Sex Differences in Dilated Cardiomyopathy: Evidence, Gaps, and Future Directions. Does sex matter in DCM care?

Abstract

Dilated cardiomyopathy (DCM), affecting 1 in 250 people, is a leading global cause of heart failure and the most common indication for heart transplantation. Evidence suggests DCM is more prevalent in males, but whether this reflects biological differences or under-diagnosis in females remains uncertain. This review explores the impact of sex on DCM, examining differences in epidemiology, etiology, clinical presentation, treatment response, and outcomes. Females often present with less severe cardiac phenotypes, including lower levels of fibrosis and better left ventricular function, yet the long-term prognosis of DCM in females is less clear. Through a systematic review and meta-analysis, we found that male DCM patients with variants in PLN, DSP, and LMNA had higher arrhythmic event rates compared with TTNtv and BAG3 carriers. In female patients with DCM, RBM20, DSP, and PLN carriers faced the highest arrhythmic risk, with TTNtv carriers the lowest. PLN and LMNA carriers had the highest heart failure risk in both sexes, while female BAG3, RBM20, and TTN carriers had lower heart failure rates compared with male carriers. These findings highlight the influence of sex and genotype on clinical outcomes. Current risk stratification tools, such as those used for implantable cardioverter-defibrillators (ICDs), may under-treat females due to reliance on sex-neutral thresholds. We highlight the role of genetic, environmental, and reproductive factors in shaping these disparities, including the influence of pregnancy, pregnancy complications and menopause. This review identifies key gaps in knowledge and calls for expanded representation of females in DCM studies and the development of sex-specific risk models. Addressing these gaps is essential to improving outcomes and advancing equitable, personalized care for all DCM patients.

Abbreviations

ARVC

arrhythmogenic right ventricular cardiomyopathy

CVD

cardiovascular disease

DCM

dilated cardiomyopathy

HCM

hypertrophic cardiomyopathy

HF

heart failure

HTx

heart transplantation

LMNA

lamin gene

LVEF

left ventricular ejection fraction

LVRR

Left ventricular reverse remodeling

PPCM

Peripartum cardiomyopathy

TTN

titin gene

Introduction

Dilated cardiomyopathy (DCM) is a common heart muscle disease, affecting roughly 1 in every 250 individuals and is a leading cause of heart transplants and mortality¹. The etiology of DCM is diverse and includes genetic, infectious and inflammatory diseases, and toxins, although many cases remain unexplained after extensive evaluation². The literature on DCM presents a complex and often contradictory narrative when it comes to comparing the sexes. We have recently shown that DCM is more prevalent in males compared to females, partly due to under-diagnosis in females and partly due to increased penetrance in males³. Factors influencing these sex biases in penetrance are incompletely understood. Our understanding of the different causes, risk factors, clinical presentation and prognosis between males and females is rapidly evolving, though this is not currently accounted for in clinical care. This variability underscores the pressing need for research dedicated to exploring the sex-specific elements of DCM. These efforts are crucial in establishing if sex-specific strategies are needed for diagnosing, treating, and managing DCM.

This review aims to synthesize current knowledge on sex differences in the epidemiology, etiology, clinical presentation, treatment response, and outcomes of genetic DCM, while highlighting gaps in understanding and suggesting directions for future research. While DCM can result from various causes, this review focuses primarily on genetic forms of DCM and the sex-specific differences associated with them. Sex differences in other causes of DCM are discussed if sex stratified data in genetic DCM are not available, for example heart failure treatment responses. Sex differences in broader causes of non-ischaemic cardiomyopathy and all-cause heart failure are not specifically evaluated.

Epidemiology

DCM is one of the most common causes of heart failure with an estimated prevalence of approximately 1:250–400⁴. The incidence of DCM is reported with 5–7 cases per 100 000 persons per year, though there is considerable geographical variation in this as confirmation of disease requires cardiovascular imaging, which may not be as available in resource poor settings⁵.

Sex differences are a notable feature of DCM epidemiology⁶. Males had consistently been reported to have a higher incidence of DCM compared to females, but it was not clear if this was due to under-diagnosis in females or a genuine increased risk in males, and whether this applied to genetic and non-genetic forms of DCM. We recently undertook a systematic review, meta-analysis and population study to evaluate this and found that DCM had a male-to-female ratio of 2:1 across all subtypes including all-cause DCM, genetic DCM, gene-specific DCM (TTNtv DCM and LMNA DCM) and gene-elusive DCM^{3, 7}. Using UK Biobank population data⁸, we applied sex specific imaging diagnostic thresholds and were able to diagnose more females with an imaging label of DCM. This reduced but did not eliminate the male sex bias entirely, demonstrating that the male bias in DCM is due to both underdiagnosis in females (due to lack of sex specific diagnostic thresholds) as well as increased susceptibility in males across genetic and non-genetic forms. These findings set the context for further exploration of why biological sex has such diverse effects in DCM.

