The role of endothelial progenitor cell in the aetiology and pathogenesis of coronary artery disease

The primary aims of the work undertaken in this thesis were to examine whether there is genetic regulation of EPC number and / or function and to determine if EPC dysfunction precedes the onset of CAD. In additional studies, the role that EPCs play in two relevant coronary pathologies - in-stent restenosis (ISR) and coronary collateralisation - was examined. Finally, an exploratory analysis was undertaken to determine if cellular senescence, assessed by telomere length, impacts on EPC function. A total of 162 subjects were studied including 24 healthy parent-healthy offspring pairs and 27 CAD parent-healthy offspring pairs for the principle objectives. The relationships between EPCs and ISR and coronary collateralisation were studied in 21 and 39 subjects, respectively. In all subjects, the number of circulating CD34+VEGFR-2+ and AC133+VEGFR-2+ EPCs, the number of EPCs grown in vitro, and the migration capacity of cultured EPCs towards VEGF were determined. There was significant correlation in the number of cultured EPCs between parents and their offspring (Healthy: R=0.492, p=0.015; CAD: R=0.751, p<0.001) Offspring of subjects with CAD had significantly higher numbers of circulating CD34+VEGFR-2+ and AC133+VEGFR-2+ cells than offspring of healthy subjects (p=0.018 and p<0.001, respectively). There was no striking relationship between EPC number or function and either ISR or degree of coronary collateralisation. Telomeres were significantly shorter in offspring of subjects with CAD than offspring of healthy subjects (5.7 +/- 0.2 kb vs 6.7 +/- 0.7 kb, p < 0.001). There was no association between telomere length and EPC function. EPC number is at least partly genetically regulated. Circulating EPC number may represent biological markers of occult vascular damage in offspring with hereditary risk of CAD

Effect of AZD9977 and spironolactone on serum potassium in heart failure with preserved or mildly reduced ejection fraction, and renal impairment: A randomized trial.

This phase Ib study compared the effects of AZD9977, a selective mineralocorticoid receptor modulator with predicted low hyperkalemia risk, with spironolactone on serum potassium (sK+ ) in patients with heart failure (HF) with preserved or mildly reduced ejection fraction (EF; ≥40%), and renal impairment. Patients with HF with EF greater than or equal to 40% and estimated glomerular filtration rate of 40-70 ml/min/1.73 m2 were randomized to once-daily AZD9977 100 mg or spironolactone 25 mg for 14 days, up-titrated to AZD9977 200 mg or spironolactone 50 mg for another 14 days. The primary end point was relative change (%) in sK+ for AZD9977 versus spironolactone (baseline to day 28). Serum/urinary electrolytes, fractional excretion (FE) of Na+ /K+ , plasma aldosterone, cortisol, and renin, and safety were also assessed. Sixty-eight patients were randomized (AZD9977, n = 33; spironolactone, n = 35). Mean (SD) age was 73.0 (8.5) years, 51.5% men. Mean sK+ change from baseline to day 28 was 5.7% (AZD9977) and 4.2% (spironolactone), and 1.5% and 4.2% at day 14. Relative change (95% confidence interval) in sK+ with AZD9977 versus spironolactone was -0.3% (-5.3% to 4.4%; day 28), and 3.4% (-0.8% to 7.5%; day 14). Median increase from baseline in plasma aldosterone at day 28 was 89.8 pmol/L for AZD9977 and 67.4 pmol/L for spironolactone. Median FE of K+ was 12.9% (AZD9977) and 10.1% (spironolactone). AZD9977 was well-tolerated. No discontinuations due to hyperkalemia occurred with either treatment. Evidence of target engagement for AZD9977 with a favorable safety profile, supports further evaluation of AZD9977 in patients with HF and renal impairment