Annals of Medicine, 2015; Early Online: 1–6 © 2015 Informa UK, Ltd. ISSN 0785-3890 print/ISSN 1365-2060 online DOI: 10.3109/07853890.2015.1025824
ORIGINAL ARTICLE
Sudden cardiac death during physical exercise: Characteristics of victims and autopsy findings Tomi Toukola1, Eeva Hookana1, Juhani Junttila1, Kari Kaikkonen1, Jani Tikkanen1, Juha Perkiömäki1, Marja-Leena Kortelainen2 & Heikki V. Huikuri1 1Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland, and 2Institute of Diagnostics, Department of
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Forensic Medicine, Oulu University Hospital, Finland
Objective. To provide data on the risk factors and characteristics of subjects who experience sudden cardiac death (SCD) during physical exercise. Methods and results. We assessed the characteristics and the medico-legal autopsy findings of SCD victims who had experienced a witnessed fatal cardiac arrest at rest (n ⴝ 876) or in relation to physical exercise (n ⴝ 328) in the Finnish Study of Genotype and Phenotype Characteristics of SCD (FinGesture). A total of 876 (73%) witnessed SCDs occurred at rest (R group) and 328 (27%) during or immediately after physical exercise (PE group). Male gender was more common in the PE group compared to the R group (309/328, 94% versus 678/876, 77%, P ⬍ 0.001). Coronary artery disease was a more common structural heart disease than non-ischemic disease at autopsy when SCD was exercisetriggered (299/328, 91% versus 657/876, 75%, P ⬍ 0.001). Myocardial scarring and cardiac hypertrophy were more commonly found at autopsy in the PE group (194/328, 59% versus 370/876, 42%, P ⬍ 0.001; 243/328, 74% versus 585/876, 67%, P ⴝ 0.012, respectively). Skiing, cycling, and snow shoveling were the most common modes of exercise at the time of SCD. Conclusions. SCD during or immediately after exercise is related to male gender, ischemic heart disease, cardiac hypertrophy, and myocardial scarring. Key words: Autopsy findings, exercise, risk factors, sudden death
Introduction Physical fitness acquired by regular physical exercise has long been advocated because of its beneficial effects on delaying atherosclerosis and lowering the risk of coronary events and all-cause mortality (1). Moreover, a recent study suggests a reversed J-shaped curve of association between intensity of exercise and cardiovascular benefits, where moderate-intensity exercise was found to be most beneficial (2). Despite its clear benefits, physical exercise, particularly unaccustomed, strenuous exertion, seems transiently to increase the risk for sudden cardiac death (SCD), and it has been reported that the risk is highest in the least-fit population
Key messages • Ischemic heart disease, cardiac hypertrophy, and myocardial scarring as autopsy findings alongside male gender were common when sudden cardiac death (SCD) was exercise-triggered. • Winter-time activities were frequent triggers of SCD.
(1,3,4). However, in the general population the incidence of SCD during physical exercise is low, from 5 to 20 cases per million person-years. Several studies have also shown that exercise-related SCD among young athletes is extremely low (5–7). It is thought that SCD usually requires a structurally abnormal heart when physical exercise acts as a trigger. Among young adults under 40 years of age, hypertrophic cardiomyopathy, coronary artery abnormalities, arrhythmogenic right ventricular cardiomyopathy, premature coronary artery disease (CAD), myocarditis, and other hereditary or congenital cardiovascular abnormalities are the most common cardiovascular abnormalities behind exercise-related SCD (6,8–11). Additionally, a morphologically normal heart at autopsy might be common among young athletes (12). Ion channelopathies, such as QT syndromes, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia are possible causes of SCD in these cases (13). In older subjects CAD is a dominant cause (1,14–16). In previously asymptomatic SCD victims, disruption of a vulnerable plaque has been shown to be a common pathological finding at autopsy when death is exercise-related (14,17). Even though much progress has been made during the last decades in recognizing the etiological mechanisms of SCD, there have been only few largescale autopsy studies of SCD victims in the general population. Our study was aimed at providing data on autopsy findings and characteristics of exercise-related SCD victims in the general population. To the best of our knowledge, the present analysis is based on the largest study population of consecutive autopsyverified victims of SCD in the general population reported so far.
Correspondence: Tomi Toukola, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland. Fax: ⫹ 358 8 315 4139. E-mail: [email protected].fi (Received 22 November 2014; accepted 24 February 2015)
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Material and methods
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Study population The Finnish study of Genotype and Phenotype Characteristics of Sudden Cardiac Death (FinGesture) is a prospective study including a consecutive series of autopsy-verified out-of-hospital victims of SCD in a specific geographical area in northern Finland. Our study population included 2,674 consecutive SCD victims in the Oulu area between the years 1998 and early 2007. The study design has previously been reported in detail (18,19). Microscopic studies and histological examinations were performed in all cases of SCD in the FinGesture study. In Finland, a medico-legal autopsy is mandatory when death is sudden and unexpected and not due to a known disease; our study thus includes virtually all unexpected sudden deaths in Oulu University Hospital District. Forensic autopsies are performed in 20%–25% of deaths in Finland, and thus the diagnostics skills of forensic pathologists are of high quality. The mechanisms of death were verified by a complete medicolegal autopsy and death certificates, the report by a police officer, who, according to Finnish law, is first called to the scene in the event of an unexpected death, and the specified questionnaires to the closest relatives of the victims. In the FinGesture study, SCD was defined as death taking place within 6 hours after the onset of symptoms or within 24 hours of the time the victim was last seen alive in normal state of health. A 6-hour window was used on purpose to include cardiac arrests caused by an acute coronary event, which usually increases the risk of out-of-hospital cardiac arrest several hours after the onset of symptoms. These criteria of the time-frame have been used in other large-scale autopsy
studies as well (20). However, in this specific substudy we included only witnessed cases, so the deaths were often instantaneous and all SCDs took place within the 1-hour time-frame after the onset of symptoms. The non-cardiac causes of sudden death were excluded according to the results of the complete autopsy and the information of the circumstances of death. Predefined criteria for diagnosing the underlying structural heart disease were used in the FinGesture study including meticulous histologic and toxicological investigation as described earlier (18,19). The diagnostic criteria for different autopsy findings are presented in Table I. Cardiac hypertrophy at autopsy was assessed using total heart weight of the victim and comparing this to normal heart weight acquired from a previous Mayo Clinic study with the information of the body surface area and gender of the victim (21). The heart of the victim was defined as hypertrophied when the weight exceeded the given total heart weight with two standard deviations. Microscopic examination was performed in all autopsy cases, and characteristic features of hypertrophy, such as hypertrophy of individual cardiomyocytes with enlarged nuclei, were observed. Scarring of the myocardium was defined by macroscopic evaluation of the right and left ventricle and by microscopic analysis of the myocardium in all cases. The information on the physical activity at the time of death was acquired through reviewing comprehensive death certificates, police reports, and information from relatives. Physical exercise was defined as activity equivalent to at least 4 METS and included a broad spectrum of activity ranging from everyday chores to serious, vigorous exertion. We assessed the metabolic equivalents of different activities according to the estimates of Jetté et al. (22).
