Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury

Barend W Florijn,Marc E A Spaanderman,Frans H Rutten,Roel Bijkerk,Gideon B Valstar,Roxana Menken,Jacques M G J Duijs,Anton Jan Van Zonneveld,Maarten J Cramer,Arco J Teske,Chahinda Ghossein-Doha,Hester M Den Ruijter

doi:10.1038/s41598-020-70848-8

Abstract

Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a, -224 and -452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R2 0.04, R = 0.21, p = 0.001, 95% CI 0.103–0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a, -224 and -452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a, -224 and -452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF.

Highlights

Abbreviations MiR MicroRNA HFpEF Heart failure with preserved ejection fraction heart failure with a reduced ejection fraction (HFrEF) Heart failure with a reduced ejection fraction left ventricular diastolic dysfunction (LVDD) Left ventricular diastolic dysfunction diabetes mellitus (DM) Diabetes mellitus X-linked X-chromosome located XIST X-inactive-specific transcript Ang-2 Angiopoietin-2 soluble fms-like tyrosine kinase-1 (sFlt-1) Plasma soluble Flt-1 soluble trombomodulin (sTM) Plasma soluble thrombomodulin PE Preeclampsia
Our main findings were (1) decreased levels of miR-34a, -224 and -452 in diabetes patients with LVDD and in female diabetes patients with an estimated glomerular filtration rate (eGFR) < 60 ml/min but increased plasma miR-224 and miR-452 in diabetic women with HFpEF versus diabetic men with HFpEF; (2) regression analysis demonstrated that sex, DM and renal dysfunction are associated with plasma miR-34a levels in patients with LVDD; and (3) Increased levels of plasma Ang-2 in diabetic women with HFpEF but not in diabetic men with HFpEF
MiRs are extensively involved in manifestations of microvascular injury following type 2 DM14

Summary

Introduction

Abbreviations MiR MicroRNA HFpEF Heart failure with preserved ejection fraction HFrEF Heart failure with a reduced ejection fraction LVDD Left ventricular diastolic dysfunction DM Diabetes mellitus X-linked X-chromosome located XIST X-inactive-specific transcript Ang-2 Angiopoietin-2 sFlt-1 Plasma soluble Flt-1 sTM Plasma soluble thrombomodulin PE Preeclampsia. We demonstrated that a select subset of circulating angiogenic miRs (among others miR-126, miR-130b, miR-223 and miR-660) are increased in plasma derived from diabetic nephropathy patients (both women and men) and associate with microvascular injury, as defined by elevated plasma levels of Ang-2 levels[8]. The present study hypothesizes that sex-specific plasma miRs are differentially expressed in (female) patients with HFpEF and its precursor LVDD (in particular in patients with diabetes) and associate with microvascular injury (defined by elevated plasma Ang-2 levels) (Fig. 1A).

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Conclusion