Precision Cardiogenomics Offers Path to Stratify Sudden Cardiac Death Risk in Athletes

Sudden cardiac death (SCD) remains the leading medical cause of death in athletes under 35 years, often being the first manifestation of underlying cardiac disease in seemingly healthy individuals. While SCD occurs in approximately 1.3 per 100,000 in the general population, this risk escalates to 1 per 66,000 to 88,000 in young athletic populations, with even higher incidences in elite male soccer and basketball players. Current understanding of the pathophysiology underlying SCD in athletes is incomplete, limiting opportunities for tailored therapies and accurate risk stratification. Intense physical activity, with its rapid shifts in autonomic balance and persistent catecholaminergic drive, creates a vulnerable electrophysiological window in genetically susceptible myocardium, highlighting the urgent need for precision approaches.

This review synthesizes existing literature on precision cardiogenomics in athletes, aiming to elucidate the molecular pathways underlying disease penetrance and identify opportunities for improved risk stratification. The authors conducted a comprehensive analysis, drawing insights from 154 studies encompassing 987 molecular associations related to cardiac health and athletic performance. Evidence was rigorously categorized into Grades 1 through 4 based on methodological rigor, omics integration, reproducibility, and translational relevance to human physiology and disease models. The focus was on identifying genetic predispositions and molecular mechanisms that contribute to SCD risk during or immediately after intense physical activity, particularly those involving autonomic nervous system shifts and myocardial excitability in susceptible individuals.

The synthesis of current knowledge highlights that while clinical syndromes associated with SCD are increasingly recognized, the molecular pathways driving disease penetrance remain poorly understood. Exertion acts as a critical trigger, with rapid shifts in parasympathetic nervous system withdrawal followed by sympathetic nervous system activation increasing myocardial excitability and lowering the threshold for ventricular arrhythmias. The transition from peak exertion to early recovery is characterized by persistent catecholaminergic drive, dynamic shifts in repolarization reserve, and transient calcium handling instability, creating a highly vulnerable electrophysiological state. The review identified 59 molecular associations (Grades 1-2) with strong methodological rigor and translational relevance, underscoring the potential of precision cardiogenomics to unravel these complex interactions.

The risk of sudden cardiac death is magnified in young athletic populations, estimated at 1 per 66,000 to 88,000, with even higher incidences in specific populations such as elite male soccer and basketball players.

This suggests that genetic predispositions, combined with the physiological stress of exercise, are key determinants of SCD risk, necessitating a more granular, personalized approach to screening and prevention.