Mora-Ayestarán, NereaOchoa, Juan PabloGómez-González, CristinaNavarro-Peñalver, MarinaGallego-Delgado, MaríaLarrañaga-Moreira, José MRobles-Mezcua, AinhoaBasurte-Elorz, María TeresaRodriguez-Palomares, Jose FernandoCliment-Paya, VicenteJiménez-Jaímez, JuanMogollón-Jiménez, Maria VictoriaGarcía-Granja, Pablo ElpidioGarcía-Álvarez, AnaPeña-Peña, María LuisaAlvarez Barredo, MaríaRipoll-Vera, TomasPalomino-Doza, JuliánBayes-Genis, AntoniTirón, ColomaFernández, Ana IsabelSabater-Molina, MaríaToranzo, InésCrespo-Leiro, María GDoncel-Abad, VictoriaLacuey-Lecumberri, GemmaLimeres-Freire, JavierGarcía-Álvarez, Maria ICabrera-Borrego, EvaKounka-Ait El Maalem, ZinebVilches, SilviaGonzález-López, EstherVillacorta, EduardoGarcía-Pinilla, José MBarriales-Villa, RobertoGimeno-Blanes, Juan RamónGarcia-Pavia, PabloDomínguez, Fernando2025-12-152025-12-152025-08-29Eur Heart J. 2025 Aug 29:ehaf605.https://hdl.handle.net/20.500.12105/27035Certain genetic forms of dilated cardiomyopathy (DCM) entail a higher arrhythmic risk. It is unknown whether DCM patients with high-risk arrhythmic genotypes also develop more advanced heart failure (AHF) complications. AHF events were studied according to DCM genotype. Clinical data from 1203 genotyped DCM patients were collected from 19 Spanish centres. Patients were classified into high-risk arrhythmic genotypes (LMNA, FLNC, desmosomal genes, PLN, TMEM43, RBM20), TTN, other genes, and genotype negative (Gen-). The primary endpoint was a composite of AHF events (ventricular assist device implantation, heart transplant, and AHF-related mortality). The secondary endpoint was a combination of malignant ventricular arrhythmias (MVA). A DCM-causing variant was identified in a high-risk arrhythmic gene in 185 patients (15.4%), 193 (16.0%) had variants in TTN, 134 (11.1%) in other genes, and 691 (57.4%) were Gen-. After a median follow-up of 5.7 years (interquartile range 2.9-9.1 years), AHF events occurred in 45 (24.3%) patients in the high-risk arrhythmic group, while in 25 (18.7%), 25 (13.0%), and 70 (10.1%) patients with other genotypes, TTN, and Gen-, respectively (hazard ratio 1.85, 95% confidence interval 1.31-2.61 for high-risk arrhythmic genes compared with other groups). MVA occurred in 55 patients (29.7%) (hazard ratio 2.52, 95% confidence interval 1.81-3.51 for high-risk genotypes vs other groups). High-risk arrhythmic genotype was the main independent predictor of AHF in multivariate analysis. High-risk arrhythmic genotype and late gadolinium enhancement were independent predictors of MVA. Patients with high-risk arrhythmic genotypes also experience more AHF events, supporting a differential therapeutic approach in this group of patients beyond sudden death prevention.This work was supported by grants from Instituto de Salud Carlos III ‘PI20/0320’ (co-funded by European Regional Development Fund/ European Social Fund ‘A way to make Europe’/‘Investing in your future’). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, Hospital Clínic, Hospital Vall Hebron, Hospital Virgen del Rocío, Hospital Universitario Gregorio Marañon, and the Hospital Universitario Virgen de la Arrixaca are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart. P.G.-P. and F.D. were funded by the Pathfinder Cardiogenomics Programme of the European Innovation Council of the European Union (DCM-NEXT project; project 101115416).engVoRhttp://creativecommons.org/licenses/by-sa/4.0/Dilated cardiomyopathyGenesHeart failurePrognosisSudden cardiac deathAttribution-ShareAlike 4.0 International40878535EUROPEAN HEART JOURNALopen access