.¹⁴ Third, there is a morning peak in frequency of MI, sudden cardiac death, and stroke^15–19 that coincides with heightened blood pressure, heart rate, vasoconstriction, and prothrombotic changes.¹ Fourth, physical and emotional stressors cause similar acute physiological changes to those seen in the morning period. These physiological changes can transiently increase the risk of plaque rupture and thrombosis and decrease the threshold for ventricular fibrillation⁴ (Figure 1). Fifth, epidemiological studies, stimulated by the development of the case-crossover study design, have confirmed and characterized several acute triggers of MI and sudden cardiac death^6,7,18–22 (Figure 2). Finally, cardioprotective agents such as aspirin and ß-blockers modify the physiological responses to acute stressors and have been shown to reduce the likelihood of morning and trigger-induced MI and sudden death.^23–26

View larger version (21K): [in this window] [in a new window]   Figure 1. Potential mechanisms by which a trigger may increase the risk of MI or sudden cardiac death. The relative contribution of each physiological change may vary depending on the specific trigger and differences in pathophysiology between infarction and sudden cardiac death. VT/VF indicates ventricular tachycardia/ventricular fibrillation.

View larger version (15K): [in this window] [in a new window]   Figure 2. Relative risk of MI during vigorous exertion. For the 640 subjects with acute MI who received primary angiographic assessment, the relative risk was 10.1 (95% CI 1.6 to 65.6) greater during vigorous exertion than at other times. Elevated relative risk was seen among individuals with very low activity (30.5, 95% CI 4.4 to 209.9) or low activity (20.9, 95% CI 3.1 to 142.1), but not among those who were moderately active (2.9, 95% CI 0.5 to 15.9) or highly active (1.2, 95% CI 0.3 to 5.2). Adapted with permission from Giri et al.20

	Triggers That Have Been Identified

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
In the Multicenter Investigation of Limitation of Infarct Size (MILIS), almost half (48%) of the patients reported a possible trigger, of whom 13% reported a combination of 2 or more possible triggers²⁷ (Figure 3). The activities most commonly reported were emotional upset (18%), moderate physical activity (14%), heavy physical activity (9%), lack of sleep (8%), and overeating (7%). This and other similar analyses²⁸ are limited by a lack of control data, because exposure to potential triggers is common, yet MI occurs rarely. To address this and other limitations in the study of triggering, Maclure and Mittleman developed the case-crossover study design, initially for the National Institutes of Health–sponsored Determinants of Onset of Myocardial Infarction Study (ONSET study).^6,29 A feature of the case-crossover design is that each person is matched against themselves, with a hazard and control period, to determine the relative risk of a potential trigger leading to MI (Figure 4).

View larger version (11K): [in this window] [in a new window]   Figure 3. Possible triggers of acute MI. A possible trigger was reported by 412 (48.5%) of 849 patients from the Multicenter Investigation of Limitation of Infarct Size (MILIS). A total of 109 patients (13%) reported 2 or more possible triggers. Adapted from Tofler et al27 with permission from Elsevier. Copyright 1990.

View larger version (27K): [in this window] [in a new window]   Figure 4. Case-crossover study design. The 2-hour period before MI onset is defined as the "hazard period." Comparison 1 contrasts exposure to potential triggering activities (such as episodes of anger) in the hazard period with the frequency of exposure expected on the basis of the reported usual frequency over the year before MI. In comparison 2, exposure in the hazard period is compared with exposure in a "control period" at the same time on the preceding day. Reproduced from Mittleman et al7 with permission from the American Heart Association. Copyright 1995.

Heavy Physical Exertion
In the ONSET study, heavy physical exertion (6 metabolic equivalents [METS]) in the hour before onset of MI symptoms was reported by 4.4% of patients and was associated with a relative risk of 5.9.⁶ In this population, heavy exertion can be considered to be the final component cause in 3.8% of cases, ie, 80% of the cases that occurred within 1 hour of exertion were triggered by it.^6,30 Triggering of MI by heavy exertion has been observed in other studies, including the Stockholm Heart Epidemiology Program (SHEEP), in which the relative risk for heavy exertion was 6.1,⁸ and the Triggers and Mechanisms of Myocardial Infarction (TRIMM) study, in which the relative risk was 2.1.²¹ Although these studies included patients with both non–ST-elevation and ST-elevation MI, a 10-fold increase in relative risk for heavy exertion triggering MI was reported among a cohort with ST-elevation MI²⁰(Figure 2). In the ST-elevation cohort, heavy exertion was reported by 10% of individuals in the hour before MI and comprised aerobic activity, such as running or jogging (40%), isometric or heavy lifting (19%), or a mixture of the 2 (41%). A similar breakdown of aerobic (30%) isometric (18%), and mixed (50%) activities was seen in ONSET.⁶ In all studies, including that by Giri et al²⁰ (Figure 2), the frequency of regular exertion modified the relative risk of MI. For instance, in ONSET, sedentary individuals had a 107-fold relative risk for heavy exertion triggering MI triggered by exertion, whereas the risk was only doubled among those reporting physical activity at least 5 times per week.

In addition to nonfatal MI, heavy exertion transiently increases the risk of sudden cardiac death. Among 21 481 US male physicians initially free of self-reported CVD, the relative risk of sudden death during and up to 30 minutes after vigorous exertion (6 METS) was 16.9 (95% confidence interval [CI] 10.5 to 25.0).³¹ The absolute risk of sudden death during any individual episode of heavy exertion, however, was very low (1 sudden death per 1.51 million episodes of exertion). The absolute risk of sudden death with moderate to vigorous exertion (5 METS) was even lower among female participants in the Nurses Health Study, at 1 per 36.5 million hours of exertion.³² Among the nurses, 3% of the 288 sudden deaths occurred during moderate to vigorous activity. This was associated with only a doubling in relative risk during exercise (2.38 [95% CI 1.23 to 4.60]), which was no longer significant in those who exercised 2 or more hours per week. In a study of men, regular activity also modified the risk of cardiac arrest during exercise; relative risk was 56 (95% CI 23 to 131) among sedentary individuals but only 5-fold among those who exercised regularly.³³ Among the habitually vigorous men, the overall risk of cardiac arrest (during and not during vigorous activity) was only 40% that of the sedentary men (95% CI 0.23 to 0.67). These data indicate that although vigorous exertion can trigger MI and sudden death, the absolute risk of any individual episode is very low. Moreover, regular exercise is protective in reducing the risk of an exercise-triggered event, in addition to its benefits on overall risk.³⁴

Sexual Activity
In ONSET, 48% of the subjects reported being sexually active in the year preceding the MI.³⁵ The usual frequency of sexual activity among the 858 sexually active patients was 1 to 11 times per year (25%), 1 to 3 times per month (30%), 1 to 2 times per week (23%), and >2 times per week (22%). Among these individuals, 3% reported sexual activity in the 2 hours before onset of symptoms, with a relative risk of 2.5 (95% CI 1.7 to 3.7) for MI.³⁵ Similar results were found in the SHEEP study.³⁶ In ONSET, the relative risk for sexual activity triggering MI was similar for individuals with prior MI (2.9, 95% CI 1.3 to 6.5) or without known prior coronary disease (2.5, 95% CI 1.7 to 3.7).

