1. health and fitness
2. disease

Clinical research
European Heart Journal (2006) 27, 562–568
doi:10.1093/eurheartj/ehi735
Heart failure
Effects of nebivolol in elderly heart failure patients with
or without systolic left ventricular dysfunction: results
of the SENIORS echocardiographic substudy
Stefano Ghio1*, Giulia Magrini1, Alessandra Serio1, Catherine Klersy2, Alessandro Fucilli3,
`ki4, Pal Karpati5, Giacomo Mordenti6, Angela Capriati6,
Aleksandr Ronasze
Philip A. Poole-Wilson7, and Luigi Tavazzi1 on behalf of the SENIORS investigators
1
Division of Cardiology, IRCCS Policlinico San Matteo, Pavia, Italy; 2 Biometry and Clinical Epidemiology Unit, IRCCS
´terfy Hospital,
Policlinico San Matteo, Pavia, Italy; 3 Cardiology Department, Arcispedale S. Anna, Ferrara, Italy; 4 Pe
Budapest, Hungary; 5 St Stepan Hospital I, Budapest, Hungary; 6 Menarini Ricerche SpA, Florence, Italy; and 7 National Heart
and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK
Received 22 July 2005; revised 20 December 2005; accepted 22 December 2005; online publish-ahead-of-print 27 January 2006
See page 506 for the editorial comment on this article (doi:10.1093/eurheartj/ehi693)
KEYWORDS
Aims The SENIORS trial recently demonstrated that nebivolol reduces the composite risk of all-cause
mortality and cardiovascular hospital admission in elderly patients with chronic heart failure and,
importantly, that ejection fraction does not influence the clinical effects of nebivolol. An echocardiographic substudy was designed to evaluate the effects of nebivolol on systolic and diastolic left ventricular (LV) function in patients stratified according to the presence or absence of systolic LV dysfunction.
Methods and results The substudy randomized 112 patients in 29 European centres, of whom 104 were
evaluable for the study; 43 had an ejection fraction (EF) 35% and 61 had an EF . 35%. LV end-systolic
volume (ESV), EF, mitral valve E/A ratio, and E-wave deceleration time were assessed at baseline and
after 12 months. Echocardiograms were submitted to a core laboratory to perform quantitative analysis
in blinded condition. In the group with EF 35%, nebivolol reduced ESV (adjusted difference between
treatments 25.8 mL, 95%CI: 246.6; 25.0, P ¼ 0.016) and improved EF (adjusted difference between
treatments 4.6%, 95%CI: 1.3;7.9, P ¼ 0.008); no changes were observed in the E/A ratio or E-wave
deceleration time. In EF . 35% group, no significant changes in either systolic or diastolic parameters
were observed.
Conclusion In patients with heart failure and advanced systolic LV dysfunction, nebivolol reduces
ventricular size and improves EF. The absence of detectable changes with standard echocardiography
in patients with predominant diastolic heart failure questions the mechanism of benefit on
morbidity/mortality in such patients.
Introduction
A better understanding of the complex pathogenesis and of
the natural history of the heart failure (HF) process has led
to substantial changes in the therapeutic approach over the
last decades. Beta-blockers, once contraindicated drugs,
are now considered a cornerstone in the treatment of
patients with HF.1–3 However, patients in the general population differ from those enrolled in HF trials by usually being
older and more frequently having a preserved left ventricular (LV) function.4–6 The SENIORS (Study of the Effects of
Nebivolol Intervention on Outcomes and Hospitalisation in
Seniors with Heart Failure) study was undertaken to evaluate the effects of nebivolol, a selective beta1-blocker with
vasodilator properties, in elderly HF patients, regardless of
*Corresponding author. Tel: þ39 0382 503718; fax: þ39 0382 501884.