Table I. Causes of death defined by medico-legal autopsy. Modified from Hookana et al. (19) with the permission of the publisher. Adjudicated causes of death
Descriptive causes of death from autopsy
Coronary artery disease Acute coronary syndrome CAD with active plaque, thrombosis, or acute myocardial infarction Chronic ischemic heart CAD with healed scar disease or fibrosis Anomalous coronary arteries Anomalous coronary arteries Valvular heart disease Valvular heart disease Inflammatory heart disease Inflammatory heart disease Structurally normal heart No cardiac abnormalities at autopsy Non-ischemic cardiomyopathy DCM DCM Hypertrophic cardiomyopathy HCM HOCM Right ventricular dysplasia
ARVD
Other cardiomyopathies
Fibrotic CM Hypertensive CM Alcoholic CM CM associated with obesity and non-specific CM
Autopsy findings Chronic atherosclerotic lesions with occlusive or non-occlusive thrombi, acute myocardial infarction, acute plaque complication in histologic examination of culprit lesions Chronic occlusive atherosclerotic lesions, with old myocardial scars or diffuse fibrosis Anomalies of origination and course, anomalies of intrinsic coronary arterial anatomy, anomalies of coronary termination, anomalous collateral vessels Aortic valve calcification, mitral valve calcification Myocarditis: inflammatory cell infiltrate of the myocardium with necrosis and/or degeneration of the adjacent myocytes Macroscopically normal heart, normal microscopic findings, with or without identified genetic abnormality
Left ventricular dilation with inadequate degree of LVH, in later stages pale and flabby myocardium and dilation of both ventricles and atria, unspecific fibrosis, and focal atrophy/hypertrophy of myocytes Concentric LVH, with myocyte disarray accompanied by various degrees of interstitial fibrosis LVH, with asymmetric septal hypertrophy, myocyte disarray, and various degrees of interstitial fibrosis Right ventricular dilation, atrophy of the right ventricular myocardium with fibro-fatty replacement of myocytes Interstitial, diffuse, or patchy myocardial fibrosis of unknown etiology, such as LVH, myocardial scarring, or other structural abnormalities Increased heart weight, LVH, unspecific fibrosis, other organ changes related to hypertension No specific macroscopic or microscopic findings, focal replacement fibrosis of the myocardium, in later stages signs of dilated CM, other organ changes related to excessive long-term alcohol consumption Heart weight increased over value predicted for normal body weight, LVH or both left and right ventricular wall hypertrophy, dilation of both atria and ventricles, excessive epicardial fat and fat infiltration of myocardium, obesity
ARVD ⫽ arrhythmogenic right ventricular dysplasia; CAD ⫽ coronary artery disease; CM ⫽ cardiomyopathy; DCM ⫽ dilated cardiomyopathy; HCM ⫽ hypertrophic cardiomyopathy; HOCM ⫽ hypertrophic obstructive cardiomyopathy; LVH ⫽ left ventricular hypertrophy.
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Sudden cardiac death during exercise On a MET scale from 1 to 12, the level of activity had to be at least 4 to be considered as physical exercise. The status of physical activity was defined as rest if the victim was sleeping, lying down, or sitting at the time of death. Only cases with witnessed death were included in the analysis. We assessed the time-frame of physical activity as the time of activity itself or within a 1-hour period after the exertion. We excluded those SCD victims whose physical activity at the time of death could not be accurately verified from witnesses, death certificates, or police reports, or if the level of physical activity did not meet the criteria of either rest or physical exercise. After the exclusions we had a total of 1,204 victims of SCD who were either at rest or associated with physical activity at the time of death. Victims suffering SCD immediately after exercise were included in the physical exercise group. We did not classify exercise according to the vigorousness of the physical activity, because the specific intensity of the physical activity at the time of death was difficult to quantify based on the available information. The information of prior cardiac symptoms was based on a specific questionnaire to the relatives of the victims of SCD. The history of cardiac disease and medications were acquired by reviewing medical records of the victims. The study complies with the Declaration of Helsinki, and the ethics committee of the University of Oulu approved the study. The National Supervisory Authority for Welfare and Health (Valvira) approved the review of post-mortem data by the investigators.
Statistical analysis We calculated the amount and percentage of a variable in the PE group and compared these to the R group. Two-sided t test for continuous variables and chi-square test for dichotomic variables were used to detect significant differences in the distribution of variables between the study groups. Unadjusted odds ratios (OR) and their 95% confidence intervals (CI) were calculated. The Statistical Package for Social Studies (SPSS) was used to perform the analyses, and two-sided P values ⬍ 0.05 were considered statistically significant.
Results Our study population consisted of 2,674 victims of SCD, 1,204 of whom could be verified as having experienced SCD either at rest (R group, n ⫽ 876) or during physical exercise (PE group, n ⫽ 328). As seen in Table II, there was no difference in the mean age between the groups. The total number of males in our study group was 987 (82%). The number of SCDs taking place within a 1-hour time-frame after exercise was 42, which was 13% (42/328) of all exercise-related SCDs. There were only few statistically significant differences between those dying during exercise compared to those dying immediately after. There were no cases of prior diagnosed acute myocardial infarction (AMI) among those who died immediately after exercise (0/42) versus 14% (40/328) among those dying during exercise (P ⫽ 0.007). Prior cardiovascular diagnosis (including CAD, hypertension, AMI, dyslipidemia) was more common among those dying during exercise (45% versus 27%; P ⫽ 0.019). The subjects who had SCD at physical exercise were more often men compared to subjects who experienced SCD at rest (Table II). The SCD victims in the PE group less frequently had a history of hypertension, diabetes, or heart failure, and more frequently a history of dyslipidemia compared with the SCD victims in the R group. The subjects in the PE group also tended to have more frequently a history of CAD and a history of myocardial infarction when compared to the subjects who had SCD at rest, but these findings were not statistically significant. The overall
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Table II. Characteristics and autopsy findings of sudden cardiac death victims. Variable Patient characteristics: Mean age (years) Body mass index (kg/m2) Male gender Prior cardiac disease Prior diagnosed AMI Prior diagnosed CAD Angina pectoris Hypertension Diabetes mellitus Dyslipidemia Congestive heart failure Medication: Beta-blocker Digoxin Warfarin Diuretics Acetylsalicylic acid Nitroglycerin Antipsychotics Antidepressants Autopsy findings: Ischemic heart disease (CAD) Non-ischemic CMP: Hypertrophic CMP Myocardial fibrosis without any known etiology Dilated CMP Alcoholic CMP CMP related to obesity Myocarditis Valvular heart disease Other autopsy findings: Myocardial scarring Hypertrophied heart
SCD at physical exercise
SCD at rest
P value
62.0 ⫾ 10.6 27.4 ⫾ 4.7 309/328 (94%) 134/316 (42%) 37/297 (12.5%) 72/298 (24%) 33/290 (11%) 88/287 (31%) 40/297 (13%) 44/290 (15%) 16/290 (5.5%)
63.1 ⫾ 12.2 27.2 ⫾ 6.6 678/876 (77%) 350/842 (42%) 71/811 (8.8%) 150/796 (19%) 76/799 (9.5%) 309/798 (39%) 160/816 (20%) 67/806 (8.3%) 89/805 (11%)
0.14 0.64 ⬍ 0.001 0.797 0.066 0.052 0.364 ⬍ 0.05 ⬍ 0.05 ⬍ 0.01 ⬍ 0.01
54/239 (23%) 12/239 (5.0%) 21/241 (8.7%) 29/240 (12%) 39/239 (16%) 46/242 (19%) 12/239 (5.0%) 9/239 (3.8%)
189/679 (28%) 53/678 (7.1%) 51/683 (7.5%) 128/679 (19%) 136/679 (20%) 151/686 (22%) 94/682 (14%) 72/682 (11%)
0.13 0.148 0.535 ⬍ 0.05 0.209 0.329 ⬍ 0.001 ⬍ 0.01
299/328 (91%)
657/876 (75%)
⬍ 0.001
18/328 (5.5%) 159/876 (18%) 3/328 (0.91%) 6/876 (0.68%) 0/328 (0%) 34/876 (3.9%)
⬍ 0.001 0.680 ⬍ 0.001
0/328 (0%) 2/328 (0.61%) 11/327 (3.3%) 3/328 (0.9%) 8/328 (2.4%)
11/876 (1.3%) 33/876 (3.7%) 59/875 (6.7%) 8/876 (0.9%) 11/876 (1.3%)
⬍ 0.05 0.004 0.026 0.998 0.142
370/876 (42%) 585/876 (67%)
⬍ 0.001 ⬍ 0.05
194/328 (59%) 243/327 (74%)
The values are mean ⫾ SD or number of patients (percentage in parenthesis). AMI ⫽ acute myocardial infarction; CAD ⫽ coronary artery disease; CMP ⫽ cardiomyopathy; SCD ⫽ sudden cardiac death.
occurrence of prior cardiac disease was very similar in the PE and R groups (Table II). The subjects in the R group had more frequently a history of diuretic, antipsychotic, and antidepressant medication use in comparison with the subjects in the PE group. Otherwise, there were no significant differences in the use of medications between the groups (Table II). When only those with ischemic heart disease at autopsy were taken into account the use of beta-blockers was less common in the PE group. In the PE group there were attempts to resuscitate in 37% of the cases and in only 4.7% of the cases in the R group, respectively. Based on the autopsy findings, the subjects who experienced SCD during physical exercise had more frequently CAD, myocardial scarring, and myocardial hypertrophy and less frequently cardiomyopathies when compared with the SCD victims at rest (Table II). There were three cases of SCD where the autopsy was normal. One of these victims died during exercise and carried the LQT mutation KCNQ1-FIN (G589D). Two of these deaths occurred at rest. Types of exertion most often related to SCD were skiing (12%), cycling (11%), snow shoveling (9.1%), jogging (8.5%), and logging (e.g. felling trees, chopping wood) (7.6%). The physical activities triggering SCD are presented in Table III. Figure 1 shows the odds ratios of exercise-related SCD compared to rest for different combinations of autopsy findings. When all three findings—CAD, myocardial scarring, and cardiac
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Table III. Type of exertion related to sudden cardiac death. Type of exertion Skiing Cycling Snow shoveling Jogging and brisk walking Logging Hunting Yard work Berry picking Fishing Dancing Ball games Running Farming Swimming Intercourse Other
Number of patients
Percentage
38 36 30 28 25 20 18 11 7 7 7 6 6 4 3 83
12% 11% 9.1% 8.5% 7.6% 6.1% 5.5% 3.3% 2.1% 2.1% 2.1% 1.8% 1.8% 1.2% 0.9% 25%
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The most common triggers of exercise-related sudden cardiac death.
hypertrophy—were present at autopsy, odds ratio increased to 6.3 (95% CI 2.7–14.8, P ⬍ 0.001). The odds ratios presented are unadjusted.
