Key result
Digenic mutations in non-compaction cardiomyopathy are linked to ~38-fold higher odds of systolic dysfunction.
Why the study?
Structural and morphological data alone without a thorough clinical assessment do not determine non-compaction cardiomyopathy (NCM), motivating investigation of NCM-related genes, phenotypic and genetic correlations, and predictors of life-threatening ventricular tachyarrhythmias and adverse clinical outcomes.
Cohort (n=60)
Answers are grounded in this paper and cite their sources.
Reveals genetic and electrophysiological predictors of adverse outcomes in non-compaction cardiomyopathy, indicating that digenic mutations and fibrosis worsen prognosis.
Non-compaction cardiomyopathy (NCM) is a rare heart disease characterized by a two-layered ventricular wall, comprising a thinner compact epicardial layer and an inner non-compacted layer. However, only structural and morphological data without a thorough clinical assessment does not determine the NCM (regardless of the diagnostic criterion used).Aim. To study the NCM-related genes, phenotypic and genetic correlations, predictors of life-threatening ventricular tachyarrhythmias (VTA) and adverse clinical outcomes.Material and methods. Of 93 individuals with identified morphological criteria of NCM (median follow-up, 5 years), the study included 60 unrelated patients (38,5±13,8 years of age; men, 33 (55%); left ventricular ejection fraction (LVEF), 42,1±12,9%) with clinical verification of NCM (>1 obligate phenotypic trait). Adverse cardiovascular events were taken as the composite end point: life-threatening VTA, death, heart transplantation.Results. Pathogenic (or probably pathogenic) mutations were detected in 33 (55%) patients with NCM. The most common variants (57,9%) were identified in the sarcomere protein genes (TTN, MYBPC3, MYH7); digenic mutations were found in 21,6% of patients. Digenic mutations were associated with low LVEF and the highest risk of systolic dysfunction (OR, 38; 95% CI, 4,74-305; p=0,0001). Multivariate regression provided a predictive model (R=0,90; R2=0,81; F (5,41) =34,8; p<0,0001) and independent predictors of adverse clinical outcomes of NCM (genetic cause of the disease (pathogenic mutation), LV systolic dysfunction, myocardial fibrosis in 2 or more ventricular segments, and QRS prolongation. Regression and ROC-analysis identified electrical predictors of life-threatening VTA (fragmented QRS, QT prolongation, spatial QRS-T angle increase) and morphofunctional markers (myocardial fibrosis, systolic dysfunction).Conclusion. The study revealed a significant clinical and genetic heterogeneity of NCM with predominant mutations in the sarcomeric protein genes and determined the criteria for identification and prognosis of NCM.
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Vaikhanskaya et al. (2020) conducted a cohort in Non-compaction cardiomyopathy (n=60). Pathogenic genetic mutations (including digenic mutations) vs. Absence of pathogenic or digenic mutations was evaluated on Composite of adverse cardiovascular events (life-threatening ventricular tachyarrhythmias, death, heart transplantation) (OR 38 (for digenic mutations and systolic dysfunction), 95% CI 4.74-305, p=0.0001). Digenic mutations in non-compaction cardiomyopathy were associated with the highest risk of systolic dysfunction (OR 38; 95% CI 4.74-305; p=0.0001) and predicted adverse outcomes (p<0.0001).
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