Etiology

Genetic factors

DCM is a multifactorial disease influenced by genetic, environmental, and comorbid factors (Figure 1). The journey from genotype to phenotype can be modified by traditional and sex specific risk factors. Genetic risk includes rare monogenic variants, oligogenic interactions, and polygenic susceptibility, but variant presence alone does not ensure disease expression. Traditional risk factors (e.g., hypertension, alcohol, infections, pregnancy) and sex-specific influences such as hormones and immune differences further modify disease onset and severity. As a result, DCM presentation reflects both genetic architecture and modifiable, sex-related variables as further evaluated in this review.

Figure 1. Impact of female reproductive life events.

The journey from genotype to phenotype can be modified by traditional and sex specific risk factors. The clinical presentation and outcome of DCM is determined by the co-existence of genetic (rare variant monogenic, oligogenic and polygenic risk) and acquired factors. Acquired stressors such as pregnancy, toxins including chemotherapy and alcohol, viruses, and auto-immune diseases have been well characterized. The impact of the reproductive lifespan on the development of DCM and modification of outcomes is not yet fully understood. Original figure for this review.

While approximately one-third of DCM cases are attributed to a genetic cause, most often inherited in an autosomal dominant manner, the expression and penetrance of these variants are notably influenced by sex⁹. While several monogenic subtypes show sex-based differences in penetrance and phenotype, the consistency of these findings across cohorts is variable, and data for many genes remain limited (summarised in Figure 2).

Figure 2. Genotype-specific sex differences in genetic DCM patients.

Sex specific genotype-phenotype associations are shown for some key DCM genes. For most genes, the disease appears to be more penetrant in males, with the exception of desmoplakin (DSP). LMNA cardiomyopathy is characterized by a worse phenotype in males. FLNC, filamin C; TNNT2, troponin T2; TTN, titin; MYH7, myosin heavy chain; DMD, dystrophin gene associated with Duchenne muscular dystrophy; LMNA, lamin; RBM20, RNA-binding motif protein 20. Original figure for this review.

Our recent analysis of 3,410 adult and pediatric patients from the international SHaRe registry (https://www.theshareregistry.org) provides new insights into sex-specific genetic architecture in DCM/AC. Across genotype-positive, gene-elusive, and variant of unknown significance (VUS) subgroups, males were more frequently affected. However, clear gene-specific sex differences emerged with TTNtv being significantly less common in females, whereas DSP variants and grouped sarcomeric variants (including MYH7 and TNNT2) were more prevalent in females. Pediatric-onset cases also showed a male predominance (60%) but were enriched for sarcomeric gene variants. These findings from SHaRe represent the largest sex-stratified genotype analysis to date and underscore the critical importance of incorporating sex into genetic risk interpretation. These findings highlight the combined influence of genetic background and sex on DCM presentation.

Previous studies have also reported sex differences in DCM genetics, including a male predominance among carriers of TTNtv, LMNA, and RBM20 variants, and a higher proportion of females with DSP-cardiomyopathy (50–69% in published cohorts) ^{7, 10–14}. X-linked forms of DCM, such as those caused by dystrophin (DMD) variants¹⁵, further illustrate the interplay between sex and inheritance, with males typically exhibiting more severe phenotypes, while female carriers present with variable and often milder disease manifestations.

Potential influence of sex hormones and reproductive factors in DCM

Sex differences in cardiac pathophysiology and immune responses to cardiac injury contribute to observed disparities in DCM, but the underlying drivers remain unclear. Sex hormones may be important mediators. These hormones influence cardiac function directly by binding to androgen and estrogen receptors on vascular endothelial cells, smooth muscle cells, fibroblasts, and myocytes, and indirectly by modulating immune responses that shape cardiac inflammation, remodeling, and thrombosis in DCM^16–18.

Testosterone promotes cardiac hypertrophy and inflammation, with studies linking genetically predicted testosterone levels to heart failure in males¹⁹. In animal models, testosterone increases myocardial inflammation and adverse remodeling, while myocardial fibrosis in males and postmenopausal females is associated with sex hormone status^{20, 21}. Conversely, estradiol reduces cardiac hypertrophy and fibrosis, prevents cardiomyocyte apoptosis, and protects against oxidative stress-induced damage²². Females have higher levels of estrogen receptors, which are cardioprotective when activated by 17β-estradiol²³. However, the relationship between physiological hormone levels and cardiac remodeling in DCM remains inconsistent in human studies, suggesting opportunities for further evaluation of sex hormones in DCM pathogenesis.

