IRUS Total

The mechanistic role of MicroRNAs in takotsubo syndrome

File Description SizeFormat 
Couch-L-2018-PhD-Thesis.pdfThesis5.98 MBAdobe PDFView/Open
Title: The mechanistic role of MicroRNAs in takotsubo syndrome
Authors: Couch, Liam
Item Type: Thesis or dissertation
Abstract: Takotsubo syndrome (TTS) is a severe but reversible acute heart failure affecting predominantly post-menopausal women. Extreme adrenaline levels arising with stress cause ventricular apical akinesis with hypercontractility at the base. We have previously shown this is likely to occur due to β2AR-Gαi coupling, which is dysregulated in TTS. A microRNA (miR) profile, with increased miR-16 and miR-26a in TTS, has been identified that enables differentiation from both healthy control and ST-segment elevation myocardial infarction, which it closely resembles at patient presentation. We hypothesise that miR-16 and miR-26a functionally interact to predispose to or exacerbate the cardiodepression seen in TTS. miRs were modulated in vitro in adult rat cardiomyocytes using Lipofectamine 3000. Cardiomyocyte percentage shortening was measured using an Ionoptix system. TTS was induced in vivo by adrenaline bolus injection through the external jugular vein of an adult male Sprague-Dawley rat, and blood sampled at defined timepoints. miRs were modulated in vivo by AAV9 injection via tail vein (called AAV-control and AAV-miR) with subsequent TTS induction after 6 weeks. miR-16 and miR-26a specifically reduce baseline contractility of apical but not basal cardiomyocytes in vitro. This includes alterations in calcium handling, with reduced calcium transient amplitude and SR calcium content. Together, miR-16 and miR-26a reduce sensitivity to adrenaline in the apex, and amplify maximal response to adrenaline in the base, but do not change β2AR response. In vivo, in our established model of TTS, serum levels of miR-16 and miR-26a are not changed acutely by adrenaline. AAV-miR treatment produces greater hypokinesis in the apex and hypercontractility in the base. When investigating the mechanism of action, this includes altered G-protein signalling and calcium current activity. TTS-associated miRs represent novel molecules that clarify the pathogenesis of this curious condition. They predispose to TTS in vivo by promoting apical hypokinesia and basal hypercontractility. This occurs by reducing sensitivity to adrenaline in the apex and increasing maximal response to adrenaline in the base through alterations in G-protein signalling and calcium handling.
Content Version: Open Access
Issue Date: Sep-2018
Date Awarded: Jan-2019
URI: http://hdl.handle.net/10044/1/73216
DOI: https://doi.org/10.25560/73216
Copyright Statement: Creative Commons Attribution NonCommercial No Derivatives Licence
Supervisor: Harding, Sian
Terracciano, Cesare
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: FS/16/52/32259
Department: Faculty of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses