Download Beneficial effect of β-adrenergic blockade on left ventricular function

Clinical Science (2001) 101, 219–225 (Printed in Great Britain)
Beneficial effect of β-adrenergic blockade
on left ventricular function in
haemodialysis patients
Yuji HARA*, Mareomi HAMADA*, Yuji SHIGEMATSU*, Bonpei MURAKAMI†
and Kunio HIWADA*
*The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu-cho, Onsen-gun, Ehime 7910925, Japan, and †The Department of Internal Medicine, Murakami Memorial Hospital, 739 Oh-machi, Saijo city, Ehime
793-0030, Japan
A
B
S
T
R
A
C
T
Congestive heart failure is a common and serious complication in patients undergoing chronic
dialysis. However, there have been no studies on preferential medical therapies to improve left
ventricular function in haemodialysis patients. β-Blocker treatment is known to improve left
ventricular function in patients with dilated cardiomyopathy ; moreover, plasma levels of
noradrenaline and natriuretic peptides are sensitive markers of left ventricular dysfunction. The
present study investigated whether β-blocker treatment could improve left ventricular function
in haemodialysis patients with a dilated left ventricle. Our study group comprised 14
haemodialysis patients with a dilated left ventricle, who had undergone maintenance haemodialysis for a mean of 11 years. The following haemodynamic parameters were evaluated before and
after 4 months of treatment with the β-blocker metoprolol : left ventricular dimension at endsystole and end-diastole, and fractional shortening. Plasma levels of noradrenaline, atrial
natriuretic peptide and brain natriuretic peptide were also determined. Dry body weight and
haemoglobin concentration showed no significant change after compared with before treatment
with metoprolol. Heart rate decreased significantly, from 79p9 beats/min to 69p9 beats/min,
but systolic blood pressure remained unchanged. The left ventricular dimension both at endsystole and at end-diastole was decreased, and fractional shortening increased significantly.
Plasma levels of noradrenaline did not change significantly, but those of atrial natriuretic peptide
and brain natriuretic peptide decreased markedly [from 100p89 pg/ml to 46p29 pg/ml (P l
0.0051) and from 549p516 pg/ml to 140p128 pg/ml (P l 0.0035) respectively]. In conclusion,
β-blocker therapy with metoprolol can markedly attenuate left ventricular remodelling and
decrease the plasma levels of natriuretic peptides in haemodialysis patients with a dilated left
ventricle.
INTRODUCTION
Congestive heart failure is a common complication in
patients undergoing chronic dialysis [1,2]. It has been
reported that, in dialysis patients, 24 % suffered from left
ventricular hypertrophy, 9 % from congestive heart
failure and 17 % from dilated cardiomyopathy, and the
prognosis of these patients was poor [2,3]. An im-
provement in left ventricular function may be important
in order to improve the prognosis in haemodialysis
patients. However, the exact mechanisms underlying left
ventricular dysfunction in dialysis patients remain to be
determined, and thus there is no specific treatment that is
used to maintain or improve left ventricular function in
haemodialysis patients, except for parathyroidectomy
and kidney transplantation [4–7].
Key words : β-blocker, dilated left ventricle, haemodialysis, natriuretic peptides, renal failure.
Correspondence : Dr Yuji Hara (e-mail yujihara!m.ehime-u.ac.jp).
# 2001 The Biochemical Society and the Medical Research Society
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Y. Hara and others
Anaemia and arteriovenous shunting seem to be related
to left ventricular dysfunction in haemodialysis patients.
In addition, anaemia and the presence of an arteriovenous
shunt are known to be major causes of high-output heart
failure. Thus high-output heart failure may contribute to
some extent to left ventricular dysfunction in haemodialysis patients. If so, treatment with β-blockers might
improve left ventricular function in haemodialysis patients. β-Blockers are also known to improve prognosis
and left ventricular function in patients with heart failure
[8,9]. To our knowledge, however, no previous studies
have investigated the effects of β-blockers on left ventricular function in haemodialysis patients. Thus, in the
present study, we have evaluated whether β-blocker
therapy using metoprolol could improve left ventricular
function in haemodialysis patients.
METHODS
Study population
The study population consisted of 14 patients who had
received maintenance haemodialysis and had a dilated left
ventricle (age range 29–73 years ; mean 56p13 years). In
accordance with the definition of a dilated left ventricle in
haemodialysis patients [10], the echocardiographically
determined left ventricular dimension was greater than
55 mm at end-diastole in all patients. Table 1 shows the
clinical characteristics of the patients studied. The aetiology of end-stage renal disease was glomerulonephritis
in 10 patients and hypertensive glomerulosclerosis in
four. The mean duration of haemodialysis was 11p7
years (range 3–23 years). Dry body weight was measured
after haemodialysis. Dry body weight at enrolment had
been well maintained in all patients. All patients were in
sinus rhythm.
The study was approved by the local ethical committee,
and all subjects participated after giving informed consent.
β-Blocker treatment
After the confirmation that the haemodynamic condition
of the patient was stable, β-blocker treatment with
metoprolol was begun. Metoprolol was initially given
orally to each patient at a very small dose of 2.5–5 mg,
and this dose was increased gradually to the maximum
tolerated dose, as determined by end points. The end
points were : a decrease in systolic blood pressure to less
than 90 mmHg, a decrease in heart rate at rest to less than
60 beats\min, or clinical deterioration. The mean maintenance dose of metoprolol was 27 mg (range 15–50 mg).
Haemodialysis schedules and other medications remained largely unchanged throughout the study. All
patients were able to tolerate β-blocker treatment. Before
and 4 months after beginning treatment with the
# 2001 The Biochemical Society and the Medical Research Society
β-blocker, haemodynamic variables and humoral factors
were measured.
Renal involvement
Creatinine was analysed by Jaffe’s method (normal range
of serum creatinine for our laboratory : 44.2–
106.1 µmol\l). Measurements of haemoglobin concentration, serum protein, serum creatinine and electrolytes
were carried out using an automatic analyser (model
TBS-60S ; Toshiba Inc., Tokyo, Japan). Blood samples
were withdrawn before haemodialysis.
Echocardiographic study
M-mode and two-dimensional echocardiographic studies
were performed in all patients after haemodialysis, using
an SSA-140 imaging system (Toshiba) with a 2.5 or 3.5
MHz transducer. M-mode echocardiographic recording
was carried out, while cardiac anatomy was visualized by
two-dimensional echocardiography. The following conventional variables were measured according to the
criteria of the American Society of Echocardiography
[11] : left atrial dimension, left ventricular dimension at
end-diastole, left ventricular dimension at end-systole,
and fractional shortening. In addition, peak E-wave and
A-wave velocities, the E\A ratio and deceleration time
were measured from transmitral Doppler recordings. All
echocardiographic parameters, both before and after
β-blocker treatment, were measured in a blinded manner.
At the time of echocardiographic analysis, arterial blood
pressure was determined in duplicate using a cuff
sphygmomanometer.
Measurement of plasma hormone levels
Plasma levels of noradrenaline (norepinephrine), atrial
natriuretic peptide and brain natriuretic peptide were
determined as reported previously [12]. Blood samples
were withdrawn after 30 min of supine rest, after haemodialysis. Blood was transferred immediately into
chilled glass tubes containing disodium EDTA (1 mg\ml)
and aprotinin (500 units\ml), and was centrifuged immediately (3000 rev.\min, 10 min) at 4 mC. The plasma
was frozen and stored at k80 mC until assayed.
Plasma levels of noradrenaline were determined by
HPLC. RIA was performed to measure plasma levels of
atrial natriuretic peptide (Shiono RIA assay kit ; Shionogi
Co., Osaka, Japan) and brain natriuretic peptide (S-1215 ;
Shionogi Co.). Normal values for plasma atrial natriuretic
peptide and brain natriuretic peptide as measured in
our institution are
43.0 pg\ml and
17.0 pg\ml
respectively.