These data provide helpful information for counseling the many patients who survive MI each year or who have existing cardiac disease. Counseling has been based in part on the presumed physiological equivalence of sexual activity and a measure of physical activity, although this equivalence does not take into account the variable emotional and physical interplay.³⁷ For sexual activity, as for other triggers, the most important information for counseling is not the relative risk of a potential trigger but the absolute difference in risk the activity produces. To estimate absolute risk, data on relative risk can be combined with baseline risk from populations similar to that from which the study patients originated. For instance, Framingham Heart Study data indicate that the risk that a 50-year-old nonsmoking, nondiabetic man will experience an MI is 1% per year, or 1 chance in 1 million per hour.^35,38 Because the relative risk of MI is doubled by sexual activity, by engaging in sexual activity, such an individual would only increase his hourly risk to 2 in 1 million, and only for a 2-hour period. Weekly sexual activity would only increase his annual risk of MI from 1% to 1.01%, a negligible effect because the absolute risk difference is small, the risk is transient, and the activity is relatively infrequent. Even if the baseline yearly risk of reinfarction or death for an individual with a prior MI is increased to 10%,³⁹ the absolute increase in risk with sexual activity would be very low. Moreover, in ONSET, the relative risk of MI after sexual activity decreased from 3.0 in sedentary individuals to 1.2 for patients who engaged in physical exertion of 6 METS 3 times per week. Although sudden death is not considered in the analysis, and bias may be introduced by reliance on self-reporting, this evidence provide reassurance that although there is a modest transient increase in risk, the absolute risk of MI with sexual activity is very low, even in individuals with known cardiac disease. In addition, they indicate that regular physical activity further lowers the risk. In those with prior MI, return to physical activity is helped by a cardiac rehabilitation program.

Psychosocial Triggers
Anger
In ONSET, 2.4% of patients reported anger that scored 5 on a 7-point anger scale in the 2-hour period before MI. This level of anger, which corresponded with "very angry, body tense, clenching fists or teeth" up to "furious or enraged," was associated with a transient 2-hour risk increase of 2.3 (95% CI 1.2 to 3.2) above baseline when the control was usual annual frequency.⁷ When the control period was the same 2-hour period the day before MI, the relative risk was 4.0 (95% CI 1.9 to 9.4). The most frequent reported contributors to anger were arguments with family members (25%), conflicts at work (22%), and legal problems (8%). In the SHEEP study, the relative risk was 9-fold for anger as a trigger.⁴⁰ Koton et al⁴¹ showed an odds ratio of 14 (95% CI 3 to 253) for anger triggering stroke in the subsequent 2 hours. A schema of possible pathophysiological mechanisms by which anger and other triggers may lead to MI and sudden cardiac death is described in Figure 1.

Anxiety
An elevated relative risk of 1.6 (95% CI 1.1 to 2.2) was associated with episodes of marked anxiety above the 75th percentile on an anxiety scale within the 2 hours before MI.⁷

Bereavement
Increased cardiac mortality in bereaved individuals is well described and has been portrayed as "the broken heart."^42–46 In a cohort of middle-aged widowers, a 40% increase in the mortality rate was observed in the first 6 months after bereavement.⁴⁴

Work-Related Stress
A high-pressure work deadline in the prior 24 hours was associated with a 6-fold increase in relative risk of MI in the SHEEP study,⁹ whereas in ONSET, the relative risk over a 7-day hazard period was 2.3 (95% CI 1.4 to 4.0) for a high-pressure deadline and 2.2 (95% CI 1.0 to 5.0) for firing somebody.⁷ The emotional significance of a job stress influenced its contribution to relative risk of MI. Thus, when increased work responsibilities affected men in a very or fairly negative way in the SHEEP study, the relative risk, adjusted for other risk factors, was 6.3 (95% CI 2.7 to 14.7), whereas the relative risk was only 1.5 (95% CI 0.9 to 2.3) when the increased work responsibilities did not mean very much and 0.7 (95% CI 0.5 to 0.9) when they had a positive effect. Corresponding relative risks among women were 3.8 (95% CI 1.3 to 11.0), 0.8 (95% CI 0.3 to 2.5), and 1.0 (95% CI 0.6 to 1.8).⁹

Population Stressors
Earthquakes^47,48 and wartime missile attack⁴⁹ have been associated with acute increases in cardiovascular risk. In the week after the Los Angeles, Calif, earthquake of 1994, which occurred at 4:31 AM, there was a 35% increase in nonfatal MI compared with the week before and a 4-fold increase in sudden cardiac death on the day of the earthquake^48,50 (Figure 5). For the 6 days after this spike, however, the number of sudden deaths fell below the baseline, which suggests that some of the initial deaths may have been moved forward by several days in individuals who were predisposed, rather than being excess deaths.⁵⁰ In contrast to the Los Angeles earthquake, the 1989 Loma Prieta, San Francisco Bay (Calif) earthquake, which occurred at 5:04 PM, was not associated with increased MI, which led Brown⁵¹ to suggest that the added stress of abrupt awakening in the 4:31 AM Los Angeles earthquake contributed to the triggered events.

View larger version (13K): [in this window] [in a new window]   Figure 5. Daily numbers of cardiovascular deaths in Los Angeles County, California, January 1993 and 1994. On the day of the Northridge earthquake (January 17, 1994), there was a sharp rise in the number of deaths related to atherosclerotic CVD (relative risk 2.6, 95% CI 1.8 to 3.7). The daily number of CVD deaths declined in the 6 days after the earthquake (P=0.002). Reproduced from Leor et al50 with permission from the Massachusetts Medical Society. Copyright 1996.

During the first week of Iraqi missile attacks on Israel in 1991, Meisel and colleagues⁴⁹ found a doubling of nonfatal MI compared with a control period 1 year previously. This was mirrored by a near doubling of sudden out-of-hospital deaths for the corresponding 1-month period.⁴⁹ More recently, Allegra et al⁵² reported a 49% increase in patients admitted with MI through 16 emergency departments within a 50-mile radius of the World Trade Center in the 60 days after September 11, 2001, compared with the 60 days beforehand (118 MIs after versus 79 before, P=0.01). Galea, in an accompanying introduction,⁵³ highlighted the need for further study of population responses to disasters.

