2016VANEZISAPPHD.pdf (77.28 MB)
Remote Ischaemic Conditioning and its Effect on Maladaptive Cardiac Remodelling Following Myocardial Infarction
thesisposted on 2016-11-14, 09:59 authored by Andrew Peter Vanezis
Remote ischaemic conditioning (rIC) has shown benefit in protecting the myocardium from ischemia/reperfusion injury. However it’s potential to attenuate maladaptive remodelling post myocardial infarction (MI) associated with the development of heart failure is less well investigated. Using cellular models of endothelin-1 (ET-1) driven hypertrophy and fibrosis, we investigated the role that serum taken from healthy volunteers undergoing rIC (rICserum) had on various markers of both hypertrophy and fibrosis as well as attempting to elucidate some of the mechanisms involved. Furthermore we established a clinical trial to assess the degree to which repeated rIC post-MI can positively influence heart failure outcomes. Hypertrophy was assessed by measuring H9c2 cardiomyoblast cell size using immunofluorescence, protein to DNA ratio and by abrogation of the expression of the pro-hypertrophic foetal genes BNP, βMHC, α-ACT and MS-1. This anti-hypertrophic mechanism was shown include the activation of the PKCε/AMPKα/eNOS/cGMP pathway and up-regulation of the anti-hypertrophic microRNAs miR-1 and miR-133. RIC-serum was also shown to attenuate ET-1 induced markers of fibrosis including differentiation of fibroblasts to pathological myofibroblasts and proliferation of fibroblasts in a neonatal rat cardiac fibroblast model. Both unconditioned serum and rICserum attenuated ET-1 induced expression of α-SMA and increased the expression of MMP-2 and TIMP-1 but neither had any effect on ET-1 induced MMP-9. Unconditioned serum also proved to have weak anti-hypertrophic properties which were greatly augmented by rIC. Increasing age diminished the innate protection afforded by unconditioned-serum and individuals with high levels of physical activity displayed higher levels of innate protection from hypertrophy akin to rIC. Finally we describe the design and management of the DREAM study (Daily Remote Ischaemic Conditioning Following Acute Myocardial Infarction), a phase 2 randomised control trial established to evaluate the role of repeated rIC post-MI in modulating maladaptive cardiac remodelling with the presentation of some preliminary secondary outcome data.
Supervisor(s)Rodrigo, Glenn; Samani, Nilesh
Date of award2016-11-10
Author affiliationDepartment of Cardiovascular Sciences
Awarding institutionUniversity of Leicester