Causes of nonischemic sudden cardiac death in the current era
Article Outline
- Abstract
- Introduction
- Methods
- Causes of death
- Statistical analysis
- Results
- Characteristics of SCD victims and location and time of death
- Underlying cardiac disease
- Causes of nonischemic SCD according to age groups
- Discussion
- Underlying cardiac disease in victims of nonischemic SCD
- Causes of SCD in victims younger than 40 years
- Possible reasons for geographical differences in the causes of SCD
- Potential study limitations
- Conclusion
- References
- Copyright
Background
Previous data have shown that various nonischemic cardiac diseases account for about 20% of sudden cardiac deaths (SCDs) and that dilated and hypertrophic cardiomyopathy (CM) are major causes of nonischemic SCD.
Objective
The purpose of this study was to define the prevalence and causes of SCD due to nonischemic CM in the current era given the substantial change in the diagnosis and treatment of cardiac diseases and in lifestyle patterns.
Methods
A total of 2661 consecutive victims of SCD from among a population of approximately 470,000 inhabitants in the Province of Oulu, Northern Finland, were included in the study. The causes of deaths were determined from the uniformly required autopsies of SCD victims in Finland, plus available medical records and standardized questionnaires.
Results
Nonischemic cause of SCD was found in 579 victims (21.8% of all the SCDs). Mean age (± SD) was 55 (±12) years; 78% were males. After subgrouping the nonischemic SCDs into various categories, SCDs associated most closely with obesity (23.7%), followed by alcoholic CM (19.0%), hypertensive CM (15.5%), and fibrotic CM (13.6%). Fibrotic CM was the most common association with SCD in subjects younger than 40 years (28.3%), whereas alcoholic CM was the most common cause of death in subjects between 40 and 59 years of age (25.8%).
Conclusion
CM related to obesity, fibrotic CM, and alcoholic CM are commonly associated with nonischemic SCD in the current era. The association of SCD with fibrotic CM is notably frequent among victims younger than 40 years.
Keywords: Alcoholic cardiomyopathy, Cardiomyopathy, Epidemiology, Fibrosis, Medicolegal autopsy, Nonischemic sudden cardiac death
Abbreviations: CAD, coronary artery disease, CM, cardiomyopathy, LV, left ventricle, SCD, sudden cardiac death
Introduction
Major advances in understanding the etiology and mechanisms of cardiovascular diseases have been achieved, associated with a concomitant reduction in age-adjusted cardiovascular disease-related mortality. Nonetheless, the causes and mechanisms of cardiac arrest and sudden cardiac death (SCD) are not completely understood, and the relative incidence of SCD has remained unchanged in the middle-aged and older population. In addition, it continues to constitute a greater proportion of deaths than other mechanisms of cardiovascular mortality among younger people.1
Lifestyle patterns, decreased physical activity, and socioeconomic development, among other factors, have changed significantly in recent decades, likely affecting the epidemiologic patterns of SCD in the current era. Obesity has become a worldwide epidemic2 and is recognized as a risk factor for cardiac diseases. In the United States, the current prevalence of obesity among adults is about 33%.3 Furthermore, it has been estimated that almost 4% of the global burden of disease is attributable to alcohol.4
In addition to these behavioral changes, primary and secondary prevention of cardiovascular diseases, as well as diagnostic methods and treatment strategies, have changed.5 Therefore, in the late 1990s we designed the FinGesture study, intending to prospectively collect the data from a consecutive series of victims of SCD who were autopsied in the province of Oulu (467,190 inhabitants), Northern Finland, an area with a high autopsy rate among victims of unexpected sudden deaths.6, 7 The aim of this study was to classify the autopsy-verified causes of nonischemic SCD in different age groups in the current era.
Methods
Study population
The study population was derived from 2661 consecutive victims of SCD in the Province of Oulu, Northern Finland, among whom postmortem examinations were performed at the Department of Forensic Medicine of the University of Oulu between 1998 and 2007. Victims with noncardiac causes of sudden death were excluded.
