Narrative review
Triggers of acute myocardial infarction: a neglected piece of the puzzle ˇ ulic´b, Nestor Lipovetzkyc, Alessandro Colomboa, Riccardo Proiettia, Viktor C Maurizio Vieccaa and Paolo Dannaa The existence of specific risk factors for the development of coronary heart disease, both chronic and acute, has been extensively investigated and is well understood by cardiology professionals. Diabetes, hypertension, hypercholesterolemia, psychological patterns and smoking are assumed to interact in a complex way with individual heritable predisposition, thus determining the long-term probability of coronary disease. However, the possibility that defined circumstances and activities may act as immediate triggers of acute coronary syndromes, particularly acute myocardial infarction, has not been given comparable attention in clinical research. For example, the recently issued 2012 European guidelines on cardiovascular disease prevention completely overlook the topic of triggers and their possible prevention. This review presents a picture
The investigation of measurable items able to predict morbidity and mortality from cardiovascular disease (CVD) – the so-called risk factors – has been given considerable attention in medical research for decades. The predictive value of risk factors has been extensively analysed and has generated quite accurate measures, recently issued in risk tables.1 The majority of research articles in the field of coronary heart disease (CHD) begin with dramatic statements about the large prevalence and the huge death burden of the illness. As a consequence, cardiovascular prevention has a key role in cardiology, and fighting CVD through specific interventions on risk factors has been – and still is – the basis of many treatment strategies in medicine today, with extensive knowledge reflected in continuously updated guidelines.1 In principle, one major aim of CVD prevention should be the lowering the rate of acute events, namely death, myocardial infarction and stroke. Therefore, studying the circumstances under which acute events occur should be the top priority for cardiologists and health policy makers. Surprisingly, this is not the case. Despite the widespread appreciation that a number of activities and emotions may be causally related to myocardial infarction and sudden death, little research has been carried out regarding these trigger factors. Thanks to coronary angiography, we know from hospital daily practice that the pathogenesis of acute myocardial 1558-2027 ß 2014 Italian Federation of Cardiology
of the most reliable evidence regarding the triggering of myocardial infarction and contributes to further investigation in the field. J Cardiovasc Med 2014, 15:1–7 Keywords: acute myocardial infarction, population attributable fraction, triggers a Cardiology Department, ‘Luigi Sacco’ Hospital, Milano, Italy, bCardiology Division, University Hospital Centre, Split, Croatia and cMaccabi Healthcare Services, Tel Aviv, Israel
Correspondence to Riccardo Proietti, MD, PhD, Cardiology Department, ‘Luigi Sacco’ Hospital, via GB Grassi, 74 Milano, Italy Tel: +39 02 39042392; fax: +39 02 39042311; e-mail: [email protected] Received 23 September 2012 Revised 18 May 2013 Accepted 29 May 2013
infarction (AMI) is mostly based on the rupture and subsequent thrombosis of an atherosclerotic plaque. There is a wide agreement that an obstructing vascular lesion can remain silent for a whole lifetime, whereas a thin atheromatous cap breakdown may more easily lead to an endoluminal thrombotic process.2 However, and in spite of the large body of literature produced, the molecular pathophysiology of vascular lesions that progress to a catastrophic acute event3 remains largely undiscovered. Often, definite behavioural, physical and psychological factors precede an acute coronary syndrome. Hence, a causal relation may exist between transient exposure to circumstantial events, atherosclerotic plaque rupture and acute clinical manifestations and, as a consequence, this information may become the basis of new strategies for the prevention of acute CVDs. The present review summarizes the current knowledge regarding the triggers of AMI and comments on available preventive strategies directed against the short-term risk posed by triggering factors.
Triggers: definitions, mechanisms and identification A trigger is defined as an external stimulus, capable of producing a pathological change leading to a clinical event. This direct association is made on the basis of a short temporal connection between stimulus and disease. DOI:10.2459/JCM.0b013e3283641351
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2 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
In the first attempt to find an appropriate terminology, the term ‘acute risk factors’ was proposed for haemodynamic, prothrombotic and vasoconstrictive processes which elevated the risk of a coronary incident over a period of several hours.4 More recently, aspects of everyday life that influence internal homeostasis and increase the risk of ACS have been described as trigger factors.5 Since the 1960s, the general opinion has been against a relation between AMI and the patient’s daily activity. It was during the eighties and the early nineties that some studies indicated a possible relation between physical exertion, anger, stress, sexual activity, lack of sleep and myocardial infarction.6,7 These studies estimated that about 50% of cases of AMI might be triggered by external factors. The basis for considering external factors as triggers for AMI comes from research from disasters such as the earthquakes in South California in 1994 and in Hanshin-Awaji (Japan) in 1995. In California, a 35% rise in AMI cases was found in the week after the disaster compared with the week that preceded it, and a five-fold increase in sudden cardiac death was found on the earthquake day.8 In most cases, the induction time was less than 1 h. In Hanshin-Awaji, a 3.5-fold increase in AMI cases was found in the month after the disaster.9 Finally, during the Iraq missiles attack on Israel in the 1991 Gulf War, a 58% increase in cardiac death was seen on the first day of the war but not during the subsequent 16 attack days.10 Over the last two decades, several studies have analysed the association of AMI with physical exertion,11,12 anger,13–15 sexual activity,16 cocaine17 and heavy meals18 in the hour before the onset of symptoms. In order to detect an event–disease association beyond what is expected by chance alone, the case-control method has long been used as a statistical reference. Groups of patients admitted to hospital as a result of AMI were compared with groups of patients admitted for different, noncardiovascular acute diseases. Recently, a different way to investigate this relation has been proposed, known as the case-crossover method. Patients are asked to precisely remember all the times they were exposed to a given trigger in the weeks or months before the AMI. Then, a critical time period, that is the time between trigger impact and AMI, is selected. The whole time of the retrospective observation (e.g. 6 months) can then be divided into hazard periods and control periods. Using this information, a rate ratio is calculated using the Mantel-Haenszel estimator, which measures the strength of the association between trigger and AMI.19 As an example, comparing hazard and control periods, the relative risk that an episode of emotional stress is followed by an AMI can
be calculated. Although not immune from bias – one of them being the limited ability of the patients to exactly report the number of exposure episodes in a retrospective time interval of months – the case-crossover method overcomes one of the major threats to the validity of a case-control study, that is inadequate matching of the control cohort with the study participants, and provides the most convincing evidence for the identification of triggers. One of the concerns when studying the relation between triggers and events is which time period is most appropriate as a timeframe for a correct identification of triggers. Most of the studies in the field yielded higher relative risks when the observation period was the day before the onset of symptoms rather than the year before. These higher relative risks can be explained by a tendency towards overreporting the annual frequency of exposures, thus leading to an underestimation of the relative risk, although underreporting the exposure in the day before the onset of symptoms would have the same consequences. However, estimates of relative risks are much more accurate when the control data are based on annual frequency because of random sampling variability.20 Moreover, it is important to underline the difference between the relative risk and the absolute risk of a trigger. The absolute risk shows the real occurrence of an endpoint per episode of exposure. For example, in the Physicians’ Health Study,21 the relative risk of sudden death during and up to 30 min after vigorous exertion was 16.9 [95% confidence interval (CI) 10.5–27.0, P < 0.001]. However, the absolute risk of sudden death during any particular episode of vigorous exertion was extremely low (one sudden death per 1.51 million episodes of exertion). This means that although relative risk is a good theoretical instrument it should not be used as a basis for practical decisions.