Discussion Almost one-third of witnessed SCDs (27%) occurred during or within 60 minutes after exercise in our series, emphasizing the important role of physical exercise as a trigger of SCD. The number of SCDs during physical activity was relatively high compared to other recent data (23,24). This could be due to the fact that we also included mild to moderate physical exercise and excluded all cases where activity could not be considered to be either physical exercise or rest. A clear majority of exercise-related deaths occurred during exercise, and only 42/328 (13%) during the 1-hour time-frame after exercise. This result further highlights the small number of SCDs taking place immediately after exercise. We revealed a significant male dominance among those whose death was exercise-related. This finding is similar to many previous studies (3,24,25). The higher incidence of female gender among those dying at rest compared to exercise-related SCDs further highlights the lower risk among women of dying in association with physical exercise. The differences between sexes can be explained by the higher rate of physical exercise participation and higher exercise intensities among males. Ischemic heart disease is fairly uncommon in young and middle-aged women compared to men, which might reduce the absolute risk of exercise-related SCD among women. More than half of those experiencing an exercise-related SCD with CAD at autopsy did not have a prior history or symptoms of CAD, and the SCD during exercise was their first event of cardiac disease. Ischemic heart disease was significantly less common among victims under the age of 40, and this finding could explain the extremely low absolute number of exercise-related SCDs in this age group, but the significance of this result is limited due to the very small sample size. The present results also show that physical exercise with underlying non-ischemic cardiomyopathy is not likely to increase significantly the risk of SCD, but the effect of physical exercise on different subgroups needs to be evaluated in the future. Certain subgroups might benefit from physical exercise without an increase in exercise-related SCD. Hypertrophic cardiomyopathy seemed to be a trigger of exercise-related SCD among younger victims, a finding that was also noted in a previous study (8).
Figure 1. Odds ratios of sudden cardiac death related to exercise versus rest for the combinations of various autopsy findings. The victims with different combinations of autopsy findings are compared to those without any of these findings. The number of cases with all three findings was 71. All P values ⬍ 0.001.
The occurrence of myocardial scarring at autopsy was high among our study population (47%), even though only 10% of our SCD victims had experienced a prior diagnosed AMI according to medical records. Myocardial scarring or ischemic tissue can act as substrate for re-entrant ventricular arrhythmias during ischemia. Myocardial scars can also occur in association with certain non-ischemic cardiomyopathies. However, the high occurrence of myocardial scarring also highlights the importance of ‘silent’ myocardial infarctions. Studies have shown that a notable number of myocardial infarctions go undiagnosed (26,27). In our study we noticed a higher incidence of myocardial scarring as an autopsy finding among exercise-related SCDs, but prior diagnosed AMI in patient history did not predict a significant difference between the PE group and the R group (Table II). This finding emphasizes the important role of screening for ‘silent’ myocardial infarctions even in the general population, especially before engaging heavy exercise programs. Many cardiac diseases lead eventually to a hypertrophic heart, and in our study up to 69% of SCD victims had an increased total heart weight. A hypertrophied heart and ischemic heart disease together with myocardial scarring thus comprise a specific highrisk substrate for exercise-triggered SCD. On the other hand, exercise itself can also result in a hypertrophied heart, and this could partly explain the presence of hypertrophy among those who died during the exercise. Beta-blockers have been shown to reduce SCD via multiple mechanisms, especially in patients with prior myocardial infarction and heart failure (28,29). For example, beta-blockers lower the heart rate during physical exertion, which could beneficially prevent SCD during exercise by lowering wall stress and therefore reducing exercise-induced ischemia. The usage of beta-blockers did not have a significant effect on exercise-related SCD in our entire study population, but when the victims were limited to those with ischemic heart disease at autopsy beta-blocker usage was less common in the PE group. Antipsychotics and antidepressants seemed to be common among those who died suddenly at rest. Psychotropic medications, especially antipsychotics, have previously been linked to SCD (30,31). Antipsychotics tend to prolong the QTc interval, most notably during low heart rate at rest. This could explain part of the rest-related deaths. However, those suffering from psychosis and other psychiatric disease often smoke, do little exercise, and have metabolic syndromes, which could explain a big part of this difference. The most common types of exertion related to SCD in our study are typical of the northern geographical area of our study population. Skiing (12%) and cycling (11%) were found to be the most common sports behind exercise-induced SCD. The role of
Sudden cardiac death during exercise cross-country skiing as a trigger of sudden death has only been presented in few case reports. Snow shoveling was also associated with a relatively high number of death cases (9.1%). This has been addressed in previous studies (32,33). Snow shoveling is regarded as high-risk activity by the American Heart Association (1). The high risk of acute coronary syndrome related to snow shoveling is partly due to the high cardiac demand and to snow shoveling often being performed by otherwise sedentary unfit men. Cycling has been an important trigger of exercise-related SCDs in other studies as well (24).
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Limitations The strength of this study lies in the fact that our study population consisted of consecutive autopsy-verified SCD victims in the general population and the high number of autopsies performed in Finland as compared to other Western countries. Furthermore, predefined criteria for diagnosing the underlying structural heart disease were used in the FinGesture study, including meticulous histologic and toxicological investigation as described earlier (18,19). A few limitations and biases can be found regarding this study, however. In some cases the general physician is allowed to write a death certificate of victims of SCD without a complete medico-legal autopsy in cases with advanced cardiac disease. Therefore, the present study does not include subjects with previously diagnosed severe cardiac disease, but the focus is mostly on subjects in whom the SCD was the first manifestation of their cardiac disease, or on those with stable cardiac disease. Compared to previous studies, the number of SCDs occurring during or immediately after physical exertion was high, probably because we included activity equivalent to at least 4 METS and a broad spectrum of activity. We excluded unwitnessed deaths, which meant that SCDs taking place unwitnessed during sleep were also excluded. This might lead to an unusually high proportion of exercise-related SCD. The level of physical activity could only be assessed for 1,204 (45%) witnessed SCD cases from the entire study population, and we have no information about the habitual exercise levels of the SCD victims of our study population. Therefore, it was not possible to analyze the impact of high versus low levels of physical activity on the results.
Implications The present findings show that CAD is the dominant underlying etiology of unexpected SCD. These findings highlight the importance of prevention and early diagnosis of CAD and perhaps counseling patients with diagnosed CAD or risk factors of ischemic heart disease that heavy exercise, e.g. snow shoveling, should be performed with caution. Funding: This study was supported by grants from the Sigrid Juselius Foundation, Helsinki, Finland, and the Finnish Foundation for Cardiovascular Research, Helsinki, Finland. Declaration of interest: The authors report no conflicts of interest.