Because postmortem studies are mandatory in Finland whenever SCD is not due to a known disease, when the deceased has not been treated by a physician during his/her last illness, or when death has been otherwise unexpected (Act on the Inquest into the Cause of Death, 459/1973, seventh paragraph: Finnish Law),8 selection bias of forensic studies in victims with unexpected SCD is minimal. Information about the SCD victims was obtained from a combination of available medical records, postmortem examination reports, medication used at the time of SCD,6 and standardized questionnaire filled out by the closest family members of the victims of SCD.
Causes of death
Definition of the cause of death was based on a combination of medical records, autopsy data, and results of a questionnaire and was reported according to ICD-10 code classes. The classification given in Table 1 was used for more detailed descriptions of the underlying cardiac disease based on postmortem findings in conjunction with data obtained from medical records and specific questionnaires of relatives. Histologic examination was performed in all cases of SCD. Toxicology investigation was performed when autopsy findings were insufficient to define a cause of death or in cases of suspicion of a toxic exposure or cause. Limited genotyping for Finnish founder mutations of long QT syndrome was performed in those victims without a definable structural basis for SCD. The study complies with the Declaration of Helsinki and was approved by the Ethics Committee of the University of Oulu. The National Authority for Medicolegal Affairs (Valvira) approved the review of postmortem data by the investigators.
Table 1. Causes of death defined by medicolegal autopsy
| Adjudicated causes of death | Descriptive causes of death from autopsy | Autopsy findings |
|---|---|---|
| Coronary atherosclerosis (CAD) | ||
 Acute coronary syndrome | CAD with active plaque, thrombosis, or acute myocardial infarction | Chronic atherosclerotic lesions, occlusive or nonocclusive thrombi, acute myocardial infarction, old myocardial scars or diffuse fibrosis |
| Chronic ischemic heart disease | CAD with healed scar or fibrosis | Chronic atherosclerotic lesions, with old myocardial scars or diffuse fibrosis |
| Anomalous coronary arteries | Anomalous coronary arteries | Anomalies of origination and course, anomalies of intrinsic coronary arterial anatomy, anomalies of coronary termination, anomalous collateral vessels |
| Valvular heart disease | Valvular heart disease | Aortic valve calcification, mitral valve calcification |
| Inflammatory heart disease | Inflammatory heart disease | Myocarditis: inflammatory cell infiltrate of the myocardium with necrosis and/or degeneration of the adjacent myocytes |
| Structurally normal heart | No cardiac abnormalities at autopsy | Macroscopically normal heart, normal microscopic findings, with or without identified genetic abnormality, long QT mutation KCNQ1 Gly589Asp |
| Nonischemic cardiomyopathy | ||
| DCM | DCM | 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 |
| Hypertrophic cardiomyopathy | HCM | Concentric LVH, with myocyte disarray accompanied by various degrees of interstitial fibrosis |
| HOCM | LVH, with asymmetric septal hypertrophy, myocyte disarray, and various degrees of interstitial fibrosis | |
| Right ventricular dysplasia/CM | ARVD | Right ventricular dilation, atrophy of the right ventricular myocardium with fibrofatty replacement of myocytes |
| Other cardiomyopathies | Fibrotic CM | Interstitial, diffuse or patchy myocardial fibrosis without LVH, myocardial scarring, or other structural abnormalities |
| Hypertensive CM | Increased heart weight, LVH, unspecific fibrosis, other organ changes related to hypertension (eg, medial hypertrophy, intimal fibrosis in renal arterioles) | |
| Alcoholic CM | No specific macroscopic or microscopic findings, focal replacement fibrosis of the myocardium, in later stages signs of dilated cardiomyopathy, other organ changes related to excessive long-term alcohol consumption (eg, liver cirrhosis and/or severe steatosis, pancreatic fibrosis) | |
| CM associated with obesity and nonspecific CM | 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 |
Statistical analysis
Two-sided t test and χ2 analyses were used for comparisons between study groups. When comparisons were made among three age groups, analysis of variance with Bonferroni post hoc analysis was used for multiple comparisons. All analyses were performed with the Statistical Package for Social Studies (version 13.0, SPSS Inc, Chicago, IL, USA). P <.05 was considered significant.
