Plasma Circulating Extracellular RNAs in Left Ventricular Remodeling Post-Myocardial Infarction
Kirsty M. Danielson,
Ravi Shah,
Ashish Yeri,
Xiaojun Liu,
Fernando Camacho Garcia,
Michael Silverman,
Kahraman Tanriverdi,
Avash Das,
Chunyang Xiao,
Michael Jerosch-Herold,
Bobak Heydari,
Siddique Abbasi,
Kendall Van Keuren-Jensen,
Jane E. Freedman,
Yaoyu E. Wang,
Anthony Rosenzweig,
Raymond Y. Kwong,
Saumya Das
Affiliations
Kirsty M. Danielson
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Surgery & Anaesthesia, University of Otago, Wellington 6242, New Zealand
Ravi Shah
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Ashish Yeri
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Xiaojun Liu
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Fernando Camacho Garcia
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Michael Silverman
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Kahraman Tanriverdi
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
Avash Das
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Chunyang Xiao
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Michael Jerosch-Herold
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Bobak Heydari
Division of Cardiology, Department of Cardiac Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada
Siddique Abbasi
Noninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Kendall Van Keuren-Jensen
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
Jane E. Freedman
Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
Yaoyu E. Wang
Dana Farber Cancer Institute Center for Computational Biology, Harvard Medical School, Boston, MA 02115, USA
Anthony Rosenzweig
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Raymond Y. Kwong
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Saumya Das
Cardiology Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding author at: Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.
Despite substantial declines in mortality following myocardial infarction (MI), subsequent left ventricular remodeling (LVRm) remains a significant long-term complication. Extracellular small non-coding RNAs (exRNAs) have been associated with cardiac inflammation and fibrosis and we hypothesized that they are associated with post-MI LVRm phenotypes. RNA sequencing of exRNAs was performed on plasma samples from patients with “beneficial” (decrease LVESVI ≥ 20%, n = 11) and “adverse” (increase LVESVI ≥ 15%, n = 11) LVRm. Selected differentially expressed exRNAs were validated by RT-qPCR (n = 331) and analyzed for their association with LVRm determined by cardiac MRI. Principal components of exRNAs were associated with LVRm phenotypes post-MI; specifically, LV mass, LV ejection fraction, LV end systolic volume index, and fibrosis. We then investigated the temporal regulation and cellular origin of exRNAs in murine and cell models and found that: 1) plasma and tissue miRNA expression was temporally regulated; 2) the majority of the miRNAs were increased acutely in tissue and at sub-acute or chronic time-points in plasma; 3) miRNA expression was cell-specific; and 4) cardiomyocytes release a subset of the identified miRNAs packaged in exosomes into culture media in response to hypoxia/reoxygenation. In conclusion, we find that plasma exRNAs are temporally regulated and are associated with measures of post-MI LVRm. Keywords: Left ventricular remodeling, Myocardial infarction, microRNA, Extracellular RNA, Cardiac magnetic resonance imaging, RNA sequencing, And inflammation
