| dc.description.abstract | Introduction: Heart failure (HF) is associated with significant morbidity and mortality. Targeting chronic inflammation as a therapeutic has been challenging, despite a key role in HF pathophysiology. Dysfunction of the canonical (classical) pathway of nitric oxide (NO) generation occurs in HF, with resultant endothelial dysfunction and chronic inflammation. Provision of dietary inorganic nitrate and bioactivation via the non-canonical pathway may redress the NO deficit and offer therapeutic potential, including reduction in a marker of both inflammation and adverse prognosis in HF, uric acid (UA). This thesis investigated the anti-inflammatory mechanisms of inorganic nitrate and therapeutic utility of restoring NO in patients with HF. Methods: Blister-NITRATE was a randomised, double-blind, placebo-controlled study of dietary nitrate supplementation versus nitrate-deplete placebo beetroot juice in 36 healthy male volunteers (NCT03183830). The cantharidin-induced blister model was utilised to characterise the anti-inflammatory mechanisms of dietary nitrate acutely (24-hours) and at resolution (72-hours). DiNOmo-HF is a randomised, double-blind, placebo-controlled study of 12-weeks of dietary nitrate supplementation in 92 symptomatic HF patients (NCT03511248). It is powered to identify a significant reduction in UA (as a pro-inflammatory marker) and improved cardiac function. Results: Blister-NITRATE delivered a 12.2mmol daily dose of inorganic nitrate causing physiologically relevant increases in plasma nitrite concentration. The Intervention led to statistically significantly increases in blister resolution at 72-hours. This was associated with reductions in inflammatory and intermediate monocytes, reduced expression of key adhesion markers (CD11b, CD62L and CD162) and a 50% reduction in neutrophil infiltrate. This was heralded at 24-hours by less activated intermediate monocytes and reduced TNF. DiNOmo-HF continues to recruit. Substantial issues with recruitment persist and refinement of inclusion criteria is key for trial continuation. Discussion: Treatment with inorganic nitrate does not impair the essential host defence response, but does accelerate resolution. This is driven by enhanced pro- to anti-inflammatory monocyte switching and curtailed neutrophil recruitment, likely via attenuated TNF production. This may have therapeutic potential in patients with HF. | en_US |
