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Title: Investigating the effects of inorganic nitrate on vascular function, inflammation and platelet reactivity in healthy volunteers and patients with stable angina
Author: Rathod, K. H. S.
ISNI:       0000 0004 7962 4966
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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This thesis is studying nitric oxide (NO) as a fundamental basis for health and disease and investigating as well as modifying its properties for therapeutic purposes. In the UK, nearly 3.5 million people have angina symptoms or have had a myocardial infarction (MI), or both. The mainstay treatment for reducing the symptoms of angina and long-term risk of MI in patients with heart disease is stent implantation in the diseased coronary artery. While this procedure has revolutionised treatment, the incidence of secondary events remains a concern. These repeat events are thought to be due, in part, to an increased inflammatory state that predisposes to continued enhanced platelet reactivity, endothelial dysfunction, and ultimately restenosis of the stented artery. In addition, CVD in general including atherosclerotic disease occurs at a lower incidence in premenopausal females compared with age-matched males. There has been considerable interest in why this might be the case but whether sex differences in inflammation underlie these differences is uncertain. Greater understanding of the role of inflammation and strategies that might selectively reduce inflammation within the CVD setting may offer novel approaches to therapeutics. Thus, I prospectively investigated whether inflammation and components of the inflammatory response are altered in females compared with males using two healthy volunteer studies. In the first study, I assessed systemic inflammatory markers and vascular function using brachial artery flow-mediated dilation (FMD). Typhoid vaccine induced mild systemic inflammation at 8 hours, reflected by increased white cell count in both sexes. Systemic inflammation in turn caused a decrease in FMD in males, but an increase in females, at 8 hours. To investigate the differences in inflammatory responses between the sexes further in a separate study, I measured inflammatory exudate mediators and cellular recruitment in cantharidin-induced skin blisters. At 24 hours, cantharidin formed blisters of similar volume in both sexes; however, at 72 hours, blisters had only resolved in females. The activation state of all major leukocytes was lower in blisters of females, which was associated with enhanced levels of the resolving lipids. Together these findings suggest that in females, resolution of inflammation is accelerated compared with males, and that within the cardiovascular system this is likely to result in improved vascular function. The second part of my thesis studies was focussed on using the techniques established in the healthy volunteer studies to investigate whether a once a day inorganic nitrate (NO3-) administration might, through modification of inflammatory pathways, favourably modulate platelet reactivity and endothelial function leading to a decrease in restenosis. This was conducted in the form of the NITRATE-OCT study, which is a phase II trial enrolling 246 patients with stable angina due to have elective stent implantation. Patients have been randomised to receive 6 months of a once a day dose of either NO3--rich beetroot juice or NO3--deplete beetroot juice (placebo) before their procedure. The primary outcome is reduction of in-stent late loss assessed by quantitative coronary angiography (QCA) and optical coherence tomography (OCT) at 6 months. Thus far, we have baseline demographic data for 200 patients in total and the study is still ongoing to ensure the investigators remain blinded. At baseline there were no significant differences in demographic or procedural characteristics between the two groups.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: inorganic nitrate ; Cardiovascular Biomedical Research ; angina