Sporting events provide another example of population stress. On the day of the 1996 European football final that Holland narrowly lost to France after penalties, Dutch men had an increased relative risk of MI or stroke of 1.5 (95% CI 1.1 to 2.1), whereas there was no increased risk among Dutch women, French men, or French women.^54,55

Respiratory Infection
Using a case-control study design, Spodick et al⁵⁶ reported a doubling of risk of MI with respiratory infection. More recently, Smeeth and colleagues¹⁰ confirmed an increased risk of MI and stroke after a respiratory tract infection, which was highest during the first 3 days (relative risk for MI 4.9 [95% CI 4.4 to 5.5] and for stroke 3.2 [95% CI 2.8 to 3.6]; Figure 6). The risks were also raised with a urinary tract infection (relative risk for MI 1.7 [95% CI 1.3 to 2.0] and for stroke 2.7 [95% CI 2.3 to 3.2]).

View larger version (17K): [in this window] [in a new window]   Figure 6. Relative risk of a first MI or stroke after respiratory infection. Age-adjusted data for MI and stroke. Stroke did not differentiate ischemic and hemorrhagic. Relative risk vs baseline period >91 days from exposure. Adapted with permission from Smeeth et al.10

Heavy Meal
In the MILIS study, 7% of individuals identified overeating as a potential trigger of their MI.²⁷ In several circadian analyses, a secondary evening peak of MI occurs at 8 PM,¹⁵ which could be due in part to the evening meal. In an analysis from Lipovetsky et al,⁵⁷ there was a 4-fold increase in relative risk of MI over baseline during the first hour after a heavy meal. Heavy fatty meals may produce a prothrombotic response,⁵⁸ an inhibition of vascular reactivity,⁵⁹ and an increase in heart rate and catecholamines, the latter more so after a high-carbohydrate meal.⁶⁰

Drugs and Recreational Habits
Cocaine has been recognized to precipitate MI.^61,62 In ONSET, a 23.7-fold increase in relative risk of MI over baseline occurred in the 1 hour after cocaine use.⁶³ Marijuana led to a 4.8-fold increased risk over baseline in the 1 hour after use.⁶⁴ The elevated risk fell rapidly thereafter.

Environmental Stress
Blizzards have been linked to increased MI, with snow shoveling receiving particular attention as a trigger.^65,66 Air pollution has also been identified as an acute trigger of MI and stroke.^67–70 Inflammatory and prothrombotic factors are potential mediators,⁷¹ although a reduction in heart rate variability may also contribute to the link between pollution and sudden cardiac death.⁷² Although the risk for ischemic stroke in 1 study was only 1% higher on days with relatively high levels of air pollution compared with low pollution days, the total number of increased strokes could be significant from a public health perspective given the large number of at-risk people exposed to the pollution.⁷⁰ Exposure to traffic and associated pollution and emotional stress has been associated with an increased relative risk of MI of 2.7 (95% CI 2.1 to 3.6).⁷³

Seasonal and Other Variations
A seasonal variation in the incidence of MI, cardiac death, and stroke is consistently described, with a winter peak up to 60% greater than the summer nadir.^74,75 The mechanisms underlying this variation, which holds true in both cold and warmer climates, are not fully understood.^76,77 Besides cold ambient temperature, hypotheses advanced include respiratory infections, hypercoagulable state, and increases in blood pressure, serum lipids, and glucose.^78,79 A daily variation in CVD and stroke has also been described, with a peak incidence on Mondays.^75,80–82 Holidays such as Christmas and New Year’s day have also been associated with increased cardiac mortality.⁸³ Timing within the menstrual cycle may also influence risk, possibly due to cyclical changes in estradiol levels.⁸⁴ Among premenopausal women in ONSET, the early follicular phase was associated with a relative risk of MI of 3.3 (95% CI 1.4 to 7.7) compared with the other 3 phases of the menstrual cycle.⁸⁵

	Strategy for TARP

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
Five broad approaches can be considered for triggered acute risk prevention (Table). Because of the limited evidence thus far, these approaches provide a framework for future research rather than a concrete guide for clinical management.

View this table: [in this window] [in a new window]   Potential Strategies for TARP

First, one can adopt a long-term behavioral and pharmaceutical approach that focuses on absolute risk reduction. This corresponds to traditional risk factor modification, which emphasizes optimal blood pressure and lipid levels, not smoking, being physically active, and maintaining optimal weight. By reducing the atherosclerotic burden and the number of vulnerable plaques, such a long-term strategy would reduce the risk that a trigger would produce an acute CVD event.

Second, a long-term preventive approach can be directed against a specific trigger. For instance, regular physical activity reduces the likelihood that MI will be triggered by heavy exertion.^6,20,33,86 Stress reduction training can be used to limit the responses of anger and anxiety. At a public health level, provision of defibrillators and rapid cardiac resuscitation capability in sporting arenas, aircraft terminals, and as part of response preparedness for natural and man-made disasters may reduce cardiac death where large numbers of people congregate and are exposed to increased stress levels.^87–89 Vaccinations can protect against the increased CVD risk posed by influenza and pneumonia. Although more prospective studies are needed and potential selection bias must be considered, influenza vaccination has been associated with a halving in the rate of primary cardiac arrest, MI, and stroke.^90,91

Third, one can determine that the absolute risk of the trigger is very low and does not require intervention. For instance, the data on sexual activity and triggering are reassuring. In an individual considered to be at low risk of having atherosclerotic disease or vulnerable plaques, even a maximal stress such as skydiving, mountain climbing, or major emotional stress should pose little absolute risk. Nonetheless, even in young individuals without significant atherosclerosis, a major extraneous, sympathetic surge that results from cocaine usage can trigger MI and sudden death^61–63,92 or be a mechanism for subclinical plaque disruption and progression of atherosclerosis.^3,93,94

Fourth, individuals at increased absolute risk could modify or avoid the specific triggering activity. Although data are limited, common-sense strategies include using a snow blower service instead of shoveling snow; avoiding an angry confrontation with a neighbor or incorporating relaxation strategies at the time of a severe emotional stress; providing social support and sensitivity at the time of bereavement; limiting hand contact with those with respiratory infection; having smaller, less lipid-rich meals accompanied by foods containing antioxidants, such as fruit and vegetables; and ensuring adequate air conditioning and limiting time outdoors during days of extreme temperatures or high pollution. Although these measures may seem obvious, they are practical, nonpharmacological, and often not followed. From a public health perspective, the recognition that pollution can acutely trigger CVD provides further impetus for tighter pollution control.

Finally, medication could be taken in an effort to sever the link between the stressor and the potential pathophysiological consequences. Although unproven, protection against triggered events may be a contributing mechanism of action for therapies that are effective in prevention, such as aspirin, ß-blockers, statins, and angiotensin-converting enzyme inhibitors.

	Areas for Future Research

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
Characterization of Triggers
Although there has been much progress in defining the triggers of acute CVD, there remains a need to better characterize the frequency of specific triggers and their relative, absolute, and attributable risks, as well as to better understand the modifiers of risk, including individual differences in response to the same trigger.^95,96 The incorporation of triggering questions into prospective trials of medication and devices, including implantable defibrillators,⁹⁷ would be useful. Further study is needed to differentiate excess CVD events from events that would have occurred several hours or days later if the patient had not been exposed to the earlier trigger.⁹⁶ The mechanisms by which stressors trigger MI, sudden cardiac death, and stroke and the potential protective role of routine and novel therapies need to be better characterized in both human and animal models. For instance, a better understanding of the role of tachycardia and acute inflammation in plaque rupture may lead to evaluation of heart rate–lowering drugs or agents such as matrix metalloproteinase inhibitors and statins against triggered events.

