Characterisation of cardiac cellular and vascular function in Ischemic heart disease

Bushdyhan, M

Abstract

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.

Citation

Bushdyhan, M. Characterisation of cardiac cellular and vascular function in Ischemic heart disease. (Dissertation). University of Salford

• Thesis Type: Dissertation
• Deposit Date: Aug 5, 2021
• Publicly Available Date: Aug 5, 2021
• Award Date: Jul 6, 2021