Known triggers of acute myocardial infarction Physical exertion
The first studies that described physical activity as a trigger of myocardial infarction were two observational trials; the Multicenter Investigation of Limitation of Infarct Size (MILIS)4 trial and the TIMI-2 (Thrombolysis in Myocardial Infarction) trial.22 The MILIS study reported that 14% of 849 patients had engaged in moderate physical activity and 9% in heavy physical activity before myocardial infarction onset. In the TIMI-2 trial, the clinical history of 3339 patients was analysed to look for exertion-related AMI. The authors reported that infarction occurred during moderate or marked physical activity in 18.7% of patients. In the myocardial infarction ONSET study,11 54 (4.4%) of 1228 patients reported heavy physical exertion (six or more metabolic equivalents) within 1 h of myocardial
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Myocardial infarction triggers Colombo et al. 3
infarction. Activities associated with AMI onset were running or jogging (40%), isometric or heavy lifting (19%), or a mixture of the two (41%). The estimated relative risk of AMI conferred by heavy physical activity was affected by the training level of the individual. Among people who usually exercised less than one, one to two, three to four, or five or more times per week, the relative risks were 107, 19.4, 8.6 and 2, respectively. Thus, habitually sedentary individuals were at the greatest risk of AMI after heavy exertion, and increasing levels of regular physical exercise were associated with progressive lower coronary risk. Several other studies reported similar findings. The Triggers and Mechanisms of Myocardial Infarction (TRIMM) study12 found in a general population of 330 000 residents and an AMI population of 1194 individuals in Augsburg, Germany, that in 7.1% of cases, patients had engaged in physical exertion (six or more metabolic equivalents) at the onset of infarction. Casecrossover analysis gave an overall relative risk of 2.1, ranging from 6.9 to 1.3 according to the frequency of regular exercise, with higher estimates for more sedentary individuals. The Stockholm Heart Epidemiology Program (SHEEP),23 a case-crossover analysis on 669 myocardial infarction patients, observed a 5.7% occurrence of heavy physical exertion in the hours before AMI. These data highlight two main aspects of this trigger: the intensity of physical exertion and the training level of the individual. Conclusions from the large case-control INTERHEART study24 confirm that leisure and occupational physical activity – whether mild or moderate – does protect from AMI across countries with low, middle and high income. The statement is further reinforced by a recent meta-analysis of epidemiological studies investigating physical activity and primary prevention of CHD,25 which highlights a dose–response relationship between activity and CHD – both fatal and nonfatal – with mild exercise conferring a 14% lower risk of CHD, and moderate exercise increasing the protective effect to a 20% lower risk. Emotional triggers
Several epidemiological studies have shown a clear association between the onset of AMI and a wide range of emotional triggers.4,26–28 Psychological factors thought to have an active role in myocardial infarction onset include chronic negative emotional states (depression, anger, anxiety) as well as situational and behavioural triggers (e.g. work-related stressors). The role of anger as a trigger of AMI has been assessed in a number of studies conducted using the case-crossover methodology.13–15 The prevalence of an anger-episode, corresponding to very angry up to furious, ranged from 1.2 to 17.4% of AMI cases reported in different cohorts.
The relative risk of AMI after a severe episode of anger varied between 4 and 9.13–15 Clinical depression, widely considered in relation to the long-term development of coronary artery disease and to the prognosis after cardiac events, was regarded as a trigger of acute cardiovascular events in a recent study29 in which acute severe episodes of depression or sadness were reported in 18.2% of patients in the 2 h before symptom onset. Case-crossover analysis indicated a relative risk of AMI after depressed mood of 4.3 (95% CI 3.4–6.1).29 In a similar fashion, bereavement may act as a trigger. In a recent case-crossover study, the death of a close relative or a friend was found to be associated with a 21-fold increase in AMI incidence rate during the first 24 h, the rate declining steadily on each subsequent day.30 Work-related stress, such as high pressure deadlines or firing, has been identified as a possible trigger of AMI in two different studies, associated with at least a doubling of the risk of myocardial infarction.13,14 Behar et al.,7 in a study carried out in 1818 consecutive patients with acute AMI, reported that a violent quarrel at work or at home, and unusual mental stress, along with heavy physical work, were the three most frequent possible triggers within 24 h of symptom onset. In addition to natural disasters8,9 and war10, exceptional sporting events31,32 have been associated with an increased incidence of cardiovascular events.9–11 Sexual activity
The role of sexual activity as a trigger of acute AMI has been analysed in different studies with similar results.33 Recent sexual activity was reported in 2–3% of the populations considered, with an average 2.5 relative risk of triggering a cardiovascular event. Baylin et al.34 reported a higher relative risk of 5.4. Concerns about the cardiovascular safety of sildenafil, a phosphodiesterase-5 inhibitor used to treat erectile dysfunction and usually taken immediately before intercourse, were raised at the beginning of its commercial availability in the late nineties. However, a 2010 review of 67 double-blind, placebo-controlled trials of sildenafil excluded a causal link between the drug and cardiovascular events.35 A case-crossover study based on nearly 10 000 patients compared the relative risk of myocardial infarction within 24 h of sildenafil consumption vs. more than 24 h after taking the drug. It found that absolute rates were very low and equivalent, thus dismissing a temporal association between sildenafil and AMI.36 Drugs
In the MIOS study17 a huge, 23.7-fold increase in the relative risk of AMI occurred in the hour after cocaine use, with a rapid decrease thereafter. Mittleman et al.37 found a 4.8-fold increased risk of AMI in the hour following marijuana use.
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4 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
Meals, coffee and alcohol
Infections
Few studies have evaluated the consumption of a large meal as a trigger for AMI. In the MILIS study,4 7% of the patients suffering an AMI identified overeating as a potential trigger. In a case-crossover study of 209 patients, Lipovetzky et al.18 reported a relative risk of 4 for the occurrence of AMI within 1 h of a heavy meal.
Patients admitted for AMI sometimes report acute respiratory infection in the previous days.46 A retrospective analysis based on 20 486 patients with a diagnosis of first AMI derived from the 1987–2001 British General Practice Database found a raised AMI rate 1–3 days after developing pneumonia, acute bronchitis or influenza47, with an incidence rate of 4.95, which fell progressively during the subsequent weeks. The study was carried out using the case-series method, a within-person comparison that, similar to the case-crossover method, divides the retrospective time frame of each individual into exposure and control periods. Of note, the risk was raised significantly, but to a lesser degree, after a diagnosis of urinary tract infection, with an incidence rate of 1.66.
In a case-crossover study of 503 patients, coffee drinking within 1 h of AMI was associated with a relative risk of 1.5 (95% CI 1.2–1.9).38 When changing the hazard period to 2 or 3 h before AMI, the relative risk decreased to 1.04 (95% CI 0.8–1.3) and 0.86 (95% CI 0.7–1.0), respectively, thus supporting a true triggering effect. Moreover, on stratifying by usual coffee intake, occasional drinkers had a higher relative risk of AMI than moderate and heavy drinkers (4.1 vs. 1.6 vs. 1.0, respectively, P ¼ 0.006 for homogeneity). There is only one study on alcohol as a potential AMI trigger,39 in which drinking any alcoholic beverage within 12 h of an AMI conferred an odds ratio of 3.1 (95% CI 1.4–6.9) in a group of 250 patients. The main limitation and confounding issue of this finding is the extended time window, which is not comparable to the 1 to 2-h period generally chosen to identify an acute trigger in nearly all other studies in this field. Air pollution
In recent years, emerging evidence points at air pollution as a potential trigger for acute coronary syndromes.40 Case-crossover analyses from the Boston area,41 Salt Lake City42 and Rome43 have reported an increase in the relative risk of acute ischemic events (unstable angina and AMI) in association with raising concentrations in air particulate matter (PM2.5 mainly) in the same or previous days. In the Salt Lake City study,42 there was a 4.5% excess event rate (95% CI 1.1–8.0) for a 10 mg/m3 increase in PM2.5 in the prior 48 h. The Rome study43 reported similar results; a 10 mg/m3 increase in total suspended particles in a time lag of 2 days resulted in a slight increase in AMI incidence (odds ratio 1.03, 95% CI 1.0–1.05). The Boston study41 found a stronger effect with more pronounced variations in PM2.5 (AMI odds ratio 1.5, 95% CI 1.1–2.0, with a 25 mg/m3 increase in PM2.5). It is worth noting that the potential triggering role of air pollution is different from that of other factors, in that it is not expected to act in the short term and needs days to exert its noxious effects. In 200444 and in 2010,45 the American Heart Association published two statements outlining the strength of evidence that link air pollution exposure to acute cardiovascular events. Specifically, although the overall increase of relative risk seems to be low – ranging from 1.03 to 2 – the size of the population at risk and the fact that it is a modifiable factor call for a special consideration.