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31. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360:225–35. 32. Chowdhury PS, Franklin BA, Boura JA, Dragovic LJ, Kanluen S, Spitz W, et al. Sudden cardiac death after manual or automated snow removal. Am J Cardiol. 2003;92:833–5. 33. Nichols RB, McIntyre WF, Chan S, Scogstad-Stubbs D, Hopman WM, Baranchuk A. Snow-shoveling and the risk of acute coronary syndromes. Clin Res Cardiol. 2012;101:11–15.
ORIGINAL ARTICLE
Sudden cardiac death during physical exercise: Characteristics of victims and autopsy findings Tomi Toukola1, Eeva Hookana1, Juhani Junttila1, Kari Kaikkonen1, Jani Tikkanen1, Juha Perkiömäki1, Marja-Leena Kortelainen2 & Heikki V. Huikuri1 1Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland, and 2Institute of Diagnostics, Department of
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Forensic Medicine, Oulu University Hospital, Finland
Objective. To provide data on the risk factors and characteristics of subjects who experience sudden cardiac death (SCD) during physical exercise. Methods and results. We assessed the characteristics and the medico-legal autopsy findings of SCD victims who had experienced a witnessed fatal cardiac arrest at rest (n ⴝ 876) or in relation to physical exercise (n ⴝ 328) in the Finnish Study of Genotype and Phenotype Characteristics of SCD (FinGesture). A total of 876 (73%) witnessed SCDs occurred at rest (R group) and 328 (27%) during or immediately after physical exercise (PE group). Male gender was more common in the PE group compared to the R group (309/328, 94% versus 678/876, 77%, P ⬍ 0.001). Coronary artery disease was a more common structural heart disease than non-ischemic disease at autopsy when SCD was exercisetriggered (299/328, 91% versus 657/876, 75%, P ⬍ 0.001). Myocardial scarring and cardiac hypertrophy were more commonly found at autopsy in the PE group (194/328, 59% versus 370/876, 42%, P ⬍ 0.001; 243/328, 74% versus 585/876, 67%, P ⴝ 0.012, respectively). Skiing, cycling, and snow shoveling were the most common modes of exercise at the time of SCD. Conclusions. SCD during or immediately after exercise is related to male gender, ischemic heart disease, cardiac hypertrophy, and myocardial scarring. Key words: Autopsy findings, exercise, risk factors, sudden death
Introduction Physical fitness acquired by regular physical exercise has long been advocated because of its beneficial effects on delaying atherosclerosis and lowering the risk of coronary events and all-cause mortality (1). Moreover, a recent study suggests a reversed J-shaped curve of association between intensity of exercise and cardiovascular benefits, where moderate-intensity exercise was found to be most beneficial (2). Despite its clear benefits, physical exercise, particularly unaccustomed, strenuous exertion, seems transiently to increase the risk for sudden cardiac death (SCD), and it has been reported that the risk is highest in the least-fit population
Key messages • Ischemic heart disease, cardiac hypertrophy, and myocardial scarring as autopsy findings alongside male gender were common when sudden cardiac death (SCD) was exercise-triggered. • Winter-time activities were frequent triggers of SCD.
(1,3,4). However, in the general population the incidence of SCD during physical exercise is low, from 5 to 20 cases per million person-years. Several studies have also shown that exercise-related SCD among young athletes is extremely low (5–7). It is thought that SCD usually requires a structurally abnormal heart when physical exercise acts as a trigger. Among young adults under 40 years of age, hypertrophic cardiomyopathy, coronary artery abnormalities, arrhythmogenic right ventricular cardiomyopathy, premature coronary artery disease (CAD), myocarditis, and other hereditary or congenital cardiovascular abnormalities are the most common cardiovascular abnormalities behind exercise-related SCD (6,8–11). Additionally, a morphologically normal heart at autopsy might be common among young athletes (12). Ion channelopathies, such as QT syndromes, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia are possible causes of SCD in these cases (13). In older subjects CAD is a dominant cause (1,14–16). In previously asymptomatic SCD victims, disruption of a vulnerable plaque has been shown to be a common pathological finding at autopsy when death is exercise-related (14,17). Even though much progress has been made during the last decades in recognizing the etiological mechanisms of SCD, there have been only few largescale autopsy studies of SCD victims in the general population. Our study was aimed at providing data on autopsy findings and characteristics of exercise-related SCD victims in the general population. To the best of our knowledge, the present analysis is based on the largest study population of consecutive autopsyverified victims of SCD in the general population reported so far.
Correspondence: Tomi Toukola, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland. Fax: ⫹ 358 8 315 4139. E-mail: [email protected].fi (Received 22 November 2014; accepted 24 February 2015)
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Material and methods
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Study population The Finnish study of Genotype and Phenotype Characteristics of Sudden Cardiac Death (FinGesture) is a prospective study including a consecutive series of autopsy-verified out-of-hospital victims of SCD in a specific geographical area in northern Finland. Our study population included 2,674 consecutive SCD victims in the Oulu area between the years 1998 and early 2007. The study design has previously been reported in detail (18,19). Microscopic studies and histological examinations were performed in all cases of SCD in the FinGesture study. In Finland, a medico-legal autopsy is mandatory when death is sudden and unexpected and not due to a known disease; our study thus includes virtually all unexpected sudden deaths in Oulu University Hospital District. Forensic autopsies are performed in 20%–25% of deaths in Finland, and thus the diagnostics skills of forensic pathologists are of high quality. The mechanisms of death were verified by a complete medicolegal autopsy and death certificates, the report by a police officer, who, according to Finnish law, is first called to the scene in the event of an unexpected death, and the specified questionnaires to the closest relatives of the victims. In the FinGesture study, SCD was defined as death taking place within 6 hours after the onset of symptoms or within 24 hours of the time the victim was last seen alive in normal state of health. A 6-hour window was used on purpose to include cardiac arrests caused by an acute coronary event, which usually increases the risk of out-of-hospital cardiac arrest several hours after the onset of symptoms. These criteria of the time-frame have been used in other large-scale autopsy
studies as well (20). However, in this specific substudy we included only witnessed cases, so the deaths were often instantaneous and all SCDs took place within the 1-hour time-frame after the onset of symptoms. The non-cardiac causes of sudden death were excluded according to the results of the complete autopsy and the information of the circumstances of death. Predefined criteria for diagnosing the underlying structural heart disease were used in the FinGesture study including meticulous histologic and toxicological investigation as described earlier (18,19). The diagnostic criteria for different autopsy findings are presented in Table I. Cardiac hypertrophy at autopsy was assessed using total heart weight of the victim and comparing this to normal heart weight acquired from a previous Mayo Clinic study with the information of the body surface area and gender of the victim (21). The heart of the victim was defined as hypertrophied when the weight exceeded the given total heart weight with two standard deviations. Microscopic examination was performed in all autopsy cases, and characteristic features of hypertrophy, such as hypertrophy of individual cardiomyocytes with enlarged nuclei, were observed. Scarring of the myocardium was defined by macroscopic evaluation of the right and left ventricle and by microscopic analysis of the myocardium in all cases. The information on the physical activity at the time of death was acquired through reviewing comprehensive death certificates, police reports, and information from relatives. Physical exercise was defined as activity equivalent to at least 4 METS and included a broad spectrum of activity ranging from everyday chores to serious, vigorous exertion. We assessed the metabolic equivalents of different activities according to the estimates of Jetté et al. (22).
