Exercise Intensity and Cardiac Disease Development in carriers of Titin variants

Aims: While the exacerbating effect of physical exercise and its correlation with arrhythmic outcomes have been demonstrated for Arrhythmogenic Right Ventricular Cardiomyopathy, the impact of physical exercise on other forms of cardiomyopathies is poorly characterized. This study aimed to investigate the relationship between lifelong exercise intensity and the development of cardiac manifestations in subjects carrying a Likely Pathogenic (LP) or Pathogenic (P) truncating variant of titin (TTNtv). Methods: TTNtv carriers - patients and family members - were interviewed regarding their exercise habits from birth until diagnosis (type of activity, hours/week, weeks/months, months/years, and number of years of exercise). Those engaging in ≥4 hours of vigorous exercise per week (equivalent to ≥1440 METs×minutes/week) for a minimum of 6 years were classified as Athletes. All others were classified as Non-athletes.The correlation between vigorous physical activity and the development of left ventricular systolic dysfunction (LVSD), defined as left ventricular ejection fraction below 45% (LVEF <45%), was explored. Additionally, secondary endpoints included the occurrence of life-threatening ventricular arrhythmias (LTA - i.e., aborted cardiac arrest due to hyperkinetic arrhythmias, documented sustained ventricular tachycardia - SVT -, or appropriate implantable cardioverter-defibrillator therapy), non-LTA ventricular arrhythmias (i.e., >1000 premature ventricular complexes/24h and/or non-sustained ventricular tachycardia - NSVT), and the development of atrial fibrillation and/or atrial flutter (AF/AFL) during follow-up. Results: Among the 117 subjects (73% male, median age 45 - IQR 35-57 years), 38 (32%) were Athletes. Vigorous exercise was not associated with the development of LVEF <45% (adjusted OR 0.663, 95%CI 0.261-1.685, p 0.388), nor with the occurrence of LTA (p = 0.607), non-LTA (p = 0.648), and supraventricular arrhythmias (p = 0.701). Comparable results were obtained when considering the total amount of METs x hours/life burned by subjects as a continuous variable. Conclusion: In carriers of TTNtv, vigorous physical activity was not associated with LVSD and LTA development.