Abstract
Aim. This study was designed to compare the risk profiles of sudden cardiac death (SCD) victims and survivors of an acute coronary event.
Method. A case-control study included consecutive victims of SCD (n=425) verified to be due to an acute coronary event at medicolegal autopsy and consecutive patients surviving an acute myocardial infarction (AMI) (n=644).
Results. Family history of SCD (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.0–2.2, P=0.03), male gender (OR 1.8, 95% CI 1.3–2.4, P<0.001), current smoking (OR 2.0, 95% CI 1.5–2.6, P<0.001), cardiac hypertrophy (OR 3.0, 95% CI 2.3–3.9, P<0.001) and three-vessel coronary artery disease (CAD) (OR 5.4, 95% CI 3.6–8.2, P<0.001) were more common among the victims of SCD as compared to survivors of AMI. There was a cumulative increase of risk of being a SCD victim versus AMI survivor when more than one risk factor was present, with the OR rising to 44.3 (95% CI 8.0–246.7) in a current male smoker with a family history of SCD and cardiac hypertrophy.
Conclusions. There are specific features that differentiate the victims of SCD from survivors of an acute coronary event. Clustering of several variables, such as family history of SCD, smoking, cardiac hypertrophy and three-vessel CAD are alarm signals of a very high risk of SCD.
Introduction
Sudden cardiac death (SCD) is often the first manifestation of an underlying coronary artery disease (CAD) and accounts for one out of every two deaths from cardiovascular disease Citation1. An acute coronary event has been considered to be the most common pathophysiologic mechanism leading to sudden cardiac arrest Citation1. Prevention of SCD caused by an acute coronary event has remained a challenge for clinicians since recognizable risk factors for this fatal consequence of an underlying CAD may be partly the same as those of a non-fatal coronary event. In fact, there is relatively little information available on possible differences in risk profiles between the subjects who survive and those who die suddenly during an acute coronary event.
We have designed this case-control study, Finnish Genetic Study of Arrhythmic Events (FinGesture) aimed at comparing genetic and various other factors between survivors and victims of SCD during an acute coronary event Citation2. For this study, we have collected a consecutive series of victims of SCD and survivors of an acute myocardial infarction (AMI) from the Oulu University Hospital District in northern Finland. Only subjects with an acute coronary event verified at medicolegal autopsy were included in the SCD group. We have previously reported the differences in the family history of SCD between these groups in a smaller sample of this population Citation2. In the present study we compared traditional coronary risk factors, cardiac hypertrophy and severity of CAD, between these two groups using the larger study population.
Key messages
There are specific features that differentiate the victims of sudden cardiac death (SCD) from survivors of an acute coronary event.
Clustering of several variables, such as family history of SCD, smoking, cardiac hypertrophy and three-vessel CAD are alarm signals of a very high risk of SCD.
Abbreviations
Materials and methods
The FinGesture study was started in 2000, after which all victims of sudden death autopsied at the Department of Forensic Medicine, University of Oulu, Oulu, Finland, were included in the study Citation2. At the end of April 2006, this study had records on 646 consecutive victims of out-of-hospital sudden death from a defined geographical area, i.e. Oulu University Hospital District in northern Finland. The qualifying criteria have been described in detail elsewhere Citation2. In short, of the out-of-hospital SCD victims, those with 1) a witnessed sudden death within 6 hours of the onset of the symptoms or within 24 hours of the time that the victim was last seen alive in a normal state of health, and 2) evidence of a coronary complication, defined as a fresh intracoronary thrombus, plaque rupture or erosion, intraplaque hemorrhage, or critical coronary stenosis (>75%) in the main coronary artery were included in the SCD group Citation3. Victims of SCD with other serious heart disease, such as severe valve disease or cardiomyopathy, were excluded. Also victims with evidence of non-cardiac causes and victims with mechanical causes of sudden death, such as a rupture of the myocardium and/or tamponade, extensive myocardial necrosis (>50%), rupture of entire papillary muscle, pulmonary edema, or any cause of death considered to be due to some reason other than ischemia-induced SCD, were also excluded. An end-point committee consisting of a forensic pathologist (M-LK), an experienced cardiologist (HVH), and the primary investigator (KK) defined the mode of death in each case. After the exclusions, 425 out of 646 victims of sudden death were defined to be due to an acute coronary event.
