Prognostic implications of genotype findings in non-ischemic dilated cardiomyopathy: a network meta-analysis

Abstract Background Evidence on the relative impact of diverse genetic backgrounds associated with non-ischemic dilated cardiomyopathy (DCM) remains contradictory. Aim This study sought to synthesize the available data regarding long-term outcomes of different gene groups in DCM. Methods Electronic databases were systematically screened to identify studies reporting prognostic data on pre-specified gene groups. Those included pathogenic/likely pathogenic (P/LP) variants, truncating titin variants (TTNtv), lamin A/C mutations (LMNA), and desmosomal proteins. Outcomes were divided into composite adverse events (CAEs), major ventricular arrhythmic events (MVAEs) and heart failure events (HFEs). Random effects meta-analyses were conducted to quantify the pooled odds ratio (ORs) for each gene group. A frequentist network meta-analysis was executed to allow indirect within-gene group comparisons. Results Twenty-six studies comprising 7,255 genotyped DCM individuals were included. Patients with P/PL variants had a higher risk for CAEs [OR, 2.10 (95% CI, 1.67-2.65)], MVAEs [OR, 1.86 (95% CI, 1.52-2.26)], and HFEs [OR, 2.01 (95% CI, 1.08-3.73)] than genotype negative patients. The presence of TTNtv was linked to a higher risk for CAEs [OR, 1.78 (95% CI, 1.20-2.63)], but not MVAEs or HFEs. LMNA and desmosomal groups suffered a higher risk for CAEs, MVAEs, and HFEs compared to non-LMNA and non-desmosomal groups respectively (Picture 1). When genes were indirectly compared, the presence of LMNA resulted in a more detrimental effect that TTNtv, with respect to all composite outcomes but no significant difference was found between LMNA and desmosomal genes. Desmosomal genes harbored a higher risk for MVAEs compared to TTNtv (Picture 2). Conclusion Different genetic substrates associated with DCM result in divergent natural histories. Routine utilization of genetic testing should be employed to refine risk stratification and inform therapeutic strategies in DCM.Natural history of DCM based on genotypeNetwork meta-analysis of gene variants