Periodic Reporting for period 1 - PREPARE (PREcision medicine to Prevent ARrhythmic Events in athletes)
Período documentado: 2024-01-01 hasta 2025-12-31
Sudden cardiac death in young athletes, although rare, has a major emotional and societal impact. In some cases, dangerous heart rhythm problems occur during intense training in people who otherwise appear healthy. One condition that may contribute to this risk is exercise-induced Long QT Syndrome (exiLQTS). Long QT Syndrome (LQTS) is a disorder of the heart’s electrical system in which the QT interval on the electrocardiogram is prolonged, increasing the risk of life-threatening arrhythmias. In most cases, LQTS is genetically mediated and the QT prolongation is persistent. In exercise-induced LQTS, however, the abnormal electrical pattern appears only during intense training and reverses with detraining. The mechanisms behind this phenomenon were largely unknown, creating uncertainty in clinical decision-making and risk assessment.
The PREPARE project aimed to uncover why some athletes develop exercise-induced QT prolongation and what are the potential targets for the future therapies. The project focused on the molecular and cellular mechanisms underlying cardiac function. To achieve this, PREPARE used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), a technology that allows to generate cardiomyocytes in the laboratory from individual athletes. This approach makes it possible to study athlete-specific cardiac cells under controlled “exercise-like” conditions in vitro.
The project combined multiple levels of analysis, including clinical data, advanced genetic testing, functional measurements of hiPSC-CMs electrophysiology and large-scale transcriptomic (gene expression) analysis.
By integrating these data, PREPARE generated new mechanistic insights into how exercise can trigger reversible electrical abnormalities. Although these discoveries are not immediately translated into clinical treatments, they provide a strong scientific foundation for improved risk stratification, future therapeutic development, and personalized approaches in cardiology.
The PREPARE project aimed to uncover why some athletes develop exercise-induced QT prolongation and what are the potential targets for the future therapies. The project focused on the molecular and cellular mechanisms underlying cardiac function. To achieve this, PREPARE used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), a technology that allows to generate cardiomyocytes in the laboratory from individual athletes. This approach makes it possible to study athlete-specific cardiac cells under controlled “exercise-like” conditions in vitro.
The project combined multiple levels of analysis, including clinical data, advanced genetic testing, functional measurements of hiPSC-CMs electrophysiology and large-scale transcriptomic (gene expression) analysis.
By integrating these data, PREPARE generated new mechanistic insights into how exercise can trigger reversible electrical abnormalities. Although these discoveries are not immediately translated into clinical treatments, they provide a strong scientific foundation for improved risk stratification, future therapeutic development, and personalized approaches in cardiology.
The PREPARE project successfully developed and validated an in vitro model to study exercise-induced Long QT Syndrome (exiLQTS) using affected athlete-specific hiPSCs and control hiPSCs from healthy athletes (six lines in total). hiPSCs were differentiated to cardiomyocytes and studied under various conditions. The project established experimental models of increasing complexity, ranging from single cardiomyocytes to cell monolayers and complex three-dimensional engineered heart tissues that better resemble real cardiac tissue. These models made it possible to reproduce the key feature of the disease: abnormal prolongation of action or field potentials (in vitro QT interval analogue) under exercise-like stimulation. Importantly, these differences were not present at baseline but appeared only under simulated training conditions, closely reflecting the clinical observations. This demonstrated that the disease phenotype could be reliably reproduced in vitro. Advanced functional measurements allowed the comparison of electrical activity and contraction in hiPSC-CMs. The results showed that cardiomyocytes from exiLQTS athletes responded differently to exercise-like stimulation, confirming altered electrophysiology and abnormal coupling between electrical excitation and mechanical contraction. To better understand these mechanisms, large-scale transcriptomic analysis were performed and integrated with the functional data. This approach identified molecular pathways linked to electrical remodeling, calcium handling, structural changes, and extracellular matrix regulation. Together, these results indicate that exiLQTS is a multifactorial condition involving both electrical and structural cardiomyocyte remodeling. All planned scientific objectives, milestones, and deliverables were achieved. The project generated a comprehensive and integrated dataset combining functional, genetic, and molecular information. Overall, PREPARE provided the first robust hiPSC-CM-based model of exercise-induced Long QT Syndrome and delivered important mechanistic insights. The results of the project were published in peer-reviewed journals or deposited on preprint platforms for early sharing.
PREPARE goes beyond the state of the art in several important ways. First, it established the unique multi-level hiPSC-CM model specifically designed to study exercise-induced Long QT Syndrome. Second, it demonstrated that this condition originates from complex interaction of genetic and acquired factors, involving both electrical and structural remodeling of cardiomyocytes. Third, it showed that laboratory-based electrophysiological measurements from patient-derived hiPSC-CMs can be linked to clinical risk prediction models, supporting the future development of personalized risk assessment tools. Further research and validation of these findings in independent cohorts are needed to confirm and extend these results.