The Natural History Investigation of In Vivo Human Coronary Endothelial Function and Atheroma Plaque Progression: Invasive Coronary Imaging Studies

Abstract

It has been well documented that coronary vasoconstriction, atheroma plaque burden, and ‘vulnerable’ plaque plays a critical role in the pathogenesis of acute coronary syndrome (ACS); yet, the dynamic interaction among these factors in vivo to date have not been evaluated, particularly in the longitudinal study. In this thesis, we described a series of in vivo experiments conducted within the intact epicardial coronary tree from patients who presented with unselected clinical presentation, with the aim to explore the underlying relationship between coronary atheroma burden, plaque composition, and coronary endothelial vasoreactive function. We particularly highlight the potential role of a novel intravascular ultrasound (IVUS) platform which co-register with near infrared spectroscopy (NIRS) in delineating plaque composition. Utilizing this technology allows us to examine the evolution of both grey scale measurement and coronary plaque composition over time. Contrary to currently available imaging platforms for plaque composition, such as virtual histology IVUS or optical coherence tomography (OCT) which is predominantly qualitative, NIRS measurements are automated and quantitative, allowing ready interpretation in the catheterization lab. Of the 2 introductory chapters, chapter 1 explores the developmental history, clinical indication, and research application of IVUS in the past three decades. Chapter 2 reviews the different resistance compartments of the coronary tree and the role of various pharmacological agent in the catheterization lab. This chapter also discusses the role of salbutamol in the evaluation of coronary endothelial function. Chapter 3-5 comprise the result section of this thesis. Chapter 3 describes the effectiveness of OCT in the evaluation of epicardial coronary endothelial function. OCT is known to have superior lateral resolution when compared to other intravascular imaging modalities currently available. In this chapter, we underscore the limitation of OCT, which relies on bolus contrast injection for blood clearance from the field of view, in the invasive coronary endothelial function assessment. A vast number of coronary vasoreactive agents, including salbutamol, are largely dependent on shear stress generated by the microvascular compartment to mediate conduit vessel vasodilation. Injection of contrast bolus at high rate hence may increase the shear stress generated and impact on the reliability of vasomotor response. Chapter 4 outlines the relationship between segmental coronary endothelial dependent and independent function with atheroma plaque volume and associated lipid rich necrotic composition in unselected patients who present with either stable chest pain syndrome or ACS. Utilizing NIRS, we demonstrated that coronary endothelial independent function in response to glyceryl trinitrate (GTN) was strongly associated with atheroma plaque volume irrespective whether the patient presented with stable chest pain or ACS. To a lesser extent, we also found a weak association between plaque containing lipid rich necrotic core with coronary endothelium independent vasodilator function. It was also surprising to note the lack of association between coronary endothelial dependent function with either atheroma volume or composition. Having reviewed previous data in the literature and scrutinised our findings, we concluded that adequate dosing of any vasoreactive agent is crucial to generate the desirable and appropriate vasomotor response. Chapter 5 describes our prospective and serial imaging analysis which aimed to identify the relationship between epicardial coronary vasomotor function and change in atheroma plaque volume and necrotic lipid laden core plaque, over time. Several key insights emerge from this experiment. We identified that epicardial coronary endothelial function seems to influence the progression of plaque volume and its composition in a unique manner. Whilst coronary endothelial dependent function was found to mediate plaque composition progression, the segmental coronary endothelial independent function was more associated with atheroma volume progression. Similar to previous observations, we also found baseline plaque burden and positive remodelling to influence formation of future fibroatheroma. Furthermore, baseline NIRS derived LCBI was independently predictive of both lipid core progression and plaque volume progression. Taken together, these findings underline the role of atheroma structure-vessel function in mediating the mechanism of atheroma plaque progression in intact human epicardial coronary tree and may provide an important prognostic tool in identifying patients who are at risk of developing future coronary event above and beyond the established cardiovascular risk predictive tools.