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Circulation. 2018;138:e272–e391. DOI: 10.1161/CIR.0000000000000549 September 25, 2018 e283 CLINICAL STATEMENTS AND GUIDELINES 2.2.2 Population Subgroups and Risk Prediction Risk prediction for SCA and SCD is complex. Risk analysis is divided into 2 general categories: population risk prediction and individual risk prediction.S2.2.2-41,S2.2.2-50 Conventional epidemiological markers provide insight into probabilities for the development of ischemic heart disease within a general class of subjects, but adequately tested and validated profiles for SCA risk stratification of individuals in the general population do not presently exist. The challenge of defining SCA risk in individuals derives from a population model characterized by large numbers of events diluted into a very large denominator (Figure 1). The overall population can be subgrouped into categories based on integration of age, presence and extent of disease, and identification of small, high-risk subgroups within the large denominator general population. Increasing age is a strong predictor of risk for SCA, but it is not linear. Risk in the general population, over time, beginning at 35 years of age has been estimated at 1 per 1000 population per year, increasing from a risk <1000 at the younger end of that spectrum to a higher risk in the elderly.S2.2.2-41 However, an analysis of lifetime risk of SCD, derived from the Framingham data, suggested that the incidence of SCD decreases in later years, especially in people >75 years of age.S2.2.2-51 The data also suggested that SCD is uniformly more common in men than in women at all age groups. In contrast, the population of children, adolescents, and young adults has an overall annual risk of 1 per 100 000, and there is somewhat a higher risk of SCD at the younger end of that age range.S2.2.2-41 An ageassociated transition range, from the mid-20s to 35 to 40 years of age, is characterized by a steep increase in risk from that of the adolescent group to the middleaged group, corresponding to the emergence of ischemic heart disease. Although ischemic heart disease remains the most common underlying substrate associated with SCD, the incidence of ischemic heart disease-related SCD appears to be decreasing,S2.2.2-52 with various forms of cardiomyopathy associated with myocardial fibrosis and LV hypertrophy increasing.S2.2.2-53 In addition, a trend over time has suggested that out-of-hospital cardiac arrest patients who are admitted alive to a hospital are becoming more likely to have high-risk clinical profiles, as opposed to manifest disease.S2.2.2-54 The younger population—children, adolescents, and young adults—is affected by a series of disorders that manifest earlier in life, including the genetic structural disorders and cardiac channelopathies, myocarditis, congenital heart disease, and other rare disorders.S2.2.2-43 During the transition range, from the mid-20s to the mid-30s, causes of SCA and SCD include a lower proportion of inherited diseases and in- creasing proportion of ischemic heart disease (>40% of cases).S2.2.2-43 Despite the small progress that has been made in risk prediction of SCA and SCD, the greatest challenge is to identify the relatively small, high-risk subgroups concealed within the large general population who have no identified disease but are at risk of SCA as their first cardiac event (Figure 1).S2.2.2-50 3 MECHANISMS OF VA 3.1 Cellular Mechanisms and Substrates Mechanisms of VA include enhanced normal automaticity, abnormal automaticity, triggered activity induced by early or late afterdepolarizations, and reentry.S3.4-1–S3.4-3 Reentry requires a trigger to initiate the arrhythmia and a substrate to sustain it. The trigger may be a PVC, which may be due to automaticity. The substrate may be structural remodeling secondary to an underlying disease process, and often includes a scar secondary to a prior MI or surgical repair, or patchy fibrosis in the setting of cardiomyopathy or hypertrophy. Changes in ion channel or transporter function and/or expression and cell to cell coupling secondary to the underlying pathology may alter the initiation or propagation of the cardiac action potential. The electrophysiological substrate is dynamically influenced by a variety of factors including cardiac metabolism, electrolytes, signaling pathways and autonomic effects. Enhanced automaticity or abnormal automaticity causing VA may arise from subordinate pacemaker cells in the His-Purkinje system or ventricular myocardium. 3.2 Automaticity Normal automaticity results from phase 4 spontaneous depolarization of the transmembrane action potential arising from a normal resting potential, reaching threshold and initiating an action potential.S3.4-1,S3.4-3 An initiating current (If) is responsible for spontaneous phase 4 depolarization in the sinus node. The rate is determined by the integration of the maximum diastolic potential at the end of repolarization, the slope of phase 4 depolarization, and the threshold potential. In contrast, abnormal automaticity arises from a partially depolarized membrane potential that is usually close to the activation potential for calcium channels in the cell membrane.S3.4-1,S3.4-3 In the acute phase of an MI or during transient ischemia, increased extracellular potassium causes partial depolarization of the resting membrane potential creating injury currents between the infarcted/ischemic tissue and healthy myocardium. These injury currents may initiate spontaneous activity. In ischemia, abnormal automaticity may occur in both Downloaded from http://ahajournals.org by on October 7, 2026