Abstract Body (Do not enter title and authors here): Background
Heart failure with mildly reduced ejection fraction (HFmrEF), defined by a left ventricular ejection fraction (LVEF) of 41–49%, is a transitional state between preserved (HFpEF) and reduced (HFrEF) ejection fractions. Postmenopausal women are disproportionately affected, likely due to reduced cardioprotective estrogen. The impact of hormone replacement therapy (HRT) on HFmrEF remains ambiguous.
Objective
To assess the effects of HRT on clinical outcomes, cardiac remodeling, and use of guideline-directed medical therapy (GDMT) in postmenopausal women with HFmrEF.
Methods
A PRISMA-guided literature review was conducted across PubMed, Embase, Cochrane, Scopus, and SciSpace. Twenty studies—including systematic reviews, meta-analyses, and observational cohorts—met inclusion criteria, focusing on postmenopausal women aged 45–65 with heart failure. Due to limited HFmrEF-specific data, findings from HFrEF populations were included due to historical classification overlap. Primary outcomes included echocardiographic parameters, natriuretic peptides, hospitalizations, and GDMT use. Due to heterogeneity across studies, a narrative synthesis approach was used.
Results
A meta-analysis of 25,047 women found no significant association between HRT and incident heart failure. However, in women with existing HF, HRT was linked to a 35% reduction in all-cause mortality (RR 0.65; 95% CI, 0.49–0.87; p = 0.003). Transdermal estradiol improved diastolic function, reducing E/e′ ratios and left atrial volume index. Conversely, a systematic review reported no significant effect on first HF hospitalization (RR 1.02; 95% CI, 0.94–1.10), suggesting limited preventative value. A meta-analysis of 33 trials (n = 44,639) found no mortality reduction overall, although early HRT use improved endothelial function. Women with HFmrEF or HFrEF were 23% less likely than men to receive GDMT (HR 0.77; 95% CI, 0.71–0.83), especially RAS inhibitors and β-blockers. Estrogen may enhance RAS inhibitor efficacy via nitric oxide and aldosterone modulation, though caution is advised due to potential hypotension and hyperkalemia.
Conclusion
Transdermal HRT, particularly estradiol, may provide structural and clinical benefits for postmenopausal women with HFmrEF. Underuse of GDMT in this group highlights a persistent care gap. Further sex-specific research is needed to clarify HRT's role and optimize outcomes in women with HFmrEF.