Physical, Psychological and Chemical Triggers of Acute Cardiovascular Events: Preventive Strategies

Introduction

In addition to the impact of chronic stressors such as sedentary lifestyle and long-term exposure to high levels of air pollution, many studies have shown that there is an increased risk of acute cardiovascular events immediately following behavioral, psychosocial and environmental triggers.^1-8 Following the landmark study documenting the increased rates of MI related to the 1981 earthquake in Athens⁹ and Muller’s description of the circadian variation in the incidence of MI,¹⁰ various studies documented the frequency of potential triggers in the period immediately preceding MI onset.

Although the observational studies examining physical, psychological and chemical triggers of acute cardiovascular events are not without limitations, studies continue to show that short-term exposures appear to play a role in the occurrence of cardiovascular events. These triggers have been discussed in previous reviews, ^1-8 with a general consensus that different preventive strategies may be appropriate for particular triggers. The purpose of this review is to bring together the evidence of the association between several triggers and cardiovascular outcomes and to discuss the common underlying pathophysiology of these triggers.

1. Proposed mechanisms of triggers of acute cardiovascular events

Rather than leading to slowly progressive atherosclerosis, triggers represent the final step in the pathophysiological process leading to cardiovascular outcomes among susceptible individuals, such as those with vulnerable atherosclerotic plaque, chronic atherosclerotic disease, disorders of the cardiac conduction system and those with microvascular disease. In the presence of a vulnerable atherosclerotic plaque, chemical, physical and psychological stressors may trigger transient vasoconstrictive and prothrombotic effects that ultimately cause plaque disruption and thrombosis. Even in the absence of an occlusive thrombus, triggers may lower the threshold for cardiac electric instability and increase cardiac sympathetic activation via centrally mediated release of catecholamines, thereby evoking primary ventricular fibrillation and sudden cardiac death.¹¹ Figure 1 depicts several potential mechanisms to show how behavioral and environmental exposures trigger cardiovascular events. For instance, physical activity and psychological stress has been shown to increase heart rate and blood pressure, partially due to direct effects on the vasculature and partially mediated by catecholamine secretion. Triggers also elicit pro-coagulatory hemostatic alterations, including increased platelet aggregation and plasma viscosity, either directly or via activation of the sympathetic nervous system. These changes may cause plaque disruption and thrombotic occlusion, resulting in an ischemic event.

Figure 1.

Pathophysiology of acute triggers. This cartoon depicts some of the proposed mechanisms linking behavioral and environmental triggers and cardiovascular outcomes. Additional direct and indirect pathways are likely to exist.

Specific mechanisms for individual triggers have been proposed. Vigorous physical activity consistently leads to higher heart rate, blood pressure, myocardial oxygen demand¹² and activation of the sympathetic nervous system;^{13, 14} abrupt onset psychological stress can lead to similar hemodynamic effects and also stimulates inflammatory cytokines and platelet aggregation;^{11, 15} sleep disturbances are associated with changes in interleukin 6 (IL-6) production and higher levels of sympathetic tone and cortisol output overnight²; and high fat meals are well-documented to cause transiently impaired endothelial function.¹⁶ Influenza infection leads to heightened systemic inflammation that in turn may lead to changes in endothelial function or cause atheroma instability and increase plaque vulnerability.⁶ It may also stimulate the production of fibrinogen and other clotting factors that increase the risk of thrombotic coronary occlusion and it could increase concentrations of inflammatory cytokines, inhibiting the vasodilating function of nitric oxide or prostaglandins. Inhaled fine particulate air pollution can cause pulmonary inflammation, which may trigger a systemic response including heightened coagulability and an autonomic nervous system response, as suggested by increased heart rate and decreased heart rate variability.⁵