E-mail address: s.ghio@smatteo.pv.it
the presence of an impairment of systolic LV function.7
This trial was successful in demonstrating that nebivolol
reduces the composite risk of all-cause mortality and cardiovascular hospital admission, regardless of the baseline
ejection fraction (EF).8 This information is of the utmost
importance because over the recent years, HF with preserved systolic function has emerged as a clinical entity,
representing a sizeable proportion of all patients with
HF.9–12 Its treatment has remained empirical, not only
because we lack evidence-based management strategies
but also because of many uncertainties concerning its definition and its pathophysiology.13–17 In particular, the role
of beta-blockers in patients with diastolic dysfunction has
been addressed in only few previously published
studies.18,19 Although the SENIORS trial has now provided
evidence that beta-blockade with nebivolol is clinically
effective in HF patients with normal or mildly reduced
LVEF, the mechanisms underlying the efficacy of nebivolol
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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Heart failure;
Diastole;
Echocardiography
Effects of nebivolol in elderly HF patients with or without systolic LV dysfunction
in these patients are still unknown. Therefore, it is important to clarify whether nebivolol can improve systolic and/or
diastolic LV function in HF patients in whom the predominant cardiac dysfunction does not lead to an impairment
of LV contractility at rest.
An echocardiographic substudy was set in the SENIORS
study to provide a mechanistic explanation for the main
clinical outcome of the trial. The specific objectives of the
substudy were to evaluate the reverse remodelling effects
of nebivolol in patients with chronic HF and advanced systolic LV dysfunction and to assess the effects of nebivolol on
both systolic and diastolic LV function in patients presenting
with either normal or mildly impaired systolic function,
classified on the basis of EF (35 or .35%).
Methodology
Design
Echocardiographic qualification
In order to join the SENIORS echocardiographic substudy, each
centre had to go through a qualification procedure. The
approval of a site for inclusion in SENIORS was based on the
assessment of videotapes submitted to the Echocardiographic
Core Laboratory of a single echo in one patient and of duplicate
echos (recorded within 24 h) in a second patient. In the event
of an initial disqualification, the centre was given one or more
opportunities to submit further recordings until approval; 95%
of the centres were qualified at the first attempt.
Recording and analysis of echocardiographic
examinations
Two-dimensional echos were recorded by the investigator by
commercially available instruments and recorded on Super
VHS videotapes. The echos were submitted to the Core
Laboratory at the Cardiology Division of Policlinico San
Matteo, Pavia, Italy, to centralize quantitative analysis in
blinded conditions. At the Core Laboratory, a specialized
software for image processing enabled the capture of
images on videotapes, the analysis and the storage of the
images together with the numerical data. Each parameter
was measured three times, and the average value of the
three measurements was taken as a data point. All readings
were made by qualified technicians and subsequently
reviewed by a senior echocardiographer. Reproducibility at
the Core Laboratory has been previously reported.20
The diastolic and systolic diameters of the left ventricle
(LV) were measured in M-mode recordings obtained in the
parasternal long-axis view. The end-diastolic volume (EDV)
and end-systolic volume (ESV) of the LV were obtained in
apical four-chamber view, using the single-plane area–
length method, and EF was calculated as (EDV 2 ESV)/
EDV 100%. The degree of mitral regurgitation (MR) was
assessed as the area of the colour flow Doppler regurgitant
jet divided by the area of the left atrium in systole in
apical four-chamber view. On the pulsed Doppler transmitral
flow velocity curve, the peak velocities of rapid LV filling
(E-wave) and atrial contraction (A-wave) and the deceleration time (DT) of the E-wave were measured and the
velocity ratio (E/A) was calculated; DT , 115 ms was used
to identify a restrictive filling pattern. The tricuspid
annular plane systolic excursion (TAPSE) was used as an indicator of right ventricular function. The areas of both left
and right atria were measured in diastole and systole and
a fractional area change was accordingly calculated.
Statistical analysis
Owing to the exploratory nature of the study, no formal
sample size calculation was performed; a total number of
100 patients were considered sufficient to investigate trial
objectives. Descriptive statistics were computed as mean
and SD for continuous variables and number of non-missing
observations and percentages for categorical variables.