Hormonal fluctuations also play a significant role in female-specific forms of DCM, such as peripartum cardiomyopathy (PPCM)²⁴. PPCM occurs in the late stages of pregnancy or postpartum and is more common in females of Black ancestry, with the highest incidence in Africa (1:100–1:1000 births), Haiti (1:200), and Pakistan (1:840)^{25, 26}. PPCM is a diagnosis of exclusion, and while pregnancy-related hormonal changes and physiological stressors contribute to its development, the presence of pathogenic genetic variants, such as TTNtv, may indicate an underlying genetic cardiomyopathy that manifests during the hemodynamic stress of pregnancy^{27, 28}. Clinical recovery often occurs as hormonal levels return to pre-pregnancy states²⁹, highlighting the interplay between genetic predisposition and sex-specific physiological stressors in this condition. Reproductive risk factors interact with the risk of developing DCM and its complications, though our knowledge in this domain is still evolving (Figure 1). Pregnancy complications appear to influence the risk of developing DCM. We have recently shown that hypertensive disorders of pregnancy (HDP), which affect 5-10% of pregnancies, are associated with a twofold increased risk of developing DCM³⁰. DCM develops on average 5 years earlier in those with HDP compared to those with normotensive first pregnancies, and increased maternal age and post-partum hypertension are independently associated with the risk of developing DCM post HDP³¹.

The role of menopause in DCM onset is not well defined. Early menopause has been associated with an increased risk of heart failure and metabolic issues such as obesity and insulin resistance³². Postmenopausal females also show reduced cardiac function, with studies reporting lower left ventricular longitudinal strain compared to premenopausal females of similar ages³³. These findings suggest that hormonal changes during menopause may contribute to sex differences in cardiac health, but require further evaluation in DCM.

Sex differences in environmental modifiers of DCM

Inflammation

Cardiac involvement in systemic immune-mediated diseases (SIDs) leading to DCM is common and linked to poor outcomes³⁴. Although autoimmune diseases are more prevalent in females, we previously found a predominance of males with SID-associated DCM³⁵. This was particularly striking in auto-inflammatory SID-DCM, where 70% of patients were male.

Auto-inflammatory diseases include conditions like sarcoidosis, gout, and inflammatory bowel disease. In the autoimmune SID-DCM group, 52% of patients were male, despite conditions like systemic lupus and rheumatoid arthritis being more common in females. These findings suggest females may have protective factors for DCM, warranting further study.

Chemotherapy

Sex differences are notable in chemotherapy-induced DCM, with females disproportionately affected, largely due to the high prevalence of breast cancer, a condition predominantly treated with cardiotoxic drugs like anthracyclines³⁶. Whether intrinsic biological differences further modulate susceptibility remains uncertain. Female sex and preexisting cardiac risk factors are recognized contributors to chemotherapy-induced cardiomyopathy³⁷. Elevated copeptin, a stable surrogate marker of vasopressin, functions as a prognostic biomarker in heart failure, with circulating concentrations typically higher in men, although its prognostic significance appears independent of sex³⁸. The mechanisms of chemotherapy-induced cardiotoxicity vary by drug and are influenced by factors such as cumulative dose, drug formulation, administration route, and age at treatment. ³⁹. Sex differences in cardiotoxicity across other drugs may be influenced by the role of female hormones in oxidative stress and mitochondrial dysfunction⁴⁰, as well as differences in drug pharmacokinetics.

Alcohol

In alcohol-induced cardiomyopathy, males comprise of 57%–100% of cases⁴¹. One study found a 9:1 male-to-female ratio among admissions for alcohol-induced cardiomyopathy, possibly driven by social factors such as greater cultural acceptance of alcohol use in males⁴². The intersection with genetics is also important. We have previously shown an interaction with TTNtv and moderate alcohol consumption in male-dominated DCM cohorts, leading to a reduction in left ventricular ejection fraction, supporting the “second-hit hypothesis,” where genetic predisposition combines with environmental stressors like alcohol to trigger disease⁴³.

Sex-based differences in DCM risk following exposure to toxins such as chemotherapy and alcohol remain incompletely understood. Dose and duration of exposure, effects on sex hormone production, and genetic predisposition may all contribute. Limited data are available on the sex-specific effects of other toxins, including immune therapies, recreational drugs like marijuana and cocaine, and pesticides, highlighting the need for further research in this area.

Presentation

Age of diagnosis

In general, there are not thought to be differences in age of diagnosis between males and females with DCM ⁴⁴. However, sex-based differences in age at presentation are more apparent when stratified by genotype. Males with TTNtv appear to present earlier than females⁴⁵, and male carriers of LMNA or RBM20 variants also show earlier disease onset than females (42 vs. 54 years for LMNA; 29 vs. 38 years for RBM20)^{46, 47}. It is important to note that social determinants of health, including access to care, socioeconomic status, and potential delays in referral, may also influence these observations of early presentation in males^{48, 49}. Some of these factors are challenging to quantify and may vary across healthcare systems, potentially confounding comparisons of age at diagnosis. Taken together, these findings highlight the combined influence of genetic background, sex, and healthcare-related factors on DCM presentation.