2. Physical Triggers

a. Physical activity and Sexual activity

Whereas regular physical activity is associated with a lower baseline risk of cardiovascular disease, each episode of physical activity is associated with a transiently increased risk of MI,^{1, 17-19} sudden cardiac death²⁰ and hemorrhagic²¹ and ischemic ^{22, 23} stroke. The risk is reduced by habitual physical activity. For instance, in the Determinants of Myocardial Infarction Onset Study (MIOS),¹⁷ the risk of MI was 5.9 times higher (95%CI 4.6–7.7) within one hour of periods of heavy physical activity compared to periods of lower levels of activity or rest. The relative risk of MI was higher among those who usually exercised less than once per week (RR=107, 95%CI 67–171) compared to those who usually exercised five or more times per week (RR=2.4, 95%CI 1.5–3.7). Similarly, in the Stockholm Heart Epidemiology Program (SHEEP),¹⁸ the risk of MI was 6.1 times greater during or within 15 minutes of exertion of 6 METs (metabolic equivalents) or higher compared to periods of lower levels of physical exertion or rest. The relative risk was greater among those who reported less than one episode of heavy physical activity per week (RR=100.7) compared to those who reported more than 4 episodes of regular physical activity per week (RR=3.3).

Healthy adults without known cardiovascular disease should be encouraged to develop gradually progressive exercise regimens. Although regular physical activity should be strongly encouraged for most adults, the AHA scientific statement on exercise and acute cardiovascular events²⁴ recommends that people who are at increased risk of underlying coronary artery disease should consult with their physician for evaluation of the need for exercise testing and to discuss a prudent exercise program including appropriate warm up and cool down periods and incorporating aerobic and resistance training as appropriate. Furthermore, some high-risk patients should be excluded from some high-intensity activities. Fitness facilities should prepare personnel for cardiovascular emergencies.²⁴

Since cardiovascular events are more frequent in the morning and studies have shown that physical activity can trigger events, some have questioned whether physical activity in the morning may be particularly risky. However, at present, there is no evidence that exercise in the morning induces a higher relative risk than exercise at other times of the day. Von Klot et al found that the relative risk of MI onset associated with physical activity was similar in the morning and at other times of the day.²⁵ Furthermore, Murray and colleagues²⁶ found no difference in risk between individuals who attended cardiac rehabilitation programs in the morning or afternoon. Finally, since the absolute risk of a cardiovascular event in any given hour is extremely low and regular physical activity lowers the baseline risk as well as the relative risk that an episode of heavy physical activity will trigger a cardiovascular event, patients should be encouraged to engage in regular physical activity regardless of the time of day.

Several studies have documented specific physical triggers of acute cardiovascular events, including studies of skiing,²⁷ shoveling snow^28-30 and sexual activity.^31-33 In the MIOS Study, there was a 2.5-fold (95%CI 1.7–3.7) increased risk of MI in the 2 hours after sexual activity,³¹ with decreasing risk among those who were regularly physically active. Compared to those without prior cardiac disease, the relative risk of triggering an MI from sexual activity was not greater among patients with a history of prior angina or prior MI. Sexual activity contributed to the onset of MI in only approximately 0.9% of the cases. Although the relative risk of MI in the period immediately following sexual activity is quite strong, the absolute risk is minimal because the baseline risk is low and exposure is both transient and infrequent. Furthermore, the risk appears to be completely eliminated among individuals who engage in vigorous physical activity 3 or more times per week.³¹ Several studies have shown that phosphodiesterase type 5 inhibitor use is not associated with an increased risk for cardiovascular events.^{34, 35}

b. Respiratory Infections and Urinary Tract Infections

A recent systematic review³⁶ reported that, based on ecologic studies using surveillance data, the proportion of all excess influenza deaths that were due to cardiovascular disease averaged around 35–50%. However, many of these studies did not properly account for population-level confounding factors such as low temperature. A number of studies have examined the association between recent infection and cardiovascular events. Recent respiratory symptoms are associated with an increased risk of MI within 1–2 weeks, with rate ratios ranging from 2.1 (95%CI 1.4–3.2) to 4.95 (95%CI 4.43–5.53).^37-39 This increased risk is higher in the days immediately after a respiratory infection and falls over time, but can still remain statistically significant at 3 months.^{38, 39} For instance, Smeeth and colleagues³⁸ found that there was an increased risk of MI and stroke after a diagnosis of systemic respiratory tract infection, which was highest during the first three days (RR for MI=4.95, 95%CI 4.43–5.53; RR for stroke=3.19, 95%CI 2.81–3.62). The risks then gradually fell during the following weeks (for MI the RR fell to 3.2 on days 4–7, 2.8 on days 8–14, and 1.4 on days 15–28). The risks were raised significantly but to a lesser degree after a diagnosis of urinary tract infection.

