Abstract 24075: Heart Failure Induced Upregulations of MicroRNAs in the Human Sinoatrial Node Associated with Pacemaker Dysfunction

Abstract

Background: Heart failure (HF), a leading cause of morbidity and mortality, involves significant dysfunction of the sinoatrial node (SAN). MicroRNAs (miRs) are abundant, non-coding RNAs that ultimately regulate protein expression at the post-transcriptional level and have been implicated in HF. However, nothing is known about the distribution and expression of miRs in the human SAN as well as their roles in regulating pacemaker channels and SAN dysfunction (SND) in HF. Methods: The human SAN was isolated and cryopreserved from failing hearts with implantable pacemakers (n=5) or non-diseased donor hearts (n=3) that were cardioplegically arrested in the surgery room. Utilizing immunohistochemistry, the intact 3D intramural SAN structure was precisely identified as the fibrotic region around the SAN artery containing Connexin43-negative pacemaker cardiomyocytes (Figure). Small biopsies from the central SAN compartment were used to characterize the expression pattern of 14 miRs and their associated pacemaker channels. Ingenuity software (Qiagen) was used to predict the relationship between miRs and their targeted mRNA of SAN ion channels Results: Out of 14 studied miRs, 3 miRs (mir-370-3p miR-133-3a and miR-1) were significantly upregulated in SAN, but not in atria, during HF. We found that mir-370-3p was predominantly expressed in the human SAN, but not atria. Whereas, both miR-133-3a and miR-1 were highly expressed in atria vs SAN. All three miRs were predicted to regulate pacemaker HCN1 and/or HCN4 channel expression. RT-PCR showed that HCN1 and HCN4 mRNA were downregulated in the HF SAN. Conclusions: This is the first study to explore the miRs profiles in healthy and diseased human SAN with SND. We demonstrate that miR-370, miR-133a and miR-1, thought to regulate SAN pacemaker HCN channel expression, are selectively upregulated in human HF SAN. We propose that understanding the function of miRs in human SAN might lead to novel SND treatments.