Results
The study data were derived from a total of 2661 SCD victims whose deaths occurred between 1998 and 2007. Based upon a population of 467,190 in the Province of Oulu in the year 2007 (Statistics Finland), the annual incidence of SCD was established at 56.9 deaths per 100,000 inhabitants (0.06% per year). Nonischemic cause of SCD was found in 579 victims (21.8% of all SCDs).
Characteristics of SCD victims and location and time of death
The characteristics of the total study population, including both ischemic and nonischemic SCD, are summarized in Table 2. Mean age of nonischemic SCD victims was 54.7 years (±12.1) and, the frequency of males was 78.1%. The age of ischemic SCD victims was significantly higher (65.1 ± 11.4 years, P <.000). There were statistically significant differences between the two groups with regard to total heart weight and history of hypertension, diabetes, and hypercholesterolemia, respectively. A large majority of all SCDs occurred in the home, with a higher proportion among nonischemic SCD victims (81.6%) compared to ischemic SCDs (71.0%) (Table 2). In addition, among nonischemic SCD victims, 60.3% of the deaths occurred during the 12-hour period between midnight and noon, compared to 51.5% of the ischemic SCDs. A lower SCD event rate (∼19%) occurred between 6 PM and midnight in both groups. SCD occurred more frequently at the first cardiac event among those with nonischemic SCD compared to ischemic SCD victims (66% vs 55%, P <.001).
Table 2. Characteristics of study subjects
| Characteristic | Victims of nonischemic SCD (n = 579) | Victims of ischemic SCD (n = 2082) | P value |
|---|---|---|---|
| Age (years) | 54.7±12.1 | 65.1±11.4 | <.001 |
| Sex (male) | 452(78.1) | 1674(80.1) | NS |
| Body mass index | 29.5±8.1 | 26.8±5.2 | <.001 |
| Total heart weight (g) | 503.6±152.8 | 477.8±119.6 | <.001 |
| Hypertension | 182(33.9) | 697(38.1) | .041 |
| Diabetes (type I or II) | 82(15.1) | 366(19.3) | .014 |
| Hypercholesterolemia | 37(6.9) | 174(9.4) | .036 |
| Location at time of SCD | |||
| Home | 81.6% | 71.0% | <.001 |
| Public location | 18.4% | 29.0% | <.001 |
| Time of death | |||
| 12 AM–12 PM | 60.3% | 51.52% | .004 |
| 12 PM–6 PM | 20.8% | 29.4% | .001 |
| 6 PM–12 AM | 18.9% | 19.1% | NS |
| Prior cardiac history (no) | 66.0% | 54.8% | <.001 |
Underlying cardiac disease
The causes of SCD are listed in Table 3. Coronary artery disease (CAD) was the most common cause of death (2082 victims [78.2%]). The prevalence of nonischemic SCDs was 21.8% of all the SCDs. After subgrouping the nonischemic SCDs into various categories, the most common cause of death was CM related to obesity (23.7%), followed by alcoholic CM (19.0%), hypertensive CM (15.5%), and idiopathic fibrotic CM (13.6%). All nine cases with no cardiac abnormalities at autopsy were screened for Finnish founder mutations for long QT syndrome. KCNQ1 mutation G589D was identified in two SCD victims.