The change in LVEF between baseline and 12 months or
last observation available (primary efficacy variable) was
analysed by means of a general linear model having treatment as major covariate and adjusted by baseline LVEF.
The same model was applied for the secondary efficacy variables. The analysis was performed separately in patients
with advanced systolic LV dysfunction (EF 35%), whereas
those with normal function (EF . 50%) and those with
mildly impaired systolic function (EF between 36 and 50%)
were pooled together. We acknowledge the fact that the discussion on how to define preserved LV function in HF is still
ongoing.13,14,21 We repeated all analysis using different EF
thresholds; however, as the results were highly consistent,
we report only on the original cut-off of EF% which reflects
the stratification of patients used in the SENIORS trial.
Stata 8 (Stata Corp., College Station, TX, USA) was used
for computations. A two-sided P-value ,0.05 was considered statistically significant. The assumptions of normal
distribution and of constant variance underneath the
applied statistical models were assessed by means of the
plots of standardized residuals against fitted values and
standardized residuals against normal probability plot
(qqplot).
Results
Study patients
Out of the 112 patients enrolled, 6 patients had to be
excluded from further analysis because of poor quality of
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The SENIORS study is an international, double-blind,
placebo-controlled, parallel-group trial, which randomly
allocated 2128 patients with chronic HF to nebivolol or
placebo.8 The major inclusion criteria were age 70 years
and a clinical history of chronic HF on top of standard background cardiovascular therapy for HF with one of the following: either documented LVEF 35% or documented hospital
admission within the previous 12 months with the discharge
diagnosis of congestive HF. Nebivolol or placebo tablets were
identical in appearance and were provided in identical
packaging. The initial dose of nebivolol or placebo was
1.25 mg once daily; uptitration was performed in a stepwise
manner every 1–2 weeks, using incremental doses of 2.5 and
5 mg up to the target dose of 10 mg or the maximum tolerated dose over a maximum of 16 weeks. The echocardiographic substudy was run in 29 centres (participants are
listed in the table in the appendix) and enrolled 112
patients. The study plan included two-dimensional and
Doppler echocardiographic examinations (echo) before randomization and after 12 months or the last available echo
for patients who prematurely terminated the study.
563
564
S. Ghio et al.
Figure 1
Effects of nebivolol in patients with LVEF 35%
Nebivolol and placebo patients of this subgroup population
were well comparable with regard to all echocardiographic
variables at baseline. After 12 months of therapy, enddiastolic and end-systolic volumes (ESV) increased in the
placebo group and decreased in the nebivolol group. Mean
LV ESV decreased from 160 to 141 mL in the nebivolol
group and increased from 159 to 166 mL under placebo,
the adjusted difference between treatments being 25.8 mL
(95%CI: 246.6; 25.0), reaching statistical significance
(P ¼ 0.016). Mean LVEF remained substantially unchanged
in the placebo group (28.1% at baseline vs. 28.0% at 12
months) and improved in the nebivolol group (from 27.0 to
31.6% at 12 months), with an adjusted difference between
treatments of 4.6% (95%CI: 1.3;7.9), P ¼ 0.008. Mean LV
EDV decreased in the nebivolol group (from 219 mL at baseline to 202 mL at 12 months), whereas it increased under
placebo (from 219 mL at baseline to 227 mL at 12 months)
with an adjusted difference between treatments of
23.3 mL, (95%CI: 248.7;2.1), P ¼ 0.071. In both treatment
groups, MR was of mild degree at baseline and remained
substantially unchanged after 12 months of treatment.
Only two patients had a restrictive filling pattern at baseline; no significant change was observed in the E/A ratio
or DT after 12 months. The TAPSE was normal at baseline
and did not change during follow-up (Table 2).
Effects of nebivolol in patients with LVEF > 35%
This subgroup includes 25 patients with an LVEF between 36
and 50% and 36 patients with LVEF . 50%. Only one patient
had a restrictive filling pattern at baseline. At baseline,
patients allocated to placebo showed a somewhat lower
mean LVEF and higher mean LV ESV and EDV compared
with nebivolol patients. After 12 months of treatment,
changes in all echocardiographic parameters related to the
systolic or the diastolic function of the left ventricle did
not differ significantly between nebivolol- and placebotreated patients (Table 3).
