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Title: The effects of xanthine oxidase inhibitors on left ventricular mass and endothelial function in patients with ischaemic heart disease
Author: Rekhraj, Sushma
ISNI:       0000 0004 5365 9036
Awarding Body: University of Dundee
Current Institution: University of Dundee
Date of Award: 2014
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Left ventricular hypertrophy is a marker of poor prognosis that commonly affects patients with ischaemic heart disease. It has been associated with an increased risk of all-cause mortality and cardiovascular events including myocardial infarction, heart failure, stroke and arrhythmias. Previous studies of mainly antihypertensive therapies have shown left ventricular hypertrophy to be a reversible risk factor. The LIFE study has shown LVH regression per se to be associated with reduced cardiovascular morbidity and mortality, independent of blood pressure reduction. Therefore, novel ways of regressing left ventricular hypertrophy, independent of blood pressure, in patients with IHD could reduce cardiovascular events and mortality in this patient group. Allopurinol is a xanthine oxidase inhibitor that received FDA approval in 1966 and has been used primarily as a prophylactic treatment for gout. It is a safe, well tolerated drug with minimal side effects. There are a number of reasons why allopurinol may reduce LV mass in patients with LVH and IHD. Firstly, allopurinol has been shown to regress LV mass in animal studies and more recently in patients with CKD. Secondly, LV afterload is the main determinant of LV mass. Previous studies have shown allopurinol to improve LV afterload by improving arterial stiffness and arterial compliance, which may result in regression of LV mass. Thirdly, patients with IHD have increased levels of oxidative stress, which contribute to both endothelial dysfunction and left ventricular hypertrophy. Xanthine oxidase is a major producer of reactive oxygen species and allopurinol therapy, being a xanthine oxidase inhibitor, has been shown to reduce vascular oxidative stress. This was a randomized, double-blinded, placebo controlled study of 66 patients with IHD and LVH, prescribed allopurinol 600mg/day or placebo therapy over a 9 month follow up study period. LV mass was measured at baseline and 9 months using cardiac magnetic resonance imaging. At baseline, 6 months and 9 months, measurements were made of endothelial function using flow-mediated dilatation and assessments of arterial stiffness by measuring augmentation index and pulse wave velocity using applanation tonometry. In this study, we demonstrated high dose allopurinol therapy over a 9 month treatment period to significantly regress LV mass, improve endothelial dysfunction and measurements of arterial stiffness without a significant reduction in BP. The improvement in endothelial function and regression of LV mass demonstrated in this study with high dose allopurinol suggests that allopurinol might reduce cardiovascular events and mortality. Future studies should investigate if this beneficial effect of allopurinol on LV mass, being a surrogate marker, results in a beneficial effect on harder clinical end points such as cardiovascular events and mortality.
Supervisor: Struthers, Allan Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available