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

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.

This study aims to explore the associations among genetic variants, CMR characteristics, and long-term prognosis in DCM.

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.

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.

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.