Discussion
The two main findings of the echocardiographic substudy of
the SENIORS trial are (i) in elderly HF patients with advanced
systolic LV dysfunction, nebivolol exerted a significant
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the echocardiographic images at baseline and another two
patients were excluded because of no post-baseline assessment (Figure 1). Therefore, the analysis population of the
present study encompasses 104 patients; their clinical
characteristics are shown in Table 1. Forty-three patients
turned out to have advanced systolic LV dysfunction
(EF 35%) and 61 had either normal systolic function or
mildly impaired systolic function. No relevant differences
were found between the two treatment groups (placebo
and nebivolol) at baseline. There were no major differences
between the treatment groups with regard to pre-treatment
of CHF. Merely antiarrhythmic treatment was more common
among placebo patients and treatment with Caþþ antagonists more common among nebivolol patients. Overall, no
major difference was found in clinical characteristics
between patients enrolled in the substudy and patients
enrolled in the SENIORS main study, with the possible exception of a higher percentage of patients with EF . 35%
enrolled in the substudy (58% in the substudy vs. 35% in
the main study). Mean values of LVEF could not be directly
compared between the substudy and the main study,
because in the main study, LVEF was assessed by local
investigators, using different imaging techniques as an
entry criterion, whereas in the substudy, it was centrally
evaluated in the echocardiographic core laboratory.
Similar to the main study, 67% of the nebivolol patients
and 72% of the placebo patients participating in the substudy reached the target dose of nebivolol 10 mg once
daily, the mean maintenance dose achieved at the end of
the titration phase being 7.4 + 3.7 mg in the nebivolol
group and 8.1 + 3.3 mg in the placebo group.
Patient flow.
Effects of nebivolol in elderly HF patients with or without systolic LV dysfunction
565
Table 1 Clinical characteristics of patients enrolled in the echocardiographic substudy and in the main study
SENIORS studya
ECHO substudy
Placebo (n ¼ 50)
Nebivolol (n ¼ 1067)
Placebo (n ¼ 1061)
75.0 + 4.4
20 (37.0)
3 (5.5)
36 (66.7)
15 (27.8)
0 (0)
27 (50.0%)
138.2 + 16.0
81.8 + 8.6
77.5 + 12
7.4 + 3.7
75.5 + 3.9
15 (30.0)
3 (6.0)
31 (62.0)
15 (30.0)
1 (2)
34 (68%)
141.0 + 19.0
83.1 + 11.2
78.7 + 11.8
8.1 + 3.3
76.1 + 4.8
410 (38.4)
32 (3)
603 (56.5)
413 (38.7)
19 (1.8)
380 (35.7%)2
138.6 + 20.1
80.5 + 10.8
79.2 + 13.6
7.7 + 3.6
76.1 + 4.6
375 (35.3)
29 (2.7)
597 (56.3)
411 (38.7)
24 (2.3)
372 (35.2%)b
139.5 + 21.1
80.6 + 11.3
78.9 + 13.7
8.5 + 3.1
43 (79.6)
34 (67.0)
42 (84.0)
36 (72.0)
815 (80.4)
688 (67.9)
881 (87.1)
805 (79.6)
41 (82.0)
43 (86.0)
1 (2.0)
11 (22.0)
17 (34.0)
5 (10.0)
13 (26.0)
6 (12.0)
24 (48.0)
12 (24.0)
42 (77.8)
48 (88.9)
2 (3.7)
17 (31.5)
17 (31.5)
17 (31.5)
15 (27.8)
4 (7.4)
27 (50.0)
6 (11.1)
915 (85.8)
872 (81.7)
66 (6.2)
307 (28.8)
415 (38.9)
122 (11.4)
217 (20.3)
149 (14.0)
456 (42.7)
114 (10.7)
907 (85.5)
876 (82.6)
75 (7.1)
280 (26.4)
422 (39.8)
145 (13.7)
238 (22.4)
164 (15.5)
441 (41.6)
122 (11.5)
Data are number of patients (%) or mean (+SD).