Symptoms at presentation and health related quality of life

The literature on sex differences in symptoms at first presentation of DCM is mixed. Some studies suggest that females present with more severe symptoms and a higher NYHA class at baseline despite having less severe cardiac dysfunction (higher LVEF), a lower burden of scar, and receiving similar heart failure pharmacological therapy compared to males⁶. Furthermore, females exhibited less severe ventricular dysfunction at first presentation than males (28% vs. 59%, adjusted for sex-specific volumes)⁵⁰. However, other studies report no significant differences in NYHA class or LVEF between sexes, a pattern consistent also in patients with late-onset DCM (age of onset over 60 years)⁵¹. These findings reveal a discrepancy between symptom severity and clinical measures of heart function in females, which remains unaddressed in clinical care. Symptoms in females may be under-recognized or under-reported, contributing to this complexity⁵².

Females with HFrEF often report worse health-related quality of life than men, despite having similar physician-assessed symptoms and comparable markers of cardiac function^{52, 53}. The underlying reasons for these differences are not fully understood, as they are not explained solely by HF severity or comorbidities. Co-existing depression and anxiety, which are more prevalent in females, may further contribute to worse quality of life and complicate clinical assessment⁵⁴. While these findings are derived from HFrEF cohorts, they likely have implications for females with DCM. These observations underscore the importance of incorporating patient-reported outcomes and psychosocial factors when evaluating and managing females with DCM.

Biomarkers

Sex differences in DCM also extend to biomarkers, which may influence how DCM is diagnosed and monitored. Females generally have higher natriuretic peptide levels (e.g., NT-proBNP) in healthy states, partly influenced by androgens, as testosterone suppression in males increases NT-proBNP⁵⁵. However, in heart failure, these differences attenuate, with levels similar or lower in females due to males having more heart failure with reduced ejection fraction, where NT-proBNP levels are higher. Conversely, cardiac injury markers (troponins) and inflammation biomarkers are typically higher in males, both in healthy individuals and heart failure patients⁵⁶.

Outcome

On average, many studies suggest that females with DCM tent to have better long-term outcomes than males, although this pattern is not uniform across all cohorts or time periods. Females with DCM have significantly lower rates of all-cause mortality, heart transplantation, and ventricular assist device implantation compared to males (22% vs. 33% over a 10-year follow-up)⁵⁰. Females under 60 years had approximately half the 5-year mortality rate of males (6.7% vs. 13.5%) ⁶. Additionally, females exhibited a 40% lower risk of life-threatening ventricular arrhythmias⁵⁷. However, in the first two years after diagnosis, female sex has been associated with worse heart failure outcomes, despite females presenting with less severe ventricular dilation and higher LVEF than males⁴⁴. Current guidelines, however, do not include sex-specific LVEF thresholds⁵⁸. Females often present with a higher LVEF compared to males, even in health, but this is not accounted for in clinical care where treatment decisions are often made on sex agnostic thresholds⁵⁹. Evidence from PARAGON-HF and TOPCAT indicates that female patients may gain greater benefit from therapies such as sacubitril/valsartan and spironolactone, at higher range LVEFs compared with males^{60 61}. These data support the concept that adopting sex-specific LVEF cutoffs may more accurately capture the pathophysiology of heart failure in female patients and improve early identification and management of at-risk female patients. Indeed, we have shown that using sex specific imaging cut offs to diagnose DCM can lead to more females being diagnosed with DCM⁶². LVEF is however influenced by heart rate, image quality and other external factors. Therefore, further research is needed to determine whether sex-specific cutoffs can improve clinical decision-making. The key remaining challenge is to evaluate whether these cutoffs provide a ‘net clinical benefit’ when evaluated against potential harms from therapy (e.g. medication side effects, inappropriate shocks from ICDs) and that the change in treatment thresholds lead to improved outcomes for female and male patients. Broadening treatment decisions beyond single factor single threshold approaches (i.e. LVEF greater or less than 35%) may enable us to capture the complex interplay between sex, cardiac function, treatment and outcomes in patients with DCM.

