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Review
. 2026 Jun 10;27(12):5250.
doi: 10.3390/ijms27125250.

Precision Cardiogenomics in Athletes

Pari Goyal  1 , Alwaleed Aljohar  1   2 , Reid A Mitchell  1   3 , Nathaniel Moulson  1   3 , James McKinney  1   3 , Saul Isserow  1   3 , Zachary Laksman  1   3
Affiliations
Review

Precision Cardiogenomics in Athletes

Pari Goyal et al. Int J Mol Sci. .

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.

Keywords: athletes; cardiomyopathies; channelopathies; exercise; genomics; sudden cardiac death.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Physiological Adaptations and Pathological Remodeling in Response to Physical Activity. Balance between the cardiovascular benefits of regular exercise and the potential structural, electrical, and clinical risks associated with high-intensity training, especially for athletes predisposed to genetic cardiovascular diseases.
Figure 2
Figure 2
Common Inherited Causes of Sudden Cardiac Death (SCD) in Young Athletes. HCM—hypertrophic cardiomyopathy, ACM—arrhythmogenic cardiomyopathy, CPVT—catecholaminergic polymorphic ventricular tachycardia, LQTS—long QT syndrome, other inherited channelopathies, and the autonomic nervous system.
Figure 3
Figure 3
(a) Cardiomyopathy Mechano-transduction Map. Increased exercise load in individuals with specific gene mutation in sarcomere- or desmosome-associated proteins can cause disruptions in signaling pathways, including enhanced cross-bridge cycling, mitogen-activated protein kinase (MAPK) signaling, Wnt/β-catenin suppression, or transforming growth factor-beta (TGF-β) activation. These pathways trigger pathological remodeling of the heart, promoting hypertrophy, hypercontractility, adipogenesis, and fibrosis in the myocardium. (b) Channelopathy Mechano-transduction Map. Increased β-adrenergic stimulation, due to high-intensity exercise or stress, in individuals with mutated cardiac ions channels or ryanodine receptor 2 (RYR2), can lead to maladaptive cascade signaling. These pathways can trigger prolonged action potentials, low adaptability to load, impaired calcium handling, and calcium/calmodulin-dependent protein kinase II (CAMKII) activation, and together, these molecular changes contribute to spontaneous electrical pulses, and even more severe arrhythmias.
Figure 4
Figure 4
Framework for Exercise Participation in Athletes with Cardiovascular Disease. Key considerations for exercise and sports participation in individuals with genetic cardiovascular conditions (both phenotype-positive and phenotype-negative individuals). High-intensity exercise activates the sympathetic nervous system (SNS) and can act as a trigger for many signaling cascades, impairing structural and electrical cardiac function. Due to environmental factors, some individuals may express abnormalities, while others remain asymptomatic, resulting in their first manifestation as SCD.
Figure 5
Figure 5
Development of Technologies for SCD Prevention. Overview of emerging wearable technologies allowing real-time arrhythmia detection and timely intervention during exercise, enhancing athlete safety.
Figure 6
Figure 6
Strategies for SCD Prevention in Athletes. Key strategies for preventing SCD in athletes include advances in genetic testing to identify individuals at risk, the use of wearable technologies and artificial intelligence (AI) for real-time monitoring of specific substrate levels and signaling such as repolarization reserve, fibro-inflammatory activation, and exercise-triggered calcium handling instability, coordinated multidisciplinary care, and emergency preparedness to help improve survival chances during cardiac events.
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