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Title: The influence of nitric oxide and nitrite on coronary vascular resistance, platelet function and inflammation in patients undergoing revascularisation after NSTEMI and stable angina
Author: Freeman, Philip
ISNI:       0000 0004 7426 6725
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2018
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Coronary blood flow (CBF) is principally controlled by changes in coronary vascular resistance (CVR). Low CVR helps to maintain myocardial perfusion in the presence of epicardial stenosis, therefore factors that impair the reduction of CVR will have a direct effect on CBF leading to either a narrower “effective” perfusion pressure range or reduced ability to compensate for increased demand on myocardial contraction. There are several mechanisms which may be important in the control CVR in humans including both endothelial dependent production of NO and reduction of the simple anion inorganic nitrite (a metabolite of NO) back to NO (via several putative mechanisms). The synthesis of NO by both nitric oxide synthase (NOS) and the reduction of nitrite in the coronary circulation has been the subject of many animal and human clinical studies. Reduced systemic endothelial dependent production of NO has an association with worse cardiovascular outcomes in humans, the number of potential mechanisms are large and perhaps central is the effect on CVR. The reduction of nitrite to NO is seen, in some ways, to be the perfect compensatory mechanism, particularly when endothelial function is impaired. It is easy to hypothesise that this stoichiometric balance of NO production might be responsible for the perfect regulation of CVR and thus CBF. Methods This thesis investigates the influence and effect of both endothelial production of NO and the reduction of nitrite to NO on CVR in man. First, an observational study assessing the impact of these mechanisms in patients undergoing percutaneous coronary intervention (PCI), in the treatment of both non-ST-elevation myocardial infarction and stable angina. Specifically, the metabolites of NO were measured from aortic root to coronary sinus together with the associated CVR both before and after PCI. Second, using a systemic infusion of sodium nitrite (NaNO2) in NSTEMI patients to assess the effect of nitrite reduction on CVR during PCI. The systemic nitrite concentration was increased 8-fold in the same experimental conditions as the observational study. Third, beyond CVR control the influence of NO and nitrite was also assessed in terms of platelet reactivity and systemic inflammatory cytokines in the NSTEMI cohort both with and without NaNO2 infusion. Results NSTEMI patients have a net increase in NO metabolites across the coronary circulation unlike healthy controls (historical data) and stable angina patients. This net increase is lost following PCI and is associated with a significant rise in CVR. Stable angina patients appear to compensate with increase collateral circulation and not NO synthesis. An 8-fold increase in nitrite concentration has no effect on CVR or platelet reactivity in NSTEMI patients. Conclusions In NSTEMI patients a net aorta to coronary sinus NO synthesis appears to be important to maintain a low CVR and thus CBF when haemodynamically significant epicardial disease is present. After the epicardial disease is treated this net increase in NOx (Nitric Oxide metabolites), is lost and is associated with an acute increase in CVR. Stable angina patients have no net increase in NOx across the coronary circulation and after revascularisation have no change in CVR, this may reflect an alternate mechanism of compensation and microvascular perfusion maintained by collateral circulation as evident by the increase CFI. Despite the perfect environment for the reduction of nitrite to NO we saw no influence of an 8-fold increase in serum nitrite concentration on CVR in patients with NSTEMI either before or after PCI, suggesting that nitrite reduction to NO plays no role in CBF regulation in NSTEMI patients. Nitrite reduction depends on conditions that are found predominantly in the capillary bed or venules, thus any mechanism would need to rely on a feedback mechanism to signal back to the arterioles (where much of resistance change is created). Despite hypotheses by others that this may occur by the close arrangement of venules to arterioles, this appears not to be the case in NSTEMI patients. Other clinically relevant and important mechanisms also appear to be unaffected by this increase in serum nitrite, residual platelet function and cytokine concentrations at 24 hours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available