Pregnancy in females with DCM carries significant maternal and fetal risks, with up to half experiencing peripartum cardiac events such as heart failure and arrhythmias, particularly in those with moderate to severe left ventricular dysfunction, NYHA class III/IV symptoms, or genetic predispositions such as TTNtv or LMNA variants, although data are limited on pregnancy outcomes stratified by genetic DCM^{63, 64}. These complications are associated with worse long-term survival ⁶⁵, while fetal risks include preterm birth, intrauterine growth restriction, and miscarriage^{66, 67}. Management should involve a multidisciplinary team, with optimization of heart failure therapies, consideration of cardiac devices, and close maternal-fetal monitoring. In severe cases, an elective cesarean section may be necessary to reduce cardiovascular stress during labor.

Outcome in genetic DCM

Sex-specific outcomes appear to differ in genetic DCM and are an area of active research. In TTNtv carriers, females experience adverse events later than males (average age 68 vs. 56 years), though rates of malignant arrhythmias and all-cause mortality appear similar⁶⁹. Females with LMNA variants have a 45% lower risk of life-threatening arrhythmias compared to males, making male sex an independent predictor of adverse outcomes in LMNA risk stratification⁷⁰. In contrast, females with a DSP variant face a higher risk of life-threatening arrhythmias than males up to 5 years follow up⁷¹. Therefore, in DSP risk stratification, female sex is currently considered an independent predictor, though whether this reflects sex differences in penetrance (increased penetrance in females) or genuine sex differences in prognosis remains to be clarified⁷².

Systematic review and meta-analysis on outcomes stratified by sex and genetic status

Indeed, the overall burden of adverse outcomes stratified by sex and genetic status in DCM has not been established. Therefore, we undertook a systematic review and meta-analysis using a random effects model to assess sex-stratified outcomes in genetic DCM⁷³ (Supplementary Methods and Results). This section presents a novel synthesis of the literature on sex-stratified outcomes in genetic DCM.

A comprehensive literature search screening 3,723 studies identified 33 studies for inclusion, comprising 3,192 carriers of pathogenic variants in one of the DCM-associated genes⁷³ (Supplemental Table 1). Studies with relevant genotype-stratified outcomes were available for only 10 of the 12 DCM-associated genes, as relevant data for TNNC1 and DES variant carriers could not be isolated. The meta-analysis analysed the pooled proportions of major arrhythmic and heart failure events, stratified by both gene and sex. Further details are outlined in Supplementary Methods and Results. Our analysis revealed notable sex-based differences in arrhythmic and heart failure events across genetic subgroups.

Outcome in genetic DCM: major arrhythmic events

Major arrhythmic events (sudden cardiac death (SCD) and malignant ventricular arrythmias (MVA, defined as sustained ventricular tachycardia associated with hemodynamic compromise or ventricular fibrillation) were significantly more common in males with DCM and LMNA variants compared with females with DCM and LMNA variants (pooled proportion 0.34 males, 0.17 females, p=0.01, Figure 3). The data are strongest for carriers of LMNA and TTNtv variants as they affect more patients with DCM. Arrhythmic events were most common in FLNC and PLN patients, and they appeared to be more common in male FLNC and PLN carriers compared with female carriers but these differences were not statistically significant, which may reflect the heterogeneity of estimates in the female subgroups due to relatively smaller sample sizes. DSP and RBM20 were associated with high rates of arrhythmic events (>20% pooled event proportion), and this risk appeared to be equal between males and females. TTN and BAG3 were associated with the lowest risk of arrhythmic events, and the risk was comparable between the sexes.

Figure 3. Combined Male and Female Risk Summary Barplot for the outcome major ventricular arrhythmias.

This barplot displays the meta analysis pooled proportions of arrhythmic events (y-axis) in males (blue bars) and females (pink bars) for each gene subgroup (x-axis) ordered by descending male event proportion. The pooled proportions are derived from the meta-analysis results for each sex, which excluded studies with less than 20 participants per sex. Effect size represents the absolute difference in event proportions between sexes (e.g., LMNA: 0.34 in males vs 0.17 in females, effect size = 0.17). Error bars indicate 95% confidence intervals. Asterisks (*) denote statistically significant sex differences (p < 0.05), highlighting effect sizes that reflect meaningful differences. Original figure for this review.

Outcome in genetic DCM: heart failure events

Carriers of PLN and LMNA variants in both sexes were at the highest risk for heart failure events, including heart failure hospitalizations, heart transplant, LVAD, and cardiovascular death. Therefore whilst LMNA cardiomyopathy has a higher risk of arrhythmic complications in males, female carriers have the same elevated risk of heart failure complications and cardiovascular death compared with male carriers. Amongst males, heart failure complications were common in BAG3, RBM20, and TTNtv carriers (>20% pooled event proportion), and these were also more likely to occur in male patients compared with female patients (Figure 4). Interestingly, heart failure complications were noted more frequently in female patients compared with male patients with FLNC variants, but these differences were not statistically significant, which again may reflect the heterogeneity of estimates in the FLNC female subgroups due to relatively smaller sample sizes.

