Characterisation of cardiac cellular and vascular function in Ischemic heart disease

Ischemic heart disease (IHD) is the most common cause of death across the globe, of which globalmortality rates are projected to continue rising into the future. Therapies used to treat the mostchronic cases of IHD are focused on the revascularisation of the ischemic region and the subsequentrestoration of blood flow. As such, the most prevalent therapeutic option is the coronary artery bypassgraft (CABG). In these procedures, the internal mammary artery (IMA) is deemed to be the “goldstandard” vascular model for use in grafting, offering a better patency (over 90%) than the next mostfrequently used model, the saphenous vein (SV). Prior to bypass grafting, endogenous adiposedeposits (perivascular adipose tissue or PVAT) surrounding the arteries are removed. PVAT acts as anendocrine organ and has vast and complex interactions with its surrounding tissues, aiding in themaintained health, reactivity and function of its underlying vasculature. Subsequently, PVAT and itsfunctions are directly and often negatively impacted in cardiovascular disease, sometimes driving andworsening disease states. PVAT exerts its effects via the production and secretion of adipocyte-derivedcytokines (adipokines), of which there are numerous, eliciting a myriad of functions. One suchmechanism of influence is the enzyme eNOS, an important protein responsible for generating nitricoxide (NO), which plays an important role in mediating healthy PVAT and vascular function, though italso becomes dysregulated in obesity.With these considerations, the aim of this study is to identify the potential for PVATs usage inrevascularisation procedures, in an effort to improve successful patient outcomes post-surgery. Thiswill be performed by investigating PVATs role on vascular contractility in the conductance vessels usedin bypass grafting, and secondarily by investigating the role and importance of eNOS in bypass graftvessels. In collaboration with the Blackpool Victoria Hospital, human IMA and SV samples wereprovided for human tissue trials, which we supported with data from murine aortic control and eNOSknockout (eNOS-/-) models, by assessing the contractile and distensile properties via myography basedassays.In control murine models it was observed that PVAT presence elicited a pro-contractile effect whensubjected to noradrenaline (NA) dose responses (P = 0.0058, n = 10) compared to PVAT-removedcontrols under the same test conditions, showing PVAT’s potential to effect vasoconstriction inresponse to a pro-contractile factor. Further investigation into the mechanisms regarding NA-inducedcontractility and PVAT’s perceived contractile augmentation effect led to us to observe that thesecontractile events are not influenced by beta-3 adrenergic receptor (β3ADR) interactions (andsubsequent NO release) (+PVAT models: P = 0.9064; -PVAT models: P = 0.9064, n = 8), nor are theyaffected by the pro-contractile adipokine chemerin (P = 0.0564, n = 9), suggesting this phenomenon isremoved of both these mechanisms, though it was observed that in PVAT-removed models subjectedto a chemerin blocker that contractility increased (P = 0.0137, n = 9). The same NA dose responseassays were also performed on eNOS-/- models, in which the same pro-contractile effect of PVAT wasobserved (P = 0.0295, n = 10), which further suggests no NO involvement in the perceivedaugmentation effect. Early, proof-of-concept myography testing of human models was able to beperformed and optimised, based around the same NA dose response assays as used within our murinemodels, 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 murinemodels, allowing us to extrapolate information to human models. PVAT’s perceived pro-contractileeffects challenge our previous understanding regarding its functionality as a vascular endocrine organand how it could affect vascular function and revascularisation, leading to new questions and excitingavenues of research.

Level dc:type.qualificationlevel

Master's Level (Level 7)

Year dc:date.issued

2021

Author dc:creator

• Bushdyhan, M

Language dc:language

en

Identifier

oai:salford-repository.worktribe.com:1339058

OAI identifier oai:identifier

oai:salford-repository.worktribe.com:1339058