There is mounting evidence that influenza triggers cardiovascular events, but definitive evidence that vaccines reduce the risk of cardiac events in vulnerable populations is not yet available.³⁶ Two randomized clinical trials and several observational studies have suggested that influenza vaccination effectively lowers cardiovascular morbidity and mortality, though the latter may have been limited by issues of confounding, since patients who receive vaccines are often healthier than those who choose to remain unvaccinated. Nevertheless, the American Heart Association and the American College of Cardiology⁴⁰ encourage physicians to provide seasonal flu vaccines to patients with cardiovascular conditions. It remains unclear whether vaccination reduces cardiovascular risk in people without established vascular disease. A well-controlled prospective study is necessary to evaluate the effectiveness of influenza vaccine on cardiovascular events and may help convince the public of the importance of preventing influenza and, in turn, prevent cardiovascular events.

3. Chemical Triggers

a. Coffee and Alcohol Consumption

Caffeinated coffee consumption may acutely trigger a myocardial infarction,⁴¹ sudden cardiac death⁴² or ischemic stroke,⁴³ particularly among non-frequent drinkers.^{41, 43} In a study of 503 incident cases of nonfatal MI,⁴¹ the risk of an MI was 1.5 times greater (95%CI 1.2–1.9) in the hour following coffee intake compared to periods with no coffee. The relative risk was greater for people who drank one or fewer cups per day (RR=4.14, 95%CI 2.0–8.4) than for those who drank 2-3 cups per day (RR=1.6, 95%CI 1.2–2.2) or four or more cups per day (RR=1.1, 95%CI 0.7–1.6).

Alcohol may be an acute trigger for MI,⁴⁴ sudden cardiac death,⁴² and ischemic^45-48 and hemorrhagic²¹ stroke⁷. In a multi-center case-crossover study of 390 patients with acute ischemic stroke,⁴⁸ the risk of stroke onset within one hour after alcohol consumption was 2.3-fold higher (95%CI 1.4–4.0) compared with periods of nonuse. The RR was 1.6 (95%CI 1.0–2.5) in the second hour after drinking, and returned to baseline thereafter. By 24 hours, there was a 30% lower risk (RR=0.7, 95%CI 0.5–0.9). The relative risks were similar for different types of alcoholic beverages. Given the research indicating beneficial effects of habitual moderate consumption but harmful effects of binge drinking, it is possible that the transiently increased stroke risk from moderate alcohol consumption is outweighed by the health benefits for the following 24 hours, whereas consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well. Consequently, individuals who drink large amounts infrequently may primarily experience the acute detrimental effect, while subjects who drink small amounts frequently experience a transiently increased risk that is at least partially offset by the subsequent reduction in risk. Since observational studies were conducted to show that the risk of a cardiovascular event following alcohol and coffee intake varies by drinking patterns, it is possible that these results are due to other lifestyle characteristics that co-vary with alcohol and coffee drinking patterns and impact cardiovascular health.

There have been discrepant findings on the relative dangers and benefits of coffee consumption on the risk of cardiovascular disease, site-specific cancers and diabetes incidence, with more recent findings suggesting that habitual consumption has salutary effects.⁴⁹ Likewise, research on the effects of alcohol consumption has been mixed. Heavy drinking is associated with an increased risk of cardiovascular disease⁵⁰ and moderate consumption may increase the risk of breast and colorectal cancers. On the other hand, there is consistent evidence that moderate intake lowers the risk of cardiovascular disease.⁵¹ Therefore, while it may not be advisable to encourage people to begin drinking, particularly if there are concerns about alcohol addiction, it may be prudent to advise patients to consume small amounts of coffee and alcohol on a regular basis rather than infrequent episodes of heavy drinking.

