Precision Cardiogenomics in Athletes

Q: What is the clinical evidence from this study?

Study design: Review. Population: Sudden cardiac death in athletes with inherited cardiovascular disorders. Intervention: Intense exercise.

Q: What does this research mean for the field?

The intersection of inherited cardiovascular genetic variants and exercise-induced physiological remodeling drives sudden cardiac death in athletes, necessitating integrated genomic and molecular approaches for precise risk stratification. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Pari Goyal; Alwaleed Aljohar; Reid A. Mitchell; Nathaniel Moulson; James McKinney; S. Isserow; Zachary Laksman

doi:10.14288/1.0453064

July 3, 2026Open Access

Precision Cardiogenomics in Athletes

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Key result

Intense exercise interacts with underlying inherited cardiovascular disorders to modulate disease penetrance and increase the risk of sudden cardiac death in athletes.

Why the study?

Sudden cardiac death in athletes often represents the first manifestation of an inherited cardiovascular disorder unmasked by exercise, requiring a clearer understanding of the molecular pathways linking genotype to arrhythmogenic phenotype to refine risk stratification.

Key Points

To examine the molecular mechanisms connecting inherited cardiovascular genotypes to arrhythmogenic phenotypes and sudden cardiac death under athletic physical stress.
Narrative synthesis of molecular architecture across inherited conditions including hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, and channelopathies.
Evaluation of biomechanical loading, adrenergic stimulation, calcium handling abnormalities, and signaling crosstalk intersecting with exercise-induced cardiac remodeling.
Assessment of translational tools including polygenic risk scores, digital phenotyping, and shared decision-making frameworks.
Mechanical strain in desmosomal arrhythmogenic cardiomyopathy triggers Hippo signaling, suppresses canonical Wnt/beta-catenin pathways, and activates TGF-beta to accelerate fibrofatty replacement and ventricular arrhythmias.
Adrenergic stress exacerbates impaired repolarization currents in type 1 long QT syndrome and destabilizes the ryanodine receptor 2 complex in catecholaminergic polymorphic ventricular tachycardia, provoking delayed afterdepolarizations via calcium leak.
Current molecular pathways are predominantly characterized in experimental models rather than athlete cohorts, requiring careful individualized clinical assessment rather than prescriptive clearance algorithms.

Structured PICO

P

Population

Athletes at risk of sudden cardiac death due to underlying inherited cardiovascular disorders, including hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), long QT syndrome (LQTS), and catecholaminergic polymorphic ventricular tachycardia (CPVT).

This review provides a mechanistic framework linking the molecular pathogenesis of inherited cardiac conditions to exercise-induced remodeling, aiding in risk stratification for sudden cardiac death in athletes.

Limitations

Much of the evidence linking inherited cardiovascular disease, exercise exposure, and sudden cardiac death risk is observational.
Randomized trials are generally not feasible for rare, potentially lethal conditions.
Estimates are limited by referral bias, survivor bias, heterogeneous ascertainment, and variable definitions of athletic exposure.
Many molecular pathways discussed are derived from experimental models rather than athlete-specific prospective cohorts.
Emerging tools such as polygenic risk scores, wearable monitoring, and artificial intelligence remain incompletely validated in athlete-specific populations.
Randomized trials are generally not feasible for rare, potentially lethal conditions, and event rates are low even in higher-risk cohorts.
Many molecular pathways discussed are derived from experimental models, animal studies, and mechanistic human studies rather than athlete-specific prospective cohorts.
Emerging tools such as polygenic risk scores, wearable monitoring, and artificial intelligence remain incompletely validated in athlete-specific inherited cardiovascular disease populations.

Implication

May warrant enhanced screening for inherited disorders in athletes; leaves open prospective validation of molecular pathways.

Abstract

Sudden cardiac death (SCD) in athletes often represents the first manifestation of an underlying inherited cardiovascular disorder exposed by adrenergic stress, altered calcium cycling, mechanical loading, and metabolic demand during intense exercise. This review focuses on the molecular architecture that links genotype to arrhythmogenic phenotype in athletes, emphasizing sarcomeric force generation and energetic inefficiency in hypertrophic cardiomyopathy, desmosomal failure and Hippo/Wnt/transforming growth factor-beta (TGF-β) signaling in arrhythmogenic cardiomyopathy, and ion-channel and calcium/calmodulin-dependent protein kinase II (CaMKII)calcium handling abnormalities in inherited channelopathies. This review further examines how exercise-induced physiological remodeling intersects with these pathways through insulin-like growth factor-1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling, mitochondrial biogenesis, oxidative stress, inflammatory signaling, and epigenetic regulation. Attention is given to the molecular basis of genotype-positive/phenotype-negative states, variable penetrance, and exercise-mediated disease expression. Finally, the integration of molecular biology with genomic data, polygenic risk, and emerging digital phenotyping is discussed to refine mechanism-based risk stratification and identify future therapeutic targets for prevention of SCD in athletes.

Discussion

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Cite This Study

Goyal et al. (2026) conducted a review in Sudden cardiac death in athletes with inherited cardiovascular disorders. Intense exercise was evaluated. Intense exercise interacts with underlying inherited cardiovascular disorders to modulate disease penetrance and increase the risk of sudden cardiac death in athletes.

synapsesocial.com/papers/6a49f4b8f5d1d45b28800010 https://doi.org/10.14288/1.0453064

View Full Paper

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Precision Cardiogenomics in Athletes

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Precision Cardiogenomics in Athletes

Key Points

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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