Genotype and left ventricular reverse remodelling in familial dilated cardiomyopathy with contemporary heart failure therapy - the ReaGEN study

Introduction

Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with a variable response to contemporary heart failure therapy. Left ventricular (LV) reverse remodelling is a key marker of treatment response and prognosis. Whether the degree of remodelling differs across specific causative genes in DCM remains incompletely defined.

Purpose

To compare LV reverse remodelling across genotypes in familial DCM in patients treated with contemporary heart failure therapy.

Methods

We conducted a multicentre retrospective cohort study of patients diagnosed with familial DCM between 2019 and 2024, according to European Society of Cardiology diagnostic criteria. Comprehensive clinical, laboratory, echocardiographic, and cardiac magnetic resonance data were collected at baseline and after initiation of guideline-directed medical therapy, with a minimum follow-up of 6 months. LV reverse remodelling was defined as an increase in left ventricular ejection fraction (LVEF) of at least 10 percentage points, assessed by echocardiography.

Results

A total of 171 patients were included, of whom 39.3% were female. At baseline, mean LVEF was 37.0 ± 11.3%, with a left ventricular end-diastolic volume index of 112.0 ± 50.7 mL/m². Left bundle branch block was present in 17.4% of patients, and median NT-proBNP was 816 pg/mL (IQR, 173–2714). A family history of DCM or premature sudden cardiac death was reported in 73.7%. The most frequently identified pathogenic or likely pathogenic variants were TTN (30.7%), followed by FLNC (11.0%), MYH7 (10.2%), LMNA A/C (10.2%), and DSP (6.3%).

Use of HF therapy was high: ACEi/ARB/ARNI in 90.6% (including ARNI in 58.3%), beta-blockers in 87.4%, MRAs in 81.9%, and SGLT2 inhibitors in 87.7%. ICD implantation was present in 32.2%.

Among patients with evaluable paired echocardiography (n=126), the median follow-up was 26.6 months. Overall, 37.3% met criteria for LV reverse remodeling. Remodeling rates differed across major genetic subgroups: TTN 35.9%, FLNC 28.6%, LMNA A/C 38.5%, MYH7 41.7%, and DSP 0%; patients with other causative genes represented by <5% evaluable cases each had remodeling in 47.5%.

Conclusion

In this multicentre familial DCM cohort treated with contemporary guideline-directed therapy, LV reverse remodelling (defined as an increase in LVEF ≥10% at >6 months follow-up) occurred in approximately one-third of the patients. Remodelling rates varied across major causative genes, with a particularly low response among DSP carriers, suggesting gene-specific remodelling patterns. Larger prospective studies are warranted to confirm these findings.Variation in LVEF by genotypeFor image description, please refer to the figure legend and surrounding text.