Effects of nebivolol on biomarkers in elderly patients with heart failure.

BACKGROUND: Heart failure activates neurohormones, and elevated levels of brain natriuretic peptide (BNP) are associated with adverse outcomes. The SENIORS trial showed that nebivolol, a highly selective beta-1 antagonist with vasodilating properties, reduced the composite outcome of all cause mortality or cardiovascular hospital admissions in older patients with heart failure. We explored the effects of nebivolol on a range of neurohormones, cytokines and markers of nitric oxide activity in heart failure. METHODS: In a subset of patients in SENIORS we measured N-terminal pro-brain natriuretic peptide (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-α), serum uric acid (SUA), symmetrical dimethyl arginine (SDMA), arginine, citrulline and asymmetrical dimethyl arginine (ADMA) at baseline (before study drug), at 6 months and 12 months in a prespecified substudy. RESULTS: One hundred and six patients were enrolled and 75 had a baseline and at least one follow-up sample. There were no significant differences in neurohormone cytokines or nitric oxide markers measured between the two groups at six or twelve months. NT-ProBNP showed a numerical increase in the nebivolol group compared to placebo (P=0.08) and sFas showed a numerical increase in patients on placebo (P=0.08). Mean baseline LVEF was 35% in both groups and at 12 months was 43% on nebivolol group and 34% on placebo group (P=0.01). CONCLUSION: There were trends but no clear changes associated with nebivolol in neurohormones, cytokines or markers of nitric oxide activity in this study of elderly patients with heart failure. Further studies are needed to understand the mechanistic effects of beta blockers on biomarkers in heart failure

FASTTRACK Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)

Aims Large randomized trials have shown that beta-Mockers reduce mortality and hospital admissions in patients with heart failure. The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain. The SENIORS study was performed to assess effects of the beta-blocker, nebivolol, in patients >= 70 years, regardless of ejection fraction. Methods and results We randomly assigned 2128 patients aged >= 70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction 35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74-0.99; P=0.039]. There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71-1.08; P=0.21). Conclusion Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly

The myosin activator omecamtiv mecarbil: a promising new inotropic agent

Heart failure became a leading cause of mortality in the past decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin-angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na+/K+ pump, b-receptor agonists and phosphodiesterase inhibitors. Theoretically, Ca2+ sensitizers may also increase cardiac contractility without resulting in Ca2+ overload nevertheless their mechanism of action is frequently complicated by other pleiotropic effects. Recently a new positive inotropic agent, the myosin activator omecamtiv mecarbil has been developed. Omecamtiv mecarbil binds directly to b-myosin heavy chain and enhances cardiac contractility by increasing the number of the active force-generating cross-bridges, presumably without major off-target effects. This review focuses on recent in vivo and in vitro results obtained with omecamtiv mecarbil, and discusses its mechanism of action at a molecular level. Based on clinical data, omecamtiv mecarbil is a promising new tool in the treatment of systolic heart failure.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

FASTTRACK Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)

Aims Large randomized trials have shown that beta-blockers reduce mortality and hospital admissions in patients with heart failure. The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain. The SENIORS study was performed to assess effects of the beta-blocker, nebivolol, in patients 70 years, regardless of ejection fraction.Methods and results We randomly assigned 2128 patients aged 70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction 35%), 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily), and 1061 to placebo. The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). Analysis was by intention to treat. Mean duration of follow-up was 21 months. Mean age was 76 years (SD 4.7), 37% were female, mean ejection fraction was 36% (with 35% having ejection fraction .35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74–0.99; P ¼ 0.039]. There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71–1.08; P ¼ 0.21). Conclusion Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly

Experience from controlled trials of physical training in chronic heart failure. Protocol and patient factors in effectiveness in the improvement in exercise tolerance. European Heart Failure Training Group

BACKGROUND: Beneficial effects of physical training on exercise tolerance, autonomic and skeletal muscle function and limb blood flow have been demonstrated in chronic heart failure. Because this rehabilitation is expensive, may involve risk, and has unknown effects on prognosis, the possibility of predicting benefit on the basis of individual patient data is intriguing. The most suitable exercise training programme has not yet been established. METHODS AND RESULTS: We reviewed the progress of 134 stable heart failure patients studied in randomized controlled trials of physical training. A significant training effect (+13% peak oxygen consumption, +17% exercise duration) was associated with improved autonomic indices (resting catecholamines and hormones, heart rate variability), without significant side-effects. No ventilatory, haemodynamic, autonomic or clinical factor at baseline was a predictor of outcome. Similar beneficial effects were observed in both male and female patients. The improvement in oxygen consumption after 16 weeks training was higher than after 6 weeks (+2.6 +/- 3.0 vs +0.3 +/- 3.1 ml.kg.min-1, P < 0.05). The combination of cycle ergometer with calisthenic exercises was more beneficial than cycle ergometer alone (+2.7 +/- 4.2 vs 1.2 +/- 2.0 ml.kg.min-1, P < 0.01). The presence of nonsustained ventricular tachycardia did not preclude a training effect. Patients older than 70 years were able to train, although less effectively than the younger ones. No difference in exercise gain was observed whether the patients trained in the hospital or at home. CONCLUSION: The positive effects of physical rehabilitation in chronic stable heart failure patients are confirmed. No baseline patient factor was significantly correlated with outcome. A tailored, moderate, home-based, combined cycle ergometer, plus calisthenic exercise training seems safe and beneficial in a large cohort of heart failure patients, with similar benefits in a variety of conditions and different hospital settings