More recent retrospective and prospective studies have given significantly lower estimates. A USA study based on 50 000 patients hospitalized for pneumonia, who were significantly older than those in the British study reported, an AMI incidence of 1.5% within 90 days after hospitalization.48 A Spanish prospective analysis of 3921 adult individuals admitted with pneumonia from 1995 to 2010 showed a 0.77% incidence of AMI during their hospital stay.49 In the previously mentioned study by Baylin et al.,34 the relative risk of AMI attributable to acute respiratory tract infection and acute gastroenteritis was 1.48 and 1.27, respectively. Researchers have long been attracted by the possible link between influenza and AMI, partly because of the demonstrated efficacy of vaccination in flu prevention. However, investigations that accurately defined influenza by serological conversion did not find a significant association with AMI.50 Two randomized controlled trials addressed the issue of reducing the incidence of major cardiac end-points with influenza vaccination in patients recovering from AMI (FLUVACS)51 or with angiographically confirmed coronary artery disease (FLUCAD).52 Both studies showed that vaccination had no significant impact on the incidence of AMI in the following year. Investigations of the effects of pneumococcal vaccination in AMI prevention have produced diverging conclusions.46 One large 2008 case-control study found a greater than 50% reduction in the incidence of AMI over a 2-year follow-up,53 whereas a later, similarly large, retrospective study, showed no significant difference.54 Similarly, a prospective cohort study of patients aged 60 years published in the last year reached negative results.55 The putative pathophysiologic links connecting respiratory infections and AMI range from hypoxia, tachycardia and increased metabolic consumption, to direct inflammatory processes of the vulnerable plaque, possibly mediated by T-lymphocytes and macrophages.56,57
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Myocardial infarction triggers Colombo et al. 5
Pathophysiology of triggers AMI might be triggered through either nervous sympathetic or parasympathetic pathways.5 Physical activity, emotional stress, sexual intercourse and cocaine are powerful sympathetic activators. A sudden surge in sympathetic activity increases heart rate, blood pressure, pulse wave, myocardial contractility and oxygen demand, and produces coronary vasoconstriction and hypercoagulability.58 However, the parasympathetic triggering of AMI has less convincing pathophysiological grounds. It is well known that local cholinergic stimulation may cause paradoxical vasoconstriction of diseased coronary segments; however, a link between external triggers and acute cholinergic activation has never been found. It may be hypothesized that heavy meals may precipitate AMI through vagal autonomic efferent drive, but we should not overlook the fact that increased sympathetic tone has been described in association with eating.59 A circadian pattern in the onset of acute coronary syndromes has been described in several observational trials. It is generally characterized by a marked morning peak, between 6 and 12 a.m.60,61 This temporal pattern reflects the consensual circadian cycle of sympathetic drive, which peaks at wake-up time,62,63 thus reinforcing the link between sympathetic rise and AMI.
Public health perspective Clinical studies of AMI triggers have almost exclusively focused on risk estimation for the individual patient. Some powerful external triggers can be extremely harmful for the exposed individual, but may have a relatively small impact on the absolute number of events in the general population. When measuring the public health relevance of an external trigger, both the strength of the association between the trigger and the acute events, and the trigger prevalence in the population must be considered. Measures that help clarify the impact of a specific factor on a composite population are known as measures of potential impact. The attributable fraction is one such method, useful in translating isolated epidemiologic associations into data relevant to public health.64 For each individual trigger, the general population can be divided into exposed and unexposed groups. The attributable risk of a given trigger within an exposed population is the difference between the incidence of the event in this population and the incidence of the event in an unexposed population. In this way, we can measure to what extent the risk derived from the exposure exceeds the background risk, which is indicated by the incidence in the unexposed group. In other words, this is a means of gauging the net excess risk connected to exposure and is identical to the main statistical conclusion of all randomized trials comparing
treated vs. untreated groups. Dividing the attributable risk by the event incidence in the exposed population, we obtain the attributable fraction of the trigger, which represents the proportion of cases in the exposed population attributable to the exposure. If we want to know the risk attributable to a trigger in a composite population that includes both exposed and unexposed individuals, we must subtract the incidence of the event in the unexposed group from the incidence in the whole population. This is the population attributable risk (PAR), and the related fraction (PAR divided by the incidence of the event in the population) is called population attributable fraction (PAF), which expresses the proportion of cases attributable to the exposure in the whole population. A recent review study65 ranked the most recognized triggers of AMI with an integrated approach on the basis of PAFs, and selection of a hazard period of 1–2 h, except for air pollution (time windows of 1–2 days) and respiratory infections (hazard period of 3–10 days). The odds ratio of the triggers were found to be inversely associated with their exposure prevalence, indicating that high risks are infrequent, whereas low risks are frequent. According to PAF, the highest percentage of AMI was attributable to traffic exposure (7.4%, 95% CI 4.8–10.5 in a single study), followed by physical exertion (PAF 6.2%, 95% CI 4.2–8.6 over six studies), alcohol or coffee (PAF 5.0% both in a single study each), 30 mg/m3 raise in air PM10 (PAF 4.8%, 95% CI 2.6–6.3 over 11 studies), negative emotions (PAF 3.9%, 95% CI 1–10 over three studies), anger (PAF 3%, 95% CI 1.2–6.2), heavy meal (PAF 2.7%, 95% CI 0–23), sexual activity (PAF 2.2%, 95% CI 0.8–4.5 over two studies), cocaine use (PAF 0.9%, 95% CI 0.3–2.6 in a single study), marijuana smoking (PAF 0.75%, 95% CI 0.4–1.7 in a single study) and respiratory infections (PAF 0.6%, 95% CI 0.2–1.3 over four studies). Notably, the combined estimates did not show heterogeneity across the different studies that considered physical exertion, sexual activity and respiratory infections (Table 1). The most obvious conclusion we may draw from these data is that adrenergic activation, prompted either by emotions or by stressful engagement in traffic, physical exercise, coffee drinking or the sympathomimetic agent cocaine, is the main recognizable trigger of AMI. Air pollution and high food or alcohol intake are the other two possibly relevant triggers. Overall, 44.8% of all AMI in an unselected population may roughly be attributed to the exposure to any known trigger. Several triggers have low public health relevance; only 1% of total AMI could, hypothetically, be avoided if susceptible people did not use cocaine, even less if they did not smoke marijuana, and only 0.6% if they had no acute respiratory infections. Important data have been gathered on the role of physical activity from the public health perspective. Regular physical activity has been correlated with a decrease in
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Prevalence of exposure to trigger factors within the population; pooled odds ratio and population attributable fractions for the triggers of myocardial infarction
Table 1
Prevalence of exposure Traffic exposure Physical exertion Alcohol Coffee Air pollution, 30 mg/mm3 raise Negative emotions Anger Heavy meal Sexual activity Cocaine use Marijuana Respiratory infection
OR (95% CI)
4.1% 2.4% 3.2% 10.6% 100% 1.2% 3.5% 0.5% 1.1% 0.04% 0.2% 0.4%
2.9 4.3 3.1 1.5 1.05 4.5 8.1 7.0 3.1 23.7% 4.8% 2.7%
CI, confidence interval; OR, odds ratio; PAF, population attributable fraction. Adapted with permission from
(2.2–3.8) (3.2–5.7) (1.4–6.9) (1.2–1.9) (1.03–1.07) (1.9–10.8) (1.8–5.4) (0.8–66) (1.8–5.4) (8.1–66) (2.9–9.15) (1.5–4.9)
65
PAF (95% CI) 7.4% 6.2% 5% 5% 4.8% 3.9% 3.1% 2.7% 2.2% 0.9% 0.75% 0.6%
(4.8–10.5) (4.2–8.6) (2.9–7) (2.1–8.7) (2.6–6.3) (1–10.3) (1.2–6.2) (0–23) (0.8–4.5) (0.3–2.6) (0.4–1.7) (0.2–1.3)
.
