Celermajer, David Stephen; (1993) Non-invasive studies of arterial physiology in children and adults at risk of atherosclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Atherosclerosis is the leading cause of death in the Western World. In clinical practice, treatment and risk factor modification usually begin only after complications of advanced disease have occurred. Pathology studies, however, have shown that atherogenesis begins much earlier and may be evident in the first decade of life. This thesis describes the development of a non-invasive method to study arterial physiology in children and adults, in order to detect early signs of vascular disease in-vivo, in presymptomatic subjects. Endothelial dysfunction is a key early event in the initiation and progression of atherosclerosis in experimental studies, preceding formation of plaques. We have used high resolution ultrasound to study endothelial and smooth muscle function in systemic arteries in man. Arterial diameter responses to reactive hyperaemia (with increased flow causing endothelium-dependent dilatation) were compared to the responses to sublingual nitroglycerine (which acts independently of endothelial function). Phantom studies have confirmed the precision of diameter measurements (accurate to 0.1-0.2mm), and serial studies have shown reproducible results within patients between visits (coefficient of variation ≅2.0%). Studies on over 200 control subjects without vascular risk factors showed that flow- mediated dilatation (FMD) occurs, and is inversely related to vessel size (r=-0.80, <0.001). The effect of ageing on arterial physiology was also assessed, and FMD was impaired in normal men older than 40 years and women older than 50 years. Twenty adults with established atherosclerosis all had impaired endothelium-dependent dilatation. Over 400 clinically well children and young adults with recognised risk factors were then studied, including children with familial hypercholesterolaemia and young adult smokers. In most, FMD was reduced compared to the relevant controls, whereas nitroglycerine- induced dilatation was preserved. Conclusions. Endothelium-dependent dilatation is impaired in children and adults with risk factors for atherosclerosis, such as smoking and hypercholesterolaemia. The availability of a non-invasive method for studying arterial physiology will facilitate prospective investigation of the progression or reversibility of early vascular disease.

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