Statistical analysis
Data are presented as meanspS.D. Differences between
baseline values and values after treatment (except for
noradrenaline, atrial natriuretic peptide and brain nat-
Effect of β-blockade in haemodialysis patients
Table 1
Clinical data
F, female ; M, male ; CGN, chronic glomerulonephritis ; HT, hypertensive glomerulosclerosis ; NYHA, New York Heart Association.
Case no.
Gender
Age
(years)
Aetiology
Duration of haemodialysis
(years)
NYHA functional class
1
2
3
4
5
6
7
8
9
10
11
12
13
14
F
F
F
M
M
M
M
M
M
M
F
M
M
M
62
56
52
61
53
34
68
47
65
58
72
29
57
73
CGN
HT
CGN
CGN
CGN
CGN
HT
CGN
CGN
HT
CGN
CGN
CGN
HT
2
5
10
23
21
3
4
14
14
14
4
16
3
5
II
III
II
II
II
I
III
III
II
I
II
I
I
III
riuretic peptide levels) were tested using Student’s paired
t test. Differences in levels of noradrenaline, atrial
natriuretic peptide and brain natriuretic peptide were
tested using the Wilcoxon signed rank test. All calculations were performed on a personal computer using the
statistical package StatView (Abacus Concepts, Inc.,
Berkeley, CA, U.S.A.). A P value of
0.05 was considered significant.
RESULTS
Changes in clinical and laboratory data
measured before and after β-blocker
treatment
Changes in clinical and laboratory parameters measured
before and after β-blocker treatment are listed in Table 2.
The cardiothoracic ratio decreased significantly. Systolic
blood pressure remained unchanged, but heart rate
Table 2
decreased significantly. Dry body weight remained unchanged. Haemoglobin concentration, serum protein,
serum creatinine and electrolytes also remained unchanged.
Changes in echocardiographically
determined haemodynamic parameters
Changes in echocardiographically determined parameters measured before and after treatment with
β-blocker are shown in Table 3. Figure 1 shows
representative M-mode echocardiogram patterns obtained
before and after treatment with β-blocker in one patient
(no. 2). In this patient, the left ventricular dimension
decreased markedly and movement of the posterior wall
improved markedly after treatment with metoprolol. Mean
values for left atrial dimension, left ventricular dimension
at end-diastole and left ventricular dimension at endsystole also decreased significantly, and fractional shortening increased significantly. Peak E-wave velocity was
Clinical and laboratory data before and after the administration of β-blocker
SBP, systolic blood pressure ; HR, heart rate ; Hb, haemoglobin.
Variable
Before treatment
After treatment
Cardiothoracic ratio (%)
SBP (mmHg)
HR (beats/min)
Dry body weight (kg)
Hb concentration (g/dl)
Serum protein (g/l)
Serum creatinine (µmol/l)
Serum sodium (mmol/l)
Serum potassium (mmol/l)
Serum calcium (mmol/l)
53.4p8.8
136p25
79p9
51.3p8.2
9.2p1.1
6.4p0.4
1093p239
138p3
5.5p0.7
2.4p0.2
51.3p7.1
129p16
69p9
50.9p8.2
9.5p1.1
6.5p0.3
1106p267
138p2
5.5p0.8
2.4p0.2
P value
0.0291
0.2331
0.0001
0.1460
0.0616
0.4702
0.6256
0.5421
0.8229
0.8171
# 2001 The Biochemical Society and the Medical Research Society
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Y. Hara and others
Table 3
Changes in echocardiographic parameters during 4 months of treatment with β-blocker
LAD, left atrial dimension ; LVDd, left ventricular dimension at end-diastole ; LVDs, left ventricular dimension at end-systole ; FS, fractional shortening ; E/A, E-wave
velocity/A-wave velocity ; DT, deceleration time ; Pre, before administration of β-blocker ; Post, after administration of β-blocker.