the risk of cardiovascular morbidity and mortality, and moderate exertion may provide an additional benefit over light exercise.12,25
the incidence of triggered AMI, and the public health relevance of such actions.
Regular physical activity has been found to significantly weaken the triggering effect of both physical and sexual activity in a recent meta-analysis.33 For every additional time of regular exercise per week, the relative risk for myocardial infarction decreased by approximately 45%. As physical activity is an efficient and inexpensive means of prevention at the population level, physicians should give patients advice about this common issue in clinical practice. However, recommendations must be tailored after exercise testing and an assessment of overall cardiovascular condition.66,67 In any case, intensity and duration of exercise might be gradually increased, in accordance with an individual patient’s capacity.
Conclusion
Future research How can we translate the information derived from trigger studies into preventive measures? One intuitive recommendation is to reduce or avoid drug addiction and heavy meals, and to stay away from air pollution. When it comes to unavoidable situations of daily life, the possibility that pharmacologic therapy, targeted at the time of the potential triggering activity, may provide some degree of protection needs to be explored. Recently, a feasibility study68 on 17 healthy individuals demonstrated that self-administration of propranolol 10 mg and aspirin 100 mg immediately before heavy physical activity, or during episodes of moderate to severe anger or anxiety, is well tolerated and acceptable, with 71% of the participants considering it feasible to continue taking medication in this manner. Another area of research is the interaction between the triggering process and chronic cardiovascular risk factors, with a special focus on the relative importance of different risk factors and their susceptibility to triggers. Finally, we should further investigate whether interventions targeting cardiovascular risk factors, in addition to standard cardiovascular drug therapies, have the ability to reduce
The primary prevention of AMI is traditionally based on fighting the development of atherosclerosis. However, modern medical efforts should aim to identify and modify the circumstances that can acutely trigger AMI, and this should be incorporated into public health prevention. To protect patients and save lives, the strength, specificities and general relevance of all possible external triggers should be explored. There is room for the research community to provide further information about the individual and public health risks of external triggers of AMI, and, by introducing new clinical and epidemiological methodologies, to suggest more personalized and effective preventive measures.
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Mittleman MA, Maclure M, Sherwood JB, et al. Triggering of acute myocardial infarction onset by episodes of anger. Circulation 1995; 92:1720–1725. Lipovetzky N, Hod H, Roth A, et al. Emotional events and anger at the workplace as triggers for a first event of acute coronary syndrome: a casecrossover study. Isr Med Assoc J 2007; 9:310–315. Strike PC, Perkins-Porras L, Whitehead DL, et al. Triggering of acute coronary syndromes by physical exertion and anger: clinical and sociodemographic characteristics. Heart 2006; 92:1035–1040. Muller JE, Mittleman MA, Maclure M, et al. Triggering myocardial infarction by sexual activity. JAMA 1996; 275:1405–1409. Mittleman MA, Mintzer D, Maclure M, et al. Triggering of myocardial infarction by cocaine. Circulation 1999; 99:2737–2741. Lipovetzky N, Hod H, Roth A, et al. 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. 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. Mittleman MA, Robins JM, Maclure M. Control sampling strategies for casecrossover studies: an assessment of relative efficiency. Am J Epidemiol 1995; 142:91–98. Albert CM, Mittleman MA, Chae CU, et al. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med 2000; 343:1355– 1361. Tofler GH, Muller JE, Stone PH, et al. Modifiers of timing and possible triggers of acute myocardial infarction in the TIMI-2 Study Group. JACC 1992; 20:1049–1055. Hallqvist J, Moller J, Ahlborn A, et al. Does heavy physical exertion trigger myocardial infarction? A case-crossover analysis nested in a populationbased case-referent study. Am J Epidemiol 2000; 151:459–467. Held C, Iqbal R, Lear SA, et al. Physical activity levels, ownership of goods promoting sedentary behaviour and risk of myocardial infarction: results of the INTERHEART study. Eur Heart J 2012; 33:452–466. Sattelmair J, Pertman J, Ding EL, et al. Dose-response between physical activity and risk of coronary heart disease. Circulation 2011; 124:789– 795. ˇ ulic´ V, Eterovic´ D, Miric´ D. Meta-analysis of possible external triggers of C acute myocardial infarction. Int J Cardiol 2005; 99:1–8. Mittleman MA, Maclure M, Nachnani M, et al. Educational attainment, anger, and the risk of triggering myocardial infarction onset. Arch Intern Med 1997; 157:769–775. Steptoe A, Brydon L. Emotional triggering of acute cardiac events. Neurosci Biobehav Rev 2009; 33:63–70. Steptoe A, Strike PC, Perkins-Porras L, et al. Acute depressed mood as a trigger of acute coronary syndromes. Biol Psychiatry 2006; 60:837–842. Mostofsky E, Maclure M, Sherwood JB, et al. Risk of acute myocardial infarction after the death of a significant person in one’s life. Circulation 2012; 125:491–496. Carroll D, Ebrahim S, Tilling K, et al. Admissions for myocardial infarction and World Cup football: database survey. Br Med J 2002; 325:1439– 1442. Wilbert-Lampen U, Leistner D, Greven S, et al. Cardiovascular events during World Cup soccer. N Engl J Med 2008; 358:475–483. Dahabreh IJ, Paulus JK. Association of episodic physical and sexual activity with triggering of acute cardiac events. Systematic review and metaanalysis. JAMA 2011; 305:1225–1233. Baylin A, Hernandez-Diaz S, Siles X, et al. Triggers of nonfatal myocardial infarction in Costa Rica: heavy physical exertion, sexual activity and infection. Ann Epidemiol 2007; 17:112–118. Giuliano F, Jackson G, Montorsi A, et al. Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database. Int J Clin Pract 2010; 64:240–255. Mittleman MA, Maclure M, Glasser DB. Evaluation of acute risk for myocardial infarction in men treated with sildenafil citrate. Am J Cardiol 2005; 96:443–446. Mittleman MA, Lewis RA, Maclure M, et al. Triggering of myocardial infarction by marijuana. Circulation 2001; 103:2805–2809. Baylin A, Hernandez-Diaz S, Kabagambe EK, et al. Transient exposure to coffee as a trigger of a first nonfatal myocardial infarction. Epidemiology 2006; 17:506–511. Gerlich MG, Kramer A, Gmel G, et al. Patterns of alcohol consumption and acute myocardial infarction: a case-crossover analysis. Eur Addict Res 2009; 15:143–149. Maitre A, Bonneterre V, Huillard L, et al. Impact of urban atmospheric pollution on coronary disease. Eur Heart J 2006; 27:2275–2284. Peters M, Dockery DW, Muller JE, Mittleman MA. Increased particulate air pollution and triggering of myocardial infarction. Circulation 2001; 103:2810–2815.
