Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy

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.

Keywords: cardiomyopathy, dilated; penetrance; sex.

Figure 1.

Preferred reporting items for systematic reviews and meta-analyses flow diagram. Flow diagram detailing the number of studies that were included in each step of the literature search screening, and the origin of the included studies, the number of duplicates removed, and the reason behind exclusion from this study. The figure was generated using Covidence.

Figure 2.

Summary results illustration. This figure displays the main summary results found in this investigation. The determined male to female ratios (M:F) are presented for both the systematic review and meta-analysis and the population study. Multiple sources of evidence demonstrate a male preponderance in dilated cardiomyopathy (DCM), which is partly mitigated by applying sex-specific diagnostic criteria. ICD-10 indicates International Classification of Diseases, 10th revision; and TTNtv, titin-truncating variant.

Figure 3.

Forest plot of general dilated cardiomyopathy cohort. This figure displays the proportion of female patients with dilated cardiomyopathy and the 95% CI for each of the included studies along with the pooled estimate of 0.30 (95% CI, 0.28–0.32; Table 2). The diamond corresponds to the pooled proportion at its center and the diamond’s width represents the 95% CI. The heterogeneity estimates are provided. The asterisk next to the study identifier indicates familial patients are included within that study’s population. RE indicates random effects.

Figure 4.

Forest plot of monogenic dilated cardiomyopathy. This figure displays the individual study and pooled proportions of female patients for the genetic dilated cardiomyopathy cohort. The genetic cohort proportion was 0.31 (95% CI, 0.26–0.36; Table 2). The asterisk indicates the study includes familial patients with dilated cardiomyopathy. The diamond’s center corresponds to the pooled proportion and the width represents the 95% CI. RE indicates random effects.

Figure 5.

Forest plot of reduced genetic and gene-elusive cohorts. This figure displays the proportions for the genetic and gene-elusive dilated cardiomyopathy (DCM) cohorts derived from the 10 studies that described both populations. The individual study and pooled proportions are provided. The gene-elusive cohort proportion was 0.30 (95% CI, 0.24–0.37) and the reduced genetic proportion was 0.30 (95% CI, 0.21–0.40; Table 2). The asterisk next to the study’s identifier indicates the inclusion of familial patients with DCM. The diamond’s center represents the pooled proportion, and the width represents the 95% CI. RE indicates random effects.

Figure 6.

Forest plot of the gene-specific dilated cardiomyopathy cohort. This figure displays the inverse-logit proportions of female participants with dilated cardiomyopathy (DCM) of the autosomal dominant genetic DCM cohort. The pooled proportion was found to be 0.34 (95% CI, 0.28–0.40; Table 2). The data are divided by gene, with certain studies falling under multiple genes. The total number of study participants included in each gene group is provided. The asterisk next to the study author and year indicates familial patients with DCM are present within the study’s cohort. The center of the diamond indicates the pooled proportion, and the width represents the 95% CI. RE indicates random effects.