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

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.

Colesevelam enhances the beneficial effects of brown fat activation on hyperlipidaemia and atherosclerosis development.

AIMS: Brown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development. METHODS AND RESULTS: APOE*3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective ß3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged ß3-AR agonism reduced faecal BA excretion (-31%), while markedly increasing plasma levels of total BAs (+258%), cholic acid-derived BAs (+295%), and chenodeoxycholic acid-derived BAs (+217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (-49%) and non-high-density lipoprotein cholesterol (-56%), tended to further attenuate atherosclerotic lesion area (-54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (+34%) and decreased the relative macrophage area within the lesion (-26%), thereby further increasing the plaque stability index (+44%). CONCLUSION: BA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases.