European Heart Journal Advance Access originally published online on January 27, 2006
European Heart Journal 2006 27(5):506-507; doi:10.1093/eurheartj/ehi693
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ß-Blockade in heart failure: adding SENIORS to the mix
Department of Medicine and Cardiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7872, San Antonio, TX 78229-3900, USA
* Corresponding author. Tel: +1 210 567 4673; fax: +1 210 567 6960. E-mail address: lindseym{at}uthscsa.edu
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 ß1-adrenergic receptor inhibitor with vasodilator properties mediated through nitric oxide release. Treatment with this agent decreased all-cause mortality or cardiovascular hospitalization (P=0.04). Although previous studies using ß-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 ß-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 ß-blocker therapy or to mechanical unloading of the heart with LV assist devices by demonstrating reduced LV end-diastolic volume and improved ejection fraction.5 Although a variety of mechanisms have been investigated, including the upregulation of various cytokines,6 the activation of NF-
B7 or MAP kinases,7 or the Akt/protein kinase B pathway,7 among others, our knowledge of the precise biology underlying this phenomenon is sparse at best.8 Even the time-course by which it takes place remains ill-defined.9 It is tempting to assume that reverse remodelling is in fact a simple retracing of the steps that led to the pathological cardiac deformation that has occurred, but proof of this concept is lacking.
Should assessment of remodelling rely on structural changes alone? It is likely that important changes in the non-myocyte component of the myocardium participate in the remodelling process, and future studies may define if monitoring evidence of such changes may be useful in tracking the remodelling process. One set of parameters that could be monitored to determine the changes in LV structure include serum markers of collagen metabolism, namely the ICTP C-terminal peptide of collagen I, the PICP C-terminal peptide of collagen I, and the PIIINP N-terminal peptide of collagen III.10 Excessive accumulation of collagen (fibrosis) is a hallmark of pathological remodelling and changes to collagen levels may be useful to reflect the changes in fibrosis. Normalization in levels of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) may also provide an important target for monitoring the process. MMP levels increase during adverse remodelling and are causally associated with changes in LV function.11 A normalization of collagen, MMP, and/or TIMP levels may provide biochemical evidence of reverse remodelling.
Finally, does this process have prognostic implications? Clinicians managing patients who have had significant increase in LVEF cite a plethora of anecdotal information on improved clinical outcomes, but experimental evidence to rigorously correlate reverse remodelling and long-term prognosis is lacking. If it cannot be shown that the process is linked to improved symptomatology or outcomes, should we be concerned about it at all? Furthermore, in the current study, reduced risk of death or admission for heart failure occurred in the absence of reverse remodelling, indicating that untangling the contributing factors may not be a trivial exercise. Clearly, much more work is needed in this field.
The major result from this study is that ß-blockade improves LV function in heart failure patients with systolic LV dysfunction and that this benefit is applicable to the elderly population. The effects of nebivolol were similar to those observed in prior studies using other ß-blockers. Hopefully, the results will serve to stimulate increased research, both clinical and basic sciences, addressing the mechanisms of beneficial remodelling, how it can be best monitored, and what role, if any, it plays in patients with heart failure and preserved LVEF.
The authors acknowledge the following grant support: HL-75360 (M.L.L.), P50HL077101 (G.L.F.), and a Merit Award from the Department of Veterans Affairs (G.L.F.).
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehi735 
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Related articles in EHJ:
- Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy
- Stefano Ghio, Giulia Magrini, Alessandra Serio, Catherine Klersy, Alessandro Fucilli, Aleksandr Ronaszèki, Pal Karpati, Giacomo Mordenti, Angela Capriati, Philip A. Poole-Wilson, Luigi Tavazzi, and on behalf of the SENIORS investigators
EHJ 2006 27: 562-568.[Abstract] [Full Text]
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