b. Heavy Meals

In one study,⁵² the relative risk of an acute coronary event during the first hour after heavy meal ingestion was 7 times greater (95%CI 0.8–65.8) than the comparable hours on the prior day and 4 times greater (95%CI 1.9–8.6) than expected based on the usual frequency of heavy meal ingestion during the previous year. Further studies are necessary to replicate this finding. However, since there is no health benefit to heavv meals, it seems appropriate to recommend that this trigger should be completely avoided.

c. Cigarette Smoking

While it seems plausible that smoking triggers cardiovascular events, it is difficult to study since most people who smoke do so throughout the day and therefore do not have a period of exposure and non-exposure that would allow them to contribute information about the short-term triggering effect of smoking. However, lack of evidence does not indicate evidence for a lack of effect; several studies have shown that smoking bans led to lower cigarette smoking and perhaps less second-hand smoke exposure,³⁵ and that these policies in turn, are associated with an abrupt decline in the rate of acute myocardial infarction, suggesting that cigarette smoking is a preventable trigger of MI.

d. Cocaine and Marijuana Use

The risk of MI onset has been reported to be elevated in the hour following cocaine use⁵³ (RR=23.7, 95%CI 8.5–66.3) and after smoking marijuana⁵⁴ (RR=4.8, 95%CI 2.4–9.5). Unlike exercise or coffee and alcohol consumption, there are no salutary effects of habitual intake of cocaine and marijuana on cardiovascular disease to offset the harmful acute effects. Furthermore, with the aging of the baby boomers, the prevalence of marijuana use among people prone to cardiovascular disease is increasing.⁵⁴ It is therefore important to counsel middle aged and older patients to refrain from using marijuana and cocaine.

4. Psychological Triggers

a. Anger

Physical activity and anger have been shown to cause similar acute physiologic responses.¹⁴ In the MIOS study,¹⁴ patients were asked about their frequency of being very angry, furious, or enraged. Compared to the usual annual frequency of episodes of anger, the odds ratio for MI within 2 hours was 2.3 (95%CI 1.7–3.2). Similarly, data from the Stockholm Heart Epidemiology Program (SHEEP)⁵⁵ indicates that people were 9.0 (95%CI 4.4–18.2) times more likely to experience an MI in the hour following episodes of anger than during other times.

b. Depression, Anxiety and Frustration

There is consistent evidence that long-term depression and anxiety increases cardiovascular risk and they may also acutely trigger cardiovascular events.^56-58 Willich et al¹⁹ reported that emotional upset was associated with a transient 2.7-fold (95%CI 1.1–6.6) higher risk of MI within 24 hours. Steptoe et al⁵⁸ found that the relative risk of acute coronary syndrome following depressed mood was 2.5 (95%CI 1.1– 6.6) times greater compared to the same period 24 hours earlier, and the relative risk was higher among patients who reported severely depressed mood (RR=5.08, 95%CI 1.07–47.0). Gullette et al⁵⁶ evaluated the risk of myocardial ischemia among 58 patients with coronary artery disease and documented exercise-induced ischemia. Patients wore ambulatory electrocardiographic (ECG) monitors and were instructed to record their levels of physical activity and several mood states for a 48 hour monitoring period. After adjusting for physical activity, the relative risk of myocardial ischemia within one hour was 2.2 (95%CI 1.1–4.5) for tension, 2.2 (95%CI 0.7–6.4) for sadness, and 2.2 (95%CI 1.1–4.3) for frustration.

c. Work Stress

In the SHEEP study, Moller et al⁵⁷ examined work-related stressful events and found that compared to 25-48 hours before an MI, there is a six-fold increased risk of MI within 24 hours of having “had a high pressure deadline at work” (95%CI 1.8–20.4). Kales et al⁵⁹ used data from the U.S. Fire Administration to identify work exposures associated with the death of 449 firefighters who died on duty that were attributed to coronary heart disease. The authors found that 60 (13.4%) deaths occurred during alarm response, which presumably involves high levels of stress. The relative risk of a CHD death was 14.1 (95%CI 9.8–20.3) times greater during alarm response than during non-emergency tasks. However, since responding to an alarm involves a combination of exposures to pollutants, extreme heat, psychological stress and physical activity, it is difficult to isolate a specific trigger that caused these deaths.