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Arden Pope C, Muhlestein JB, May HT, et al. Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution. Circulation 2006; 114:2443–2448. D’Ippoliti D, Forastiere F, Ancona C, et al. Air pollution and myocardial infarction in Rome: a case-crossover analysis. Epidemiology 2005; 16:41– 48. Brook RD, Franklin B, Cascio W, et al. 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 2004; 109:2655–2671. Brook RD, Rajagopalan S, Pope CA, et al. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010; 121:2331–2378. Bazaz R, Marriott HM, Francis SE, Dockrell DH. Mechanistic links between acute respiratory tract infections and acute coronary syndromes. J Infect 2013; 66:1–12. Smeeth L, Thomas SL, Hall AJ, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004; 351:2611–2618. Perry TW, Pugh MJV, Waterer GW, et al. Incidence of cardiovascular events after hospital admission for pneumonia. Am J Med 2011; 124:244–251. Viasus D, Garcia-Vidal C, Manresa F, et al. Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia. J Infect 2013; 66:27–33. Mattila KJ. Viral and bacterial infections in patients with acute myocardial infarction. J Int Med 1989; 225:293–296. Gurfinkel EP, Leon de la Fuente R, Mediz O, Mautner B. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) study. Eur Heart J 2004; 25:25–31. Ciszewski A, Bilinska ZT, Brydak LB, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J 2008; 29:1350–1358. Lamontagne F, Garant MP, Carvalho JC, et al. Pneumococcal vaccination and risk of myocardial infarction. CMAJ 2008; 179:773–777. Tseng HF, Slezak JM, Quinn VP, et al. Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men. JAMA 2010; 303:1699– 1706. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, et al. Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up. BMC Public Health 2012; 12:222. Yla-Herttuala S, Bentzon JF, Daemen M, et al. Stabilization of atherosclerotic plaques. Position paper of the European Society of Cardiology Working Group on atherosclerosis and vascular biology. J Thromb Haemost 2011; 106:1–19. Madjid M, Vela D, Khalili-Tabrizi H, et al. Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Texas Heart Inst J 2007; 34:11–18. Muller JE, Kaufmann PG, Luepker RV, et al. Mechanisms precipitating acute cardiac events. Review and recommendations of an NHLBI workshop. Circulation 1997; 96:3233–3239. Matsukawa K, Honda T, Ninomiya I. Renal sympathetic nerve activity and plasma catecholamines during eating in the cat. Am J Physiol 1989; 257:R1034–R1039. ISIS-2 Collaborative Group. Morning peak in the incidence of myocardial infarction. Eur Heart J 1992; 13:594–598. Cohen MC, Rohtla KM, Lavery CE, et al. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol 1997; 79:1512–1616. Furlan G, Guzzetti S, Crivellaro W, et al. Continuous 24-h assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects. Circulation 1990; 81:537–547. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to sympathetic vasoconstrictor activity. N Engl J Med 1991; 325:986–990. Perez L, Ku¨nzli N. From measures of effects to measures of potential impact. Int J Public Health 2009; 54:45–48. Nawrot TS, Perez L, Ku¨nzli N, et al. Public health importance of triggers of myocardial infarction: a comparative risk assessment. Lancet 2011; 377:732–740. Tanasescu M, Leitzmann MF, Rimm EB, et al. Exercise type and intensity in relation to coronary heart disease in men. JAMA 2002; 288:1994–2000. Bo¨rjesson M, Assanelli D, Carre´ F, et al. ESC Study Group of Sports Cardiology: recommendations for participation in leisure-time physical activity and competitive sports for patients with ischaemic heart disease. Eur J Cardiovasc Prev Rehab 2006; 13:137–149. Shaw E, Tofler GH, Buckley T, et al. Therapy for triggered acute risk prevention: a study of feasibility. Heart Lung Circ 2009; 18:347–352.
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Triggers of acute myocardial infarction: a neglected piece of the puzzle ˇ ulic´b, Nestor Lipovetzkyc, Alessandro Colomboa, Riccardo Proiettia, Viktor C Maurizio Vieccaa and Paolo Dannaa The existence of specific risk factors for the development of coronary heart disease, both chronic and acute, has been extensively investigated and is well understood by cardiology professionals. Diabetes, hypertension, hypercholesterolemia, psychological patterns and smoking are assumed to interact in a complex way with individual heritable predisposition, thus determining the long-term probability of coronary disease. However, the possibility that defined circumstances and activities may act as immediate triggers of acute coronary syndromes, particularly acute myocardial infarction, has not been given comparable attention in clinical research. For example, the recently issued 2012 European guidelines on cardiovascular disease prevention completely overlook the topic of triggers and their possible prevention. This review presents a picture
The investigation of measurable items able to predict morbidity and mortality from cardiovascular disease (CVD) – the so-called risk factors – has been given considerable attention in medical research for decades. The predictive value of risk factors has been extensively analysed and has generated quite accurate measures, recently issued in risk tables.1 The majority of research articles in the field of coronary heart disease (CHD) begin with dramatic statements about the large prevalence and the huge death burden of the illness. As a consequence, cardiovascular prevention has a key role in cardiology, and fighting CVD through specific interventions on risk factors has been – and still is – the basis of many treatment strategies in medicine today, with extensive knowledge reflected in continuously updated guidelines.1 In principle, one major aim of CVD prevention should be the lowering the rate of acute events, namely death, myocardial infarction and stroke. Therefore, studying the circumstances under which acute events occur should be the top priority for cardiologists and health policy makers. Surprisingly, this is not the case. Despite the widespread appreciation that a number of activities and emotions may be causally related to myocardial infarction and sudden death, little research has been carried out regarding these trigger factors. Thanks to coronary angiography, we know from hospital daily practice that the pathogenesis of acute myocardial 1558-2027 ß 2014 Italian Federation of Cardiology
of the most reliable evidence regarding the triggering of myocardial infarction and contributes to further investigation in the field. J Cardiovasc Med 2014, 15:1–7 Keywords: acute myocardial infarction, population attributable fraction, triggers a Cardiology Department, ‘Luigi Sacco’ Hospital, Milano, Italy, bCardiology Division, University Hospital Centre, Split, Croatia and cMaccabi Healthcare Services, Tel Aviv, Israel
Correspondence to Riccardo Proietti, MD, PhD, Cardiology Department, ‘Luigi Sacco’ Hospital, via GB Grassi, 74 Milano, Italy Tel: +39 02 39042392; fax: +39 02 39042311; e-mail: [email protected] Received 23 September 2012 Revised 18 May 2013 Accepted 29 May 2013
infarction (AMI) is mostly based on the rupture and subsequent thrombosis of an atherosclerotic plaque. There is a wide agreement that an obstructing vascular lesion can remain silent for a whole lifetime, whereas a thin atheromatous cap breakdown may more easily lead to an endoluminal thrombotic process.2 However, and in spite of the large body of literature produced, the molecular pathophysiology of vascular lesions that progress to a catastrophic acute event3 remains largely undiscovered. Often, definite behavioural, physical and psychological factors precede an acute coronary syndrome. Hence, a causal relation may exist between transient exposure to circumstantial events, atherosclerotic plaque rupture and acute clinical manifestations and, as a consequence, this information may become the basis of new strategies for the prevention of acute CVDs. The present review summarizes the current knowledge regarding the triggers of AMI and comments on available preventive strategies directed against the short-term risk posed by triggering factors.
