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Background: Neurohormonal activation in heart failure (HF) may be associated with adverse outcomes. Overall beta blockers (BB) reduce the risk of death and hospital admissions in HF. The SENIORS study showed that Nebivolol, a beta-1 antagonist with vasodilating properties. reduced composite risk of all cause mortality or cardiovascular admissions [OR 0.86, 95% CI 0.740.99; P=0.039] in 2135 patients ?7Oyrs with stable heart failure and a broad range of LV ejection fractions. The subgroup analysis showed the main reduction ih risk of death appears to be in those with lower LVEF & age ~75 yrs with least in >75yrs & LVEF>35%.. However the underlying mechanisms of benefit of BB in HF. and possible effects on neurohormones and cytokines remain poorly und~rstood especially in elderly patients. Aim and Hypothesis: We therefore investigated the effects of a beta-1 receptor antagonist (Nebivolol) on natriuretic peptides. endothelin-1. norepinephrine, nitric oxide markers of endothelial function. markers of apoptosis and ventricular remodelling in a subgroup of patients enrolled into the SENIORS trial. Our primary hypothesis was that nebivolol would reduce levels of NT- Pro Brain Natriuretic peptides compared to placebo. Methods: Patients?70 years with dinical evidence of chront HF. who were enrolled into the main randomised SENIORS trial were eligible for the substudy. A subgroup of patients was enrolled without further randomisation into the substudy. We measured levels of NT-Pro Brain natriuretic peptide(Pro-NT BNP), Pro Atrial natriuretic peptide (Pro-ANP), Endothelin-1(ET-1), peripheral norepinephrine(PNE). soluble Fas (sFas), soluble Fas-ligand (sFas-L). Tumour necrosis factor-alpha (TNF-a). Tumour necrosis factor receptor-1 (TNFR1), serum uric acid (SUA) and Asymmetrical dimethyl argi'1ine (ADMA) at baseline (before study drug). at 6 months and 12 months. Samples were stored at -20�°C or lower and sent to core laboratory for analysis. LVEF was measured at baseline and 12 months. NYHA class at 12 months was also compared in the 2 groups. Results: 106 patients with an overall response rate of 85% were enrolled into this substudy. However. there were 19 drop outs by 12 months of follow-up. 8 samples each at baseline and at 6 months were either missing or received in unsatisfactory condition. Analysis was carried out on 75 patients at baseline, 74 patients at six months and 71 patients at 12 months follow up. Mean age was 76 yrs and 80% had prior CAD. Baseline characteristics including treatments were similar in the 2 arms. Mean baseline LVEF was 35% but after 12 months mean LVEFwas 43% on Nebivolol group and 34% on placebo (P=0.01). There was improvement observed in the NYHA class in both the groups but there was more improvement in the patients on Nebivolol. There were no significant differenceS in all ten neurohormones and cytokines measured between the two groups at six or twelve months. although non-significant trends were observed by 12 months in most. NT-Pro BNP showed a slight increase in Nebivolol group and decrease in patients on placebo (P=O.08). Pro-ANP showed slight decrease in the mean level in patients from the nebivolol group. Mean leve!s of sTNFR-1 was observed to increase in both the groups by 12 months. sFas showed a trend towards slight increase in patients on placebo (P=0.08). Fas-L levels showed reduction in the placebo group. ET-1 increased slightly in both the groups. However PNE did decrease slightly in the Nebivolol group. SUA levels were seen to increase marginally in the Nebivolol group. Correlation analyses of the changes in levels of the 10 parameters and LVEF and NYHA class from baseline till 12 months showed only weak correlations. Limitations: Patients were entered into the substudy based on their availability and therefore the comparison of nebivolol versus placebo in the substudy was not strictly randomised. The number of patients enrolled was below our original sample size estimate and the standard deviations of the measurements were much larger than expected. Both of these aspects mean that study power was low to detect differences between the two groups. Conclusion: There were no clear differences in the results between patients allocated nebivolol or pla~bo for NT pro BNP ~r other markers. This may be because in reality beta blockers do not have consistent effects on these biomarkers, or that our study was too underpowered to show genuine effects. Other studies have also failed to show clear effects of beta blockers on NT pro BNP and therefore further work is needed to darify the effects of beta blockers Ort the neurohormonal sY$tem in heart failure

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