Figure 4. Combined Male and Female Risk Summary Barplot for composite outcome of heart failure events and cardiovascular death.

This barplot displays the pooled proportions of the events (y-axis) in males (blue bars) and females (pink bars) for each gene subgroup (x-axis) ordered by descending male event proportion. The pooled proportions are derived from the meta-analysis results for each sex, which excluded studies with less than 20 participants per sex. Effect size represents the absolute difference in event proportions between sexes. Error bars indicate 95% confidence intervals. Asterisks (*) denote statistically significant sex differences (* for p < 0.05, ** for p < 0.01), highlighting effect sizes that reflect meaningful differences. Original figure for this review.

These findings underscore the importance of considering both sex and gene specific status when assessing risk and tailoring management strategies for genetic DCM. These findings also highlight the need for sex stratified reporting of outcome studies in genetic DCM. Further research into sex-specific genetic modifiers and hormonal impacts on gene expression could advance personalized strategies for risk assessment and treatment.

LVEF recovery in genetic DCM and sex effects

Female sex is associated with greater improvement in LVEF, particularly within the first 12 months, as demonstrated in studies of DCM and supported by data from cardiac resynchronization therapy (CRT) in non-ischaemic cardiomyopathy cohorts⁷⁴. While some studies report similar rates of recovery (often defined as the significant and sustained improvement of LVEF, typically involving an increase of at least 10 percentage points or reaching a normal value (≥50%) at follow-up), between sexes, females who achieve recovery tend to have superior long-term outcomes compared to both males and females without recovery ⁵⁰.

Treatment response

Current treatment for DCM primarily follows heart failure management guidelines, which do not differentiate dosages based on sex. However, females’ lower body weight, higher fat percentage, and reduced plasma volume suggest that standard dosing may not always be optimal for them, potentially increasing their risk of adverse effects, such as ACE inhibitor–related cough, which females experience twice as often as males^{75. 6}.

Evidence for sex differences in treatment efficacy for DCM is mixed. While typical neurohormonal blockade, such as ARNI (angiotensin receptor-neprilysin inhibitor), ACE inhibitors, and mineralocorticoid receptor antagonists (MRAs), appears equally effective for males and females, some studies suggest females achieve greater benefits at higher LVEF levels. For example, the CHARM trial, which evaluated candesartan across both ischaemic and non-ischaemic HF, did not demonstrate a statistically significant sex-by-treatment interaction, yet females had lower risks of fatal and nonfatal outcomes, including cardiovascular and noncardiovascular death as well as HF-related hospitalizations⁷⁶. Importantly, these findings were not explained by cause of HF or baseline LVEF, suggesting that additional biological or clinical factors may contribute to the observed sex differences ⁷⁷. In addition, compared to valsartan, sacubitril-valsartan appeared to reduce the risk of heart failure hospitalization more in females than in males⁷⁸. Sex-specific analyses of digoxin from the DIG trial, however, demonstrated increased mortality in females, although pharmacokinetic studies indicate that when serum digoxin levels remain within the therapeutic range, females derive similar benefit to males⁷⁹. Other major trials, including DAPA-HF (dapagliflozin, an SGLT2 inhibitor), and EMPEROR-Reduced (empagliflozin, another SGLT2 inhibitor), reported universal benefits without significant sex differences^{80, 81}. Importantly, females are underrepresented in these trials (21%–40% of participants), raising concerns about the generalizability of findings and highlighting the need for more balanced inclusion in future research.

Notably, large trials with balanced sex representation have provided important insights. For example, in PARADIGM-HF, which enrolled patients with HFrEF, sacubitril/valsartan was associated with consistent benefit across sexes, with no significant interaction between sex and outcome⁸². The PARAGON-HF study, which primarily focused on heart failure with preserved ejection fraction (HFpEF) but also included patients with heart failure with mid-range ejection fraction (HFmrEF, EF ≥45%), found that sacubitril/valsartan reduced the risk of heart failure hospitalizations in females compared to males⁸³. These findings underscore the need for adequately powered sex-specific analyses and for deeper investigation into the biological mechanisms that may underlie differential responses. A clearer understanding of these mechanisms will be essential to optimize treatment strategies for both males and females with HF. Optimizing dosage for females may further improve outcomes. Post-hoc analyses from the BIOSTAT-CHF and ASIAN-HF trials revealed that males benefit most from full guideline-recommended doses of ACE inhibitors, ARBs, and beta-blockers, whereas females achieved similar risk reductions at half the recommended dose, with no added benefit at higher doses⁸⁴. These findings suggest that tailored dosing for females could provide equivalent long-term outcomes while reducing adverse effects, though further evidence from adequately powered clinical trials are needed to support guideline changes.