a
The SENIORS study (n ¼ 2128) includes the population of the ECHO substudy (n ¼ 104).
b
Echo measurements in the main SENIORS study were not centralized.
reverse remodelling effect, the extent of which is comparable with that previously documented with other betablockers in younger populations, and (ii) in patients with
either normal systolic function or mild systolic dysfunction,
no difference was observed in echocardiographic indices of
systolic or diastolic LV function compared with placebo.
Beneficial effects of nebivolol in HF patients with LV
systolic dysfunction
Several studies have shown that beta-blockers improve LV
function in HF patients with systolic LV dysfunction.22–25
The echocardiographic substudy of the SENIORS trial
extends the evidence of the benefits with beta-blockade to
nebivolol, a third generation highly selective beta1-blocker
with associated vasodilator activity mediated through
increased nitric oxide release.26,27 The changes in LV diameters and volumes and EF lead to the conclusion that the
effects of nebivolol are substantially similar to those of previously tested beta-blockers. The model-adjusted reduction
in ESV by 25.8 mL and the model-adjusted increase in EF by
4.6% obtained by nebivolol when compared with placebo
are in line with the 15.3 mL/m2 decrease in ESV index and
the 5.8% increase in EF observed after 12 months of carvedilol
treatment compared with placebo reported in the echocardiographic substudy of the Australia–New Zealand trial.23
Directionally similar changes of LV geometry and function
have been obtained with bisoprolol.24 In fact, the M-mode
data from the CIBIS echocardiographic substudy demonstrate
that 5-month therapy with this beta-blocker did not change
end-diastolic dimensions but improved LV fractional shortening. LVEF has been reported to improve by 8% and ESV index to
decrease by 26 mL/m2 after 6 months of metoprolol treatment in the MERIT-HF substudy. These data are not directly
comparable because the authors used magnetic resonance
imaging to assess the reverse remodelling effects of
therapy.25 In the SENIORS substudy, the echocardiographic
examination also included the recording of Doppler variables
related to the LV filling and of the TAPSE as an index of right
ventricular function. None of those parameters was significantly improved by nebivolol. However, the reduction in
the E/A ratio, the prolongation in E-wave DT, and the increase
in left atrial fractional change point towards a reduction in
end-diastolic pressure, and the slight improvement in TAPSE
points towards a reduction in pulmonary artery pressure,
given that the systolic function of the right ventricle is
highly dependent on afterload.28 Overall, the reverse remodelling effect of nebivolol in chronic HF patients with systolic
LV dysfunction could be the key explanation for the improvement in the composite end-point of all-cause death or cardiovascular hospital admission found in the SENIORS trial.8
Nebivolol in patients with normal or mildly impaired
LV systolic function
Although the importance of HF with normal or mildly
impaired systolic LV function has been increasingly recognized
over the last years, there were no large, randomized, controlled clinical outcome trials in patients having this condition until recently. The CHARM-Preserved study showed a
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Age (years)
Women (%)
NYHA class I (%)
II (%)
III (%)
IV (%)
EF .35%
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Heart rate (b.p.m)
Maintenance dose (mg)
Maintenance dose level reached
5 mg(%)
10 mg(%)
CHF pre-treatment
Diuretic
ACE-inhibitor (%)
Angiotensin II antagonist (%)
Aldosterone antagonist (%)
Cardiac glycoside (%)
Antiarrhythmic (%)
Lipid-lowering drug (%)
Vitamin K antagonist (%)
Aspirin (%)
Calcium antagonist (%)
Nebivolol (n ¼ 54)
