Low yield of genetic testing and predominance of males in athletes with ventricular arrhythmias and non-ischemic left ventricular scar

Abstract Introduction Non-ischemic left ventricular scar (NILVS) is a recognized substrate for ventricular tachycardia (VT) and sudden cardiac death (SCD) in athletes, detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR). The proposed etiologies include myocardial inflammation, genetically determined cardiomyopathies and exercise-induced myocardial damage. This study investigates athletes' clinical and genetic profiles with NILVS to enhance diagnostic and management strategies. Methods We retrospectively enrolled athletes evaluated at our sports cardiology clinic and diagnosed with NILVS via CMR. CMR was performed based on the presence of high-risk premature ventricular beats (PVBs) detected during exercise testing at pre-participation screening or because of sudden cardiac arrest (SCA). The screening protocol and indications to further testing was not influenced by gender. Genetic testing screened for 256 gene mutations linked to cardiomyopathies. Follow-up data included arrhythmic events and continuation of sports activities. Results We enrolled 40 athletes, including 35 men and 5 women, all diagnosed with NILVS, as evidenced by LGE in at least two myocardial segments with the subepicardial-mid myocardial distribution. Among the athletes, none of them had a history of myocarditis, 4 (10%) reported palpitations, while 1 had previous SCA and received an ICD. The remaining 33 (82.5%) were asymptomatic. Forty percent of athletes had minimal ECG alterations, and none of them had significant echocardiographic abnormalities. At exercise testing, all showed exercise induces PVBs, which were monomorphic RBBB-like in 43% and polymorphic in 57%. Genetic testing identified mutations in desmoplakin (2), filamin C (2), and RYR1 (1) in 13%of athletes, although 87% tested negative. All athletes with positive results had a family history of SCD or cardiomyopathy. Two additional athletes showed familial NILVS with negative genetic testing. The other 33 athletes had neither positive family history nor positive genetic testing. In 80% a beta-blocker therapy was started. At follow-up, 87% remained asymptomatic, 83% continued training according to our prescription. During the follow-up (median 21 months), 1 experienced appropriate ICD shocks and 1 sustained VT both with family history but negative genetic testing. Conclusions The frequent absence of a family history and pathogenic gene mutations suggests a predominant role for non-genetic factors in the pathogenesis of NILVS in athletes. Furthermore, the disproportionate male prevalence suggests a possible role of androgenic hormones. These findings underscore the necessity of further in-depth studies on a larger population sample other than a multidisciplinary approach to optimize diagnosis, management, and long-term outcomes in this population.