Triggers: definitions, mechanisms and identification A trigger is defined as an external stimulus, capable of producing a pathological change leading to a clinical event. This direct association is made on the basis of a short temporal connection between stimulus and disease. DOI:10.2459/JCM.0b013e3283641351
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2 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
In the first attempt to find an appropriate terminology, the term ‘acute risk factors’ was proposed for haemodynamic, prothrombotic and vasoconstrictive processes which elevated the risk of a coronary incident over a period of several hours.4 More recently, aspects of everyday life that influence internal homeostasis and increase the risk of ACS have been described as trigger factors.5 Since the 1960s, the general opinion has been against a relation between AMI and the patient’s daily activity. It was during the eighties and the early nineties that some studies indicated a possible relation between physical exertion, anger, stress, sexual activity, lack of sleep and myocardial infarction.6,7 These studies estimated that about 50% of cases of AMI might be triggered by external factors. The basis for considering external factors as triggers for AMI comes from research from disasters such as the earthquakes in South California in 1994 and in Hanshin-Awaji (Japan) in 1995. In California, a 35% rise in AMI cases was found in the week after the disaster compared with the week that preceded it, and a five-fold increase in sudden cardiac death was found on the earthquake day.8 In most cases, the induction time was less than 1 h. In Hanshin-Awaji, a 3.5-fold increase in AMI cases was found in the month after the disaster.9 Finally, during the Iraq missiles attack on Israel in the 1991 Gulf War, a 58% increase in cardiac death was seen on the first day of the war but not during the subsequent 16 attack days.10 Over the last two decades, several studies have analysed the association of AMI with physical exertion,11,12 anger,13–15 sexual activity,16 cocaine17 and heavy meals18 in the hour before the onset of symptoms. In order to detect an event–disease association beyond what is expected by chance alone, the case-control method has long been used as a statistical reference. Groups of patients admitted to hospital as a result of AMI were compared with groups of patients admitted for different, noncardiovascular acute diseases. Recently, a different way to investigate this relation has been proposed, known as the case-crossover method. Patients are asked to precisely remember all the times they were exposed to a given trigger in the weeks or months before the AMI. Then, a critical time period, that is the time between trigger impact and AMI, is selected. The whole time of the retrospective observation (e.g. 6 months) can then be divided into hazard periods and control periods. Using this information, a rate ratio is calculated using the Mantel-Haenszel estimator, which measures the strength of the association between trigger and AMI.19 As an example, comparing hazard and control periods, the relative risk that an episode of emotional stress is followed by an AMI can
be calculated. Although not immune from bias – one of them being the limited ability of the patients to exactly report the number of exposure episodes in a retrospective time interval of months – the case-crossover method overcomes one of the major threats to the validity of a case-control study, that is inadequate matching of the control cohort with the study participants, and provides the most convincing evidence for the identification of triggers. One of the concerns when studying the relation between triggers and events is which time period is most appropriate as a timeframe for a correct identification of triggers. Most of the studies in the field yielded higher relative risks when the observation period was the day before the onset of symptoms rather than the year before. These higher relative risks can be explained by a tendency towards overreporting the annual frequency of exposures, thus leading to an underestimation of the relative risk, although underreporting the exposure in the day before the onset of symptoms would have the same consequences. However, estimates of relative risks are much more accurate when the control data are based on annual frequency because of random sampling variability.20 Moreover, it is important to underline the difference between the relative risk and the absolute risk of a trigger. The absolute risk shows the real occurrence of an endpoint per episode of exposure. For example, in the Physicians’ Health Study,21 the relative risk of sudden death during and up to 30 min after vigorous exertion was 16.9 [95% confidence interval (CI) 10.5–27.0, P < 0.001]. However, the absolute risk of sudden death during any particular episode of vigorous exertion was extremely low (one sudden death per 1.51 million episodes of exertion). This means that although relative risk is a good theoretical instrument it should not be used as a basis for practical decisions.
Known triggers of acute myocardial infarction Physical exertion
The first studies that described physical activity as a trigger of myocardial infarction were two observational trials; the Multicenter Investigation of Limitation of Infarct Size (MILIS)4 trial and the TIMI-2 (Thrombolysis in Myocardial Infarction) trial.22 The MILIS study reported that 14% of 849 patients had engaged in moderate physical activity and 9% in heavy physical activity before myocardial infarction onset. In the TIMI-2 trial, the clinical history of 3339 patients was analysed to look for exertion-related AMI. The authors reported that infarction occurred during moderate or marked physical activity in 18.7% of patients. In the myocardial infarction ONSET study,11 54 (4.4%) of 1228 patients reported heavy physical exertion (six or more metabolic equivalents) within 1 h of myocardial
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Myocardial infarction triggers Colombo et al. 3
infarction. Activities associated with AMI onset were running or jogging (40%), isometric or heavy lifting (19%), or a mixture of the two (41%). The estimated relative risk of AMI conferred by heavy physical activity was affected by the training level of the individual. Among people who usually exercised less than one, one to two, three to four, or five or more times per week, the relative risks were 107, 19.4, 8.6 and 2, respectively. Thus, habitually sedentary individuals were at the greatest risk of AMI after heavy exertion, and increasing levels of regular physical exercise were associated with progressive lower coronary risk. Several other studies reported similar findings. The Triggers and Mechanisms of Myocardial Infarction (TRIMM) study12 found in a general population of 330 000 residents and an AMI population of 1194 individuals in Augsburg, Germany, that in 7.1% of cases, patients had engaged in physical exertion (six or more metabolic equivalents) at the onset of infarction. Casecrossover analysis gave an overall relative risk of 2.1, ranging from 6.9 to 1.3 according to the frequency of regular exercise, with higher estimates for more sedentary individuals. The Stockholm Heart Epidemiology Program (SHEEP),23 a case-crossover analysis on 669 myocardial infarction patients, observed a 5.7% occurrence of heavy physical exertion in the hours before AMI. These data highlight two main aspects of this trigger: the intensity of physical exertion and the training level of the individual. Conclusions from the large case-control INTERHEART study24 confirm that leisure and occupational physical activity – whether mild or moderate – does protect from AMI across countries with low, middle and high income. The statement is further reinforced by a recent meta-analysis of epidemiological studies investigating physical activity and primary prevention of CHD,25 which highlights a dose–response relationship between activity and CHD – both fatal and nonfatal – with mild exercise conferring a 14% lower risk of CHD, and moderate exercise increasing the protective effect to a 20% lower risk. Emotional triggers
Several epidemiological studies have shown a clear association between the onset of AMI and a wide range of emotional triggers.4,26–28 Psychological factors thought to have an active role in myocardial infarction onset include chronic negative emotional states (depression, anger, anxiety) as well as situational and behavioural triggers (e.g. work-related stressors). The role of anger as a trigger of AMI has been assessed in a number of studies conducted using the case-crossover methodology.13–15 The prevalence of an anger-episode, corresponding to very angry up to furious, ranged from 1.2 to 17.4% of AMI cases reported in different cohorts.