566
S. Ghio et al.
Table 2 Effects of nebivolol in patients with LVEF 35%
.Nebivolol (n ¼ 27)
LVEF (%)
MR
E/A
EDT (ms)
TAPSE (mm)
LVEDV (mL)
LVESV (mL)
LAESA (cm2)
LAFAC (%)
Placebo (n ¼ 16)
Baseline
12 months
Baseline
12 months
27.0 + 4.9
5.3 + 3.4
1.7 + 1.1
172 + 50
1.7 + 0.4
219 + 63
160 + 50
24.8 + 6.6
24.0 + 13.3
31.6 + 7.3
5.2 + 4.2
1.1 + 0.7
207 + 46
1.9 + 0.4
202 + 63
141 + 50
25.9 + 6.0
29.1 + 9.9
28.1 + 4.6
5.0 + 3.9
0.9 + 0.7
183 + 54
1.8 + 0.3
219 + 41
159 + 35
24.1 + 10.4
28.6 + 11.0
28.0 + 6.9
5.2 + 4.1
0.9 + 0.8
185 + 72
1.7 + 0.4
227 + 54
166 + 48
26.5 + 9.5
26.2 + 9.8
Estimated treatment
difference (95%CI)
P-value
4.58
21.10
20.30
10.70
0.21
223.30
225.80
21.39
3.52
0.008
0.345
0.350
0.691
0.067
0.071
0.016
0.608
0.363
(1.27; 7.89)
(23.45; 1.24)
(20.95; 0.36)
(245.61; 67.02)
(20.02; 0.44)
(248.67; 2.07)
(246.60; 25.00)
(26.99; 4.20)
(24.39; 11.44)
A general linear regression model having treatments as major covariate and adjusted by baseline value is adopted. Data are presented as mean + SD. The
P-value refers to the estimated treatment difference in echo parameters of the placebo vs. the nebivolol group. The comparison is adjusted for the baseline
value of the relevant echo parameter.
LVEDD, LV end-diastolic diameter; E/A, ratio of early to late peak mitral velocity; EDT, E-wave deceleration time; LVEDV, LV end-diastolic volume; LVESV,
LV end-systolic volume; LAESA, left atrial end-systolic area; LAFAC, left atrial fractional area change.
Table 3 Effects of nebivolol in patients with LVEF .35%
Nebivolol (n ¼ 27)
Baseline
12 months
Baseline
12 months
54.5 + 8.9
2.8 + 1.7
0.9 + 0.6
200 + 39
2.2 + 0.3
118 + 42
56 + 30
21.5 + 5.6
29.15 + 11.1
55.5 + 8.2
2.7 + 2.5
0.9 + 0.7
207 + 37
2.3 + 0.3
112 + 39
54 + 29
19.3 + 5.3
36.7 + 13.5
49.0 + 8.1
4.2 + 3.4
0.9 + 0.5
192 + 37
2.0 + 0.3
145 + 48
77 + 35
25.5 + 6.8
27.2 + 11.4
50.2 + 8.6
4.5 + 4.0
1.0 + 0.5
202 + 50
2.1 + 0.3
137 + 46
71 + 35
26.0 + 7.3
28.4 + 9.7
Estimated treatment
difference (95%CI)
P-value
0.02 (23.05; 3.10)
20.50 (23.25; 2.25)
20.01 (20.34; 0.32)
10.04 (219.97; 40.06)
0.20 (20.04; 0.44)
21.92 (213.92; 10.08)
21.49 (211.55; 8.57)
20.66 (23.29; 1.97)
5.63 (21.84; 13.09)
0.988
0.711
0.956
0.500
0.098
0.750
0.768
0.614
0.135
A general linear regression model having treatments as major covariate and adjusted by relevant baseline echo parameter is adopted.
non-significant reduction in the composite end-point of cardiovascular death or HF hospitalization with candesartan.29 The
SENIORS trial showed both a significant overall treatment
effect and a virtually identical estimate of risk reduction
for patients with low or preserved EF. The echocardiographic
substudy of the SENIORS trial gives us the possibility to verify
whether the clinical benefit of nebivolol treatment in
patients with mildly impaired or preserved LV systolic function can be explained by an improvement in LV function.
