The most common clinical finding associated with sudden cardiac death is coronary artery disease () and approximately 80% of sudden cardiac deaths are attributed to this disease condition (5
). Based on our knowledge of the stages of the natural history of coronary artery disease, there are two major mechanisms of fatal ventricular arrhythmias. Acute coronary ischemia usually associated with plaque rupture and occlusion of one or more major coronary arteries is more likely to result in polymorphic ventricular tachycardia. It is likely that such patients have relatively normal LV systolic function or mildly depressed LV function. Those with ischemic cardiomyopathy following one or more myocardial infarctions are more likely to have monomorphic ventricular tachycardias resulting from re-entrant loops around areas of scarred myocardium. Either arrhythmia if untreated will eventually degenerate into ventricular fibrillation.
Previously silent coronary artery disease is likely to be the predominant disease condition contributing to sudden cardiac death in the general population.
Another 10–15% occur in patients who have cardiomyopathies such as hypertrophic cardiomyopathy, dilated cardiomyopathies, arrhythmogenic right ventricular dysplasia and the myocardial infiltrative diseases (sarcoid, amyloidosis). Given the ubiquitous nature of coronary disease, it is likely that there is significant overlap of this condition with the cardiomyopathies, i.e. there are patients who will have both conditions and it is likely that both etiologies contribute to risk of sudden cardiac death (). The remaining 5–10% are composed of either structurally abnormal congenital cardiac conditions (coronary anomalies, cyanotic/non-cyanotic diseases) or patients with structurally normal but electrically abnormal heart. It is likely that some proportion of these patients eventual develop structural heart disease if they survive their sudden cardiac arrest or this event is successfully prevented by an intervention (). Besides the relatively rare genetic diseases such as long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia, patients with autopsy-negative sudden cardiac death (no genetic abnormalities identified) may comprise a larger part of this subgroup than previously anticipated (9
). In fact, while this may not be true in all populations, Behr and co-workers estimated the incidence to be as high as 11/100,000, in a nationwide epidemiological survey of unexpected sudden cardiac death in England, UK, among healthy individuals aged 16–64 years (14
). The latter study did not evaluate all cases of sudden cardiac death in the general population – analysis was limited to cases of presumed sudden cardiac death that underwent postmortem evaluation by a sampling of coroners in the UK. Also the incidence is likely to be lower if older age groups, who experience most sudden cardiac deaths were included in this analysis. Subjects with sudden unexplained death have also been termed as having idiopathic ventricular fibrillation or sudden arrhythmic death syndromes (6
). It is possible that some proportion of these patients had heritable monogenic disorders such as the long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (6
). Defects in the SCN5A gene, also causing long QT syndrome 3 and the Brugada syndrome, have been reported in some cases of the sudden infant death syndrome (25
). A retrospective postmortem molecular analysis of sudden cardiac death with structurally normal heart was conducted from a sudden cardiac death autopsy series based at the Edwards Registry of Cardiovascular Disease in St Paul, Minnesota. Using a candidate gene-based approach, only 2 of 12 patients (17%) had identifiable defects among five candidate genes tested (13
). Behr and co-workers evaluated the families of 32 individuals with unexplained sudden cardiac death (15
). Seven of 32 families (22%) were found to have one of several heritable cardiac conditions – the long QT syndrome (n=4), an unidentified non-structural cardiac electrophysiological condition (n=1), myotonic dystrophy (n=1) and hypertrophic cardiomyopathy (n=1). However, in five of the seven probands that led to these families, a genetic abnormality could not be identified. In the Minnesota study, there was a family history of sudden cardiac death in only 3 of 18 cases (17%) – indicating that family history may be a reliable predictor of clinical risk for only a minority of SUD cases in the general population. Similar to overall sudden cardiac death, SUD seems to be more common in males (mean age range 24–32 years), with published autopsy series reporting 63–68% of affected subjects as males (23
). However, given the lower overall sudden cardiac death rates in females, SUD cases are likely to comprise a higher proportion of sudden cardiac death cases in women compared to men, particularly among younger adults. From the Edwards Registry 270-patient autopsy series of sudden cardiac death, the age-group 35–44 years contained 72 patients, of which 27 were women (32% of total women) and 45 men (24% of total men) (25
). Detailed cardiac pathologic examinations revealed significant gender-related differences in prevalence of SUD. There was a significantly higher rate of SUD in these younger women. Following detailed autopsy, cardiac pathologic examination and analysis of available clinical findings, 50% of women had sudden cardiac death of undetermined etiology compared to 24% of men 18 (). In a separate study of even younger women, clinical information was reviewed for 852,300 female army recruits, who entered basic military training from 1977 to 2001 (26
). During this period, there were 13 sudden cardiac death cases (median age 19 years, 73% African-American), occurring at a median of 25 days after arrival for training. Of these, eight recruits (53%) suffered SUD, and anomalous coronary origins were found in two (13%). Therefore, SUD was the leading cause of non-traumatic sudden death in young female recruits during military training. These findings suggest that the overall burden of SUD in younger women could be higher than anticipated.
Figure 5 Sex-based distribution of presumed etiologies of sudden cardiac death. These data represent comparisons between 27 women and 45 men ages 35–44 years. CAD, Coronary artery disease; CA, coronary artery; HCM, hypertrophic cardiomyopathy; WPW, Wolff-Parkinson-White (more ...)
It is worth mentioning that the importance of a careful postmortem histological examination in patients with sudden death and apparently normal heart cannot be underestimated (21
). Besides uncovering relatively mild structural manifestations of rare conditions such as arrhythmogenic right ventricular dysplasia, there is a possibility that novel phenotypes can be uncovered. From the autopsy series at the Edwards Registry described above, several patients with a heart that appeared structurally normal were found to have abnormalities consistent with idiopathic myocardial fibrosis on histologic examination. Following a detailed characterization of this phenotype in six patients (17
) we observed a diffuse but heterogeneous increase in myocardial collagen content with a predilection for the left ventricular inferior wall. The increase in collagen was exclusively interstitial, without evidence of myocyte necrosis or stigmata of myocarditis. Transforming growth factor-beta 1 was implicated as a mediator of idiopathic myocardial fibrosis but specific triggers as well as sub-cellular signaling pathways have yet to be determined.