Multiple Triggers
One fourth of MILIS study subjects who reported a possible trigger identified 2 possible triggers.²⁷ Further study is required on the effect on risk of multiple concurrent triggers, such as heavy exertion during a respiratory infection, or at the time of emotional stress, such as rushing to catch a plane while carrying a suitcase.

Progression of Atherosclerosis
The contribution of triggers such as severe emotional stress to the progression of vascular disease, mediated by catecholamine-induced uptake of low-density lipoprotein into vessel walls,⁹³ endothelial dysfunction,^98,99 and asymptomatic plaque rupture,³ requires further study. It may be difficult to separate patients for whom MI is the first clinical event from those with premonitory symptoms that may have been triggered by a stressor or those in whom culprit plaque rupture occurred unrecognized 1 to 2 weeks before the MI. In the SHEEP study, the relative risk of exertion triggering MI, which was 3.3 overall, increased to 6.1 among those without premonitory symptoms.⁸

Relationship Between Triggering and Plaque Vulnerability
An inverse relation probably exists between the degree of plaque vulnerability and the intensity of the trigger required to produce rupture and thrombosis. Thus, an individual with an extremely vulnerable plaque or severe stenosis may develop occlusion without a demonstrable trigger, whereas someone with no vulnerable lesions or stenosis may require a major identifiable stressor to trigger plaque rupture and thrombosis. Plaque disruption is often present at >1 location in the same individual. For instance, Takano et al¹⁰⁰ reported an average of 1.67 ruptured plaques per person in nonculprit vessels of patients with acute coronary syndromes. This may reflect a general increase in vascular inflammatory activity associated with higher CRP levels.¹⁰¹ These considerations suggest that transient increases in plaque vulnerability may occur over weeks and months in association with bereavement or other longer-term stressors.¹⁰² A preventive approach, which would require validation in randomized trials, would be to initiate or increase the dose of an agent that may reduce inflammation and plaque vulnerability over these hazard intervals. Such a therapeutic approach would be aided by a means to assess plaque vulnerability.⁵ Although most plaque vulnerability detectors under investigation require an invasive approach, in the future there may be plasma markers or noninvasive tests to assess vulnerability as a guide to preventive therapy.

Therapeutic Approach
Many individuals at moderate to high risk of CVD are already taking daily medication that, as part of their mechanism of action, may be protective against triggered events. Indeed, protection against triggers, some of which cannot be anticipated, provides a further rationale for daily evidence-based therapy that is active over a 24-hour period. Trigger-related considerations do not in any way detract from the recommendation for long-term daily use of medication established to be effective in primary and secondary prevention.

For those taking daily evidence-based therapy or for whom regular therapy is not indicated, it remains unknown whether incremental therapy during a hazard period of increased risk is useful. Large numbers of randomized individuals would be required to test whether short-term strategies directed at specific triggers would be feasible or would lower the occurrence of CVD events beyond current preventive approaches. However, the recognition that bereavement and other prolonged periods of severe stress are associated with increased CVD risk should provide an impetus for physicians to review such individuals more closely for symptoms or changes in blood pressure, lipids, and other risk factors. Although the physician is best placed to initiate and monitor therapy, the active involvement of patients in their care is consistent with moves toward greater patient awareness and may improve compliance and stimulate individuals to lower their overall cardiac risk.¹⁰³ Underutilization of evidence-based therapies, such as ß-blockers, is well recognized among patients before MI, despite known CVD or risk factors,¹⁰⁴ and long-term adherence in secondary prevention remains suboptimal.¹⁰⁵ The demonstration that ß-blockers reduce somatic symptoms associated with anxiety has led to an informal use for performance anxiety.¹⁰⁶ Patients accept the prophylactic use of sublingual nitroglycerin for exercise-induced angina and "pill in the pocket" strategies for supraventricular tachycardia. Although the focus has been on prevention, a potential benefit that needs to be evaluated of having medication such as aspirin in the wallet or handbag is that it is immediately available if symptoms of MI develop.

Absolute Risk Versus Relative Risk
Triggering findings, such as the observation that up to 10% of ST-elevation MIs may be triggered by heavy physical exertion, provide insight into the mechanism of the onset of CVD and its prevention. These data, however, together with those of relative risk, must be balanced by the recognition that the absolute risk for any potential triggering activity to cause MI is the most important clinical measure. If the absolute risk is extremely small, then even a substantial increase in that risk may not be clinically meaningful nor warrant a specific therapy. It would be cause for significant concern if a focus on small risks associated with stressors of daily living led to excessive caution and reduced enjoyment of life, because many pleasures of life are associated with adrenergic activation. Hopefully, recognition of the low absolute risk for stressors such as heavy physical activity, and the ability of regular moderate activity to attenuate the immediate risk, would alleviate anxiety and provide reassurance and support for current recommendations regarding regular activity. Public health measures such as curbs on pollution, vaccinations for influenza, wider provision of public-access defibrillators, and optimal acute response to disasters³¹ may have a significant impact on numbers of triggered MIs and sudden cardiac deaths, even though the risk reduction for any individual is low.

	Conclusion

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
It has now been established that nonfatal MI, stroke, and sudden cardiac death can be precipitated by triggers; however, the clinical utility of these findings remains unclear. We have presented a hypothetical framework for acute risk reduction that complements long-term preventive strategies and emphasizes short-term changes in risk of plaque rupture and thrombosis due to triggering. Greater understanding of triggering, from the basic science to the epidemiological level, should facilitate progress. The means of prevention would not be to eliminate all potential triggering activities (an undesirable and unattainable goal) but to design strategies that can be evaluated in randomized studies for their ability to sever the linkage between a trigger and its potentially adverse consequence. A preventive approach to short-term risk could have made a significant difference to John Hunter (1728–1793), surgeon and medical educator at St George’s Hospital, London, United Kingdom, who presciently stated, "My life is at the mercy of any rogue who chooses to provoke me" and indeed died shortly after an acrimonious meeting with hospital administrators.

	Acknowledgments

 
The authors thank Drs Oswald Tofler, Martin Albert, John Gunning, Peter Caspari, and Michael Ward for review of the manuscript and helpful comments.

Disclosures

Dr Muller is an employee of InfraReDx. Dr Tofler reports no conflicts.

	Footnotes

 
Dr Muller is on leave from his positions at Massachusetts General Hospital and Harvard Medical School to serve as the Chief Executive Officer of InfraReDx, Inc.

