Sex differences in circulating microRNA profiles in heart failure with preserved and reduced ejection fraction

Circulating microRNAs (miRNAs) are informative markers of heart failure (HF); however, sex differences in HF-associated miRNA changes remain unclear. We performed sex-stratified analyses to assess whether HF-associated circulating miRNA changes differ by sex in HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).

In this prospective multicentre cohort study in Japan, we analysed 235 participants, including 82 controls (41 males and 41 females), 76 patients with HFpEF (39 males and 37 females), and 77 patients with HFrEF (54 males and 23 females). Unbiased whole-blood miRNA sequencing detected 1767 unique miRNAs, of which 229 were retained for the primary analysis after abundance filtering. Age- and body mass index (BMI)-adjusted differential-expression analyses identified 50 miRNAs in males with HFpEF and 59 miRNAs in males with HFrEF, whereas no miRNAs reached statistical significance in females with either HF phenotype. Importantly, HF-associated log2 fold changes in males and females were positively correlated for both HF phenotypes, although the absolute magnitudes of change were greater in males than in females, indicating partly shared directions of change between sexes. Age- and BMI-adjusted permutational multivariate analysis of variance revealed more pronounced phenotype-associated differences in global miRNA profiles in males than in females; these findings were consistent across alternative abundance filters.

Sex-stratified analyses of circulating miRNAs in HFpEF and HFrEF showed that HF-associated expression changes were consistently more pronounced in males than in females. These findings highlight the importance of sex stratification when interpreting circulating miRNA alterations in HF.

UMIN000052673 (UMIN Clinical Trials Registry; observational study).