Subclinical Myocardial Phenotype in Genotype-Positive Relatives Attending Clinical and Genetic Screening for Familial Dilated Cardiomyopathy

Abstract Aim To investigate if asymptomatic relatives carrying genetic variants associated with familial dilated cardiomyopathy (DCM) show early signs of myocardial disease assessed by echocardiography. Methods and Results Asymptomatic relatives without a DCM-phenotype (n=176, 46% males, mean age 39 years ± 16) of 111 DCM index patients carrying likely pathogenic or pathogenetic variants in TTN, RBM20, and FLNC genes were recruited from two tertiary referral centers for inherited cardiac diseases. All participants underwent echocardiographic examinations focusing on left ventricular (LV) ejection fraction (LVEF), LV global longitudinal strain (LVGLS), and LV end-diastolic diameter (LVEDD), with operators blinded to genetic results. The participants were grouped into genotype positive ([G+], n=82) or genotype negative relatives ([G-], n=94) carrying or not carrying the disease-causing variant. The G+ group had significantly lower systolic LV parameters compared to G- individuals with a mean LVGLS of -18.7% ± 2.4 versus -20.1% ± 2.8, p: 0.0029; and a mean ejection fraction of 57.8% ± 3.7 versus 59.7% ± 2.4, p: <0.0001. The proportion of G+ individuals with an abnormal LVGLS (defined as less than -18%) was 46% compared to 18% in the G- group. 26 % of G+ individuals had an LVEF in the interval between 50 - 55% compared to of 5% G- individuals[MOU1] . Mean LVEDD did not differ significantly between G+ and G-groups (49.7 mm ± 4.9 versus 48.8 mm ± 4.7). However, LVEDD indexed to BSA were significantly increased in G+ individuals (26.7 mm/m2 ± 2.8 versus 25.4 mm/m2 ± 2.5, p-value 0.001). Conclusion Overall, the absolute mean values of LVGLS, LVEF, and LVEDD were within normal ranges in both G+ and G- groups of individuals. However, compared to non-carrier relatives, almost half of the asymptomatic G+ DCM relatives had signs of subclinical myocardial dysfunction with significantly lower values of LVGLS, LVEF, and larger left ventricular dimensions.