Table 3. Underlying cardiac disease of victims of SCD
| Cause of nonischemic SCD | Victims of nonischemic SCD (n = 579) |
|---|---|
| Anomalous coronary arteries | 3(0.5) |
| Valvular heart disease | 29(5.0) |
| Inflammatory cardiac disease | 24(4.1) |
| Structurally normal heart | 9(1.6) |
| DCM | 23(4.0) |
| HCM | 11(1.9) |
| HOCM | 4(0.7) |
| ARVD | 7(1.2) |
| Fibrotic CM | 79(13.6) |
| Hypertensive CM | 90(15.5) |
| Alcoholic CM | 110(19.0) |
| CM related to obesity | 137(23.7) |
| Nonspecified CM | 53(9.1) |
Causes of nonischemic SCD according to age groups
Causes of nonischemic SCD were analyzed separately for subjects younger than 40 years, between 40 and 59 years, and older than 60 years (Table 4). Only 53 of 579 nonischemic SCDs (9.2%) occurred in those younger than 40 years. Fibrotic CM was the most common association, observed in 28.3% of SCDs, and CM associated with obesity was adjudicated as the cause of death in 26.4% of victims. Among those between the ages of 40 and 59 years, the incidence of alcoholic CM increased to 25.8%, and CM in the presence of obesity was observed in 23.7% of the victims. In victims older than 60 years, the prevalence of CM related to obesity was 22.8%, and hypertensive CMs accounted for 20.6%.
Table 4. Underlying cardiac disease of victims of SCD at different age groups
| Cause of nonischemic SCD | 0–39 years (n = 53) | 40–59 years (n = 337) | >60 years (n = 189) | P value |
|---|---|---|---|---|
| Anomalous coronary arteries (n = 3; 0.5%) | 1/53(1.9) | 1/337(0.3) | 1/189(0.5) | NS |
| Valvular heart disease (n = 29; 5.0%) | 1/53(1.9) | 10/337(3.0) | 18/189(9.5) | .002 ⁎ |
| Inflammatory cardiac disease (n = 24; 4.1%) | 2/53(3.8) | 15/337(4.5) | 7/189(3.7) | NS |
| Structurally normal heart (n = 9; 1.6%) | 2/53(3.8) | 6/337(1.8) | 1/189(0.5) | NS |
| DCM (n = 23; 4.0%) | 3/53(5.7) | 9/337(2.7) | 11/189(5.8) | NS |
| HCM (n = 11, 1.9%) | 3/53(5.7) | 6/337(1.8) | 2/189(1.1) | NS |
| HOCM (n = 4, 0.7%) | 0/53(0.0) | 2/337(0.6) | 2/189(1.1) | NS |
| ARVD (n = 7; 1.2%) | 2/53(3.8) | 2/337(0.6) | 3/189(1.6) | NS |
| Fibrotic CM (n = 79; 13.6%) | 15/53(28.3) | 43/337(12.8) | 21/189(11.1) | .004⁎† |
| Hypertensive CM (n = 90; 15.5%) | 4/53(7.5) | 47/337(13.9) | 39/189(20.6) | .031 |
| Alcoholic CM (n = 110; 19.0%) | 3/53(5.7) | 87/337(25.8) | 20/189(10.6) | <.001⁎‡ |
| CM related to obesity (n = 137; 23.7%) | 14/53(26.4) | 80/337(23.7) | 43/189(22.8) | NS |
| Nonspecified CM (n = 53; 9.1%) | 3/53(5.7) | 29/337(8.6) | 21/189(11.1) | NS |
⁎Statistically significant P value between age groups 40–59 years and >60 years. |
†Statistically significant P value between age groups 0–39 years and >60 years. |
‡Statistically significant P value between age groups 40–59 years and >60 years. |
Discussion
The results of this study confirm, in part, the previous data on the proportions of CAD and CM as causes of SCD among the general population in the current era. The novel finding in this study is the observation of higher prevalences of CM-associated SCDs related to obesity, alcoholic CM, and myocardial fibrosis as clinical and/or pathologic bases for nonischemic SCDs. Obesity is a well-recognized risk factor for coronary atherosclerosis, and an association with ischemic SCD would be anticipated. However, the stronger association with nonischemic SCD in this study was not anticipated and is not yet explained. The greater frequency of nocturnal SCD in the nonischemic group, in connection with the obesity data, supports a possible contribution of a sleep apnea–related mechanism of SCD. The incidence of 51.2 SCDs per 100,000 inhabitants is in line with other similar studies in western countries.9, 10 As reported earlier, a large proportion of SCDs occur in home (75%) compared to public places.11 A minor circadian pattern of SCD was noted, with a lower rate in the evening hours, but the proportion was evenly distributed across the other 6-hour intervals between midnight and 6 PM. SCD was also more commonly a first event of cardiac disease (two-thirds of the victims) among those with nonischemic compared to ischemic SCD.
