β-Blockade in heart failure: adding SENIORS to the mix

This editorial refers to ‘Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy’ † by S. Ghio et al., on page 562 In early 2005, results of the SENIORS trial, a Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure was published. 1,2 A total of 2128 patients over the age of 70 were randomized to receive either nebivolol or placebo for a mean follow-up time of 21 months. Nebivolol is a third generation highly selective b1-adrenergic receptor inhibitor with vasodilator properties mediated through nitric oxide release. Treatment with this agent decreased all-cause mortality or cardiovascular hospitalization (P ¼ 0.04). Although previous studies using b-blockers (bisoprolol, carvedilol, or metroprolol) demonstrated a decreased relative risk of death in heart failure, 3 they enrolled younger patients (excluding patients .80 years of age) and focused on those with low left ventricular ejection fraction (LVEF). Thus, these studies may not be representative of patients seen in the general population, who may be older and have a higher prevalence of preserved systolic function. By demonstrating the morbidity and mortality benefits of b-blockade in elderly patients with heart failure, regardless of whether the LVEF was low, the SENIORS trial expands our understanding of this therapy. Ghio et al. 4 present results of an echocardiographic substudy performed on 104 of the original 2128 patients, reporting the impact of nebivolol on LV structure and function in patients stratified on the basis of LVEF, using 35% as a cut-point. In this subgroup, 59% of the patients had LVEF .35%, a considerably higher percentage than that was present in the overall study (35%). In the low LVEF group, nebivolol led to a decrease in LV end-systolic volume and an improved LVEF, changes indicative of reverse remodelling. In the group with preserved LV systolic function, nebivolol did not alter the LV size or function. The authors conclude that nebivolol reduces LV size and improves LVEF in patients with LVEF � 35% but this mechanism does not explain the improved morbidity and mortality in those patients with primarily diastolic dysfunction. The results of this study provoke a number of interesting questions. First, why should there be a unique remodelling response of patients with low LVEF? Is it fair to argue that, because patients with preserved LVEF did not have cardiac dilatation, reverse remodelling would not entail reductions in LV end-diastolic volume? Indeed, is there a reason to suspect that a patient who began the study with a normal LV end-diastolic volume should end it with anything else? It is worth noting that although ongoing debate attempts to clarify just what diastolic heart failure is, a considerable fraction of such patients have hypertensive cardiac hypertrophy and in such patients, reverse remodelling may simply represent hypertrophy regression. Whether this was the case in the current study is unknown because data on LV thickness or mass were not presented. On the other hand, if there is a large population of patients with diastolic heart failure in the absence of cardiac hypertrophy, how would reverse remodelling be recognized? It may be safe to conclude that this process uniquely impacts patients with low LVEF. Given the fact that reverse remodelling can be quantified (by means of cardiac size and function) in patients with low LVEF, important questions remain regarding its causes. Clearly, a subset of patients with dilated cardiomyopathy will respond to b-blocker therapy or to mechanical unloading of the heart with LV assist devices by demonstrating