LAUSR

The clinical outcomes of non-compaction cardiomyopathy (NCM) range from mild-symptomatic to progressive HF, arrhythmias, thromboembolism, and SCD. The genetic spectrum and clinical outcomes of verified NCM were investigated. The study enrolled 72 unrelated pts (aged 39.2±14.1 years; 43/59.7% male; LVEF 44.7±13.2%) with morphological signs of non-compaction myocardium, confirmed by any three accepted criteria: Echo (Jenni and Stöllberger), MRI (Petersen and Jacquier). During the follow-up 59,7±16,2 months, diagnosis of NCM has been revised by supporting diagnostic elements based on clinical evidence: a family history of cardiomyopathy, coexisting neuromuscular disorders, abnormal 12-lead ECG findings, presence of arrhythmias, heart failure or thromboembolic events. After exclusion 19 cases with isolated asymptomatic and reversible (athletic/peripartum) LVNC, a group (53 persons) for NGS (174 genes) was formed. All variants considered as pathogenic and likely pathogenic were confirmed by a Sanger sequencing. Forty-nine (likely) pathogenic variants were identified in 38/71,7% carriers (gene positive pts), including 27/50,9% pts with single variant and 11/20,8% pts with complex genotypes. The most prevalent mutations involved genes were TTNtv (11), MYBPC3 (8), LMNA (4), then MYH7 (3), and two each ILK, HCN4, LAMP2, RAF1, SDHA, RYR2. One mutation is found in the genes TAZ, HADHA, ACTC1, ACTN2, MYH6, DSP, SLC25A4, FBN1, BAG3, SCN5A, TBX20. Clinical features and adverse outcomes during follow-up were compared between groups of the gene-positive and gene-negative pts. Combined adverse clinical outcomes were taken as composite endpoints: death due to HF, SCD, HTx, life-threatening VTA (VT/VF, successful resuscitation, ICD discharges). To analyze composite endpoints, a multivariate regression analysis was performed with step-by-step exclusion. As a result, a prognostic model was constructed (R=0.89; R2=0.78; F=32.9; p<0.ehz748.05261) and independent predictors of adverse outcomes were identified: gene-positivity (β=0.45; p=0.ehz748.05261), 6MWT (β=−0.30; p=0.0002), PQ interval (β=0.23; p=0.0008), syncope history (β=0.29; p=0.ehz748.05263), mTWA (β=0.23; p=0.0005), LVDD (β=0.27; p=0.0001) and RVEF (β=−0.40; p=0.ehz748.05261). As a strongest factor of adverse outcome was gene-positivity, Kaplan-Meier survival curves were constructed. According to the Cox F-criterion (F=24.9) a high level of significance of differences to achieving combined endpoints in the groups (p=0.0001) was determined. These results show that NCM is basically a genetic disease with significant heterogeneity and predominant TTNtv mutations; the patients with (likely) pathogenic variants have a worse prognosis with an increased risk for the composite end point of death, transplantation, and defibrillator implantation. Genetic evaluation is an important for prediction and subsequent management NCM pts considering genetic status.