	References

Top Introduction Long-Term Risk Factor Management Terminology Evidence for Triggering of... Triggers That Have Been... Strategy for TARP Areas for Future Research Conclusion References

 
1. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989; 79: 733–743.[Abstract/Free Full Text]

2. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985; 53: 363–373.[Free Full Text]

3. Burke AP, Kolodgie FD, Farb A, Weber DK, Malcom GT, Smialek J, Virmani R. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation. 2001; 103: 934–940.[Abstract/Free Full Text]

4. 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]

5. Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon J-J, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Airaksinen KEJ, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang I-K, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr, Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies, part 1. Circulation. 2003; 108: 1664–1672.[Abstract/Free Full Text]

6. Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ, Muller JE; 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.[Abstract/Free Full Text]

7. Mittleman MA, Maclure M, Sherwood JB, Mulry RP, Tofler GH, Jacobs SC, Friedman R, Benson H, Muller JE. Triggering of acute myocardial infarction onset by episodes of anger. Circulation. 1995; 92: 1720–1725.[Abstract/Free Full Text]

8. Hallqvist J, Moller J, Ahlbom A, Diderichsen F, Reuterwall C, de Faire U. Does heavy physical exertion trigger myocardial infarction? A case-crossover analysis nested in a population-based case-referent study. Am J Epidemiol. 2000; 151: 459–467.[Abstract/Free Full Text]

9. Moller J, Theorell T, de Faire U, Ahlbom A, Hallqvist J. Work related stressful life events and the risk of myocardial infarction: case-control and case-crossover analyses within the Stockholm Heart Epidemiology Programme (SHEEP). J Epidemiol Commun Health. 2005; 59: 23–30.[Abstract/Free Full Text]

10. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med. 2004; 351: 2611–2618.[Abstract/Free Full Text]

11. Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman SP, Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC. Neurohormonal features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005; 352: 539–548.[Abstract/Free Full Text]

12. Strike PC, Steptoe A. Behavioural and emotional triggers of acute coronary syndromes: a systematic review and critique. Psychosom Med. 2005; 67: 179–186.[Abstract/Free Full Text]

13. Tofler GH. The role of psychosocial and other social factors in acute myocardial infarction. In: Rose BD, ed. UpToDate 13.1. Wellesley, Mass: UpToDate; 2005.

14. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988; 12: 56–62.[Abstract]

15. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R, Robertson T, Sobel BE, Willerson JT, Braunwald E. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985; 313: 1315–1322.[Abstract]

16. Willich SN, Levy D, Rocco MB, Tofler GH, Stone PH, Muller JE. Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol. 1987; 60: 801–806.[CrossRef][Medline] [Order article via Infotrieve]

17. Marler JR, Price TR, Clark GL, Muller JE, Robertson T, Mohr JP, Hier DB, Wolf PA, Caplan LR, Foulkes MA. Morning increase in onset of ischemic stroke. Stroke. 1989; 20: 473–476.[Abstract/Free Full Text]

18. Behar S, Halabi M, Reicher-Reiss H, Zion M, Kaplinsky E, Mandelzweig L, Goldbourt U; SPRINT Study Group. Circadian variation and possible external triggers of onset of myocardial infarction. Am J Med. 1993; 94: 395–400.[CrossRef][Medline] [Order article via Infotrieve]

19. Tofler GH, Muller JE, Stone PH, Forman S, Solomon RE, Knatterud GL, Braunwald E. Modifiers of timing and possible triggers of acute myocardial infarction in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) Study Group. J Am Coll Cardiol. 1992; 20: 1049–1055.[Abstract]

20. Giri S, Thompson PD, Kiernan FJ, Clove J, Fram DB, Mitchel JF, Hirst JA, McKay RG, Waters DD. Clinical and angiographic characteristics of exertion-related acute myocardial infarction. JAMA. 1999; 282: 1731–1736.[Abstract/Free Full Text]

21. Willich SN, Lewis M, Lowel H, Arntz H-R, Schubert F, Schroder R, for the Triggers and Mechanisms of Myocardial Infarction Study Group. Physical exertion as a trigger of acute myocardial infarction. N Engl J Med. 1993; 329: 1684–1690.[Abstract/Free Full Text]

22. Strike PC, Perkins-Porras L, Whitehead DL, McEwan JR, Steptoe A. Triggering of acute coronary syndromes by physical exertion and anger: clinical and sociodemographic characteristics. Heart. 2006; 92: 1035–1040.[Abstract/Free Full Text]

23. Hennekens CH, Buring JE, Sandercock P. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation. 1989; 80: 749–756.[Free Full Text]

24. Peters RW, Muller JE, Goldstein S, Byington R, Friedman LM. Propranolol and the morning increase in the frequency of sudden cardiac death (BHAT Study). Am J Cardiol. 1989; 63: 1518–1520.[CrossRef][Medline] [Order article via Infotrieve]

25. Ridker PM, Manson JE, Buring JE, Muller JE, Hennekens CH. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation. 1990; 82: 897–902.[Abstract/Free Full Text]

26. Parker JD, Testa MA, Jimenez AH, Tofler GH, Muller JE, Parker JO, Stone PH. Morning increase in ambulatory ischemia in patients with stable coronary artery disease: importance of physical activity and increased cardiac demand. Circulation. 1994; 89: 604–614.[Abstract/Free Full Text]

27. Tofler GH, Stone PH, Maclure M, Edelman E, Davis VG, Robertson T, Antman EM, Muller JE. Analysis of possible triggers of acute myocardial infarction (the MILIS Study). Am J Cardiol. 1990; 66: 22–27.[CrossRef][Medline] [Order article via Infotrieve]

28. Sumiyoshi T. Evaluation of clinical factors involved in onset of myocardial infarction. Jpn Circ J. 1986; 50: 164–173.[Medline] [Order article via Infotrieve]

29. Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991; 133: 144–153.[Abstract/Free Full Text]

30. Rothman KJ, Greenland S. Modern Epidemiology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998.

31. Albert CM, Mittleman MA, Chae CU, Lee I-M, Hennekens CH, Manson JE. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med. 2000; 343: 1355–1361.[Abstract/Free Full Text]

32. Whang W, Manson JE, Hu FB, Chae CU, Rexrode KM, Willett WC, Stampfer MJ, Albert CM. Physical exertion, exercise, and sudden cardiac death in women. JAMA. 2006; 295: 1399–1403.[Abstract/Free Full Text]

33. Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med. 1984; 311: 874–877.[Abstract]

34. Curfman GD. Is exercise beneficial—or hazardous—to your heart? N Engl J Med. 1993; 329: 1730–1731.[Free Full Text]

35. Muller JE, Mittleman MA, Maclure M, Sherwood JB, Tofler GH. Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion. JAMA. 1996; 275: 1405–1409.[Abstract/Free Full Text]

36. Moller J, Ahlborn A, Hulting J, Diderichsen F, de Faire U, Reuterwall C, Hallqvist J. Sexual activity as a trigger of myocardial infarction: a case-crossover analysis in the Stockholm Heart Epidemiology Program (SHEEP). Heart. 2001; 86: 387–390.[Abstract/Free Full Text]

37. Falk RH. The cardiovascular response to sexual activity: do we know enough? Clin Cardiol. 2001; 24: 271–275.[Medline] [Order article via Infotrieve]

38. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J. 1993; 121: 293–298.

