Olivia Ziegler, Ravi Shah, Kirsty Danielson, Chun Yang Xiao, Dustin Rabideau, Kristina Hanspers, Venkatesh Murthy, Arianna Belcher, Michael Tackett, Pablo Pinzon-Quintero, Avash Das, Alexander Pico, James Januzzi, and Saumya Das
Introduction: Left ventricular reverse remodeling (LVRR) in heart failure (HF) is linked to improved patient outcomes. Current strategies to identify individuals who respond favorably to therapy in HF are limited. Though circulating microRNAs (miRs) show epigenetic regulation of LVRR in vivo , there is little clinical data linking plasma-circulating miRs to LVRR. Here we employ a point-of-care microRNA assay, Firefly, in silico analyses, and murine models of HF to characterize profiles of circulating miRs that prognosticate LVRR in patients with HF undergoing guideline directed therapy. Hypothesis: Profiles of miRs in circulating plasma will prognosticate LVRR in patients with HF better than the current clinical model alone and may play a functional role in LVRR. Methods: Plasma from 64 patients from the PROTECT study who had serial echocardiography and available plasma at pre-randomization study visit were run on Abcam’s Firefly platform to assay levels of 51 miRs, selected on prior sequencing efforts (for discovery) and published roles in CVD. miR levels were subject to PC analysis to predict LVRR. Candidate miRs were then validated in a murine model of transverse aortic constriction-induced heart failure (TAC-HF) and their function assessed in cardiomyocyte culture systems. Results: Principle component analysis revealed 4 PCs accounting for 62.4% of the observed variation without significant association with extant markers of HF. When PC2 miR levels were added to the clinical model prognostic ability for LVRR improved substantially (AIC 79.5, (OR=6.84, 95% CI 1.81-25.80, P= 0.005). In silico analysis was then applied to generate networks of mRNAs regulated by PC2 miRs. In the murine TAC-HF model, miRs 423, 212, 221, 193b were differentially regulated, as were the predicted targets of these miRs. These miRs, particularly in combination, appeared to be regulators of cardiac hypertrophy in vitro . Conclusions: Circulating miR profiles in HF improve prognosticative ability for patients who will undergo LVRR over the clinical model alone. Additionally these miRs and their targets are dynamically regulated in murine models of HF, suggesting they may have functional and potential therapeutic utility in addition to their prognostic power.