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Observational Study
. 2024 Feb;12(2):352-363.
doi: 10.1016/j.jchf.2023.10.009. Epub 2023 Nov 29.

Sex Differences in the Clinical Presentation and Natural History of Dilated Cardiomyopathy

Ruth Owen  1 , Rachel Buchan  2 , Michael Frenneaux  2 , Julian W E Jarman  2 , Resham Baruah  3 , Amrit S Lota  2 , Brian P Halliday  2 , Angharad M Roberts  2 , Cemil Izgi  2 , Harriette G C Van Spall  4 , Erin D Michos  5 , John J V McMurray  6 , James L Januzzi  7 , Dudley J Pennell  2 , Stuart A Cook  2 , James S Ware  8 , Paul J Barton  2 , John Gregson  1 , Sanjay K Prasad  2 , Upasana Tayal  9
Affiliations
Observational Study

Sex Differences in the Clinical Presentation and Natural History of Dilated Cardiomyopathy

Ruth Owen et al. JACC Heart Fail. 2024 Feb.

Abstract

Background: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved.

Objectives: This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors.

Methods: The authors conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events.

Results: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P < 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors.

Conclusions: The authors identified a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.

Keywords: females; heart; males; sex.

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by the UK Medical Research Council (MR/W023830/1), the National Heart Lung Institute Research Foundation, Royston Centre for Cardiomyopathy Research, NIHR Biomedical Research Unit Royal Brompton Hospital, NIHR Imperial College Biomedical Research Centre, British Heart Foundation (RE/18/4/34215; SP/10/10/28431; SP/17/11/32885; BH FS/ICRF/21/26019), Wellcome Trust (107469/Z/15/Z), Rosetrees Trust, Sir Jules Thorn Charitable Trust [21JTA], and Alexander Jansons Myocarditis UK. Dr Januzzi has been supported in part by the Hutter Family Professorship. Dr Van Spall has been funded by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada. Dr Michos has participated in advisory boards for Novo Nordisk, Novartis, Bayer, Esperion, AstraZeneca, and Amarin. Dr Januzzi has been a trustee of the American College of Cardiology; has been a board member of Imbria Pharmaceuticals; has been a director at Jana Care; has received grant support from Abbott Diagnostics, Applied Therapeutics, HeartFlow, Innolife, and LivaNova; has received consulting fees from Abbott, Bayer, Beckman-Coulter, Boehringer-Ingelheim, Janssen, Novartis, Quidel, Roche Diagnostics, and Siemens; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Intercept, Pfizer, and Takeda. Dr Pennell has received consulting fees from Bayer and Chiesi; has received research support from Bayer and Siemens; and has received speaker fees from Chiesi and Bayer. Dr Cook has been a co-founder and shareholder with Enleofen Bio PTE LTD. Dr Ware has received consulting fees from MyoKardia and Foresite Labs; and has received research support from MyoKardia/Bristol Myers Squibb. Dr Halliday has participated in an advisory board with AstraZeneca. Dr Baruah is working full-time for AstraZeneca. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Cumulative Incidence of the Composite of Cardiovascular Death or Heart Failure by Sex Kaplan-Meier plot showing cumulative incidence of the composite outcome of cardiovascular death or heart failure over the study follow-up period (time since enrollment; baseline defined as first diagnostic cardiac magnetic resonance image). Within 2 years, females had more primary outcome events than males. Between 2 and 5 years, males and females had similar outcomes. The numbers in brackets in the risk table are the number of events.
Figure 2
Figure 2
Cumulative Incidence of Cardiovascular Death, Major Heart Failure, and All-Cause Death Kaplan Meier plots showing cumulative incidence of cardiovascular (CV) death, major heart failure events, and all-cause death.
Figure 3
Figure 3
Baseline Variables Associated With the Composite of Cardiovascular Death or Heart Failure Stratified by Sex Forest plot showing the HR for the primary outcome associated with each variable separated by sex. P values are calculated from tests for interaction. LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction.
Figure 4
Figure 4
The Association of Other Dilated Cardiomyopathy Prognostic Factors With the Composite of Cardiovascular Death or Heart Failure Stratified by Sex Forest plot showing the HR for the primary outcome associated with each variable separated by sex. P values are calculated from tests for interaction. LAVi = left atrial volume index; LBBB = left bundle branch block; NT-proBNP = N-terminal pro–B-type natriuretic peptide.
Central Illustration
Central Illustration
Female Paradox in Dilated Cardiomyopathy Prognosis A novel paradox in prognosis for females with dilated cardiomyopathy (DCM). This study shows that female sex is an adverse marker in the early natural history of DCM (first 2 years) with a higher risk of major heart failure events. This was observed despite a seemingly more favorable phenotype at presentation characterized by less ventricular dilatation, higher left ventricular ejection fraction (LVEF) and less prevalent myocardial fibrosis in females compared to males with no differences in DCM duration, age at presentation, N-terminal pro–B-type natriuretic peptide levels, fibrosis extent, genetic status, or heart failure medication use. These findings highlight that sex is a relevant prognostic variable in the care of patients with DCM.
See this image and copyright information in PMC

Comment in

References

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