Interaction Between Genotype, Phenotype, and Prognosis in Patients With Dilated Cardiomyopathy

BACKGROUND: Dilated cardiomyopathy (DCM) is a heterogeneous myocardial disease with variable clinical outcomes. Although both genetic variants and cardiac magnetic resonance (CMR)-derived fibrosis markers are associated with prognosis, their interactions and relative contributions to disease progression remain incompletely understood. OBJECTIVES: This study aims to explore the associations among genetic variants, CMR characteristics, and long-term prognosis in DCM. METHODS: The authors prospectively enrolled patients diagnosed with DCM who underwent whole-genome sequencing and CMR examination. DCM-associated genetic status was classified as TTN variant, non-TTN variant, and genotype-negative. CMR evaluation included cardiac structure and function, late gadolinium enhancement (LGE), and T1 mapping. Clinical outcomes included cardiovascular death/heart transplantation, sudden cardiac death, and arrhythmic events. RESULTS: Of the 837 enrolled patients, 163 (19.5%) carried pathogenic/likely pathogenic variants, including 78 (9.3%) non-TTN and 85 (10.2%) TTN variants. Patients with non-TTN variants demonstrated the greatest fibrosis burden, with higher LGE prevalence (69.2% vs 24.7% in patients with TTN variants and 46.6% in genotype-negative patients, P < 0.001), greater LGE extent, more frequent ring-like and subepicardial patterns, and higher native T1 and extracellular volume fraction (ECV) values. In multivariable Cox regression analysis, non-TTN variants independently predicted cardiovascular death/heart transplantation (adjusted HR: 2.39; 95% CI: 1.46-3.92; P < 0.001) and sudden cardiac death (adjusted HR: 3.26; 95% CI: 1.59-6.65; P = 0.001), together with left ventricular end-diastolic volume index, LGE, and ECV. Patients with non-TTN variants consistently had worse outcomes among patients with LGE presence, greater LGE extent, elevated ECV, and in both left ventricular ejection fraction strata (≤35% and >35%) (log-rank P < 0.05). Mediation analysis showed LGE (indirect HR: 1.26; 95% CI: 1.11-1.47; P = 0.008) and ECV (indirect HR: 1.29; 95% CI: 1.12-1.53; P = 0.006) partly mediated the association between non-TTN variants and adverse outcomes, whereas left ventricular end-diastolic volume index and left ventricular ejection fraction did not show significant mediating effects. CONCLUSIONS: Genetic background was associated with distinct myocardial fibrosis phenotypes and provided prognostic information beyond conventional CMR-derived fibrosis and functional phenotypes in DCM. Myocardial fibrosis partly mediates the association between non-TTN variants and adverse outcomes.