The relative risk of AMI after a severe episode of anger varied between 4 and 9.13–15 Clinical depression, widely considered in relation to the long-term development of coronary artery disease and to the prognosis after cardiac events, was regarded as a trigger of acute cardiovascular events in a recent study29 in which acute severe episodes of depression or sadness were reported in 18.2% of patients in the 2 h before symptom onset. Case-crossover analysis indicated a relative risk of AMI after depressed mood of 4.3 (95% CI 3.4–6.1).29 In a similar fashion, bereavement may act as a trigger. In a recent case-crossover study, the death of a close relative or a friend was found to be associated with a 21-fold increase in AMI incidence rate during the first 24 h, the rate declining steadily on each subsequent day.30 Work-related stress, such as high pressure deadlines or firing, has been identified as a possible trigger of AMI in two different studies, associated with at least a doubling of the risk of myocardial infarction.13,14 Behar et al.,7 in a study carried out in 1818 consecutive patients with acute AMI, reported that a violent quarrel at work or at home, and unusual mental stress, along with heavy physical work, were the three most frequent possible triggers within 24 h of symptom onset. In addition to natural disasters8,9 and war10, exceptional sporting events31,32 have been associated with an increased incidence of cardiovascular events.9–11 Sexual activity
The role of sexual activity as a trigger of acute AMI has been analysed in different studies with similar results.33 Recent sexual activity was reported in 2–3% of the populations considered, with an average 2.5 relative risk of triggering a cardiovascular event. Baylin et al.34 reported a higher relative risk of 5.4. Concerns about the cardiovascular safety of sildenafil, a phosphodiesterase-5 inhibitor used to treat erectile dysfunction and usually taken immediately before intercourse, were raised at the beginning of its commercial availability in the late nineties. However, a 2010 review of 67 double-blind, placebo-controlled trials of sildenafil excluded a causal link between the drug and cardiovascular events.35 A case-crossover study based on nearly 10 000 patients compared the relative risk of myocardial infarction within 24 h of sildenafil consumption vs. more than 24 h after taking the drug. It found that absolute rates were very low and equivalent, thus dismissing a temporal association between sildenafil and AMI.36 Drugs
In the MIOS study17 a huge, 23.7-fold increase in the relative risk of AMI occurred in the hour after cocaine use, with a rapid decrease thereafter. Mittleman et al.37 found a 4.8-fold increased risk of AMI in the hour following marijuana use.
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4 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
Meals, coffee and alcohol
Infections
Few studies have evaluated the consumption of a large meal as a trigger for AMI. In the MILIS study,4 7% of the patients suffering an AMI identified overeating as a potential trigger. In a case-crossover study of 209 patients, Lipovetzky et al.18 reported a relative risk of 4 for the occurrence of AMI within 1 h of a heavy meal.
Patients admitted for AMI sometimes report acute respiratory infection in the previous days.46 A retrospective analysis based on 20 486 patients with a diagnosis of first AMI derived from the 1987–2001 British General Practice Database found a raised AMI rate 1–3 days after developing pneumonia, acute bronchitis or influenza47, with an incidence rate of 4.95, which fell progressively during the subsequent weeks. The study was carried out using the case-series method, a within-person comparison that, similar to the case-crossover method, divides the retrospective time frame of each individual into exposure and control periods. Of note, the risk was raised significantly, but to a lesser degree, after a diagnosis of urinary tract infection, with an incidence rate of 1.66.
In a case-crossover study of 503 patients, coffee drinking within 1 h of AMI was associated with a relative risk of 1.5 (95% CI 1.2–1.9).38 When changing the hazard period to 2 or 3 h before AMI, the relative risk decreased to 1.04 (95% CI 0.8–1.3) and 0.86 (95% CI 0.7–1.0), respectively, thus supporting a true triggering effect. Moreover, on stratifying by usual coffee intake, occasional drinkers had a higher relative risk of AMI than moderate and heavy drinkers (4.1 vs. 1.6 vs. 1.0, respectively, P ¼ 0.006 for homogeneity). There is only one study on alcohol as a potential AMI trigger,39 in which drinking any alcoholic beverage within 12 h of an AMI conferred an odds ratio of 3.1 (95% CI 1.4–6.9) in a group of 250 patients. The main limitation and confounding issue of this finding is the extended time window, which is not comparable to the 1 to 2-h period generally chosen to identify an acute trigger in nearly all other studies in this field. Air pollution
In recent years, emerging evidence points at air pollution as a potential trigger for acute coronary syndromes.40 Case-crossover analyses from the Boston area,41 Salt Lake City42 and Rome43 have reported an increase in the relative risk of acute ischemic events (unstable angina and AMI) in association with raising concentrations in air particulate matter (PM2.5 mainly) in the same or previous days. In the Salt Lake City study,42 there was a 4.5% excess event rate (95% CI 1.1–8.0) for a 10 mg/m3 increase in PM2.5 in the prior 48 h. The Rome study43 reported similar results; a 10 mg/m3 increase in total suspended particles in a time lag of 2 days resulted in a slight increase in AMI incidence (odds ratio 1.03, 95% CI 1.0–1.05). The Boston study41 found a stronger effect with more pronounced variations in PM2.5 (AMI odds ratio 1.5, 95% CI 1.1–2.0, with a 25 mg/m3 increase in PM2.5). It is worth noting that the potential triggering role of air pollution is different from that of other factors, in that it is not expected to act in the short term and needs days to exert its noxious effects. In 200444 and in 2010,45 the American Heart Association published two statements outlining the strength of evidence that link air pollution exposure to acute cardiovascular events. Specifically, although the overall increase of relative risk seems to be low – ranging from 1.03 to 2 – the size of the population at risk and the fact that it is a modifiable factor call for a special consideration.
More recent retrospective and prospective studies have given significantly lower estimates. A USA study based on 50 000 patients hospitalized for pneumonia, who were significantly older than those in the British study reported, an AMI incidence of 1.5% within 90 days after hospitalization.48 A Spanish prospective analysis of 3921 adult individuals admitted with pneumonia from 1995 to 2010 showed a 0.77% incidence of AMI during their hospital stay.49 In the previously mentioned study by Baylin et al.,34 the relative risk of AMI attributable to acute respiratory tract infection and acute gastroenteritis was 1.48 and 1.27, respectively. Researchers have long been attracted by the possible link between influenza and AMI, partly because of the demonstrated efficacy of vaccination in flu prevention. However, investigations that accurately defined influenza by serological conversion did not find a significant association with AMI.50 Two randomized controlled trials addressed the issue of reducing the incidence of major cardiac end-points with influenza vaccination in patients recovering from AMI (FLUVACS)51 or with angiographically confirmed coronary artery disease (FLUCAD).52 Both studies showed that vaccination had no significant impact on the incidence of AMI in the following year. Investigations of the effects of pneumococcal vaccination in AMI prevention have produced diverging conclusions.46 One large 2008 case-control study found a greater than 50% reduction in the incidence of AMI over a 2-year follow-up,53 whereas a later, similarly large, retrospective study, showed no significant difference.54 Similarly, a prospective cohort study of patients aged 60 years published in the last year reached negative results.55 The putative pathophysiologic links connecting respiratory infections and AMI range from hypoxia, tachycardia and increased metabolic consumption, to direct inflammatory processes of the vulnerable plaque, possibly mediated by T-lymphocytes and macrophages.56,57
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Myocardial infarction triggers Colombo et al. 5
Pathophysiology of triggers AMI might be triggered through either nervous sympathetic or parasympathetic pathways.5 Physical activity, emotional stress, sexual intercourse and cocaine are powerful sympathetic activators. A sudden surge in sympathetic activity increases heart rate, blood pressure, pulse wave, myocardial contractility and oxygen demand, and produces coronary vasoconstriction and hypercoagulability.58 However, the parasympathetic triggering of AMI has less convincing pathophysiological grounds. It is well known that local cholinergic stimulation may cause paradoxical vasoconstriction of diseased coronary segments; however, a link between external triggers and acute cholinergic activation has never been found. It may be hypothesized that heavy meals may precipitate AMI through vagal autonomic efferent drive, but we should not overlook the fact that increased sympathetic tone has been described in association with eating.59 A circadian pattern in the onset of acute coronary syndromes has been described in several observational trials. It is generally characterized by a marked morning peak, between 6 and 12 a.m.60,61 This temporal pattern reflects the consensual circadian cycle of sympathetic drive, which peaks at wake-up time,62,63 thus reinforcing the link between sympathetic rise and AMI.
