Sex Differences in Prognosis of Patients With Genetic Dilated Cardiomyopathy

Sophie L V M Stroeks^{1

2

3

4}, Marco Merlo^{4

5}, Nerea Mora-Ayestaran^{4

6}, Max Jason⁷, Upasana Tayal^{8

9}, Ping Wang^{3

4}, Antonio Cannatà^{4

5

10

11}, Maurits A Sikking^{1

4}, Matteo Dal Ferro^{4

5}, Belen Peiro^{4

6}, Myrthe Willemars¹², Debby M E I Hellebrekers^{3

4}, Rick E W van Leeuwen¹, Martina Setti^{4

5

13}, Esther Gonzalez-Lopez⁶, Ingrid P C Krapels^{3

4}, Carola Pio Loco Detto Gava^{4

5}, Arthur van den Wijngaard^{3

4}, Michiel T H M Henkens^{1

14

15}, Manuela Iseppi^{4

5}, Anne G Raafs¹, Martijn F Hoes^{1

3}, Vanessa P M van Empel^{4

16}, Elizabeth A V Jones^{1

2}, Miranda Nabben^{3

12}, Matthew Taylor⁷, Han G Brunner^{3

4

17}, Juan Pablo Ochoa^{13

18}, Fernando Dominguez^{4

6

18}, Neal K Lakdawala¹⁹, Gianfranco Sinagra^{4

5}, Pablo Garcia-Pavia^{4

6

18}, Luisa Mestroni⁷, Stephane R B Heymans^{1

2}, Job A J Verdonschot^{1

3

4}

Affiliations

¹ Department of Cardiology, Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), the Netherlands (S.L.V.M.S., M.A.S., R.E.W.v.L., M.T.H.M.H., A.G.R., M.F.H., E.A.V.J., S.R.B.H., J.A.J.V.).
² KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.).
³ Department of Clinical Genetics, Maastricht University Medical Center, the Netherlands (S.L.V.M.S., P.W., D.M.E.I.H., I.P.C.K., A.v.d.W., M.F.H., M.N., H.G.B., J.A.J.V.).
⁴ Members of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart) (S.L.V.M.S., M.M., N.M.-A., P.W., A.C., M.A.S., M.D.F., B.P., D.M.E.I.H., M.S., I.P.C.K., C.P.L.D.G., A.v.d.W., M.I., V.P.M.v.E., H.G.B., F.D., G.S., P.G.-P., J.A.J.V.).
⁵ Cardiovascular Department, Azienda Sanitaria-Universitaria Integrata Trieste ASUITS, Italy (M.M., A.C., M.D.F., M.S., C.P.L.D.G., M.I., G.S.).
⁶ Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, IDIPHISA, CIBERCV, Madrid, Spain (N.M.-A., B.P., E.G.-L., F.D., P.G.-P.).
⁷ Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora (M.J., M.T., L.M.).
⁸ National Heart and Lung Institute, Imperial College London, United Kingdom (U.T.).
⁹ Royal Brompton and Harefield Clinical Group, Guy's and St Thomas' NHS Foundation Trust, United Kingdom (U.T.).
¹⁰ School of Cardiovascular Medicine and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, King's College London, United Kingdom (A.C.).
¹¹ Department of Cardiology, King's College Hospital London, United Kingdom (A.C.).
¹² Department of Genetics and Cell Biology, Maastricht University, the Netherlands (M.W., M.N.).
¹³ University of Verona, Section of Cardiology, Italy (M.S., J.P.O.).
¹⁴ Department of Pathology, Maastricht University Medical Centre, the Netherlands (M.T.H.M.H.).
¹⁵ Netherlands Heart Institute (NLHI), Utrecht, the Netherlands (M.T.H.M.H.).
¹⁶ Department of Cardiology, University of Maastricht, Medical University Center Maastricht, the Netherlands (V.P.M.v.E.).
¹⁷ Radboud University Medical Center, Human Genetics, Nijmegen, Netherlands (H.G.B.).
¹⁸ Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.P.O., F.D., P.G.-P.).
¹⁹ Brigham and Women's Hospital, Division of Cardiovascular Medicine, Harvard Medical School, Boston, MA (N.K.L.).

PMID: 40988625
DOI: 10.1161/CIRCHEARTFAILURE.124.012592

Sex Differences in Prognosis of Patients With Genetic Dilated Cardiomyopathy

Sophie L V M Stroeks et al. Circ Heart Fail. 2025.

. 2025 Sep 24:e012592.

doi: 10.1161/CIRCHEARTFAILURE.124.012592. Online ahead of print.

Authors

Affiliations

¹ Department of Cardiology, Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), the Netherlands (S.L.V.M.S., M.A.S., R.E.W.v.L., M.T.H.M.H., A.G.R., M.F.H., E.A.V.J., S.R.B.H., J.A.J.V.).
² KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.).
³ Department of Clinical Genetics, Maastricht University Medical Center, the Netherlands (S.L.V.M.S., P.W., D.M.E.I.H., I.P.C.K., A.v.d.W., M.F.H., M.N., H.G.B., J.A.J.V.).
⁴ Members of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart (ERN GUARD-Heart) (S.L.V.M.S., M.M., N.M.-A., P.W., A.C., M.A.S., M.D.F., B.P., D.M.E.I.H., M.S., I.P.C.K., C.P.L.D.G., A.v.d.W., M.I., V.P.M.v.E., H.G.B., F.D., G.S., P.G.-P., J.A.J.V.).
⁵ Cardiovascular Department, Azienda Sanitaria-Universitaria Integrata Trieste ASUITS, Italy (M.M., A.C., M.D.F., M.S., C.P.L.D.G., M.I., G.S.).
⁶ Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, IDIPHISA, CIBERCV, Madrid, Spain (N.M.-A., B.P., E.G.-L., F.D., P.G.-P.).
⁷ Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora (M.J., M.T., L.M.).
⁸ National Heart and Lung Institute, Imperial College London, United Kingdom (U.T.).
⁹ Royal Brompton and Harefield Clinical Group, Guy's and St Thomas' NHS Foundation Trust, United Kingdom (U.T.).
¹⁰ School of Cardiovascular Medicine and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, King's College London, United Kingdom (A.C.).
¹¹ Department of Cardiology, King's College Hospital London, United Kingdom (A.C.).
¹² Department of Genetics and Cell Biology, Maastricht University, the Netherlands (M.W., M.N.).
¹³ University of Verona, Section of Cardiology, Italy (M.S., J.P.O.).
¹⁴ Department of Pathology, Maastricht University Medical Centre, the Netherlands (M.T.H.M.H.).
¹⁵ Netherlands Heart Institute (NLHI), Utrecht, the Netherlands (M.T.H.M.H.).
¹⁶ Department of Cardiology, University of Maastricht, Medical University Center Maastricht, the Netherlands (V.P.M.v.E.).
¹⁷ Radboud University Medical Center, Human Genetics, Nijmegen, Netherlands (H.G.B.).
¹⁸ Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.P.O., F.D., P.G.-P.).
¹⁹ Brigham and Women's Hospital, Division of Cardiovascular Medicine, Harvard Medical School, Boston, MA (N.K.L.).

PMID: 40988625
DOI: 10.1161/CIRCHEARTFAILURE.124.012592

Abstract

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.

Keywords: genotype; heart failure; humans; phenotype; prognosis.

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Sex Differences in Prognosis of Patients With Genetic Dilated Cardiomyopathy

Affiliations

Sex Differences in Prognosis of Patients With Genetic Dilated Cardiomyopathy

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources