Holdright, Diana R.; (1994) An in vivo assessment of endothelium-dependent vasodilatation and coronary flow reserve in human coronary arteries in health and disease. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Coronary vasomotor responses to endothelium-dependent and endothelium-independent agents have been examined in man in specific conditions in which they may be altered, namely syndrome X, idiopathic dilated cardiomyopathy and coronary artery disease studied at the time of angioplasty. Coronary blood flow was measured using an intracoronary Doppler flow probe and quantitative angiography. The Doppler probe was validated in vitro. Measurements of coronary blood flow velocity depended on the location of the Doppler crystal, which was either side-mounted or end-mounted. Velocities measured with both probes correlated with known velocities over a wide range, but absolute velocities were significantly overestimated using the side-mounted probe. Additional experiments revealed considerable variation in the mounting angle of the side-crystal, which would cause velocity to be overestimated. Quantitative angiography was performed on data acquired either digitally or on cinefilm. The accuracy and precision of measurements made from a phantom validation were similar for both modalities. Intraobserver variability and the variability of repeated measurements over time were small. Endothelium-dependent responses of large coronary arteries, measured as the change in epicardial coronary artery dimension to acetylcholine and substance P, were not impaired in a group of patients with syndrome X compared with a control group. Coronary blood flow velocities and calculated coronary blood flow to acetylcholine and substance P were lower in syndrome X patients compared with a control group, suggesting that endothelium-dependent vasodilator responses in the resistance vessels may be impaired in some patients. Measurements of coronary flow reserve and coronary vascular resistance index with adenosine and papaverine were similar in syndrome X patients but responses to dipyridamole were lower. These results suggest that certain features of syndrome X result from alterations within the resistance vessels. Endothelium-dependent vasodilatation in response to substance P, measured as the change in epicardial coronary artery area, coronary blood flow velocity and calculated coronary blood flow, was demonstrated in both large and small coronary arteries in heart failure patients. These findings contrast with other studies that have shown significantly impaired responses to acetylcholine. Several in vitro studies have demonstrated selective attenuation of acetylcholine-induced dilatation with preservation of substance P responses. Although responses to acetylcholine were not determined in the patients reported in this thesis, the demonstration of endothelium-dependent responses to substance P suggests that the muscarinic receptor and/or transduction mechanism is particularly vulnerable in chronic heart failure. Coronary flow reserve measured with papaverine in patients with idiopathic dilated cardiomyopathy was not significantly different from a control group, but examination of individual responses revealed considerable variation. There was no correlation between coronary flow reserve and various parameters of left ventricular function, including left ventricular end-diastolic pressure, maximum oxygen consumption with exercise and radionuclide left ventricular ejection fraction. Despite the presence of overt atheroma, vasodilatation of epicardial coronary arteries, measured prior to angioplasty at stenotic sites and at sites proximal and distal to the stenosis, could be demonstrated in response to substance P. Angiographically successful coronary angioplasty of a discrete stenosis improved, but did not normalise, coronary flow reserve measured as the response to papaverine. Papaverine dilated stenotic segments prior to angioplasty, whereas vasoconstriction occurred following the procedure. There was a significant negative correlation between the degree of vasodilatation occuring prior to angioplasty with papaverine and the magnitude of the constrictor response after angioplasty. Alterations of vasomotor tone may explain why some patients develop features suggestive of myocardial ischaemia in the absence of restenosis.

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