39. Moss AJ, Benhorin J. Prognosis and management after a first myocardial infarction. N Engl J Med. 1990; 322: 743–753.[Medline] [Order article via Infotrieve]

40. Moller J, Hallqvist J, Diderichsen F, Theorell T, Reuterwall C, Ahlbom A. Do episodes of anger trigger myocardial infarction? A case-crossover analysis in the Stockholm Heart Epidemiology Program (SHEEP). Psychosom Med. 1999; 61: 842–849.[Abstract/Free Full Text]

41. Koton S, Tanne D, Bornstein NM, Green MS. Triggering risk factors for ischaemic stroke: a case-crossover study. Neurology. 2004; 63: 2006–2010.[Abstract/Free Full Text]

42. Jacobs S. An epidemiological review of the mortality of bereavement. Psychosom Med. 1977; 39: 344–357.[Abstract/Free Full Text]

43. Stroebe MS. The broken heart phenomenon: an examination of the mortality of bereavement. J Comm Applied Social Psych. 1994; 4: 47–61.[CrossRef]

44. Young M, Benjamin B, Wallis C. The mortality of widowers. Lancet. 1963; 2: 454–456.[Medline] [Order article via Infotrieve]

45. O’Connor M, Allen J, Kasniak A. Autonomic and emotion regulation in bereavement and depression. J Psychosom Res. 2002; 52: 183–185.[CrossRef][Medline] [Order article via Infotrieve]

46. Tennant C. Life stress, social support and coronary heart disease. Aust NZ J Psych. 1999; 33: 636–641.[CrossRef]

47. Trichopoulos D, Zavitsanos X, Katsouyanni K, Tzonou A, Dalla-Vorgia P. Psychological stress and fatal heart attack: the Athens earthquake natural experiment. Lancet. 1983; 1: 441–443.[CrossRef][Medline] [Order article via Infotrieve]

48. Leor J, Kloner RA. The Northridge earthquake as a trigger for acute myocardial infarction. Am J Cardiol. 1996; 77: 1230–1232.[CrossRef][Medline] [Order article via Infotrieve]

49. Meisel SR, Kutz I, Dayan KI, Pauzner H, Chetboun I, Arbel Y, David D. Effect of Iraqi missile war on incidence of acute myocardial infarction and sudden death in Israeli civilians. Lancet. 1991; 338: 660–661.[CrossRef][Medline] [Order article via Infotrieve]

50. Leor J, Poole WK, Kloner RA. Sudden cardiac death triggered by an earthquake. N Engl J Med. 1996; 334: 413–419.[Abstract/Free Full Text]

51. Brown DL. Disparate effects of the 1989 Loma Prieta and 1994 Northridge earthquakes on hospital admissions for acute myocardial infarction: importance of superimposition of triggers. Am Heart J. 1999; 137: 830–836.[CrossRef][Medline] [Order article via Infotrieve]

52. Allegra JR, Mostashari F, Rothman J, Milano P, Cochrane DG. Cardiac events in New Jersey after the September 11, 2001, terrorist attack. J Urban Health. 2005; 82: 358–363.[Medline] [Order article via Infotrieve]

53. Galea S. Disasters and the health of urban populations. J Urban Health. 2005; 82: 347–349.[Medline] [Order article via Infotrieve]

54. Witte DR, Bois MI, Hoes AW, Grobbee DE. Cardiovascular mortality in Dutch men during 1996 European football championship: longitudinal population study. BMJ. 2000; 321: 1552–1554.[Abstract/Free Full Text]

55. Toubiana L, Tanslik T, Letrilliart L. French cardiovascular mortality did not increase during football championship. BMJ. 2001; 322: 1306. Letter.[CrossRef][Medline] [Order article via Infotrieve]

56. Spodick DH, Flessas AP, Johnson MM. Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched control patients. Am J Cardiol. 1984; 53: 481–482.[CrossRef][Medline] [Order article via Infotrieve]

57. Lipovetsky N, Hod H, Roth A, Kishon Y, Sclarovsky S, Green MS. Heavy meals as a trigger for a first event of the acute coronary syndrome: a case-crossover study. Isr Med Assoc J. 2004; 6: 728–731.[Medline] [Order article via Infotrieve]

58. Miller GJ, Martin JC, Mitropolous KA. Plasma factor VII is activated by post-prandial triglyceridaemia irrespective of dietary fat composition. Atherosclerosis. 1991; 86: 163–166.[CrossRef][Medline] [Order article via Infotrieve]

59. Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fat meal on endothelial function in healthy subjects. Am J Cardiol. 1997; 79: 350–354.[CrossRef][Medline] [Order article via Infotrieve]

60. Baliga RR, Burden L, Sidhu MK, Rampling MW, Kooner JS. Effects of components of meals (carbohydrate, fat, protein) in causing postprandial exertional angina pectoris. Am J Cardiol. 1997; 79: 1397–1400.[CrossRef][Medline] [Order article via Infotrieve]

61. Rezkalla SH, Hale S, Kloner RA. Cocaine-induced heart diseases. Am Heart J. 1990; 120: 1403–1408.[CrossRef][Medline] [Order article via Infotrieve]

62. Hollander JE, Hoffman RS, Burstein JL, Shih RD, Thode HCJ, for the Cocaine-Associated Myocardial Infarction Study Group. Cocaine-associated myocardial infarction. Arch Intern Med. 1995; 155: 1081–1086.[Abstract/Free Full Text]

63. Mittleman MA, Mintzer D, Maclure M, Tofler GH, Sherwood JB, Muller JE. Triggering of myocardial infarction by cocaine. Circulation. 1999; 99: 2737–2741.[Abstract/Free Full Text]

64. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering of myocardial infarction by marijuana. Circulation. 2001; 103: 2805–2809.[Abstract/Free Full Text]

65. Glass RI, Zack MMJ. Increase in deaths from ischemic heart diseases after blizzards. Lancet. 1979; 1: 485–487.[Medline] [Order article via Infotrieve]

66. Franklin BA, Bonzheim K, Gordon S, Timmis GC. Snow shoveling: a trigger for acute myocardial infarction and sudden coronary death. Am J Cardiol. 1996; 77: 855–858.[CrossRef][Medline] [Order article via Infotrieve]

67. Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Lipsett M, Luepker R, Mittleman MA, Samet J, Smith SCJ, Tager I. Air pollution and cardiovascular disease: a statement for healthcare professionals from the expert panel on population and prevention science of the American Heart Association. Circulation. 2005; 109: 2655–2671.[CrossRef]

68. Ruidavets J-B, Cournot M, Cassadou S, Giroux M, Meybeck M, Ferrieres J. Ozone air pollution is associated with acute myocardial infarction. Circulation. 2005; 111: 563–569.[Abstract/Free Full Text]