Table I. Causes of death defined by medico-legal autopsy. Modified from Hookana et al. (19) with the permission of the publisher. Adjudicated causes of death
Descriptive causes of death from autopsy
Coronary artery disease Acute coronary syndrome CAD with active plaque, thrombosis, or acute myocardial infarction Chronic ischemic heart CAD with healed scar disease or fibrosis Anomalous coronary arteries Anomalous coronary arteries Valvular heart disease Valvular heart disease Inflammatory heart disease Inflammatory heart disease Structurally normal heart No cardiac abnormalities at autopsy Non-ischemic cardiomyopathy DCM DCM Hypertrophic cardiomyopathy HCM HOCM Right ventricular dysplasia
ARVD
Other cardiomyopathies
Fibrotic CM Hypertensive CM Alcoholic CM CM associated with obesity and non-specific CM
Autopsy findings Chronic atherosclerotic lesions with occlusive or non-occlusive thrombi, acute myocardial infarction, acute plaque complication in histologic examination of culprit lesions Chronic occlusive atherosclerotic lesions, with old myocardial scars or diffuse fibrosis Anomalies of origination and course, anomalies of intrinsic coronary arterial anatomy, anomalies of coronary termination, anomalous collateral vessels Aortic valve calcification, mitral valve calcification Myocarditis: inflammatory cell infiltrate of the myocardium with necrosis and/or degeneration of the adjacent myocytes Macroscopically normal heart, normal microscopic findings, with or without identified genetic abnormality
Left ventricular dilation with inadequate degree of LVH, in later stages pale and flabby myocardium and dilation of both ventricles and atria, unspecific fibrosis, and focal atrophy/hypertrophy of myocytes Concentric LVH, with myocyte disarray accompanied by various degrees of interstitial fibrosis LVH, with asymmetric septal hypertrophy, myocyte disarray, and various degrees of interstitial fibrosis Right ventricular dilation, atrophy of the right ventricular myocardium with fibro-fatty replacement of myocytes Interstitial, diffuse, or patchy myocardial fibrosis of unknown etiology, such as LVH, myocardial scarring, or other structural abnormalities Increased heart weight, LVH, unspecific fibrosis, other organ changes related to hypertension No specific macroscopic or microscopic findings, focal replacement fibrosis of the myocardium, in later stages signs of dilated CM, other organ changes related to excessive long-term alcohol consumption Heart weight increased over value predicted for normal body weight, LVH or both left and right ventricular wall hypertrophy, dilation of both atria and ventricles, excessive epicardial fat and fat infiltration of myocardium, obesity
ARVD ⫽ arrhythmogenic right ventricular dysplasia; CAD ⫽ coronary artery disease; CM ⫽ cardiomyopathy; DCM ⫽ dilated cardiomyopathy; HCM ⫽ hypertrophic cardiomyopathy; HOCM ⫽ hypertrophic obstructive cardiomyopathy; LVH ⫽ left ventricular hypertrophy.
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Sudden cardiac death during exercise On a MET scale from 1 to 12, the level of activity had to be at least 4 to be considered as physical exercise. The status of physical activity was defined as rest if the victim was sleeping, lying down, or sitting at the time of death. Only cases with witnessed death were included in the analysis. We assessed the time-frame of physical activity as the time of activity itself or within a 1-hour period after the exertion. We excluded those SCD victims whose physical activity at the time of death could not be accurately verified from witnesses, death certificates, or police reports, or if the level of physical activity did not meet the criteria of either rest or physical exercise. After the exclusions we had a total of 1,204 victims of SCD who were either at rest or associated with physical activity at the time of death. Victims suffering SCD immediately after exercise were included in the physical exercise group. We did not classify exercise according to the vigorousness of the physical activity, because the specific intensity of the physical activity at the time of death was difficult to quantify based on the available information. The information of prior cardiac symptoms was based on a specific questionnaire to the relatives of the victims of SCD. The history of cardiac disease and medications were acquired by reviewing medical records of the victims. The study complies with the Declaration of Helsinki, and the ethics committee of the University of Oulu approved the study. The National Supervisory Authority for Welfare and Health (Valvira) approved the review of post-mortem data by the investigators.
Statistical analysis We calculated the amount and percentage of a variable in the PE group and compared these to the R group. Two-sided t test for continuous variables and chi-square test for dichotomic variables were used to detect significant differences in the distribution of variables between the study groups. Unadjusted odds ratios (OR) and their 95% confidence intervals (CI) were calculated. The Statistical Package for Social Studies (SPSS) was used to perform the analyses, and two-sided P values ⬍ 0.05 were considered statistically significant.
