The in vivo evaluation of coronary atheroma and endothelium-dependent vasomotor reactivity in humans with coronary artery disease: studies utilizing intravascular ultrasound.

Abstract

Although many consider plaque burden and vasoconstriction as critical components of ‘vulnerable’ coronary atheroma, their intrinsic relationship in vivo remains relatively unexplored. This thesis, presented as a series of experiments conducted in intact humans with coronary artery disease, explores the fundamental in vivo relationships between coronary atheroma volume, composition and topography in relation to underlying segmental epicardial coronary endothelium-dependent vasomotor reactivity. The contributions of segmental wall shear stress (WSS), and the first-in-man assessment of left main coronary arterial endothelium-dependent vasomotor reactivity and its determinants, are also explored. A novel feature was the utility of intravascular ultrasound (IVUS) for all coronary structural and functional assessments. In these experiments, IVUS was pivotal in enabling the first-in-man validation of intracoronary salbutamol as a novel epicardial endothelium-dependent stimulus. Of the 3 introductory chapters, chapters 1 and 2 outline the utility of IVUS for exploring coronary atherosclerosis and ‘vulnerable’ plaques. Chapter 3 draws specific attention to the nature of endothelium-dependent stimulus required to safely explore, with greater precision, the coronary structure-function relationship in humans in vivo. Chapters 4-9 comprise the results sections of this thesis. Chapter 4 outlines the utility of ‘provocation intravascular imaging’ [IVUS-upon-Doppler Flowire imaging during simultaneous intracoronary (IC) infusions] to validate IC salbutamol as a novel endothelium-dependent epicardial coronary and microvascular stimulus. Chapter 5 describes the coronary structure-function relationship in patients with stable, minimally diseased coronary arteries (i.e. the population studied in chapter 4) compared with patient with non ST-segment elevation myocardial infarction (NSTEMI). Irrespective of the nature of clinical presentation, the magnitude of segmental lumen vasoreactivity, controlled for by the degree of atheroma volume, did not differ. Our results also suggested possible interactions between systemic inflammation and coronary atheroma in mediating coronary vasomotor reactivity. Utilizing a custom-built IVUS console to deliver radio-frequency IVUS signals, Chapter 6 outlines the relationship between plaque composition and segmental vasomotor reactivity in the NSTEMI population evaluated in chapter 5. Both the volumes of lipidic and necrotic core composition predicted vasoconstriction, whereas greater fibrotic plaque predicted vasodilatation. Chapter 7 describes a unique investigation into in vivo relationships between segmental WSS, arterial remodeling and vasomotor function in paients with stable, minimally diseased coronaries (population studied in chapter 4). Independent of plaque burden, WSS directly related to vasomotor reactivity, and inversely to arterial remodeling. Regions of high plaque burden associated with lower WSS, expansive remodeling and greater plaque eccentricity, thus providing a novel link between these known individual features of plaque vulnerability. Chapter 8 outlines the first-in-man description of left main coronary arterial (LMCA) vasomotor reactivity, in comparison to downstream epicardial segments. The study population comprised of all patients across study protocols who underwent left-sided coronary imaging with evaluable matched LMCA images. LMCA and proximal epicardial segments were least reactive, compared to more distal conduit segments, which may relate to higher WSS in smaller caliber distal segments. These results may also explain the propensity for culprit plaques to cluster proximally in humans. Chapter 9 describes a unique comparison of in vivo lumen dimensions measured with IVUS, Fourier-domain optical coherence tomography (FD-OCT) and 3D quantitative coronary angiography (3D-QCA). Lumen dimensions were greater with IVUS compared to FD-OCT and 3D-QCA, and were magnified within smaller coronary segments. We concluded that specific cut-off values validated with IVUS should not be arbitrarily translated into the OCT hemisphere for clinical decision making.