802 diagnostic yield and predictive value on left ventricular reverse remodeling of genetic testing in dilated cardiomyopathy

Abstract Background Genetic testing is one essential element in the diagnostic workup of patients with idiopathic dilated cardiomyopathy (DCM), and genotype-phenotype correlations are still poorly understood. We assessed the diagnostic yield of genetic testing in a selected DCM cohort including both familial and nonfamilial cases and evaluated phenotypic differences and the relationship of left ventricular reverse remodeling (LVRR) with the presence of pathogenic (P) or likely pathogenic (LP) variants of disease-associated DCM genes. Methods From 680 outpatients with heart with reduced ejection fraction followed at our Heart Failure Outpatient Clinic we selected subjects with a diagnosis of DCM before 65 years of age and without secondary causes of DCM including ischemic, valvular, hypertensive, or drug-induced heart disease or myocarditis. All patients underwent extensive clinical, laboratory, and imaging evaluation at the time of diagnosis and during regular follow-up visits and were offered genetic investigations with Next Generation Sequencing (NGS) of 42 disease-associated DCM genes. Results Of 680 DCM outpatients, 70 fulfilled the definition of idiopathic DCM and 66 gave consent to undergo genetic investigation (median age at diagnosis 57 years, 68% males). A total of 18 pathogenic/likely pathogenic (P/LP) variants were identified in 16 patients (diagnostic yield 24%), the most common (7, 39% of all variants) involving the TTN gene, followed by lamin A/C (n=3), cytoskeleton Z-disk (n=3), motor sarcomeric (n=2), desmosomal (n=1), and ion channel (n=1) gene variants. At the time of DCM diagnosis, patients with P/LP had a higher left ventricular (LV) ejection fraction (LVEF) compared with subjects (31±11% vs 28±8%, p=0.17). After a median follow-up of 53 (IQR 20-111) months, P/LP-positive patients had lower systolic and diastolic blood pressure and higher plasma natriuretic peptide levels than patients without P/LP variants. Patients without P/LP variants exhibited a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, p=0.0008) and decrease in LVEDDi (-3 vs. -1 mm/m2, p=0.03) compared with subjects carrying P/LP variants (Figure). Conclusions Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer left ventricular reverse remodeling in response to guideline-directed medical therapy.