Pathophysiological understanding of HFpEF: microRNAs as part of the puzzle

Abstract

Half of all heart failure patients have preserved ejection fraction (HFpEF). Comorbidities associated with and contributing to HFpEF include obesity, diabetes and hypertension. Still, the underlying pathophysiological mechanisms of HFpEF are unknown. A preliminary consensus proposes that the multi-morbidity triggers a state of systemic, chronic low-grade inflammation, and microvascular dysfunction, causing reduced nitric oxide bioavailability to adjacent cardiomyocytes. As a result, the cardiomyocyte remodels its contractile elements and fails to relax properly, causing diastolic dysfunction, and eventually HFpEF. HFpEF is a complex syndrome for which currently no efficient therapies exist. This is notably due to the current one-size-fits-all therapy approach that ignores individual patient differences. MicroRNAs have been studied in relation to pathophysiological mechanisms and comorbidities underlying and contributing to HFpEF. As regulators of gene expression, microRNAs may contribute to the pathophysiology of HFpEF. In addition, secreted circulating microRNAs are potential biomarkers and as such, they could help stratify the HFpEF population and open new ways for individualized therapies. In this review, we provide an overview of the ever-expanding world of non-coding RNAs and their contribution to the molecular mechanisms underlying HFpEF. We propose prospects for microRNAs in stratifying the HFpEF population. MicroRNAs add a new level of complexity to the regulatory network controlling cardiac function and hence the understanding of gene regulation becomes a fundamental piece in solving the HFpEF puzzle.

Heart Failure with Preserved Ejection Fraction—a Concise Review

“…Compared to patients with HFrEF, patients with HFpEF have significantly higher blood pressure ( p = 0.04), lower resting heart rate, and lower levels of potassium in the plasma [ 16 ]. Many studies point out that patients with HFpEF are usually older women with hypertension [ 15 , 16 , 18 , 19 ]. Indeed, arterial hypertension is one of the main factors leading to increased stiffness of blood vessels and increased afterload of LV [ 20 ].…”

“…Although the pathophysiology of HFpEF is yet to be understood, systemic low-grade inflammation, mediated through tumor necrosis factor (TNF) alpha and transforming growth factor (TGF) beta 1, was proposed as a cause of disease [ 18 , 30 ]. However, the degree of diffuse myocardial fibrosis is not related to the severity of impairment of diastolic function in HFpEF [ 31 ].…”

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

“…In the setting of HFpEF, the X-linked miR-545-5p differentiated HFpEF patients from healthy controls 15 while X-linked miR-221 distinguished HFpEF patients from patients with heart failure with a reduced ejection fraction (HFrEF) 16 . Nonetheless, statistical analysis of these miR expression results were not stratified for women and men, and the identified miRs were not related to molecular pathways involved in microvascular injury 17 . In this study, plasma miR-34a levels were decreased in diabetic patients with LVDD, while miR-34a, -224 and -452 were decreased in diabetic women with LVDD and an eGFR < 60 ml/min.…”

Transcriptomic Research in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives

“…23 At the molecular level, gene expression produces messenger RNA Therefore, they have become attractive targets for biomarker studies and may potentially be used as treatment targets in the future. 24,25 The lncRNAs act as transcriptional factors and are more tissue specific than mRNA. Generally, lncRNAs have been less well-studied in human pathophysiology, because of methodological limitations in the past.…”