Public health perspective Clinical studies of AMI triggers have almost exclusively focused on risk estimation for the individual patient. Some powerful external triggers can be extremely harmful for the exposed individual, but may have a relatively small impact on the absolute number of events in the general population. When measuring the public health relevance of an external trigger, both the strength of the association between the trigger and the acute events, and the trigger prevalence in the population must be considered. Measures that help clarify the impact of a specific factor on a composite population are known as measures of potential impact. The attributable fraction is one such method, useful in translating isolated epidemiologic associations into data relevant to public health.64 For each individual trigger, the general population can be divided into exposed and unexposed groups. The attributable risk of a given trigger within an exposed population is the difference between the incidence of the event in this population and the incidence of the event in an unexposed population. In this way, we can measure to what extent the risk derived from the exposure exceeds the background risk, which is indicated by the incidence in the unexposed group. In other words, this is a means of gauging the net excess risk connected to exposure and is identical to the main statistical conclusion of all randomized trials comparing
treated vs. untreated groups. Dividing the attributable risk by the event incidence in the exposed population, we obtain the attributable fraction of the trigger, which represents the proportion of cases in the exposed population attributable to the exposure. If we want to know the risk attributable to a trigger in a composite population that includes both exposed and unexposed individuals, we must subtract the incidence of the event in the unexposed group from the incidence in the whole population. This is the population attributable risk (PAR), and the related fraction (PAR divided by the incidence of the event in the population) is called population attributable fraction (PAF), which expresses the proportion of cases attributable to the exposure in the whole population. A recent review study65 ranked the most recognized triggers of AMI with an integrated approach on the basis of PAFs, and selection of a hazard period of 1–2 h, except for air pollution (time windows of 1–2 days) and respiratory infections (hazard period of 3–10 days). The odds ratio of the triggers were found to be inversely associated with their exposure prevalence, indicating that high risks are infrequent, whereas low risks are frequent. According to PAF, the highest percentage of AMI was attributable to traffic exposure (7.4%, 95% CI 4.8–10.5 in a single study), followed by physical exertion (PAF 6.2%, 95% CI 4.2–8.6 over six studies), alcohol or coffee (PAF 5.0% both in a single study each), 30 mg/m3 raise in air PM10 (PAF 4.8%, 95% CI 2.6–6.3 over 11 studies), negative emotions (PAF 3.9%, 95% CI 1–10 over three studies), anger (PAF 3%, 95% CI 1.2–6.2), heavy meal (PAF 2.7%, 95% CI 0–23), sexual activity (PAF 2.2%, 95% CI 0.8–4.5 over two studies), cocaine use (PAF 0.9%, 95% CI 0.3–2.6 in a single study), marijuana smoking (PAF 0.75%, 95% CI 0.4–1.7 in a single study) and respiratory infections (PAF 0.6%, 95% CI 0.2–1.3 over four studies). Notably, the combined estimates did not show heterogeneity across the different studies that considered physical exertion, sexual activity and respiratory infections (Table 1). The most obvious conclusion we may draw from these data is that adrenergic activation, prompted either by emotions or by stressful engagement in traffic, physical exercise, coffee drinking or the sympathomimetic agent cocaine, is the main recognizable trigger of AMI. Air pollution and high food or alcohol intake are the other two possibly relevant triggers. Overall, 44.8% of all AMI in an unselected population may roughly be attributed to the exposure to any known trigger. Several triggers have low public health relevance; only 1% of total AMI could, hypothetically, be avoided if susceptible people did not use cocaine, even less if they did not smoke marijuana, and only 0.6% if they had no acute respiratory infections. Important data have been gathered on the role of physical activity from the public health perspective. Regular physical activity has been correlated with a decrease in
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6 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
Prevalence of exposure to trigger factors within the population; pooled odds ratio and population attributable fractions for the triggers of myocardial infarction
Table 1
Prevalence of exposure Traffic exposure Physical exertion Alcohol Coffee Air pollution, 30 mg/mm3 raise Negative emotions Anger Heavy meal Sexual activity Cocaine use Marijuana Respiratory infection
OR (95% CI)
4.1% 2.4% 3.2% 10.6% 100% 1.2% 3.5% 0.5% 1.1% 0.04% 0.2% 0.4%
2.9 4.3 3.1 1.5 1.05 4.5 8.1 7.0 3.1 23.7% 4.8% 2.7%
CI, confidence interval; OR, odds ratio; PAF, population attributable fraction. Adapted with permission from
(2.2–3.8) (3.2–5.7) (1.4–6.9) (1.2–1.9) (1.03–1.07) (1.9–10.8) (1.8–5.4) (0.8–66) (1.8–5.4) (8.1–66) (2.9–9.15) (1.5–4.9)
65
PAF (95% CI) 7.4% 6.2% 5% 5% 4.8% 3.9% 3.1% 2.7% 2.2% 0.9% 0.75% 0.6%
(4.8–10.5) (4.2–8.6) (2.9–7) (2.1–8.7) (2.6–6.3) (1–10.3) (1.2–6.2) (0–23) (0.8–4.5) (0.3–2.6) (0.4–1.7) (0.2–1.3)
.
the risk of cardiovascular morbidity and mortality, and moderate exertion may provide an additional benefit over light exercise.12,25
the incidence of triggered AMI, and the public health relevance of such actions.
Regular physical activity has been found to significantly weaken the triggering effect of both physical and sexual activity in a recent meta-analysis.33 For every additional time of regular exercise per week, the relative risk for myocardial infarction decreased by approximately 45%. As physical activity is an efficient and inexpensive means of prevention at the population level, physicians should give patients advice about this common issue in clinical practice. However, recommendations must be tailored after exercise testing and an assessment of overall cardiovascular condition.66,67 In any case, intensity and duration of exercise might be gradually increased, in accordance with an individual patient’s capacity.
Conclusion
Future research How can we translate the information derived from trigger studies into preventive measures? One intuitive recommendation is to reduce or avoid drug addiction and heavy meals, and to stay away from air pollution. When it comes to unavoidable situations of daily life, the possibility that pharmacologic therapy, targeted at the time of the potential triggering activity, may provide some degree of protection needs to be explored. Recently, a feasibility study68 on 17 healthy individuals demonstrated that self-administration of propranolol 10 mg and aspirin 100 mg immediately before heavy physical activity, or during episodes of moderate to severe anger or anxiety, is well tolerated and acceptable, with 71% of the participants considering it feasible to continue taking medication in this manner. Another area of research is the interaction between the triggering process and chronic cardiovascular risk factors, with a special focus on the relative importance of different risk factors and their susceptibility to triggers. Finally, we should further investigate whether interventions targeting cardiovascular risk factors, in addition to standard cardiovascular drug therapies, have the ability to reduce
The primary prevention of AMI is traditionally based on fighting the development of atherosclerosis. However, modern medical efforts should aim to identify and modify the circumstances that can acutely trigger AMI, and this should be incorporated into public health prevention. To protect patients and save lives, the strength, specificities and general relevance of all possible external triggers should be explored. There is room for the research community to provide further information about the individual and public health risks of external triggers of AMI, and, by introducing new clinical and epidemiological methodologies, to suggest more personalized and effective preventive measures.
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