Implantable defibrillators and sudden cardiac death.

Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. It is estimated that more than 3 million people die yearly from SCD, with a survival rate of less than 1%. In the United States, the Center for Disease Control recently estimated an annual incidence of 450 000 sudden deaths,1 with a survival rate of approximately 5%, although this probably is an overestimation. Although there has been a reduction in total cardiac mortality from 728 115 in 1989 to 719 456 in 1999, the percentage of deaths that are sudden has actually increased from 38% to 47%. The increase was greatest in women older than 65 years of age, from 56.3% to 63.9%. This has resulted primarily from an increase in out-of-hospital sudden deaths. There is a comparable incidence of SCD and survival rate in Western Europe.2 The magnitude of this problem can be understood by noting that SCD accounts for more deaths each year than the total number of deaths from AIDS, breast cancer, lung cancer, and stroke (Figure 1). Unfortunately, it is the first presentation of cardiac disease in 33% to 50% of patients and is 3 times as common in men than in women. Coronary artery disease, with or without myocardial infarction, is by far the most common underlying disease for SCD in the western world, being responsible for approximately 75% of all SCDs.3,4 Cardiomyopathies (dilated and hypertrophic) and primary electrical heart disease account for most of the remainder. The two most important risk factors for SCD (ie, those with highest predictive value) are left ventricular ejection fraction (LVEF) less than 40% and clinical congestive heart failure.3,4 These are followed by significant ventricular arrhythmias (particularly nonsustained ventricular tachycardia [VT] or frequent ventricular premature complexes [VPCs]), ischemia, and left ventricular hypertrophy.3,4 The risk of mortality related to ejection fraction is nonlinear, with a marked increase beginning when the LVEF falls below 40%.4 The mortality in heart failure is bimodal. As one goes from class I to class IV heart failure, there is an increased annual risk of total mortality, whereas there is a decreased risk of SCD. Thus, in class II patients, more than half will die suddenly, whereas in patients with class IV heart failure, 10% to 40% will die of a cardiac arrhythmic event.4 The role of coronary artery disease and ischemia can never be underestimated. It has been known for nearly 20 years that surgical revascularization decreases the risk of SCD as well as total mortality in patients with 2and 3-vessel disease, particularly those who have low ejection fractions.3 The relationship of SCD to genetic abnormalities is under intense investigation.5,6 Although inherited disorders of lethal arrhythmias have been recognized, they make up a small proportion of SCDs. These include the long-QT syndromes, Brugada syndrome, and exercise-induced polymorphic VT. Specific genetic defects in ion channels or intracellular calcium handling have been identified. Mutations in cytoskeletal, contractile, and structural proteins also have been associated with SCD. What is evident is that genetic abnormalities alone cannot explain the occurrence or timing of SCD. Multiple factors regulate gene expression and function, including intracellular signaling proteins and environmental factors. Thus, phenotypic variability with the same genotype is commonly manifested by incomplete penetrance (eg, absence of long QT on ECG) or clinical course (eg, absence of arrhythmias). Just as disturbing is the fact that the same phenotype may be produced by several different genotypes (eg, long QT). The clinical problem in understanding the genetic basis for SCD is that it is a phenotypic expression of multiple factors. The observation that men die more often of SCD than women1–4 and that there is a familial tendency to SCD7 should promote more studies of the underlying molecular mechanisms for VT and ventricular fibrillation (VF). Understanding the mechanisms of the final common pathways of SCD would allow a better understanding of the specific interactions of proteins and external factors on the genetic substrate of individual patients.