Not unexpectedly, given that LV volumes and EF were not
markedly impaired at baseline in these patients, nebivolol
had no effect on parameters of LV systolic function. The
absence of detectable changes in diastolic parameters is a
finding that needs to be explained. Theoretically, there are
several reasons why nebivolol might improve diastolic function. Beta-blockade may improve diastolic function by prolonging the diastolic filling time more than the ejection time, thus
improving myocardial perfusion and metabolism.30 The
increased nitric oxide release caused by nebivolol might also
improve early relaxation.31 Although the SENIORS echocardiographic substudy showed no difference in Doppler parameters,
it would be simplistic to conclude that nebivolol had no effect
on diastolic LV function. Rather, the possibility should be considered that standard Doppler echocardiography is not sensitive enough to detect the changes in diastolic function
caused by this drug. Doppler filling parameters must be interpreted cautiously when used as indices of diastolic function.
Filling velocities reflect the pressure gradients between the
left atrium and the left ventricle, which depend not only on
the diastolic LV properties but also on loading conditions
and atrial compliance; heart rate may also play an important
role.32,33 Cardiac catheterization using high-fidelity micromanometer-tipped catheters is necessary to identify abnormalities in active relaxation or in diastolic stiffness of the left
ventricle.17 Future studies using more specific echocardiographic approaches to the evaluation of diastolic function34–36
are planned to determine how beta-blockade affects diastolic
function. Further studies should also differentiate patients
with normal EF from patient with mildly impaired EF; pooling
these patients is, in fact, another limitation of the present
study.
Whether or not nebivolol can improve LV diastolic function
leaves another question unanswered, namely whether a
change in cardiac function is the explanation for the improvement in the composite end-point of all-cause mortality or cardiovascular hospital admission observed in patients with
slightly impaired LV systolic function in the SENIORS trial.
The efficacy of beta-blockade in patients with systolic HF is
strongly associated with an improvement in systolic function,
but this should not lead to the conclusion that beta-blockade
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LVEF (%)
MR
E/A
EDT (ms)
TAPSE (mm)
LVEDV (mL)
LVESV (mL)
LAESA (cm2)
LAFAC (%)
Placebo (n ¼ 34)
Effects of nebivolol in elderly HF patients with or without systolic LV dysfunction
has to be effective in patients with preserved systolic function because of the direct effect of beta-blockers on diastolic
function. There are many differences between systolic HF
and diastolic HF. Diastolic HF may be more fluctuating both
symptomatically and pathophysiologically than systolic HF.
The destabilization which dominates the clinical picture of
diastolic HF is often precipitated by the onset of tachyarrhythmias or by a sudden severe blood pressure increase
that most probably exacerbates a condition of latent asymptomatic diastolic dysfunction.37 Diastolic HF is common in
elderly and hypertensive patients, and ageing and hypertension are characterized by increased deposition of interstitial
collagen, perivascular fibrosis in the myocardium, and
stiffening of the vascular wall.38 The efficacy of nebivolol
in the syndrome of diastolic HF might, therefore, be
related not only or not predominantly to an improvement in
baseline diastolic function. Possibly, the prevention of episodes of excessive tachycardia and of severe blood pressure
rise, as well as a modulation of the vascular tone and of
the elasticity of the vascular system exerted by nebivolol,
may also play a significant role in improving the outcome in
such patients. In the light of this hypothesis, the peculiar
pharmacological properties of nebivolol, which is not only
567
an highly selective beta1-blocker but is also able to induce
nitric oxide endothelial release, might underlie a specific
beneficial action of this beta-blocker in predominantly diastolic HF, similar to that observed in patients with arterial
hypertension.19
Conclusions
Nebivolol showed a beneficial reverse remodelling effect in HF
patients with systolic LV dysfunction. This effect is comparable
with those previously documented with other beta-blockers.
In patients with preserved systolic function or mild systolic
dysfunction, the absence of detectable changes in Doppler
echocardiographic indices raises the issue of how nebivolol
improves the morbidity–mortality outcome in these patients.
Several hypotheses need to be investigated in future studies.