69. Tsai S-S, Goggins WB, Chiu H-F, Yang C-Y. Evidence for an association between air pollution and daily stroke admissions in Kaohsiung, Taiwan. Stroke. 2003; 34: 2612–2616.[Abstract/Free Full Text]

70. Wellenius GA, Schwartz J, Mittleman MA. Air pollution and hospital admissions for ischemic and hemorrhagic stroke among Medicare beneficiaries. Stroke. 2005; 36: 2549–2553.[Abstract/Free Full Text]

71. Ghio AJ, Hall A, Bassett MA, Cascio WE, Devlin RB. Exposure to concentrated ambient air particles alters hematologic indices in humans. Inhal Toxicol. 2003; 15: 1465–1478.[Medline] [Order article via Infotrieve]

72. Pope CA, Verrier RL, Lovett EG, Larson AC, Raizenne ME, Kanner RE, Schwartz J, Villegas GM, Gold DR, Dockery DW. Heart rate variability associated with particulate air pollution. Am Heart J. 1999; 138: 890–899.[CrossRef][Medline] [Order article via Infotrieve]

73. Peters A, von Klot S, Heier M, Trentiaglia I, Hormann A, Wichmann E, Lowel H, for the Cooperative Health Research in the Region of Augsburg Study Group. Exposure to traffic and the onset of myocardial infarction. N Engl J Med. 2004; 351: 1721–1730.[Abstract/Free Full Text]

74. Ornato JP, Siegel L, Craren EJ, Nelson N. Increased incidence of cardiac death attributed to acute myocardial infarction during winter. Coron Artery Dis. 1990; 1: 199–203.

75. Kelly-Hayes M, Wolf PA, Kase CS, Brand FN, McGuirk JM, D’Agostino RB. Temporal patterns of stroke onset: the Framingham Study. Stroke. 1995; 26: 1343–1347.[Abstract/Free Full Text]

76. Spencer FA, Goldberg RJ. Seasonal distribution of acute myocardial infarction in the National Registry of Myocardial Infarction. J Am Coll Cardiol. 1998; 31: 1226–1233.[Abstract/Free Full Text]

77. Seto TB, Mittleman MA, Davis RB, Taira DA, Kawachi I. Seasonal variation in coronary artery disease mortality in Hawaii: observational study. BMJ. 1998; 316: 1946–1947.[Free Full Text]

78. Woodhouse PR, Khaw KT, Plummer M, Foley A, Meade TW. Seasonal variation of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease. Lancet. 1994; 343: 435–439.[CrossRef][Medline] [Order article via Infotrieve]

79. Mavri A, Guzic-Salobir B, Salobir-Pajnic B, Keber I, Stare J, Stegnar M. Seasonal variation of some metabolic and hemostatic risk factors in subjects with and without coronary artery disease. Blood Coagul Fibrinolysis. 2001; 12: 359–365.[CrossRef][Medline] [Order article via Infotrieve]

80. Gnecchi-Ruscone T, Piccaluga E, Guzzetti S, Contini M, Montano N, Nicolis E. Morning and Monday: critical periods for the onset of acute myocardial infarction: the GISSI 2 study experience. Eur Heart J. 1994; 15: 882–887.[Abstract/Free Full Text]

81. Peters RW, McQuillan S, Kaye SA, Gold MR. Increased Monday incidence of life-threatening ventricular arrhythmias: experience with a third-generation implantable defibrillator. Circulation. 1996; 94: 1346–1349.[Abstract/Free Full Text]

82. Barnett AG, Dobson AJ. Excess in cardiovascular events on Mondays: a meta-analysis and prospective study. J Epidemiol Commun Health. 2005; 59: 109–114.[Abstract/Free Full Text]

83. Phillips DP, Jarvinen JR, Abramson IS, Phillips RR. Cardiac mortality is higher around Christmas and New Year’s than at any other time. Circulation. 2004; 110: 3781–3788.[Abstract/Free Full Text]

84. Kawano T, Motoyama M, Ohgushi K, Kugiyama K, Ogawa H, Yasue H. Menstrual cyclic variation of myocardial ischemia in premenopausal women with variant angina. Ann Intern Med. 2001; 135: 977–981.[Abstract/Free Full Text]

85. Mukamal KJ, Muller JE, Maclure M, Sherwood JB, Mittleman MA. Variation in the risk of onset of acute myocardial infarction during the menstrual cycle. Am J Cardiol. 2002; 90: 49–51.[CrossRef][Medline] [Order article via Infotrieve]

86. Albert CM, Mittleman MA, Chae CU, Lee I-M, Hennekens CH, Manson JE. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med. 2000; 343: 1355–1361.[Abstract/Free Full Text]

87. O’Rourke MF, Donaldson E, Geddes JS. An airline cardiac arrest program. Circulation. 1997; 96: 2849–2853.[Abstract/Free Full Text]

88. Hallsrom AP, Ornato JP, Weisfeldt M, Travers A, Christenson J, McBurnie MA, Zalenski R, Becker LB, Schron EB, Proschan M, Public Access Defibrillation Trial Investigators. Public-access defibrillation and survival after out-of-hospital cardiac arrest. N Engl J Med. 2004; 351: 637–646.[Abstract/Free Full Text]

89. Hazinski MF, Idris AH, Kerber RE, Epstein A, Atkins D, Tang W, Lurie K. Lay rescuer automated external defibrillator ("public access defibrillation") programs: advisory statement from the American Heart Association Emergency Cardiovascular Committee; the Council on Cardiopulmonary, Perioperative, and Critical Care; and the Council on Clinical Cardiology. Circulation. 2005; 111: 3336–3340.[Abstract/Free Full Text]

90. Siscovick DS, Raghunathan TE, Lin D, Weinmann S, Arbogast P, Lemaitre RN, Psaty BM, Alexander R, Cobb LA. Influenza vaccination and the risk of primary cardiac arrest. Am J Epidemiol. 2005; 152: 674–677.[CrossRef]

91. Madjid M, Naghavi M, Litovsky S, Casscells SW. Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies. Circulation. 2003; 108: 2730–2736.[Free Full Text]

92. Siegel AJ, Sholar MB, Mendelson JH, Lukas SE, Kaufman MJ, Renshaw PF, McDonald JC, Lewandrowski KB, Apple FS, Stec JJ, Lipinska I, Tofler GH, Ridker PM. Cocaine-induced erythrocytosis and increase in von Willebrand factor. Arch Int Med. 1999; 159: 1925–1930.[Abstract/Free Full Text]

93. Cardona-Sanclemente LE, Born GV. Adrenaline increases the uptake of low-density lipoproteins in carotid arteries of rabbits. Atherosclerosis. 1992; 96: 215–218.[CrossRef][Medline] [Order article via Infotrieve]

94. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001; 104: 1477–1482.[Abstract/Free Full Text]

