Characterisation of cardiac cellular and vascular function in Ischemic heart disease

Bushdyhan, M 2021, Characterisation of cardiac cellular and vascular function in Ischemic heart disease , MRes thesis, University of Salford.

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Ischemic heart disease (IHD) is the most common cause of death across the globe, of which global mortality rates are projected to continue rising into the future. Therapies used to treat the most chronic cases of IHD are focused on the revascularisation of the ischemic region and the subsequent restoration of blood flow. As such, the most prevalent therapeutic option is the coronary artery bypass graft (CABG). In these procedures, the internal mammary artery (IMA) is deemed to be the “gold standard” vascular model for use in grafting, offering a better patency (over 90%) than the next most frequently used model, the saphenous vein (SV). Prior to bypass grafting, endogenous adipose deposits (perivascular adipose tissue or PVAT) surrounding the arteries are removed. PVAT acts as an endocrine organ and has vast and complex interactions with its surrounding tissues, aiding in the maintained health, reactivity and function of its underlying vasculature. Subsequently, PVAT and its functions are directly and often negatively impacted in cardiovascular disease, sometimes driving and worsening disease states. PVAT exerts its effects via the production and secretion of adipocyte-derived cytokines (adipokines), of which there are numerous, eliciting a myriad of functions. One such mechanism of influence is the enzyme eNOS, an important protein responsible for generating nitric oxide (NO), which plays an important role in mediating healthy PVAT and vascular function, though it also becomes dysregulated in obesity. With these considerations, the aim of this study is to identify the potential for PVATs usage in revascularisation procedures, in an effort to improve successful patient outcomes post-surgery. This will be performed by investigating PVATs role on vascular contractility in the conductance vessels used in bypass grafting, and secondarily by investigating the role and importance of eNOS in bypass graft vessels. In collaboration with the Blackpool Victoria Hospital, human IMA and SV samples were provided for human tissue trials, which we supported with data from murine aortic control and eNOS knockout (eNOS-/-) models, by assessing the contractile and distensile properties via myography based assays. In control murine models it was observed that PVAT presence elicited a pro-contractile effect when subjected to noradrenaline (NA) dose responses (P = 0.0058, n = 10) compared to PVAT-removed controls under the same test conditions, showing PVAT’s potential to effect vasoconstriction in response to a pro-contractile factor. Further investigation into the mechanisms regarding NA-induced contractility and PVAT’s perceived contractile augmentation effect led to us to observe that these contractile events are not influenced by beta-3 adrenergic receptor (β3ADR) interactions (and subsequent NO release) (+PVAT models: P = 0.9064; -PVAT models: P = 0.9064, n = 8), nor are they affected by the pro-contractile adipokine chemerin (P = 0.0564, n = 9), suggesting this phenomenon is removed of both these mechanisms, though it was observed that in PVAT-removed models subjected to a chemerin blocker that contractility increased (P = 0.0137, n = 9). The same NA dose response assays were also performed on eNOS-/- models, in which the same pro-contractile effect of PVAT was observed (P = 0.0295, n = 10), which further suggests no NO involvement in the perceived augmentation effect. Early, proof-of-concept myography testing of human models was able to be performed and optimised, based around the same NA dose response assays as used within our murine models, from which future studies can be based and rapidly scaled from. The results of this study gave new insights into the vascular reactivity to vasoconstrictors in murine models, allowing us to extrapolate information to human models. PVAT’s perceived pro-contractile effects challenge our previous understanding regarding its functionality as a vascular endocrine organ and how it could affect vascular function and revascularisation, leading to new questions and exciting avenues of research.

Item Type: Thesis (MRes)
Contributors: Withers, SB (Supervisor)
Schools: Schools > School of Environment and Life Sciences
Depositing User: Matthew Bushdyhan
Date Deposited: 05 Aug 2021 08:20
Last Modified: 05 Sep 2021 02:30

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