Consecutive AMI survivors (n=644) were recorded at the Division of Cardiology, University of Oulu from the same geographical area as the victims of SCD Citation2, Citation4. All SCD victims in this area have their autopsies at the same Department of Forensic Medicine, and all AMI patients in this area are hospitalized in the same University Hospital. Survivors of AMI were recruited to participate during the first 7 days after the diagnosis of AMI, which was confirmed by using the contemporary guide-lines existing at the beginning of the study. The qualifying diagnostic criteria and characteristics of the patients have previously been described in detail elsewhere Citation2, Citation4. Advanced age (>75 years) was used as an exclusion criterion in the AMI population Citation4.
Characterization of demographic variables and coronary risk factors were based on data obtained from the interviews with AMI survivors and the persons most closely related to the victim of SCD. Ascertainment of family history of SCD and AMI has been described earlier in a smaller sample size of the same study population Citation2. The severity of CAD was defined as the number of critically stenosed (>75%) main coronary arteries (left main, left anterior descending, left circumflex, or right coronary artery) obtained in autopsy or in coronary angiography. When coronary angiography had been performed within 3 months in relation to the AMI (225 patients, 35%), the results were included in the comparisons.
For AMI survivors, cardiac hypertrophy was defined by echocardiography using M-mode recordings under 2D guidance according to the recommendations of the American Society of Echocardiography (ASE) Citation5. Left ventricular mass (LVM) was calculated from the ASE measurements according to the corrected equation, and cardiac hypertrophy was defined when the ratio between the LVM and body surface area (BSA) was over 134 g/m2 for men and over 110 g/m2 for women Citation6–9.1 where IVS=end-diastolic interventricular septum thickness, LVID=end-diastolic left ventricular internal dimension, and PWT=end-diastolic posterior wall thickness.
2 by the Dubois Citationequation 8.
At autopsy, the total heart weight (THW) was measured. THW was indexed by dividing it by the BSA. These values were compared to normal values drawn from the population-based table for normal THW separately for women and men in a previous Mayo Clinic study Citation10. In this study the mean THW±2 SD plotted against BSA for 392 normal women and 373 normal men was reported. We used these data to identify the normal heart weight. The cut-off points for hypertrophy were estimated by line fitting using the least squares method for the given THW values exceeding +2 SD plotted against BSA separately for males and females.
The study complies with the Declaration of Helsinki, The Ethics Committee of the University of Oulu approved the study, and the subjects or a close relative of each deceased provided informed consent.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agreed to the manuscript as written.
Statistical analyses
Two-sided t test and chi-square analyses were used for comparisons between study groups. All analyses were performed with the Statistical Package for Social Studies version 12.0 (SPSS Inc, Chicago, Ill). Odds ratios (OR) and their 95% confidence intervals (CI), sensitivity, specificity, and predictive values of each variable were calculated. Analysis of variance was used to compare the significance of differences between more than two variables. Two-sided P-values <0.05 were considered significant. No corrections were applied for multiple parameter testing, and P-values close to 0.05 should be treated with caution.
Results
Demographic data and coronary risk factors are presented in . Of the common CAD risk factors, family history of SCD (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.0–2.2, P=0.03), male gender (OR 1.8, 95% CI 1.3–2.4, P<0.001), and current smoking (OR 2.0, 95% CI 1.5–2.6, P<0.001) were more common among the victims of SCD than AMI survivors. Interestingly, a history of hypercholesterolemia was less common in victims of SCD than survivors of AMI (OR 0.18, 95% CI 0.14–0.24, P<0.001). Similarly, a history of diabetes (OR 0.71, 95% CI 0.52–0.97, P=0.03) and previous myocardial infarction (OR 0.61, 95% CI 0.44–0.86, P=0.04) tended to be less common among the SCD victims. No differences in body mass index (BMI), family history of AMI, history of hypertension, or angina pectoris were observed.
