Circulating microRNAs for predicting and monitoring response to mechanical circulatory support from a left ventricular assist device

Abstract

AimsThere are few non-invasive techniques to predict and monitor patients' responses to left ventricular assist device (LVAD) therapy. MicroRNAs (miRs) are small non-coding RNAs with intricate roles in cardiovascular disease. They are stable in the circulation, readily quantified, and may be useful as new biomarkers. This study sought to identify candidate miR biomarkers for further investigation.Methods and resultsWe studied 53 plasma and 20 myocardial samples from 19 patients who underwent HeartMate II LVAD implantation, and used a screening microarray to analyse the change in expression of 1113 miRs after 6 months LVAD support. Twelve miRs showed significant variation and underwent validation, yielding miR-1202 and miR-483-3p as candidate biomarkers. In the test cohort, circulating miR-483-3p showed early and sustained up-regulation with LVAD support, with median (interquartile range) fold changes from baseline of 2.17 (1.43–2.62; P = 0.011), 2.27 (1.12–2.42; P = 0.036), 1.87 (1.64–4.36; P = 0.028), and 2.82 (0.70–10.62; P = 0.249) at 3, 6, 9, and 12 months, respectively, whilst baseline plasma miR-1202 identified good vs. poor LVAD responders [absolute expression 1.296 (1.293–1.306) vs. 1.311 (1.310–1.318) arbitrary units; P = 0.004]. Both miRs are enriched in ventricular myocardium, suggesting the heart as the possible source of the plasma fraction.ConclusionsThis is the first report of circulating miR biomarkers in LVAD patients. We demonstrate the feasibility of this approach, report the potential for miR-483-3p and miR-1202, respectively, to monitor and predict response to LVAD therapy, and propose further work to study these hypotheses and elucidate roles for miR-483-3p and miR-1202 in clinical practice and in underlying biological processes.

miR-483-3p regulates hyperglycaemia-induced cardiomyocyte apoptosis in transgenic mice

“…For example, miR-483-5p has been reported to control angiogenesis in vitro by targeting the transcription factor SRF1 and it is a potential therapeutic target for improving neovascularization in ischemic heart disease [14]. Abue et al proposed that miR-483-3p in blood could be a potential biomarker that can be used to predict the heart function after getting a left ventricular assist device [25]. However, there was no specific evidence to demonstrate the function of miR-483-3p in regulating cardiomyocyte apoptosis in diabetic cardiomyopathy.…”

“…In vascular smooth muscles, abundantly found in blood vessels, angiotensin II-regulated miR-483-3p negatively affects homeostasis between the components of the renin-angiotensin system [24]. It has also been suggested that circulating miR-483-3p can serve as a potential biomarker in predicting and monitoring patient response to left ventricular assist device therapy [25]. However, there are no reports describing the function of miR-483-3p in diabetes-associated heart disease.…”

Elevated serum microRNA 483-5p levels may predict patients at risk of post-operative atrial fibrillation

“…Recent work by Morley-Smith et al . [26] has demonstrated an acute and sustained increase in circulating mir-483-3p (which originates from the opposite arm of the same pre-miRNA as miR-483-5p) in heart failure patients after left ventricular assist device insertion, mirroring suppression of NT-pro-BNP secretion. Alongside our results, these findings may suggest that transcription of serum pre-miRNA-483 may be stimulated in states of cardiac stress, the mature products of which may then be detected in the systemic circulation.…”

August 2016 at a glance: the new ESC guidelines, and pathophysiology, epidemiology and prognosis of heart failure

“…Marques et al have measured microRNAs in arterial and coronary sinus venous samples in healthy volunteers and HF patients . Upregulation or downregulation of different microRNAs and cardiac release of micro‐RNAs was found in the failing hearts, compared with controls, confirming the potential role of microRNAs as biomarkers and/or targets of treatment …”