Conflict of interest: S.G. receives honoraria for consultancy to an
electro-medical company. L.T and P.A.P.-W. have received honoraria
for speaking on aspects of heart failure at meetings funded by companies in the pharmaceutical industry. G.M. and A.C. are employees
of Menarini Ricerche S.p.A. All have participated in or are involved
in other studies or research projects funded by industry.
Appendix
Hospital
City
Country
Main investigator
Sonographer
I. Interni Klinika FN U SVATe
´ Anny
Brno
Czech Republic
Lenka Spinarova
Kardiologicka’ Ambulance INT. ODD.
Nemocnice Milosrdnych Bratri
Statni Slezka Nemocnice I INT. ODD.
Nemocnice TGM INT. ODD.
Nemocnice S. Poliklinikon V Teplice
Kardiologicke Oddeleni, FN Bohunice
Hospital Jablonec NAD Nisou
NSP Ivancice INT. ODD. Nemocnice
Hungarian Institute of Cardiology
Uzsoki Hospital I, Medical Department
Karolyi Hospital Cardiology
Elisabeth Hospital I, Medical Department
Jahn F. DEL_PESTI Hospital
Gottsegen Gyo
¨rgu Hungarian Institute
of Cardiology
St Ference Hospital
State Hospital of Cardiology
St Stephan Hospital
Policlinico S. Matteo
Arcispedale S. Anna
Ospedale S. Vit O E S. Spirito
OSP. S. Luca
CNR
Institute of Cardiolgy of Academy of
Medical Science of Ukraine
Lugansk Clinical Multiprophil City
Hospital No. 1
Kyiv Medical Academy of Post-graduate
Education
Crimea State Medical University
Institute of Urgent and Recovery Surgery
Zaporizzhia State Medical University
Northwick Park Hospital
Trebic
Brno
Opava
Hodonin
Teplice
Brno Bohunice
Jablonec NAD Nisou
Ivancice
Budapest
Budapest
Budapest
Budapest
Budapest
Budapest
Czech Republic
Czech Republic
Czech Republic
Czech Republic
Czech Republic
Czech Republic
Czech Republic
Czech Republic
Hungary
Hungary
Hungary
Hungary
Hungary
Hungary
Jiri Toman Lenka
Spinarova
Jiri Carda
Bohumil Filipensky
Pollak
Pospisil
Reichert
Borivoj Semrad
Dag Tichy
Vales
Josef Borbola
Bela Palossy
Laszlo Regos
Aladar Ronaszeki
Karoly Toth
Josef Vanyi
Miskolc
Balatonfu
¨rED
Budapest
Pavia
Ferrara
Alcamo (TP)
Milano
Pisa
Kiev
Hungary
Hungary
Hungary
Italy
Italy
Italy
Italy
Italy
Ukraine
Lugansk
Mudr Jiri Carda
Bohumil Filipensky
Pollak
P. Obrtlik
J. Vana
J. Ziembova
Dag Tichy
Vales
Gizella Vigh
Peter Fu
¨p
¨lo
Laszlo Csuro
¨s
Erzsebet Sperr
Janos Fiok
De Gizella Vigh
Istvan Varga
Jozsef Masszi
Imre Lukacs
Alessandra Serio
Fucilli
Figlia
Sa Branzi
A. Morales
Lutay
Ukraine
Istvan Varga
Gabor Veress
Pal Karpati
L. Uigi Tavazzi
Roberto Ferrari
Francesco Ippolito
Gianfranco Parati
Danilo Neglia
Aleksandr
Parkhomenko
Yuriy Koltchin
Kiev
Ukraine
Volodymyr Kovalenko
E. Rey
Simferopol
Donetsk
Zaporizhzhia
Harrow
Ukraine
Ukraine
Ukraine
UK
Volodymir Kubyshkin
Nikolaj Vatunin
Vadimi Vizir
Roxy Senior
A.V. Legkonogov
Stolika
A. Berezin
R. Janarhandran,
L. Burden
Potapenko
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Table A1 Participating sites
568
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