Genotype-derived risk hierarchy in dilated cardiomyopathy

Background The risk of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF) in dilated cardiomyopathy (DCM) may vary by genotype.1 Comparative analyses remain limited. Purpose To compare clinical outcomes and risk predictors across genotypes. Methods Carriers of pathogenic/likely pathogenic variants in DCM-associated genes were identified from a dedicated database. Clinically affected variant-carriers from the five most prevalent genotypes were compared with genotype-negative patients for a composite primary endpoint of MVA or ESHF. Incidence rates for the primary endpoint were calculated. Results The cohort comprised 484 patients: 254 genotype-negative patients and 101 TTN, 57 DSP, 39 LMNA, 18 RBM20 and 15 FLNC variant-carriers. Fifty-seven (11.8%) met the primary endpoint after 5 years. Genotype-negative patients had the lowest rates of the primary endpoint (1.4 [0.7–2.1] per 100 person-years), whereas LMNA had the highest (6.2 [3.0–9.5]). With a genotype-negative reference, incidence rate ratios were 1.3 for TTN, 1.7 for FLNC, 2.0 for DSP, 2.7 for RBM20 and 4.4 for LMNA (Figure 1). Rates were higher in LMNA and RBM20 than genotype-negative patients (p <0.001 and p = 0.003, respectively) and higher in LMNA than TTN (p = 0.001) (Figure 2). Conclusion Genotype stratification in DCM reveals a risk hierarchy with risk lowest in genotype-negative and TTN patients, two-fold higher in DSP and FLNC, and three- and four-fold higher in RBM20 and LMNA, respectively. Accounting for genotype improves risk prediction.