While baseline therapy may appear similar between males and females in some cohorts, recent real-world data reveal substantial sex disparities in GDMT utilization⁸⁵. In a national U.S. cohort of over 60,000 newly diagnosed HFrEF patients, females were less likely than males to receive any GDMT or achieve optimal therapy within the first year after diagnosis, with a 23% lower probability of attaining guideline-recommended treatment targets⁸⁶. Similarly, an analysis of over 2,000 patients with incident HFrEF found that female patients were more often prescribed only single-agent therapy, highlighting persistent under-treatment⁸⁷. Contributing factors include differences in comorbidity burden, under-referral to cardiology or heart failure specialists, and potential physician bias or therapeutic inertia. While meta-analytic data confirm that the efficacy of HFrEF therapies is largely comparable between sexes⁸⁸, these real-world findings indicate that female patients might be systematically undertreated. This disparity underscores the urgent need for targeted implementation strategies to ensure equitable care and maximize therapeutic benefit for females with HFrEF.

Device-based therapies are a cornerstone of heart failure management, yet sex-specific responses and utilization patterns warrant careful consideration. Data from the MADIT-CRT trial, which evaluated CRT-D, indicate more favorable outcomes in females than males, suggesting potential sex-specific benefits of device therapy⁸⁹. A meta-analysis of patient-level data from multiple CRT-D trials demonstrated that females with left bundle branch block experienced a mortality benefit at shorter QRS durations (≥130 ms) compared with men (≥150 ms), despite primarily having mild heart failure ⁹⁰. However, these sex-specific differences are not implemented in current guidelines. Importantly, female patients remain less likely than men to receive CRT-D in practice, highlighting a persistent sex gap in device utilization. In SCD-HeFT, ICD therapy reduced mortality in patients with HFrEF⁹¹. Female patients comprised only 23% of participants, limiting the ability to detect sex-specific differences, though available data suggest benefits were broadly similar between males and females. In SCD-HeFT, pre-specified subgroup analyses did not show a greater benefit of ICD therapy in females, with hazard ratios numerically more favorable in males⁹². These findings suggest that ICDs reduce mortality in HFrEF in both sexes, but the trial was not powered to evaluate sex-specific effects. More broadly, the consistent underrepresentation of females in ICD trials makes it challenging to draw firm conclusions regarding sex differences in treatment response⁹³. Contemporary analyses support similar overall efficacy of ICDs in male and female patients, though emerging data indicate that the mode of death may differ by sex, being more comparable in non-ischaemic cardiomyopathy and higher in men with ischaemic cardiomyopathy⁹⁴. These results underscore the need to consider sex-specific thresholds when evaluating patients for CRT-D and ICD, as well as adequately powered sex-specific analyses and the broader potential of pooled trial data to inform guideline development and optimize outcomes for female patients.

Sex differences in the utilization and outcomes of advanced heart failure therapies, including left ventricular assist devices (LVADs) and heart transplantation, are increasingly recognized. Female patients remain underrepresented among LVAD recipients, comprising only about 20% of patients, and are less likely than men to undergo heart transplantation after implantation ⁹⁵. Post-implantation, female patients experience higher mortality and more adverse events, including rehospitalization, bleeding, stroke, and device complications. Younger female patients (<50 years) are particularly affected, while outcomes are similar in those ≥65 years⁹⁵. Structural factors, such as delayed referral, lower access to specialized centers, and social determinants of health, further contribute to these disparities⁹⁶. These findings highlight the need for strategies to ensure equitable access and outcomes for female patients requiring advanced heart failure therapies.

Major gaps in our understanding of sex differences in DCM

Female-specific risk factors for DCM

There are observed sex-based differences in the prevalence and onset of DCM, which might partially be explained by genetic and environmental disease modifiers. Although we have gained insight into some of these factors, such as chemotherapy and alcohol consumption, sex-specific risk factors remain largely unknown. These risk factors might include hormonal fluctuations like hormonal contraception, pregnancy-related factors, such as pre-eclampsia, peripartum cardiomyopathy, lactation, and repeated hemodynamic stress, and menopause. The impact of female-specific risk factors on DCM onset and progression is poorly understood and are not currently incorporated into DCM management. Younger menarche age, premature menopause, and infertility are associated with heart failure risk, but their specific impact on DCM remains unclear⁹⁷. Menopause is a known period of accelerated coronary risk⁹⁸, yet its influence on DCM development is undefined. A comprehensive evaluation of reproductive risk factors represents an opportunity to identify individuals at risk for DCM and refine risk calculators for adverse outcomes, enabling better disease management and reducing the burden of DCM in females.

We have recently evaluated sex differences in the underlying genetic architecture of DCM. There appears to be a male predominance for most of the common genetic causes of DCM, with the exception of DSP cardiomyopathy which has a female predominance and has an earlier disease onset in females⁹⁹. Understanding the genetic and environmental drivers for why DSP appears to be more penetrant in females may help us gain insights into the sex specificity of DCM.

