Non-coding RNAs in the pathophysiology of heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is the largest unmet clinical need in cardiovascular medicine. Despite decades of research, the treatment option for HFpEF is still limited, indicating our ongoing incomplete understanding on the underlying molecular mechanisms. Non-coding RNAs, comprising of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are non-protein coding RNA transcripts, which are implicated in various cardiovascular diseases. However, their role in the pathogenesis of HFpEF is unknown. Here, we discuss the role of miRNAs, lncRNAs and circRNAs that are involved in the pathophysiology of HFpEF, namely microvascular dysfunction, inflammation, diastolic dysfunction and cardiac fibrosis. We interrogated clinical evidence and dissected the molecular mechanisms of the ncRNAs by looking at the relevant in vivo and in vitro models that mimic the co-morbidities in patients with HFpEF. Finally, we discuss the potential of ncRNAs as biomarkers and potential novel therapeutic targets for future HFpEF treatment.

Keywords: HFpEF; HFpEF pathophysiology; biomarkers; circRNAs; lncRNAs; non-coding RNAs: miRNAs; therapeutic targets.

Figure 1

Pathophysiology of HFpEF. HFpEF patients are older, mostly female, and exhibit a higher burden of non-cardiac comorbidities, such as DM, obesity, hypertension and renal dysfunction. These comorbidities lead to systemic inflammation, causing microvascular damage. This drives endothelial dysfunction, leading to reduced NO levels, higher infiltration of monocytes and activation of cardiac resident macrophages, which express profibrotic factors TGFβ, IFNγ, Galectin-3 and CTGF, leading to proliferation and activation of cardiac fibroblasts, promoting the deposition of ECM proteins and collagen. Endothelial dysfunction also impairs paracrine signaling of CMECs to cardiomyocytes. Cardiomyocyte remodeling is also evident from cardiomyocyte hypertrophy, altered calcium handling, increased energy consumption and increased passive stiffness. Eventually, this leads to diastolic dysfunction and HFpEF. DM, diabetes mellitus; CRP, C-reactive protein; CMEC, cardiac microvascular endothelial cell; CM, cardiomyocyte; ECM, extracellular matrix; NO, nitric oxide; HFpEF, heart failure with preserved ejection fraction.

Figure 2

Involvement of ncRNAs in HFpEF pathophysiology. miRNA, microRNA; lncRNA, long non-coding RNA; circRNA, circular RNA; ⊣, inhibition; →, activation.