LAD (mm)
LVDd (mm)
LVDs (mm)
FS (%)
Subject
Pre
Post
Pre
Post
Pre
Post
Pre
1
2
3
4
5
6
7
8
9
10
11
12
13
14
45.3
44.5
46.0
40.2
37.8
34.5
48.8
40.0
46.5
40.1
43.5
37.8
42.1
54.1
43.0
40.3
46.0
33.7
37.4
36.5
45.3
39.5
47.0
35.6
39.8
35.8
40.5
53.8
65.9
67.3
55.6
59.5
55.8
57.0
71.6
56.2
56.2
55.3
56.1
67.2
58.4
66.2
64.4
61.3
52.1
52.3
54.1
56.3
60.3
55.0
53.4
51.9
48.8
66.2
54.5
63.9
50.2
58.0
38.0
40.5
40.1
39.8
58.0
40.2
38.8
37.5
37.1
51.5
38.6
56.3
42.5
40.7
35.0
33.7
36.1
37.3
45.7
37.2
33.8
32.1
33.9
50.0
34.3
52.1
23.8
13.8
31.7
31.9
28.1
30.2
19.0
28.5
31.0
32.2
33.9
23.4
33.9
15.0
Mean
S.D.
P
42.9 41.0
5.1
5.5
0.0085
Figure1
60.6 56.7
5.7
5.5
0.0004
44.6 38.9
8.2
6.4
0.0002
E-wave velocity (m/s)
A-wave velocity (m/s)
E/A
Post
Pre
Post
Pre
Post
Pre
Post
Pre
Post
34.0
33.6
32.8
35.6
33.3
33.7
24.2
32.4
36.7
38.2
30.5
24.5
37.1
18.5
0.80
1.14
0.97
0.87
0.63
0.97
1.18
0.80
0.53
0.71
0.66
0.91
0.99
1.19
0.75
0.73
0.78
0.58
0.60
0.80
0.32
0.72
0.57
0.65
0.48
0.59
0.77
1.10
0.71
0.77
1.27
0.98
0.73
0.87
0.92
0.86
0.81
0.95
0.91
0.87
1.24
0.63
0.72
0.85
0.80
0.86
0.59
0.58
0.74
0.72
0.72
0.99
0.77
0.80
0.89
0.95
1.13
1.48
0.76
0.89
0.86
1.12
1.28
0.93
0.65
0.75
0.73
1.05
0.80
1.89
1.04
0.86
0.97
0.67
1.02
1.38
0.43
1.00
0.79
0.66
0.62
0.74
0.87
1.16
236
131
142
260
249
160
150
144
181
164
362
232
116
125
205
275
230
235
222
248
181
205
213
287
203
200
180
150
0.88
0.21
0.0043
0.67
0.18
0.89
0.18
0.0532
0.78
0.12
1.02 0.87
0.34 0.25
0.1407
190
70
0.2340
216
38
26.9 31.8
6.8
5.6
0.0039
DT (ms)
M-mode echocardiographic findings in a haemodialysis patient
(A) Before treatment with β-blocker ; (B) after treatment. The left ventricular dimension was decreased markedly, and movement of the posterior wall was improved.
RV, right ventricle ; IVS, interventricular septum ; LV, left ventricle ; PW, posterior wall.
decreased significantly, while the E\A ratio and deceleration time remained unchanged.
Plasma levels of noradrenaline, atrial
natriuretic peptide and brain natriuretic
peptide
Changes in the plasma levels of noradrenaline, atrial
natriuretic peptide and brain natriuretic peptide are
# 2001 The Biochemical Society and the Medical Research Society
shown in Figure 2. Plasma levels of noradrenaline
remained high and unchanged by treatment when all
patients were considered (before, 821p421 pg\ml ; after,
738p268 pg\ml). However, in patients who were in
New York Heart Association Classes II and III, plasma
levels of noradrenaline decreased significantly from
918p405 pg\ml to 751p239 pg\ml (P l 0.0469). Plasma
levels of both atrial natriuretic peptide and brain natriuretic peptide decreased markedly, from 100p89 pg\ml to
Effect of β-blockade in haemodialysis patients
Figure2 Plasma levels of noradrenaline, atrial natriuretic peptide and brain natriuretic peptide before and after β-blocker
treatment
Plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were decreased significantly, while those of noradrenaline (norepinephrine) were
unchanged.