Though research in this area has been limited, it seems highly plausible that a behavioral intervention may prevent the triggering effects of psychological stressors by teaching patients how to avoid stressful situations and by improving coping skills to mitigate the physiologic response to such stressors. Randomized clinical trials would help to evaluate whether behavioral interventions could effectively lower the risk of a cardiovascular event in response to psychological triggers.

d. Population-Based Triggers

The advantage of studying population-level triggers is that the timing of exposure can be objectively identified and a population-based sampling frame prevents issues of selection bias that may arise when studying triggers that are only experienced by a subgroup of the population. However, because aggregate population-level data were used, the observed associations may be due to individual-level confounding. Furthermore, these events may also involve multiple stressors, so it is difficult to isolate which, if any, are responsible for the empirically observed higher incidence.

i. Earthquakes

Increased cardiovascular events in the days following earthquakes have been reported in many regions,^{4, 9, 60} and the psychological stress endured by survivors poses an increased risk of both primary and secondary cardiovascular events, particularly when it is superimposed on the increased cardiovascular risk during early morning hours.^61-63 Although earthquakes cannot be prevented, decreasing the baseline risk of disease and assuring that proper medical care is available in the event of an earthquake may help prevent cases of stress-related cardiovascular disease in the following hours and days.

ii. Industrial Accident

The rate of MI and coronary death was 3.5 times higher than usual in the initial days following an agricultural chemical plant explosion.⁶⁴ However, it is not clear whether the observed increased rate is due to the emission of ammonium nitrate, the anxiety of such an experience or both of these factors.

iii. War and Terror Attacks

Similar to studies of earthquakes, a war or terrorist attack exposes an entire population to a stressful environment. Kark et al⁶⁵ reported a 58% (95%CI, 34%–86%) increase in total mortality among Israelis during the 1991 Persian Gulf War and the subsequent Iraqi missile attacks on Israel. Some of the increased risk may have been due to breathing difficulties from gas masks⁶⁶ and hypoxia from remaining in sealed rooms. Therefore, while the anxiety of living through a war may play a large role, other physical stressors cannot be excluded.

Most but not all studies have found that the World Trade Center (WTC) attack on September 11, 2001 was associated with an increased risk of MI^{67, 68} and arrhythmia,^{69, 70} even among people living as far as Massachusetts and Florida. Ho et al⁷¹ reported that the stress of the attacks led to changes in health behaviors that may predispose to cardiovascular disease, including decreased eating, sleeping, exercising and socializing and increased smoking and alcohol consumption. Therefore, some of the increased cardiovascular risk may be due to adverse behavioral changes.

In addition to the psychological stress of the 9/11 attacks, the population in metropolitan New York was simultaneously exposed to several toxicants in the air. Therefore, some of the increase in cardiovascular events that was observed in the New York area following the 9/11 attacks may have been triggered by a combination of chemical and psychological triggers. However, since there was an increase in cardiovascular events in regions far from New York City,^{68, 69} it seems likely that the psychological stress of a terror attack can trigger cardiovascular events.

iv. Sporting events

The excitement of sporting events has been studied as a potential trigger of cardiovascular events^72-74. For example, Witte et al⁷² found that there was a significant increase in mortality due to coronary heart disease and stroke on the day that the Dutch team was eliminated by the French from the 1996 European football (soccer) championship compared with the five days before and after the match. However, subsequent analyses^{73, 74} found no evidence of increased total or cardiovascular mortality associated with the five major football games played between 1988 and 1994 by the Dutch national team, suggesting that the original study may have been a chance finding. Additionally, such findings may be due to the ecologic fallacy, whereby an association found with group level data is used to make inferences about an association between the corresponding variables at the individual level. Unlike wars and earthquakes that can be assumed to impact the entire population, it is not appropriate to assume that the people who experienced an acute cardiovascular event following a sports competition are the people who watched the event.