Sex differences in risk stratification

Females with DCM often exhibit a “milder-looking” phenotype, with less hypertrophy, fibrosis, and better cardiac function than males. However, despite this, females have a two-fold higher risk of adverse outcomes, such as cardiovascular death and heart failure, compared to males⁴⁴. Current risk stratification for DCM, including recommendations for ICDs, relies on a sex-agnostic threshold of LVEF <35%. This approach may under-treat females by failing to account for sex-specific differences in disease progression and outcomes.

Efforts to refine risk stratification are beginning to address these gaps. For instance, sex has been integrated into the LMNA cardiomyopathy risk prediction model, which estimates the likelihood of life-threatening arrhythmias in LMNA variant carriers⁷⁰. Similarly, risk prediction tools have been developed for DSP, FLNC, and PLN cardiomyopathies^{72, 100, 101}, enhancing individualized risk assessment by incorporating genotype-specific features and clinical variables. The incorporation of sex in such models underscores its relevance in predicting outcomes and guiding interventions in genetic forms of DCM.

Conclusion

Sex differences in DCM are observed in aspects of prevalence, age at onset, clinical presentation, risk factors, and outcomes, though the strength and consistency of these differences vary across domains. Despite significant strides in understanding DCM pathophysiology, current clinical care and risk stratification remain largely sex-neutral, potentially overlooking critical differences that influence disease progression and prognosis. Emerging evidence underscores the role of genetic, environmental, and reproductive factors in shaping sex-specific risks, but much remains unknown. Advancing DCM care requires prioritizing sex-specific research that will not only enhance outcomes for females but also provide more holistic and equitable care for all DCM patients.

Clinical Take-Home and Practical Considerations: Sex Differences in DCM. What Should Clinicians Consider?

• Increased vigilance is needed to diagnose DCM in females

Females might be underdiagnosed due to sex-neutral imaging thresholds and atypical presentations. Apply sex-specific volumetric criteria and recognize that symptoms may be more severe despite milder cardiac dysfunction.

• DCM differs significantly by sex across the disease course

Males more often carry TTNtv, LMNA, and RBM20 variants and present younger with arrhythmia; females more often carry DSP and sarcomeric variants and experience worse outcomes post-pregnancy. Clinicians should incorporate sex and variant type when counselling patients on disease trajectory.

• Sex and genotype must be evaluated together when assessing prognosis

  Meta-analysis shows that risk varies by both sex and gene:

  • LMNA confer greater malignant ventricular arrythmias risk in males.

  • BAG3, RBM20, and TTNtv confer greater heart failure risk in males.

  • Similar risk of arrhythmia and heart failure is observed in both male and female carriers of FLNC, PLN, DSP, and TNNT2 variants.

  • Risk stratification tools should reflect these results.

• Reproductive history directly influences DCM risk

Conditions like hypertensive disorders of pregnancy (HDP) double the risk of future DCM. Peripartum events worsen long-term outcomes in females with DCM. Ask about pregnancy history and monitor accordingly.

• Do not delay or de-escalate treatment in females

Despite better average LVEF and fewer scar findings, females remain at high risk for early adverse heart failure outcomes. Delayed initiation or dose down-titration based on “milder” phenotype may worsen outcomes.

• Sex-specific biology necessitates tailored management

Differences in immune modulation, hormone response, drug metabolism, and gene penetrance mean DCM management must be tailored by sex. Uniform dosing and thresholds may not yield equal benefit or safety. Clinicians should individualize therapy, monitor drug response, and adjust dosing considering sex-specific pharmacology.

• Equal access does not ensure uniform quality of care

Female patients are less likely to receive ICDs and advanced heart failure therapies,, despite comparable or higher risk in some genotypes. Apply clinical judgment to avoid undertreatment based on sex-neutral LVEF thresholds. Clinicians should advocate for equitable device therapy and consider individualized risk assessment beyond LVEF alone.

• Data inclusivity drives equitable and evidence-based care

Females are underrepresented in most DCM trials. Support and advocate for sex-stratified analyses, sex-specific risk tools, and inclusive study design to guide more equitable, evidence-based care.

Central Illustration.

Evaluating sex differences in dilated cardiomyopathy (DCM). DCM appears to be more common in males, but it is not clear if this is due to systematic under-diagnosis in females, or whether males are truly at higher risk. Our review explores the impact of sex on the epidemiology, presentation, and outcomes of disease. We summarize the latest research including a meta-analysis on sex differences in outcome and identify the gaps and inconsistencies in our current understanding of sex differences in DCM, as well as steps to resolve these. Original figure for this review.