Results Our study population consisted of 2,674 victims of SCD, 1,204 of whom could be verified as having experienced SCD either at rest (R group, n ⫽ 876) or during physical exercise (PE group, n ⫽ 328). As seen in Table II, there was no difference in the mean age between the groups. The total number of males in our study group was 987 (82%). The number of SCDs taking place within a 1-hour time-frame after exercise was 42, which was 13% (42/328) of all exercise-related SCDs. There were only few statistically significant differences between those dying during exercise compared to those dying immediately after. There were no cases of prior diagnosed acute myocardial infarction (AMI) among those who died immediately after exercise (0/42) versus 14% (40/328) among those dying during exercise (P ⫽ 0.007). Prior cardiovascular diagnosis (including CAD, hypertension, AMI, dyslipidemia) was more common among those dying during exercise (45% versus 27%; P ⫽ 0.019). The subjects who had SCD at physical exercise were more often men compared to subjects who experienced SCD at rest (Table II). The SCD victims in the PE group less frequently had a history of hypertension, diabetes, or heart failure, and more frequently a history of dyslipidemia compared with the SCD victims in the R group. The subjects in the PE group also tended to have more frequently a history of CAD and a history of myocardial infarction when compared to the subjects who had SCD at rest, but these findings were not statistically significant. The overall
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Table II. Characteristics and autopsy findings of sudden cardiac death victims. Variable Patient characteristics: Mean age (years) Body mass index (kg/m2) Male gender Prior cardiac disease Prior diagnosed AMI Prior diagnosed CAD Angina pectoris Hypertension Diabetes mellitus Dyslipidemia Congestive heart failure Medication: Beta-blocker Digoxin Warfarin Diuretics Acetylsalicylic acid Nitroglycerin Antipsychotics Antidepressants Autopsy findings: Ischemic heart disease (CAD) Non-ischemic CMP: Hypertrophic CMP Myocardial fibrosis without any known etiology Dilated CMP Alcoholic CMP CMP related to obesity Myocarditis Valvular heart disease Other autopsy findings: Myocardial scarring Hypertrophied heart
SCD at physical exercise
SCD at rest
P value
62.0 ⫾ 10.6 27.4 ⫾ 4.7 309/328 (94%) 134/316 (42%) 37/297 (12.5%) 72/298 (24%) 33/290 (11%) 88/287 (31%) 40/297 (13%) 44/290 (15%) 16/290 (5.5%)
63.1 ⫾ 12.2 27.2 ⫾ 6.6 678/876 (77%) 350/842 (42%) 71/811 (8.8%) 150/796 (19%) 76/799 (9.5%) 309/798 (39%) 160/816 (20%) 67/806 (8.3%) 89/805 (11%)
0.14 0.64 ⬍ 0.001 0.797 0.066 0.052 0.364 ⬍ 0.05 ⬍ 0.05 ⬍ 0.01 ⬍ 0.01
54/239 (23%) 12/239 (5.0%) 21/241 (8.7%) 29/240 (12%) 39/239 (16%) 46/242 (19%) 12/239 (5.0%) 9/239 (3.8%)
189/679 (28%) 53/678 (7.1%) 51/683 (7.5%) 128/679 (19%) 136/679 (20%) 151/686 (22%) 94/682 (14%) 72/682 (11%)
0.13 0.148 0.535 ⬍ 0.05 0.209 0.329 ⬍ 0.001 ⬍ 0.01
299/328 (91%)
657/876 (75%)
⬍ 0.001
18/328 (5.5%) 159/876 (18%) 3/328 (0.91%) 6/876 (0.68%) 0/328 (0%) 34/876 (3.9%)
⬍ 0.001 0.680 ⬍ 0.001
0/328 (0%) 2/328 (0.61%) 11/327 (3.3%) 3/328 (0.9%) 8/328 (2.4%)
11/876 (1.3%) 33/876 (3.7%) 59/875 (6.7%) 8/876 (0.9%) 11/876 (1.3%)
⬍ 0.05 0.004 0.026 0.998 0.142
370/876 (42%) 585/876 (67%)
⬍ 0.001 ⬍ 0.05
194/328 (59%) 243/327 (74%)
The values are mean ⫾ SD or number of patients (percentage in parenthesis). AMI ⫽ acute myocardial infarction; CAD ⫽ coronary artery disease; CMP ⫽ cardiomyopathy; SCD ⫽ sudden cardiac death.
occurrence of prior cardiac disease was very similar in the PE and R groups (Table II). The subjects in the R group had more frequently a history of diuretic, antipsychotic, and antidepressant medication use in comparison with the subjects in the PE group. Otherwise, there were no significant differences in the use of medications between the groups (Table II). When only those with ischemic heart disease at autopsy were taken into account the use of beta-blockers was less common in the PE group. In the PE group there were attempts to resuscitate in 37% of the cases and in only 4.7% of the cases in the R group, respectively. Based on the autopsy findings, the subjects who experienced SCD during physical exercise had more frequently CAD, myocardial scarring, and myocardial hypertrophy and less frequently cardiomyopathies when compared with the SCD victims at rest (Table II). There were three cases of SCD where the autopsy was normal. One of these victims died during exercise and carried the LQT mutation KCNQ1-FIN (G589D). Two of these deaths occurred at rest. Types of exertion most often related to SCD were skiing (12%), cycling (11%), snow shoveling (9.1%), jogging (8.5%), and logging (e.g. felling trees, chopping wood) (7.6%). The physical activities triggering SCD are presented in Table III. Figure 1 shows the odds ratios of exercise-related SCD compared to rest for different combinations of autopsy findings. When all three findings—CAD, myocardial scarring, and cardiac
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Table III. Type of exertion related to sudden cardiac death. Type of exertion Skiing Cycling Snow shoveling Jogging and brisk walking Logging Hunting Yard work Berry picking Fishing Dancing Ball games Running Farming Swimming Intercourse Other
Number of patients
Percentage
38 36 30 28 25 20 18 11 7 7 7 6 6 4 3 83
12% 11% 9.1% 8.5% 7.6% 6.1% 5.5% 3.3% 2.1% 2.1% 2.1% 1.8% 1.8% 1.2% 0.9% 25%
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The most common triggers of exercise-related sudden cardiac death.
hypertrophy—were present at autopsy, odds ratio increased to 6.3 (95% CI 2.7–14.8, P ⬍ 0.001). The odds ratios presented are unadjusted.