5. Environmental

a. Pollution

Some but not all studies of environmental pollutants have demonstrated an increased risk of cardiovascular events following exposure to traveling in traffic or increased levels of particulate matter <2.5 μm in diameter (PM_2.5).^{5, 75, 76} As noted in a recent review,⁵ though the increased risk of MI due to ambient pollution for a given individual at any single time point may be minute, the public health burden of such a ubiquitous risk is quite large; these short-term increases in PM_2.5 levels are associated with the early mortality of tens of thousands of people per year in the United States alone.

In order to have a sizable impact on the risk of cardiovascular events due to PM_2.5 exposure, policy changes will be required. In the meantime, addressing traditional cardiovascular risk factors should be emphasized. Although there is currently no detailed evidence that avoiding exposure on high pollution days lowers cardiovascular risk in vulnerable populations, a recent scientific statement from the American Heart Association⁵ recommends “reducing optional or unnecessary exposures. Additional measures could include eliminating or reducing non-mandatory travel to highly polluted regions and avoiding exposures or outdoor activities (e.g., exercising, commuting) during highly polluted times (e.g., rush hours) or in proximity to major sources of pollution (e.g., roadways, industrial sources). Choosing to exercise indoors with windows closed and using efficient air conditioning and filtering systems may be prudent for certain high-risk patients, particularly during peak pollution periods. Indeed, not only can central air conditioners reduce the indoor exposure level to PM from outdoor sources, there is some evidence that they might reduce the risk for cardiovascular hospitalizations associated with higher ambient pollution levels. If travel/commutes cannot be avoided, maintaining optimal car filter systems, driving with windows closed, and recycling inside vehicle air may help reduce PM exposures.”

b. Temperature Changes

Recent evidence suggests that temperature changes may play a role in MI^{77, 78} and stroke⁷⁹ incidence. For instance, Bhaskaran and colleagues⁷⁸ reported a statistically significant increase in MI risk over the 28 days following a 1°C reduction in daily mean temperature. Adults aged 75-84 and those with a history of heart disease were more vulnerable to the effects of cold than other age groups, whereas those taking aspirin were less vulnerable. Many of the studies evaluating the association between temperature change and cardiovascular risk did not account for strong confounding variables such as ambient air pollution and circulating influenza levels, which are likely to be associated with both temperature and the risk of cardiovascular disease. In addition, weather is also likely to influence behavioral factors that impact cardiovascular risk, such as physical activity.

6. Therapeutic Strategies

Given the ubiquitous exposure to many of these triggers, these findings need to be put into perspective. The increased risk is limited to a susceptible subset of the population. Since most of the studies discussed above only include vulnerable people, the relative risks of a cardiovascular event after a potential trigger are greater than if the study had included the total population.

The identification of acute triggers may seem to suggest that triggering activities should be entirely avoided by those who are most susceptible. However, for some potential triggers, it is not possible to prevent individual exposure (e.g. natural and man-made disasters), elimination may be an unreasonable goal (e.g. sexual activity, spectator sports) or even increase long-term cardiovascular risk and the risk from each episode of acute exposure (e.g. coffee, physical activity). Therefore, the best strategies for minimizing risk lies in focusing on lowering baseline cardiovascular risk and assuring that, whenever possible, immediate assistance is available.

