Early identification of risk factors for sudden cardiac death

Abstract

Sudden cardiac death (SCD) is a global health issue. The unexpected nature of this devastating condition compounds the urgency of discovering methods for early detection of risk, which will lead to more effective prevention. However, the complex and dynamic nature of SCD continues to present a considerable challenge for the early identification of risk factors. Measurement of the left ventricular ejection fraction (LVEF) is currently the only major risk factor used for stratification in clinical practice. Severely decreased LVEF is likely to manifest late in the natural history of SCD, however, and may only affect a small subgroup of patients who will suffer SCD. A growing body of literature describes novel risk markers and predictors of SCD, such as high-risk phenotypes, genetic variants and biomarkers. This Review will discuss the potential utility of these markers as early identifiers of risk, and suggests a framework for the conduct of future studies for the discovery, validation, and deployment of novel SCD risk factors.

Figure 1. Contribution of severe LV systolic dysfunction to SCD in the general population

Findings from the Oregon Sudden Unexpected Death Study. Measured by LVEF≤35% and currently the risk predictor most widely used in clinical practice, severe LV dysfunction affects less than a third of all cases of sudden cardiac death in the general population. Abbreviations: SCD, sudden cardiac death; LVEF, left ventricular ejection fraction. Figure modified by permission of Progress in Cardiovascular Diseases ©2008.

Figure 2. Risk factors associated with SCD in patients with coronary artery disease

This schematic focuses on the subgroup of patients with CAD who suffer SCD; the complexity of the SCD phenotype presents considerable challenges for the discovery of risk factors early in the natural history of the condition. Abbreviations: CAD, coronary artery disease; HTN, hypertension; LVH, left ventricular hypertrophy; LVSD, left ventricular systolic dysfunction; SCD, sudden cardiac death.

Figure 3. Electrocardiographic patterns in genetically distinct forms of the long QT syndrome

ECG recordings from leads II, aVF, and V5 in three patients from families with long QT syndrome linked to genetic markers on chromosomes 3, 7, and 11. Chromosome 3, 15-year-old boy (family 1) with a mutation in the cardiac sodium channel gene SCN5A; the QTc in lead II is 570 ms with late-onset T waves of normal duration and amplitude. Chromosome 7, 21-year-old woman (family 3); the QTc in lead II is 583 ms with low-amplitude T waves. Chromosome 11, 31-year-old woman (family 6); the QTc in lead II is 573 ms with early onset of broad-based T waves. Abbreviation: QTc, corrected QT interval.

Figure 4. Electrocardiographic findings and manifestation of arrhythmia in the Brugada syndrome

(A) Twelve-lead electrocardiogram of a patient with the Brugada syndrome. The right precordial leads, V1 to V3, display a down-sloping ST segment elevation. QRS is normal but QT dispersion between V2 and V6 is larger than normal (120 ms). (B) Self-terminating polymorphic ventricular tachycardia (continuous recording) in a patient with the Brugada syndrome. Closely coupled premature ventricular contractions precede the onset of tachyarrhythmia. Note the disappearance of the repolarization abnormalities following the arrhythmia.

Figure 5. Schematic of genome-wide association study design

(1) Appropriately matched cases and controls are subjected to genome-wide SNP genotyping (shown here using Affymetrix chips), (2) SNP allele frequencies are compared to identify regions associated with disease, (3) disease-associated regions are scanned for known functional elements and cross-species comparisons can be used to identify unknown regulatory elements, and (4) direct sequencing of functional elements to identify causal variants. Abbreviation: SNP, single nucleotide polymorphism

Figure 6. Survival curves (free of sudden cardiac death) stratified by the protective rs3864180 genotype

In the combined Atherosclerosis Research in Communities and Cardiovascular Health Study cohort, Cox proportional hazards model was adjusted for age, sex, and race/ethnicity. Individuals homozygous for the protective allele (GG) are shown in green, heterozygotes (AG) in blue, and homozygous for the risk allele (AA) are in red.

Figure 7. Kaplan-Meier SCD-Free Curves after Cardiac Metaiodobenzylguanidine Imaging

(Left) Left ventricular ejection fraction (LVEF) >35%. (Right) LVEF 35%. Abbreviation: WR, washout rate of cardiac metaiodobenzylguanidine.

Figure 8. Development of an early detection risk score for SCD

The discovery of novel genetic variants and biomarkers, and the advancement of molecular imaging, will allow the development of an early detection risk score. The score will predict an individual’s likelihood of suffering SCD. Abbreviation: SCD, sudden cardiac death.