95. Greenland S, Robins JM. Conceptual problems in the definition and interpretation of attributable fractions. Am J Epidemiol. 1988; 128: 1185–1197.[Free Full Text]

96. Strike C, Magid K, Whitehead DL, Brydon L, Bhattacharrya MR, Steptoe A. Pathophysiological processes underlying emotional triggering of acute cardiac events. Proc Natl Acad Sci U S A. 2006; 103: 4322–4327.[Abstract/Free Full Text]

97. Whang W, Mittleman MA, Rich D, Wang PJ, Ruskin JN, Muller JE, Tofler GH, Albert CM, for the TOVA investigators. Heart failure and the risk of shocks in patients with implantable cardioverter defibrillators: results from the Triggers of Ventricular Arrhythmias (TOVA) study. Circulation. 2004; 109: 1386–1391.[Abstract/Free Full Text]

98. Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, O’Connor G, Betteridge J, Klein N, Steptoe A, Deanfield JE. Mental stress induces transient endothelial dysfunction in humans. Circulation. 2000; 102: 2473–2478.[Abstract/Free Full Text]

99. Kaplan JR, Manuck SB, Adams MR, Weingand KW, Clarkson TB. Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet. Circulation. 1987; 76: 1364–1372.[Abstract/Free Full Text]

100. Takano M, Inami S, Ishibashi F, Okamatsu K, Seimiya K, Ohba T, Sakai S, Mizuno K. Angioscopic follow-up study of coronary ruptured plaques in nonculprit lesions. J Am Coll Cardiol. 2005; 45: 652–658.[Abstract/Free Full Text]

101. Kolodgie FD, Virmani R, Burke AP, Farb A, Weber DK, Kutys R, Vinn AV, Gold HK. Pathologic assessment of the vulnerable human coronary plaque. Heart. 2004; 90: 1385–1391.[Free Full Text]

102. Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, Blackett KN, Sitthi-amorn C, Sato H, Yusuf S, for the INTERHEART Investigators. Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study):case-control study. Lancet. 2004; 364: 953–962.[CrossRef][Medline] [Order article via Infotrieve]

103. Rosner F. Patient noncompliance: causes and solutions. Mt Sinai J Med. 2006; 773: 553–559.

104. Miller RR, Li Y-F, Sun H, Kopjar B, Sales AE, Pineros SL, Fihn SD. Underuse of cardioprotective medications in patients prior to acute myocardial infarction. Am J Cardiol. 2003; 92: 209–211.[CrossRef][Medline] [Order article via Infotrieve]

105. Newby LK, Allen LaPointe NM, Chen AY, Kramer JM, Hammill BG, DeLong ER, Muhlbaier LH, Califf RM. Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation. 2006; 113: 203–212.[Abstract/Free Full Text]

106. Sherman DG, Easton JD. Beta-adrenergic blockade and anxiety. Lancet. 1976; 2: 911–912.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				N. S. Granado, T. C. Smith, G. M. Swanson, R. B. Harris, E. Shahar, B. Smith, E. J. Boyko, T. S. Wells, M. A.K. Ryan, and for the Millennium Cohort Study Team Newly Reported Hypertension After Military Combat Deployment in a Large Population-Based Study Hypertension, November 1, 2009; 54(5): 966 - 973. [Abstract] [Full Text] [PDF]

				C. J. Lavie, T. C. Gerber, and W. L. Lanier Hurricane Katrina: The Infarcts Beyond the Storm Disaster Med Public Health Preparedness, October 1, 2009; 3(3): 131 - 135. [Full Text] [PDF]

				R. D. Brook, B. Urch, J. T. Dvonch, R. L. Bard, M. Speck, G. Keeler, M. Morishita, F. J. Marsik, A. S. Kamal, N. Kaciroti, et al. Insights Into the Mechanisms and Mediators of the Effects of Air Pollution Exposure on Blood Pressure and Vascular Function in Healthy Humans Hypertension, September 1, 2009; 54(3): 659 - 667. [Abstract] [Full Text] [PDF]

				J. T. Dvonch, S. Kannan, A. J. Schulz, G. J. Keeler, G. Mentz, J. House, A. Benjamin, P. Max, R. L. Bard, and R. D. Brook Acute Effects of Ambient Particulate Matter on Blood Pressure: Differential Effects Across Urban Communities Hypertension, May 1, 2009; 53(5): 853 - 859. [Abstract] [Full Text] [PDF]

				S. K. Williams and K. W. Davidson Psychological stress and cardiovascular disease with emphasis on acute coronary syndromes. J. Am. Coll. Cardiol., April 14, 2009; 53(15): 1339 - 1339. [Full Text] [PDF]

				A. Vaananen, A. Koskinen, M. Joensuu, M. Kivimaki, J. Vahtera, A. Kouvonen, and P. Jappinen Lack of Predictability at Work and Risk of Acute Myocardial Infarction: An 18-Year Prospective Study of Industrial Employees Am J Public Health, December 1, 2008; 98(12): 2264 - 2271. [Abstract] [Full Text] [PDF]

				S. von Klot, M. A. Mittleman, D. W. Dockery, M. Heier, C. Meisinger, A. Hormann, H.-E. Wichmann, and A. Peters Intensity of physical exertion and triggering of myocardial infarction: a case-crossover study Eur. Heart J., August 1, 2008; 29(15): 1881 - 1888. [Abstract] [Full Text] [PDF]

				R. D. Brook Potential health risks of air pollution beyond triggering acute cardiopulmonary events. JAMA, May 14, 2008; 299(18): 2194 - 2196. [Full Text] [PDF]

				T. C. Turin, Y. Kita, Y. Murakami, N. Rumana, H. Sugihara, Y. Morita, N. Tomioka, A. Okayama, Y. Nakamura, R. D. Abbott, et al. Higher Stroke Incidence in the Spring Season Regardless of Conventional Risk Factors: Takashima Stroke Registry, Japan, 1988-2001 Stroke, March 1, 2008; 39(3): 745 - 752. [Abstract] [Full Text] [PDF]

				U. Wilbert-Lampen, D. Leistner, S. Greven, T. Pohl, S. Sper, C. Volker, D. Guthlin, A. Plasse, A. Knez, H. Kuchenhoff, et al. Cardiovascular Events during World Cup Soccer N. Engl. J. Med., January 31, 2008; 358(5): 475 - 483. [Abstract] [Full Text] [PDF]

				Authors/Task Force Members, J.-P. Bassand, C. W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernandez-Aviles, K. A.A. Fox, D. Hasdai, E. M. Ohman, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology Eur. Heart J., July 1, 2007; 28(13): 1598 - 1660. [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tofler, G. H. Articles by Muller, J. E. Search for Related Content PubMed PubMed Citation Articles by Tofler, G. H. Articles by Muller, J. E. Related Collections Behavioral/psychosocial - treatment Cardiovascular Pharmacology Compliance/Adherence Pathophysiology Risk Factors Arterial thrombosis Acute coronary syndromes