The baseline risk of acute cardiovascular events in any given hour is higher in the presence of risk factors such as cigarette smoking, hypertension, hypercholesterolemia, diabetes or the presence of subclinical or established cardiovascular disease. Thus, the absolute impact of triggering activities will be higher among individuals with known risk factors. For example, in a population of relatively low risk individuals (10 year risk of cardiovascular disease of 5% based on the Framingham risk equation⁸⁰), the absolute impact of 2 episodes of anger per day would be approximately 1 excess cardiovascular event per thousand per year. On the other hand, among higher risk individuals (10 year risk of 20%), a similar frequency of anger would be associated with approximately 5 excess cardiovascular events per thousand per year. The increasing risk from triggers with increasing baseline CHD risk is also evident in estimations of the number of exposed individuals required to lead to one excess case (number needed to harm). As presented in Table 1, there is approximately one excess cardiovascular event for every 657,307 people with low CHD risk who experience two episodes of anger per day; on the other hand, there is approximately one excess cardiovascular event for every 151,094 people with high CHD risk who experience two episodes of anger per day. In other words, as baseline CHD risk increases, fewer exposures are necessary to lead to an excess case of CHD.^81,82,83

Table 1.

Individual-level exposures and absolute risk of acute cardiovascular events for individuals at low (5%), intermediate (10%) and high (20%) ten-year risk of acute cardiovascular events according to the Framingham Risk Score.

			Number Needed to Harm by Ten- Year Framingham Risk of CHD
Exposure	Outcome	RR per Episode	5%	10%	20%
physical activity, sedentary
	MI17	107.0	16,123	7,850	3,707
	MI18	100.7	17,142	8,346	3,941
	MI19	6.9	289,661	141,018	66,584
	MI81	30.5	57,933	28,204	13,317
	MI33	27.5	64,515	31,409	14,830
	MI82	26.0	68,360	33,281	15,714
	ischemic stroke83	6.8	294,655	143,449	67,732
	sudden death20	74.1	46,758	22,764	10,749
physical activity, active
	MI17	2.4	1,220,712	594,287	280,602
	MI18	3.3	743,042	361,740	170,801
	MI19	1.3	5,696,655	2,773,339	1,309,475
	MI81	1.2	8,544,982	4,160,008	1,964,212
	MI33	1.3	5,178,777	2,521,217	1,190,432
	MI82	1.2	8,544,982	4,160,008	1,964,212
	ischemic stroke83	2.0	1,708,997	832,002	392,843
	sudden death20	10.9	345,252	168,082	79,362
sexual activity
	MI31	2.5	569,666	277,335	130,948
	MI32	2.1	1,553,634	756,365	357,130
	MI33	5.5	191,164	93,066	43,943
respiratory tract infection
	MI33	1.5	24,728	12,040	5,686
	MI38	5.0	6,010	2,926	1,382
	ischemic/hemorrhagic stroke38	3.2	10,839	5,277	2,492
caffeinated coffee, frequent
	MI41	1.1	28,483,272	13,866,692	6,547,372
	ischemic stroke43	1.0	35,604,090	17,333,365	8,184,215
caffeinated coffee, infrequent
	MI41	4.1	544,267	264,969	125,110
	ischemic stroke43	3.1	798,597	388,786	183,572
alcohol	ischemic stroke48	2.3	1,314,613	640,002	302,187
heavy meals	ACS52	4.0	569,666	277,334	130,948
cocaine	MI53	23.7	75,287	36,653	17,306
marijuana	MI54	4.8	449,736	218,948	103,380
anger	MI14	2.3	657,307	320,001	151,094
anger	MI55	9.0	106,813	52,001	24,553
depressed mood	ACS58	4.3	513,213	249,851	117,971
work stress	MI57	6.0	14,242	6,934	3,274

Number Needed to Harm: number of exposed individuals required to lead to one excess case

Note: These estimates do not account for the decrease in baseline risk with increasing frequency of habitual physical activity. Estimates for the absolute and relative increase per year can also be constructed using the exponential formula fir relating rates and risks.⁸⁶

The acute and chronic effects of an exposure may operate in the same or opposite directions. For example, high levels of depressive symptoms are associated with higher cardiovascular risk⁸⁴ and transient depressed mood appears to trigger acute cardiovascular events.⁵⁸ On the other hand, isolated bouts of physical activity can trigger cardiovascular events, but frequent habitual vigorous activity is known to lower the long-term baseline risk and also lower the risk that an isolated episode of physical activity might trigger an acute cardiovascular event^{17, 20, 24} (Figure 2).

