TY - JOUR
T1 - Sex Differences in Prognosis of Patients With Genetic Dilated Cardiomyopathy
AU - Stroeks, Sophie L V M
AU - Merlo, Marco
AU - Mora-Ayestaran, Nerea
AU - Jason, Max
AU - Tayal, Upasana
AU - Wang, Ping
AU - Cannatà, Antonio
AU - Sikking, Maurits A
AU - Dal Ferro, Matteo
AU - Peiro, Belen
AU - Willemars, Myrthe
AU - Hellebrekers, Debby M E I
AU - van Leeuwen, Rick E W
AU - Setti, Martina
AU - Gonzalez-Lopez, Esther
AU - Krapels, Ingrid P C
AU - Pio Loco Detto Gava, Carola
AU - van den Wijngaard, Arthur
AU - Henkens, Michiel T H M
AU - Iseppi, Manuela
AU - Raafs, Anne G
AU - Hoes, Martijn F
AU - van Empel, Vanessa P M
AU - Jones, Elizabeth A V
AU - Nabben, Miranda
AU - Taylor, Matthew
AU - Brunner, Han G
AU - Ochoa, Juan Pablo
AU - Dominguez, Fernando
AU - Lakdawala, Neal K
AU - Sinagra, Gianfranco
AU - Garcia-Pavia, Pablo
AU - Mestroni, Luisa
AU - Heymans, Stephane R B
AU - Verdonschot, Job A J
PY - 2025/11/1
Y1 - 2025/11/1
N2 - BACKGROUND: Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease, presenting diverse clinical phenotypes and outcomes based on the underlying gene affected. The influence of sex on the gene-specific long-term prognosis of patients with genetic DCM remains unclear. This study aims to determine the effect of sex on the long-term prognosis per underlying genogroup. METHODS: A retrospective cohort study was conducted using data from 4 international referral centers. Baseline and longitudinal clinical data of patients with DCM, with a median follow-up of 6.7 years (interquartile range, 3.5-11.9 years), were collected. The study included men and women with DCM who had undergone genetic testing. Patients were categorized into 7 genotype groups: cytoskeletal/Z-disk, desmosomal, nuclear envelope, motor sarcomeric, TTN, other genetic, and genotype negative. The main outcomes measured were left ventricular reverse remodeling, mortality, heart failure hospitalization, heart transplantation, and malignant ventricular arrhythmias. RESULTS: Among 1716 patients, 1130 (66%) were men and 510 (30%) had a (likely) pathogenic variant. Ventricular remodeling was gene-dependent in women, with TTN patients exhibiting the highest rate (P=0.003) and desmosomal patients the lowest (P=0.04) compared with the genotype-negative group. After a median follow-up of 6.7 years, 334 men (29%) and 140 women (24%) reached the primary end point. Men with a (likely) pathogenic variant had the poorest prognosis, showing a higher rate of major adverse events (adjusted hazard ratio, 1.48 [95% CI, 1.12-1.95]; P=0.02) and malignant ventricular arrhythmias (adjusted hazard ratio, 1.83 [95% CI, 1.16-2.88]; P=0.009) compared with genotype-negative women. Prognosis varied by gene in men (log-rank P<0.0001) but not in women (log-rank P=0.1). The cytoskeletal/Z-disk, desmosomal, and nuclear envelope groups had the worst prognosis in men. CONCLUSIONS: The genetic architecture and sex are critical predictors of left ventricular reverse remodeling and long-term prognosis in DCM. These factors should be integrated into individualized risk prediction models to enhance clinical outcomes in patients with DCM.
AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease, presenting diverse clinical phenotypes and outcomes based on the underlying gene affected. The influence of sex on the gene-specific long-term prognosis of patients with genetic DCM remains unclear. This study aims to determine the effect of sex on the long-term prognosis per underlying genogroup. METHODS: A retrospective cohort study was conducted using data from 4 international referral centers. Baseline and longitudinal clinical data of patients with DCM, with a median follow-up of 6.7 years (interquartile range, 3.5-11.9 years), were collected. The study included men and women with DCM who had undergone genetic testing. Patients were categorized into 7 genotype groups: cytoskeletal/Z-disk, desmosomal, nuclear envelope, motor sarcomeric, TTN, other genetic, and genotype negative. The main outcomes measured were left ventricular reverse remodeling, mortality, heart failure hospitalization, heart transplantation, and malignant ventricular arrhythmias. RESULTS: Among 1716 patients, 1130 (66%) were men and 510 (30%) had a (likely) pathogenic variant. Ventricular remodeling was gene-dependent in women, with TTN patients exhibiting the highest rate (P=0.003) and desmosomal patients the lowest (P=0.04) compared with the genotype-negative group. After a median follow-up of 6.7 years, 334 men (29%) and 140 women (24%) reached the primary end point. Men with a (likely) pathogenic variant had the poorest prognosis, showing a higher rate of major adverse events (adjusted hazard ratio, 1.48 [95% CI, 1.12-1.95]; P=0.02) and malignant ventricular arrhythmias (adjusted hazard ratio, 1.83 [95% CI, 1.16-2.88]; P=0.009) compared with genotype-negative women. Prognosis varied by gene in men (log-rank P<0.0001) but not in women (log-rank P=0.1). The cytoskeletal/Z-disk, desmosomal, and nuclear envelope groups had the worst prognosis in men. CONCLUSIONS: The genetic architecture and sex are critical predictors of left ventricular reverse remodeling and long-term prognosis in DCM. These factors should be integrated into individualized risk prediction models to enhance clinical outcomes in patients with DCM.
KW - genotype
KW - heart failure
KW - humans
KW - phenotype
KW - prognosis
U2 - 10.1161/CIRCHEARTFAILURE.124.012592
DO - 10.1161/CIRCHEARTFAILURE.124.012592
M3 - Article
SN - 1941-3289
VL - 18
SP - e012592
JO - Circulation-Heart Failure
JF - Circulation-Heart Failure
IS - 11
M1 - 012592
ER -