Underlying cardiac disease in victims of nonischemic SCD
The most prevalent subtypes of CM among victims of nonischemic SCD were alcoholic CM, fibrotic CM, and CM related to obesity (Table 3). CM subtype related to obesity is characterized by cardiomegaly, left ventricular (LV) dilation, and myocyte hypertrophy in the absence of interstitial fibrosis or evidence of CAD.12 Obesity has become a global epidemic and is recognized as a risk factor for cardiac diseases. The existence of CM of obesity as a distinct disease association causing SCD has not been generally recognized,13 and better understanding and identification of this CM subtype are needed in the increasing population of obese patients. The association of CM with obesity in the present study was relatively common, even in subject younger than 40 years.
Alcoholic CM is a specific heart muscle disease characterized by dilated LV, normal or reduced LV wall thickness, and increased LV mass. The diagnosis of alcoholic CM is made only if other causes of death are excluded. The key factor in the diagnosis is a long-term history of heavy alcohol abuse and findings of other organ changes related to excessive long-term alcohol consumption (Table 1). If there is no history of alcohol abuse but there is a distinct alcohol disease at autopsy (eg, liver cirrhosis or evidence of prior pancreatitis in addition to CM), the diagnosis of alcoholic CM can be made after careful consideration. The prevalence of alcoholic CM among alcoholics is variable (from 23% to 40%), and it occurs more frequently in men than in women.14, 15 The prevalence of alcoholic CM as a distinct disease etiology causing SCD in the general population has been evaluated in only a few previous studies,10, 16 with a much lower prevalence reported, perhaps because it often may have been affiliated as a part of dilated CM.17
Nonspecific fibrotic CM, defined as unexplained myocardial fibrosis without evidence of other macroscopic or histologic abnormalities, was also a more common underlying cardiac abnormality at autopsy than reported previously. Concurrent with the present study, Chugh et al18 reported on several victims of SCD whose hearts were structurally normal except for the presence of myocardial fibrosis on histologic examination. The increase in fibrosis was exclusively interstitial, without evidence of myocyte necrosis or stigmata of myocarditis, similar to the present study. A strong association between myocardial fibrosis and sudden death in otherwise normal hearts has also been described previously in two other studies.19, 20 It seems evident that lack of histologic examination in many previous studies has underestimated myocardial fibrosis as a potential factor leading to SCD. Genetic factors, such as mutations in LMNA gene encoding for nuclear lamin A/C protein21 and overexpression of transforming growth factor β1,20 might be potential mediators of interstitial remodeling leading to myocardial fibrosis, but the exact reasons for myocardial fibrosis leading to SCD are largely unknown.
The role of other causes of SCD, such as coronary anomalies, valvular heart disease, inflammatory cardiac disease, or suspected primary electrical abnormalities combined, was much smaller than that reported earlier, representing only 2.4% of all SCDs and 11.2% of nonischemic SCDs. In previous studies among Caucasians, the prevalence of structurally normal heart at autopsy in victims of SCD varied considerably (between 4% and 52%).16, 17 The high prevalence most probably is due to a lack of meticulous histologic examination. It also is possible that even in Caucasian populations the causes of SCD may vary significantly from one country to another.
