Akhtar, Mohammed MajidLorenzini, MassimilianoCicerchia, MarcosOchoa, Juan PabloHey, Thomas MorrisSabater Molina, MariaRestrepo-Cordoba, Maria AlejandraDal Ferro, MatteoStolfo, DavideJohnson, ReneeLarrañaga-Moreira, José MRobles-Mezcua, AinhoaRodriguez-Palomares, Jose FCasas, GuillemPeña-Peña, Maria LuisaLopes, Luis RochaGallego-Delgado, MariaFranaszczyk, MariaLaucey, GemmaRangel-Sousa, DiegoBasurte, MaytePalomino-Doza, JulianVillacorta, EduardoBilinska, ZofiaLimeres Freire, JavierGarcia Pinilla, José MBarriales-Villa, RobertoFatkin, DianeSinagra, GianfrancoGarcia-Pavia, PabloGimeno, Juan RMogensen, JensMonserrat, LorenzoElliott, Perry M2023-02-092023-02-092020-09-23http://hdl.handle.net/10668/16299Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.encardiomyopathy, dilatedconnectinheart failurephenotypesexAdultAgedAged, 80 and overArrhythmias, CardiacCardiomyopathy, DilatedConnectinEuropeFemaleGenetic Predisposition to DiseaseGenetic VariationHeart FailureHumansLongitudinal StudiesMaleMiddle AgedNew South WalesPhenotypePrognosisRisk AssessmentRisk FactorsSex FactorsStroke VolumeTime FactorsVentricular Dysfunction, LeftVentricular Function, LeftVentricular Remodelingresearch article32964742open access10.1161/CIRCHEARTFAILURE.119.0068321941-3297https://www.ahajournals.org/doi/pdf/10.1161/CIRCHEARTFAILURE.119.006832