G. Schiattarella

HFpEF in Asia Distinct Phenotypes, Shared Mechanisms, and Emerging Insights

HFpEF in Asia: Distinct Phenotypes, Shared Mechanisms, and Emerging Insights.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous, comorbidity-driven syndrome of increasing global prevalence, with Asian patients displaying a distinctive and clinically relevant epidemiologic and biological profile. Compared with Western cohorts, Asian patients are often younger and less overtly obese based on body mass index. However, they carry substantial burdens related to diabetes, chronic kidney disease, anemia, and hypertension, resulting in adverse health outcomes that are disproportionate to chronological age. Asian HFpEF shows marked region-specific patterns: Northeast Asian cohorts exhibit an older, leaner, atrial fibrillation-related phenotype, whereas South and Southeast Asian cohorts exhibit earlier onset, greater metabolic-renal multimorbidity, and worse prognosis. Mechanistically, visceral adiposity, systemic inflammation, immunometabolic dysregulation, structural remodeling, and accelerated cardiac aging converge to drive HFpEF across Asian patients, often at lower body mass index thresholds than recognized in Western models. Current diagnostic frameworks require Asian-specific validation, and dedicated multiomics and phenotyping studies are essential to advance precision medicine for HFpEF globally.

Frailty may confound the association between MASLD and cardiovascular mortality in people with cardiometabolic risk factors.

BACKGROUND While metabolic dysfunction-associated steatotic liver disease (MASLD) has been consistently associated with increased cardiovascular risk in the general population, its association with cardiovascular disease (CVD) mortality in adults with established cardiometabolic risk factor (including obesity, hypertension, diabetes mellitus, or dyslipidemia) remains inconsistent. We aimed to determine whether frailty confounds the MASLD-CVD mortality association. METHODS We analyzed 10,413 US NHANES III adults with ≥ 1 cardiometabolic risk factor. Frailty was quantified using a 49-item frailty index (FI, ranging from 0 [maximal robustness] to 1 [severe frailty]) and categorized into quartiles. Associations between MASLD and CVD mortality were assessed using multivariable Cox proportional hazards models with and without frailty adjustment. Interaction and mediation analyses were also performed. RESULTS Over a mean follow-up of 23.36 years, 1,375 (13.20%) CVD deaths occurred. Frailty was significantly associated with both MASLD and CVD mortality. There was no evidence of interaction between MASLD and frailty, and mediation analysis showed no indirect effect of MASLD on CVD mortality through frailty. In absence of frailty adjustment, MASLD was not associated with CVD mortality (HR = 0.92, 95% CI: 0.78-1.10). After adjustment for frailty, MASLD was independently associated with higher CVD mortality (HR = 1.19, 95% CI: 1.07-1.32). Stratified by FI quartiles, significant associations were observed only in the higher frailty quartiles (Q3: HR = 1.35, 95% CI: 1.03-1.77; Q4: HR = 1.70, 95% CI: 1.07-2.69). The population attributable fraction of MASLD for CVD mortality was 10.1-12.5% after frailty adjustment. CONCLUSIONS Frailty may confound the MASLD-CVD mortality relationship in people with cardiometabolic risk factors. The association between MASLD and CVD mortality is detected only when frailty is adjusted for.