Figure 2.

Schematic representation of MI risk in active and sedentary subjects. The dashed line shows the large transient increase in the risk of MI associated with an isolated episode of vigorous exertion in sedentary subjects. The solid line shows that subjects who habitually exercise have a lower risk of MI while at rest and also a much smaller transient increase in risk associated with each episode of exercise.

Additionally, one must consider the important distinction between relative and absolute risk. While the relative risk of a cardiovascular event in response to a trigger may seem large, the effect period is short, and so the net absolute impact on disease burden tends to be low for many of these exposures, especially if they are rare and intermittent ^{20, 31}. For instance, in the Stockholm Heart Epidemiology Program (SHEEP),¹⁸ the relative risk of MI from vigorous activity was 6.1. However, this led to only an average of 1.5 excess cases of acute MI per million hours of physical activity.

For common exposures, the transient effects can accumulate, leading to a larger clinical impact. Consider the effect of outbursts of anger and sexual activity. Both are associated with a 2.5-fold elevated risk of MI within 2 hours. However, the accumulated effect of weekly sexual activity is only a relative 4% annual increase in MI risk. On the other hand, the risk of MI associated with 5 episodes of anger per day would result in an approximate relative 129% annual risk of MI.

Studies of acute triggers of cardiovascular events suggest that it may be possible to prevent sudden plaque rupture. Steptoe and Brydon⁴ suggest that improved access to defibrillators and programs to increase public and clinical awareness of triggering may help address the risks associated with sporting events, natural and industrial disasters and wars and terror attacks. Tofler and Muller³ proposed five potential strategies for preventing triggered cardiovascular events: (1) long-term standard preventive therapy focused on reducing the absolute baseline risk (e.g. management of cholesterol and blood pressure, weight management, smoking cessation, moderate alcohol consumption and physical activity); (2) long-term trigger-specific preventive therapy, such as anger and anxiety reduction and enhancing coping mechanisms; (3) if a person has a low absolute risk of cardiovascular events, avoidance is not necessary; (4) if a person is at increased absolute risk, one could modify or avoid certain triggers, such as avoiding heavy meals or snow shoveling; and (5) aspirin, β-blockers, statins, and angiotensin-converting enzyme inhibitors may be useful in severing the link between a trigger and its potential adverse cardiovascular consequences.

Though there is no definitive evidence indicating that medications (e.g. aspirin, beta blockers, ACE inhibitors and statins) prevent cardiovascular events from specific triggers, they are proven effective for primary and secondary prevention, lowering the baseline risk of a cardiovascular event. Due to the circadian variation in cardiovascular events, some researchers have noted that physicians should be sure that patients taking anti-ischemic and antihypertensive therapy are adequately covered during the morning hours, and some have proposed that vulnerable patients take aspirin and/or short-acting β-blockers before engaging in activities suspected to trigger cardiovascular events.⁸⁵ In the MIOS study, the acute effects of anger on the risk of MI¹⁴ was statistically significantly 2 times larger among subjects who did not use aspirin compared to those who did. However, the difference in the relative risks of MI following heavy physical activity was not statistically significant between aspirin users and non-users.¹⁷ Though speculative, this may suggest that pharmacologic interventions may prevent triggering of cardiovascular events.

Since the studies discussed in this review are observational, there is always some concern of residual confounding. However, consistent results have been found across independent carefully conducted studies that incorporated state of the art methods to reduce and control confounding caused by differences in underlying risks and behaviors across individuals. Based on the totality of the evidence, there is strong evidence that there are acute effects of certain physical, psychological and chemical triggers of acute cardiovascular events. Aside from habitual physical activity, there is limited empiric evidence to recommend interventions targeted at reducing the effects of a particular trigger. Further studies are needed to evaluate the effectiveness of behavioral interventions, to determine whether seasonal influenza vaccines can protect against flu-related cardiovascular morbidity and mortality and to identify novel preventive strategies that address not only baseline cardiovascular risk, but also the risk of a cardiovascular event in response to a physical, psychological and chemical triggers of cardiovascular events.