Systematic review, meta-analysis and population study to determine the biological sex ratio in dilated cardiomyopathy
Author(s)
Type
Journal Article
Abstract
BACKGROUND:
Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias.
METHODS:
A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n<100), pediatric, or peripartum population. Meta-analysis and metaregression compared the proportion of female participants for an overall DCM cohort and the following subtypes: all genetic DCM, individual selected DCM genes (TTN and LMNA), and gene-elusive DCM. Population DCM sex ratios generated from diagnostic codes were also compared with those from sex-specific means using the UK Biobank imaging cohort; this established ICD coded, novel imaging-first, and genotype first determined sex ratios.
RESULTS:
A total of 99 studies, with 37 525 participants, were included. The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28–0.32), corresponding to a male:female ratio (M:F) of 2.38:1. This was similar to patients with an identified DCM variant (0.31 [95% CI, 0.26–0.36]; M:F 2.22:1; P=0.56). There was also no significant difference when compared with patients with gene-elusive DCM (0.30 [95% CI, 0.24–0.37]; M:F 2.29:1; P=0.81). Furthermore, the ratio within autosomal dominant gene variants was not significantly different for TTN (0.28 [95% CI, 0.22–0.36]; M:F 2.51:1; P=0.82) or LMNA (0.35 [95% CI, 0.27–0.44]; M:F 1.84:1; P=0.41). Overall, the sex ratio for DCM in people with disease attributed to autosomal dominant gene variants was similar to the all-cause group (0.34 [95% CI, 0.28–0.40]; M:F 1.98:1; P=0.19). In the UK Biobank (n=47 549), DCM defined by International Classification of Diseases, 10th revision, coding had 4.5:1 M:F. However, implementing sex-specific imaging-first and genotype-first diagnostic approaches changed this to 1.7:1 and 2.3:1, respectively.
CONCLUSIONS:
This study demonstrates that DCM is twice as prevalent in male patients. This was partially mitigated by implementing sex-specific DCM diagnostic criteria. The persistent male excess in genotype-positive patients with an equally prevalent genetic risk suggests additional genetic or environmental drivers for sex-biased penetrance.
REGISTRATION:
URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42023451944.
Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias.
METHODS:
A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n<100), pediatric, or peripartum population. Meta-analysis and metaregression compared the proportion of female participants for an overall DCM cohort and the following subtypes: all genetic DCM, individual selected DCM genes (TTN and LMNA), and gene-elusive DCM. Population DCM sex ratios generated from diagnostic codes were also compared with those from sex-specific means using the UK Biobank imaging cohort; this established ICD coded, novel imaging-first, and genotype first determined sex ratios.
RESULTS:
A total of 99 studies, with 37 525 participants, were included. The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28–0.32), corresponding to a male:female ratio (M:F) of 2.38:1. This was similar to patients with an identified DCM variant (0.31 [95% CI, 0.26–0.36]; M:F 2.22:1; P=0.56). There was also no significant difference when compared with patients with gene-elusive DCM (0.30 [95% CI, 0.24–0.37]; M:F 2.29:1; P=0.81). Furthermore, the ratio within autosomal dominant gene variants was not significantly different for TTN (0.28 [95% CI, 0.22–0.36]; M:F 2.51:1; P=0.82) or LMNA (0.35 [95% CI, 0.27–0.44]; M:F 1.84:1; P=0.41). Overall, the sex ratio for DCM in people with disease attributed to autosomal dominant gene variants was similar to the all-cause group (0.34 [95% CI, 0.28–0.40]; M:F 1.98:1; P=0.19). In the UK Biobank (n=47 549), DCM defined by International Classification of Diseases, 10th revision, coding had 4.5:1 M:F. However, implementing sex-specific imaging-first and genotype-first diagnostic approaches changed this to 1.7:1 and 2.3:1, respectively.
CONCLUSIONS:
This study demonstrates that DCM is twice as prevalent in male patients. This was partially mitigated by implementing sex-specific DCM diagnostic criteria. The persistent male excess in genotype-positive patients with an equally prevalent genetic risk suggests additional genetic or environmental drivers for sex-biased penetrance.
REGISTRATION:
URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42023451944.
Date Issued
2025-02-18
Date Acceptance
2025-01-12
Citation
Circulation, 2025, 151 (7), pp.442-459
ISSN
0009-7322
Publisher
Lippincott, Williams & Wilkins
Start Page
442
End Page
459
Journal / Book Title
Circulation
Volume
151
Issue
7
Copyright Statement
© 2025 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
License URL
Sponsor
Medical Research Council (MRC)
The Royal Society
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
10.1161/CIRCULATIONAHA.124.070872
Grant Number
MR/W023830/1
RG\R2\232551
PA7460
Subjects
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1117 Public Health and Health Services
Cardiovascular System & Hematology
Publication Status
Published
Date Publish Online
2025-02-03