Table I. Characteristics of the study subjects.
In SCD victims the mean THW was 497 g (±97 g) for males and 403 g (±97 g) for females. In survivors of AMI, the mean LVM was 274 g (±101 g) for males and 225 g (±95 g) for females. After indexing for BSA, cardiac hypertrophy was more common among the victims of SCD compared to AMI survivors (OR 3.0, 95% CI 2.3–3.9, P<0.001). History of hypertension was present in 55% of SCD victims and in 57% of AMI survivors with cardiac hypertrophy. In the analysis of other factors than hypertension as a cause of cardiac hypertrophy, the heart weight increased along with the number of critically stenosed coronary arteries. The mean THW was 429±80 g, 458±82 g, and 471±92 g in the normotensive SCD victims with one-, two-, and three-vessel CAD, respectively (P=0.027). A similar trend was observed in normotensive AMI survivors in whom the mean LVM was 243±64 g, 242±77 g, and 295±68 g according to one-, two-, and three-vessel CAD, respectively (P=0.06). Victims of SCD with a healed myocardial infarction at autopsy also had significantly higher THW (476±95 g) than subjects without signs of a previous infarction (436±89 g, P=0.002). No other factors were related to cardiac hypertrophy in either group.
The presence of critical stenosis in three coronary arteries was significantly more common among the SCD victims than in AMI survivors (47% versus 14%, respectively, OR 5.4, 95% CI 3.6–8.2, P<0.001). No significant differences in the location of the stenosis were observed in subjects with one-vessel CAD. In the comparison of victims of SCD to AMI subjects, it was noted that the affected artery was the left main artery in 4% versus 1% of cases (P=0.31), the left anterior descending in 59% versus 47% of cases (P=0.11), the left circumflex in 9% versus 16% of cases (P=0.13), and the right coronary artery in 32% versus 37% of cases (P=0.54).
shows the odds ratios for the combination of various risk factors. Formulation of the risk combinations was based on the clinical practice beginning with the patient history, followed by the factors requiring non-invasive and invasive testing, respectively. There was a cumulative increase of risk of being a SCD victim versus AMI survivor when more than one risk factor was present, the odds ratio being 44.3 (95% CI 8.0–246.7, P<0.001) in a current male smoker with a family history of SCD and cardiac hypertrophy. When the presence of three-vessel CAD was added to the other four significant risk factors, 15 patients were identified with all five risk factors present, and all of them had died suddenly (positive predictive value 100%). shows the sensitivity, specificity, and predictive accuracy of each variable and the combination of the variables in differentiating the patients who had died suddenly and those who had survived an acute coronary event.
Figure 1. Odds ratios for the combinations of risk factors showing the risk of sudden cardiac death from an acute coronary event. SCD=sudden cardiac death; CI=95% confidence interval.
Table II. Sensitivity, specificity, and predictive accuracy of the risk factors. Values are expressed as% (95% confidence interval).
Discussion
Family history of SCD, male gender, current smoking, cardiac hypertrophy, and three-vessel CAD were the most significant differences between the SCD victims and survivors of an acute coronary event in this case-control study. A combination of various risk factors yielded a high odds ratio and a high positive predictive value in separating the SCD victims from AMI survivors. Surprisingly, a history of hypercholesterolemia was less common among those who died suddenly during the acute coronary event
Risk factors of SCD in previous follow-up studies
Previous observational follow-up studies have identified several risk factors for SCD, such as left ventricular hypertrophy, age, serum cholesterol, smoking, relative weight, blood pressure, hematocrit, vital capacity, diabetic status, heavy alcohol drinking, changes in electrocardiography, and parental history of SCD Citation11–15. The majority of these studies, e.g. Framingham study, have compared victims of SCD to survivors Citation11. In studies where victims of SCD have been compared to those who have died due to non-sudden coronary disease death, only a few risk factors have shown an independent association with SCD. In the Paris Prospective Study, body mass index (BMI), diabetes status, and parental history of SCD was associated with SCD but not with fatal myocardial infarction Citation14, and in the study by Escobedo et al. current smoking was a specific risk factor for SCD Citation13. Only Wannamethee et al. examined cases of non-fatal AMI Citation12. They found a specific or particular association of elevated heart rate, heavy alcohol drinking, and the presence of cardiac arrhythmias to SCD when compared to non-sudden coronary disease death and non-fatal AMI. The role of risk factors has also been shown to operate differently in subjects with and without previous coronary heart disease Citation11, Citation12. In the Framingham study, only left ventricular hypertrophy and intraventricular block were predictors of SCD in men with a prior CAD, and hematocrit in women with a prior CAD Citation11. The low incidence of SCD in women has led to exclusion of women from many observational studies Citation12, Citation14, Citation15. However, results from the Framingham and Nurses’ Health studies indicate that women are subject to the same risk factors as men Citation16, Citation17.
To the best of our knowledge, there have been no carefully designed case-controlled studies, including autopsy-verified victims of SCD, that have evaluated the risk profiles, the severity of CAD, and cardiac hypertrophy, comparing victims of SCD and survivors of an acute coronary event. One evident difference between the previous studies and the present report is that we included only patients with unequivocal evidence of acute coronary event in our group of SCD victims. It is well known that many mechanisms other than acute coronary events can lead to a diagnosis of SCD when generally accepted definitions of SCD are used in epidemiological studies Citation18, Citation19. The present study was specifically designed to avoid this bias by including only those victims of SCD in whom there was evidence of an acute coronary event. In fact, a large proportion of patients were excluded from our study group of SCD victims after the autopsy data were assessed.
Male gender, family history, and smoking
Male gender, family history of SCD, and smoking have all been identified in several previous studies as risk factors for SCD. We also identified the same risk variables in our previous smaller study of the same population, where only individuals who had a SCD as their first manifestation of CAD were included Citation2. Males who were smokers and had a family history of SCD had a high odds ratio of being in the group of SCD victims in the present study.
Cardiac hypertrophy and severity of coronary artery disease
The present study confirms the previous results of cardiac hypertrophy as a risk factor for SCD Citation20, Citation21. Notably, the history of hypertension did not differ between the SCD victims and AMI survivors despite the higher incidence of cardiac hypertrophy among the SCD victims, suggesting that other factors in addition to hypertension which lead to cardiac hypertrophy may play an important role as risk factors of SCD. Similarly to the results by Burke et al., higher THW and LVM were observed in normotensive subjects, along with the number of critically stenosed coronary arteries, and in victims of SCD cardiac hypertrophy was associated with a healed infarct at autopsy Citation22. The role of the genetic factors and their interactions with the other variables leading to the hypertrophic response of the myocardium need to be addressed in future studies.
In accordance with the present findings, diffuse and advanced CAD has been a consistent finding in victims of SCD in previous autopsy studies Citation23, Citation24. Despite the similar, or even lower, overall coronary risk score, victims of SCD had more three-vessel CAD than AMI survivors, suggesting that factors which result in advanced CAD without the presence of common coronary risk factors may play an important role in the SCD, and genetic factors may play some role in this respect.
Hypercholesterolemia
The lower incidence of previously diagnosed hypercholesterolemia among the SCD victims was somewhat surprising compared to previous epidemiological follow-up studies. In the recently published study including subjects with a first ST-elevation AMI, elevated serum cholesterol level was also a less frequent finding among the subjects with a primary ventricular fibrillation than among those without life-threatening arrhythmias Citation25. Taken together, these results suggest that subjects who have hypercholesterolemia as an underlying risk factor for an acute coronary event are less likely to suffer the kind of event that evokes fatal arrhythmias.
Mechanisms of SCD
SCD is the simultaneous interplay of many factors, i.e. anatomic or functional substrate, transient initiating event, and distinct mechanisms acting in conjunction to trigger fatal arrhythmias Citation26. Comparing victims of SCD to survivors of AMI, it is important to evaluate how the possible risk factors can modulate these anatomical and functional substrates.
The presence of left ventricular hypertrophy has been related to a higher frequency and complexity of ventricular arrhythmias in several clinical studies Citation27–29. In animal models, left ventricular hypertrophy has been associated with longer action potential durations, increased dispersion of repolarization, and increased vulnerability to arrhythmia induction Citation30. The combination of silent myocardial ischemia and left ventricular hypertrophy seems to be independently associated with ventricular arrhythmias Citation29. In general, CAD is considered to be the most common underlying pathology in the fatal arrhythmias triggered by acute myocardial ischemia Citation1. Based on these results, it seems evident that both cardiac hypertrophy and three-vessel CAD independently increase the vulnerability of the myocardium to ventricular arrhythmias during an acute coronary event, and they act as potential pathways to fatal arrhythmias. In addition to the anatomic substrates, current smoking can modify the outcome of an acute coronary event by increasing the propensity towards arrhythmias and by affecting the acute thrombosis Citation13, Citation31, Citation32. The exact role of family history of SCD and hypercholesterolemia in the genesis of SCD at the time of the coronary event remains to be established in future studies.
Limitations
A potential limitation is that information on previous medical history is prone to both inaccuracy and missing data, particularly regarding the family history of SCD and exact smoking history form the victims of SCD. To minimize this bias, we used a standardized and comprehensive questionnaire to cover all possible existing information regarding the patient's history. While interpreting these results, it is also worth noting that the risk factor analysis was based on patient history reflecting the awareness of subjects’ personal risk profile in real life. For example, a high prevalence (∼30%) of unrecognized impaired glucose intolerance and diabetes has been detected in patients with acute myocardial infarction in previous studies Citation33–35. Similarly, silent unrecognized myocardial infarctions seem to be relatively common among the victims of SCD Citation23, Citation36. Finally, the time from onset of symptoms to SCD versus medical attention of AMI survivors could not be compared between the groups, because of the unawareness of the onset of symptoms in the majority of the victims of SCD.
Coronary angiography was performed only in one out of every three patients with AMI within a 3-month time-frame, making the comparison of the severity of CAD less reliable. Obviously, symptomatic patients with evidence of active ischemia underwent coronary angiography more often because of their clinical symptoms. Therefore, the present results may in fact underestimate the importance of the severity of underlying CAD as a risk factor for SCD. Due to the low frequency of coronary angiograms (35%) among the AMI survivors the finding has to be considered as a preliminary result for the further studies.
Cardiac hypertrophy was defined in different ways between the study groups. However, a previous study has confirmed the relatively good concordance of diagnosing cardiac hypertrophy from autopsy and echocardiography, respectively Citation7. Therefore, it is unlikely that the higher prevalence of cardiac hypertrophy among the victims of SCD is simply due to these methodological aspects.
Implications and conclusions
One challenge in the overall global problem of SCD is to identify the subjects at increased risk of SCD in the general population. The present results show that the risk of SCD at the time of an acute coronary event can be assessed by generally available methods. If a subject is a male smoker and has a family history of SCD, the risk of SCD is substantially increased. Echocardiography and coronary angiography should perhaps be performed with more liberal indications in these high-risk subjects to diagnose cardiac hypertrophy and severe CAD, in attempts to target more actively therapy to achieve regression of hypertrophy and adequate treatment of CAD. A history of hypertension and the presence of angina pectoris do not appear to be very helpful in identifying these high-risk individuals.
Acknowledgements
The present study was supported by the Foundation for Cardiovascular Research (Helsinki, Finland), and by the Sigrid Juselius Foundation (Helsinki, Finland).
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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