Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, affecting approximately 30% of the global population [1]. Metabolic dysfunction plays a pathogenic role in the development of NAFLD and advanced liver morbidities, while the term NAFLD has limitations as it does not consider metabolic factors [2]. Therefore, in 2023, metabolic dysfunction-associated steatotic liver disease (MASLD) was proposed to replace NAFLD to highlight the close association with the metabolic syndrome and enhance our understanding of the underlying pathophysiology [3]. Epidemiological evidence suggests that MASLD is an independent risk factor for cardiovascular disease (CVD) [4]. Vascular physiology is potentially sex-specific across the life course and women often show greater sensitivity in vascular response to chronic metabolic exposures than men [5]. However, sex-specific associations between MASLD and CVD remains incompletely understood. We aimed to assess the sex-specific relationships of MASLD with long-term risk of CVD.

We analyzed data from 502,411 individuals who participated in the UK Biobank study between 2006 and 2010. According to the recently published expert consensus recommendations [6], the presence of MASLD was defined as hepatic steatosis index >30, or an ICD (International Classification of Diseases) code for NAFLD plus a metabolic risk factor, excluding individuals drinking alcohol >140 grams per week (women) or >210 grams per week (men), or those with alcohol dependency or a non-NAFLD cause of liver disease. Moreover, those who had CVD or cancer at baseline were also excluded. A total of 140,716 men and 196,414 women were included in the current analysis, among whom 110,465 men and 151,195 women had prevalent MASLD. The outcomes of interest were any new-onset CVD and specific cardiovascular outcomes including coronary heart disease, myocardial infarction, ischemic stroke, hemorrhagic stroke, heart failure, atrial fibrillation, and CVD mortality, which were assessed through algorithm definitions, death registrations, and hospital inpatient data summaries, as reported elsewhere [7]. We used multivariable Cox proportional hazards regression models to estimate sexspecific hazard ratios (HRs) and 95% confidential intervals (CIs) of the cardiovascular outcomes associated with the presence of MASLD. Covariates included age, race/ethnicity, Townsend deprivation index, smoking status, packyears of smoking (for current smokers), alcohol consumption, and total physical activity. For women, the analyses were further adjusted for menopausal status and ever use of hormone replacement therapy. Interactions between MASLD and sex were tested in the multivariable models with interaction terms by likelihood ratio test. As menopausal women are more prone to metabolic dysfunction than non-menopausal women, we repeated the sex-specific analysis by including women who self-reported as having been menopausal at baseline and the age-matched men.

Median follow-up time was 11.7 years for men and 12.2 years for women. Among men, 21,811 participants (17,730 [16.1%] in MASLD and 4,081 [13.5%] in non-MASLD participants) developed incident CVD. Among women, 17,453 participants (14,410 [9.5%] in MASLD and 3,043 [6.7%] in non-MASLD participants) developed incident CVD. After the multivariable adjustment, MASLD was associated with a higher risk of total CVD in both sexes, with HRs (95% CIs) of 1.23 (1.19–1.27) in men and 1.26 (1.20–1.31) in women, with no evidence of sex difference (P_interaction=0.17) (Fig. 1A). MASLD was also associated with a higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation regardless of sex (all P_interaction ≥0.05). However, MASLD was associated with a higher risk of ischemic stroke in women (HR 1.21; 95% CI 1.08–1.37) but not in men (HR 1.07; 95% CI 0.97–1.17) (P_interaction=0.019). MASLD was not associated with atrial fibrillation or CVD mortality in either sex. These MASLD-CVD associations in men and women were similar in the analyses that included menopausal women and the age-matched men (Fig. 1B).

Men and women have apparent physiological disparities, which may contribute to the sex differences in the prevalence, risk factors, and progression of CVD [8]. Applications of the updated MASLD nomenclature to investigate the sex-specific relationships with cardiovascular outcomes may have important clinical implications for better understanding the pathogenesis of CVD and further optimizing the prevention strategies for CVD. Recent epidemiological findings have shown that the associations between hepatic steatosis and vascular events were significantly stronger in women than in men, possibly indicating that the presence of metabolic disturbance might disproportionately affect female cardiovascular health [9,10]. One nationwide cohort study from Korea found that the relationship between MASLD and incident CVD was more pronounced in men than in women [11]. However, in the present analysis of UK adults, MASLD was associated with a higher risk of total CVD and several specific cardiovascular outcomes similarly for women and men. The inconsistency of the findings may be related to the more evident sex-specific distributions of unhealthy lifestyles and metabolic dysfunctions in East Asians than in European population [12]. The observed women-only association between MASLD and risk of ischemic stroke merits future verification in additional studies especially those including multiethnic populations. Our findings contribute to the limited evidence on the sex-specific relationships between MASLD and cardiovascular outcomes, and may inform future preventive and therapeutic strategies that incorporate MASLD as a CVD risk factor.