Discussion Almost one-third of witnessed SCDs (27%) occurred during or within 60 minutes after exercise in our series, emphasizing the important role of physical exercise as a trigger of SCD. The number of SCDs during physical activity was relatively high compared to other recent data (23,24). This could be due to the fact that we also included mild to moderate physical exercise and excluded all cases where activity could not be considered to be either physical exercise or rest. A clear majority of exercise-related deaths occurred during exercise, and only 42/328 (13%) during the 1-hour time-frame after exercise. This result further highlights the small number of SCDs taking place immediately after exercise. We revealed a significant male dominance among those whose death was exercise-related. This finding is similar to many previous studies (3,24,25). The higher incidence of female gender among those dying at rest compared to exercise-related SCDs further highlights the lower risk among women of dying in association with physical exercise. The differences between sexes can be explained by the higher rate of physical exercise participation and higher exercise intensities among males. Ischemic heart disease is fairly uncommon in young and middle-aged women compared to men, which might reduce the absolute risk of exercise-related SCD among women. More than half of those experiencing an exercise-related SCD with CAD at autopsy did not have a prior history or symptoms of CAD, and the SCD during exercise was their first event of cardiac disease. Ischemic heart disease was significantly less common among victims under the age of 40, and this finding could explain the extremely low absolute number of exercise-related SCDs in this age group, but the significance of this result is limited due to the very small sample size. The present results also show that physical exercise with underlying non-ischemic cardiomyopathy is not likely to increase significantly the risk of SCD, but the effect of physical exercise on different subgroups needs to be evaluated in the future. Certain subgroups might benefit from physical exercise without an increase in exercise-related SCD. Hypertrophic cardiomyopathy seemed to be a trigger of exercise-related SCD among younger victims, a finding that was also noted in a previous study (8).
Figure 1. Odds ratios of sudden cardiac death related to exercise versus rest for the combinations of various autopsy findings. The victims with different combinations of autopsy findings are compared to those without any of these findings. The number of cases with all three findings was 71. All P values ⬍ 0.001.
The occurrence of myocardial scarring at autopsy was high among our study population (47%), even though only 10% of our SCD victims had experienced a prior diagnosed AMI according to medical records. Myocardial scarring or ischemic tissue can act as substrate for re-entrant ventricular arrhythmias during ischemia. Myocardial scars can also occur in association with certain non-ischemic cardiomyopathies. However, the high occurrence of myocardial scarring also highlights the importance of ‘silent’ myocardial infarctions. Studies have shown that a notable number of myocardial infarctions go undiagnosed (26,27). In our study we noticed a higher incidence of myocardial scarring as an autopsy finding among exercise-related SCDs, but prior diagnosed AMI in patient history did not predict a significant difference between the PE group and the R group (Table II). This finding emphasizes the important role of screening for ‘silent’ myocardial infarctions even in the general population, especially before engaging heavy exercise programs. Many cardiac diseases lead eventually to a hypertrophic heart, and in our study up to 69% of SCD victims had an increased total heart weight. A hypertrophied heart and ischemic heart disease together with myocardial scarring thus comprise a specific highrisk substrate for exercise-triggered SCD. On the other hand, exercise itself can also result in a hypertrophied heart, and this could partly explain the presence of hypertrophy among those who died during the exercise. Beta-blockers have been shown to reduce SCD via multiple mechanisms, especially in patients with prior myocardial infarction and heart failure (28,29). For example, beta-blockers lower the heart rate during physical exertion, which could beneficially prevent SCD during exercise by lowering wall stress and therefore reducing exercise-induced ischemia. The usage of beta-blockers did not have a significant effect on exercise-related SCD in our entire study population, but when the victims were limited to those with ischemic heart disease at autopsy beta-blocker usage was less common in the PE group. Antipsychotics and antidepressants seemed to be common among those who died suddenly at rest. Psychotropic medications, especially antipsychotics, have previously been linked to SCD (30,31). Antipsychotics tend to prolong the QTc interval, most notably during low heart rate at rest. This could explain part of the rest-related deaths. However, those suffering from psychosis and other psychiatric disease often smoke, do little exercise, and have metabolic syndromes, which could explain a big part of this difference. The most common types of exertion related to SCD in our study are typical of the northern geographical area of our study population. Skiing (12%) and cycling (11%) were found to be the most common sports behind exercise-induced SCD. The role of
Sudden cardiac death during exercise cross-country skiing as a trigger of sudden death has only been presented in few case reports. Snow shoveling was also associated with a relatively high number of death cases (9.1%). This has been addressed in previous studies (32,33). Snow shoveling is regarded as high-risk activity by the American Heart Association (1). The high risk of acute coronary syndrome related to snow shoveling is partly due to the high cardiac demand and to snow shoveling often being performed by otherwise sedentary unfit men. Cycling has been an important trigger of exercise-related SCDs in other studies as well (24).
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Limitations The strength of this study lies in the fact that our study population consisted of consecutive autopsy-verified SCD victims in the general population and the high number of autopsies performed in Finland as compared to other Western countries. Furthermore, predefined criteria for diagnosing the underlying structural heart disease were used in the FinGesture study, including meticulous histologic and toxicological investigation as described earlier (18,19). A few limitations and biases can be found regarding this study, however. In some cases the general physician is allowed to write a death certificate of victims of SCD without a complete medico-legal autopsy in cases with advanced cardiac disease. Therefore, the present study does not include subjects with previously diagnosed severe cardiac disease, but the focus is mostly on subjects in whom the SCD was the first manifestation of their cardiac disease, or on those with stable cardiac disease. Compared to previous studies, the number of SCDs occurring during or immediately after physical exertion was high, probably because we included activity equivalent to at least 4 METS and a broad spectrum of activity. We excluded unwitnessed deaths, which meant that SCDs taking place unwitnessed during sleep were also excluded. This might lead to an unusually high proportion of exercise-related SCD. The level of physical activity could only be assessed for 1,204 (45%) witnessed SCD cases from the entire study population, and we have no information about the habitual exercise levels of the SCD victims of our study population. Therefore, it was not possible to analyze the impact of high versus low levels of physical activity on the results.
Implications The present findings show that CAD is the dominant underlying etiology of unexpected SCD. These findings highlight the importance of prevention and early diagnosis of CAD and perhaps counseling patients with diagnosed CAD or risk factors of ischemic heart disease that heavy exercise, e.g. snow shoveling, should be performed with caution. Funding: This study was supported by grants from the Sigrid Juselius Foundation, Helsinki, Finland, and the Finnish Foundation for Cardiovascular Research, Helsinki, Finland. Declaration of interest: The authors report no conflicts of interest.
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