Causes of SCD in victims younger than 40 years
The reported causes of SCD in young people are variable among different populations. In an Italian population, CAD was the most frequent cause (21%) and arrhythmogenic right ventricular dysplasia the second most common cause (14%) of SCD in a study population aged 1 to 35 years.22 In contrast, in an Australian population, presumed primary arrhythmia was the most common cause of SCD (29%) in persons aged 5 to 35 years.23 In the present study, fibrotic CM was the most common association with SCD, followed by CM related to obesity in subjects younger than 40 years. The prevalences of arrhythmogenic right ventricular dysplasia and structurally normal hearts were relatively low, highlighting the possible geographical differences in the causes of SCD among young subjects. Even if the data are limited to young athletes, the incidence and causes of SCD vary depending on the country in which the individuals live. Maron et al24 described hypertrophic CM as the most common cause (36%) of SCD in competitive athletes over a 10-year period in the United States, whereas two Italian studies identified arrhythmogenic right ventricular dysplasia as the most common cause (25%) of SCD in young competitive athletes.25, 26
Possible reasons for geographical differences in the causes of SCD
The divergent results, especially in young SCD victims, may relate to differences in data gathering, definitions of SCD, or autopsy techniques, or they may be an outcome of genetic and ethnic diversity. Due to the few initial inhabitants, national isolation, and population bottlenecks,27 some haplotypes have become enriched in the Finnish population. These features of the Finnish population (ie, with regard to the nonstructural genetic arrhythmia syndromes) may not be generalizable to other areas of the world. However, the known prevalence of those disorders is sufficiently low as to not override the general observations in this report. The lack of meticulous autopsy examinations in many previous studies, including histology, probably has resulted in underestimation of myocardial fibrosis and CM related to obesity as etiologic factors of SCD. Our findings emphasize the importance of careful histologic studies in the postmortem evaluation of SCD victims.
The specific socioeconomic and cultural background of the individual countries may have an impact on the etiology of SCD.28 For example, differences in alcohol consumption habits may partly explain the excess alcoholic CM as a cause of SCD in the present series. In a recent study, alcoholic CM was established to be an underdiagnosed disease in Finland.29 In the United States, long-term heavy alcohol consumption is the leading cause of nonischemic dilated cardiomyopathy,30 with ethanol consumption per capita of approximately 8.7 L in 2007.31 In Finland, ethanol consumption per capita was as high as 10.4 L in 200832 and has been continuously increasing over the years.
Potential study limitations
Classifications of CMs have proved to be exceedingly complex and, in many respects, contradictory. Updates of the existing classification schemes have been presented recently.33, 34 Despite this, general etiologic classifications of CMs are problematic given that diseases with the same (or similar) anatomic and histologic findings can arise from diverse origins and mechanisms. For example, establishing a comprehensible link between obesity and SCD is problematic.13 Whether cardiac hypertrophy in obese patients is directly caused by increased adiposity or by the effects of comorbid conditions such as hypertension, diabetes, and sleep-disordered breathing is not known. Also, whether functional changes (eg, mild reductions in systolic and diastolic function) in obese patients develop over time to the stage where they cause SCD or other cardiac conditions is not clear. The existing diagnostic testing of various CMs may improve in the future, following the recognition of novel genetic abnormalities as well as other novel causes, and the subgroupings of CM might be altered entirely. In order to define the most probable cause of SCD, postmortem examination, including histologic examination, is the most reliable method for confirming or excluding antemortem structural disease and defining a cause of death.7 In appropriate cases, postmortem genetic studies may add to the clarification of causes that cannot be identified anatomically. In addition, all findings must be considered in the context of prior medical records and the circumstances of SCD, in order to distinguish between association and causation.
Conclusion
CM associated with obesity, myocardial fibrosis, and alcoholic CM were the more prevalent causes of nonischemic SCD in Finland than has been reported elsewhere. Population-based strategies to reduce obesity and heavy alcohol intake are one of the means to reduce the number of nonischemic SCDs. Research on reasons leading to myocardial fibrosis may be needed to further elucidate the mechanisms of this disease entity. The observations should be confirmed in other western populations before the present results are generalized.
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This work was supported by the Sigrid Juselius Foundation, Helsinki, Finland, and the Finnish Foundation for Cardiovascular Research, Helsinki, Finland, (Dr. Huikuri); the Fondation Leducq, Paris, France, (Drs. Junttila and Myerburg); and the Florida Heart Research Foundation, Miami, Florida, (Dr. Myerburg).
PII: S1547-5271(11)00786-7
doi:10.1016/j.hrthm.2011.06.031
© 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
