Hemodynamic and transcriptomic studies suggest early left ventricular dysfunction in a preclinical model of severe mitral regurgitation

• Type of Material: Article
• Authors: Daniella Corporan, Emory University Hospital Midtown; Daisuke Onohara, Emory University; Alan Amedi, Emory University Hospital Midtown; Maher Saadeh, Emory University Hospital Midtown; Robert Guyton, Emory University; Sandeep Kumar, Emory University; Muralidhar Padala, Emory University
• Language: English
• Date: 2021-03-01
• Publisher: MOSBY-ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jtcvs.2020.08.119
• Title of Journal or Parent Work: JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
• Volume: 161
• Issue: 3
• Start Page: 961
• End Page: +
• Keywords: Cardiac & Cardiovascular Systems; Life Sciences & Biomedicine; mitral regurgitation; ventricular remodeling; Science & Technology; Surgery; primary mitral regurgitation; Cardiovascular System & Cardiology; heart murmur; ejection fraction; neo-chordoplasty; mitral valve prolapse; Respiratory System

Abstract

Objective: Primary mitral regurgitation is a valvular lesion in which the left ventricular ejection fraction remains preserved for long periods, delaying a clinical trigger for mitral valve intervention. In this study, we sought to investigate whether adverse left ventricular remodeling occurs before a significant fall in ejection fraction and characterize these changes. Methods: Sixty-five rats were induced with severe mitral regurgitation by puncturing the mitral valve leaflet with a 23-G needle using ultrasound guidance. Rats underwent longitudinal cardiac echocardiography at biweekly intervals and hearts explanted at 2 weeks (n = 15), 10 weeks (n = 15), 20 weeks (n = 15), and 40 weeks (n = 15). Sixty age- and weight-matched healthy rats were used as controls. Unbiased RNA-sequencing was performed at each terminal point. Results: Regurgitant fraction was 40.99 ± 9.40%, with pulmonary flow reversal in the experimental group, and none in the control group. Significant fall in ejection fraction occurred at 14 weeks after mitral regurgitation induction. However, before 14 weeks, end-diastolic volume increased by 93.69 ± 52.38% (P < .0001 compared with baseline), end-systolic volume increased by 118.33 ± 47.54% (P < .0001 compared with baseline), and several load-independent pump function indices were reduced. Transcriptomic data at 2 and 10 weeks before fall in ejection fraction indicated up-regulation of myocyte remodeling and oxidative stress pathways, whereas those at 20 and 40 weeks indicated extracellular matrix remodeling. Conclusions: In this rodent model of mitral regurgitation, left ventricular ejection fraction was preserved for a long duration, yet rapid and severe left ventricular dilatation, and biological remodeling occurred before a clinically significant fall in ejection fraction.