Clinical stratification of genotype group in dilated cardiomyopathy
S Inoue, T Hiruma, S Nomura, I KomuroAbstract
Background
Genetic architecture is a major determinant of clinical course in dilated cardiomyopathy (DCM). The Madrid Genetic Score (MGS) was developed in European cohorts to predict the presence of pathogenic variants in DCM.(Ref: 1) Because clinical trajectories differ according to the affected gene (Ref: 2 and 3), accurate prediction of both variant positivity and high-risk genotype groups may improve prognostic assessment and cascade screening.
Purpose
We aimed to validate the MGS in non-European patients with DCM and to identify clinical predictors of genotype groups stratified by prognostic impact.
Methods
Patients with clinically diagnosed DCM who underwent genetic testing were included from a Japanese multicenter cohort. Pathogenic variant carriers were defined as genotype-positive. The MGS (range, 0–5) was calculated using five clinical variables: family history of DCM, skeletal myopathy, low limb-lead QRS amplitude, absence of hypertension, and absence of left bundle branch block (LBBB). Predictive performance was assessed using the area under the receiver operating characteristic curve (AUROC). Genotype-positive patients were classified into sarcomere, arrhythmogenic, and other gene groups. Sarcomere genes consisted of TTN, MYH7, TNNT2, MYBPC3, TPM1, ACTC1, and TNNC1, and arrhythmogenic genes consisted of LMNA, DSP, DSG2, FLNC, RBM20, TMEM43, EMD, and PLN. Logistic regression analysis was performed to assess associations between genotype groups and clinical features.
Results
The cohort comprised 738 patients with DCM, of whom 280 (37.9%) carried pathogenic variants. Genotype-positive patients more frequently had a family history of DCM and skeletal myopathy, whereas hypertension and LBBB were less common (all P < 0.001). The AUROC of the MGS was 0.78. The arrhythmogenic group exhibited the highest incidence of all-cause death, malignant ventricular arrhythmias, and end-stage heart failure (overall P < 0.001, Figure 1). Left ventricular hypertrabeculation was most prevalent in the sarcomere group. Atrioventricular block (AVB) was less frequent in the sarcomere group and more common in the arrhythmogenic group (4.9% vs. 28.1%, P < 0.001). Multivariable analysis demonstrated that MGS score, hypertrabeculation, and absence of AVB independently predicted the sarcomere genotype, whereas MGS score and AVB independently predicted the arrhythmogenic genotype (all P < 0.001). Bootstrap analysis, calibration plots, and decision curve analysis supported the incremental value of these predictors (Figure 2).
Conclusions
The MGS demonstrated reasonable performance in an East Asian population. Incorporating AVB and hypertrabeculation refined stratification of high-risk genotype groups, with hypertrabeculation particularly associated with the sarcomere genotype.Kaplan-Meier curveFor image description, please refer to the figure legend and surrounding text.Decision curve analysisFor image description, please refer to the figure legend and surrounding text.