46p29 pg\ml (P l 0.0051) and from 549p516 pg\ml to
140p128 pg\ml (P l 0.0035) respectively.
DISCUSSION
The present study shows, for the first time, the efficacy of
β-blocker treatment in improving left ventricular function in haemodialysis patients. After treatment with
metoprolol, left ventricular dimension both at enddiastole and at end-systole decreased in all patients, and
fractional shortening increased significantly. In addition,
plasma levels of both atrial natriuretic peptide and brain
natriuretic peptide in the haemodialysis patients were
decreased significantly by this treatment. These data
suggest that β-blocker therapy may have potential utility
in the treatment of haemodialysis patients with a dilated
left ventricle.
The effects of metoprolol on left ventricular function
in patients with chronic heart failure have been demonstrated in a large number of studies [13–16]. Such previous
studies reported that β-blocker therapy with metoprolol
resulted in an increase of 4–11 % in the ejection fraction
in patients with chronic heart failure [13,14]. In our
study, treatment with metoprolol for 4 months increased
fractional shortening by 6 % in the haemodialysis patients. We reported previously that treatment with
metoprolol (40 mg) for 6 months increased fractional
shortening by 4.5 % in patients with chronic heart failure
[16]. Although the dose of metoprolol in the present
study was small, fractional shortening was increased by
6 %. Because metoprolol is metabolized largely in the
liver, it is unlikely that dosage accumulation would occur
due to renal failure. We concluded that the major reason
for the small dosage was the small size of the patients,
whose mean dry body weight was 50 kg.
It is well recognized that both atrial natriuretic peptide
and brain natriuretic peptide are increased in relation to
the severity of left ventricular dysfunction in patients
with congestive heart failure [17–19]. It was also reported
previously that β-blocker treatment decreases atrial
natriuretic peptide levels in patients with chronic heart
failure [16,20,21]. In patients during haemodialysis,
plasma levels of atrial natriuretic peptide and brain
natriuretic peptide were markedly higher than those in
normal controls, and these plasma levels were decreased
significantly by haemodialysis [22]. In the present study,
plasma levels of atrial natriuretic peptide and brain
natriuretic peptide decreased markedly after treatment
with the β-blocker, although the plasma level of noradrenaline remained unchanged. The decreases in plasma
atrial natriuretic peptide and brain natriuretic peptide
levels are likely to be due mainly to an improvement in
left ventricular function during metoprolol treatment.
Thus plasma atrial natriuretic peptide and brain natriuretic peptide concentrations may be useful markers for the
estimation of left ventricular function even in haemodialysis patients.
In haemodialysis patients, repeated vascular access for
haemodialysis may be commonly related to the creation
of a subcutaneous arteriovenous fistula. Arteriovenous
fistulas cause reduced vascular resistance and a subsequent increase in cardiac output. Although arteriovenous fistulas associated with haemodialysis may rarely
precipitate high-output failure [23], such a condition due
to excessive shunting associated with haemodialysis may
# 2001 The Biochemical Society and the Medical Research Society
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Y. Hara and others
occur in some haemodialysis patients [24,25]. In fact,
surgical closure and banding of arteriovenous fistulas
improves heart failure [24,25]. Although we did not
confirm whether shunting flow was excessive in our
patients, β-blocker therapy may act beneficially to reduce
shunting flow. In the present study, E-wave velocity was
decreased significantly by β-blocker therapy. Nishimura
et al. [26,27] reported that there was a relationship
between E-wave velocity and the maximum left-atrial–
left-ventricular gradient, and that preload reduction
resulted in decreases in E-wave velocity. In our study, the
left ventricular dimension both at end-diastole and at
end-systole was decreased significantly after treatment
with the β-blocker. This finding may be associated with
decreases in both or either left atrial pressure and left
ventricular diastolic pressure. Thus the decreases in
preload and in the left-atrial–left-ventricular pressure
gradient may be responsible for the decrease in E-wave
velocity. The pathophysiology behind left ventricular
dysfunction associated with haemodialysis remains unknown. In addition, any beneficial effect of β-blockers on
a dilated left ventricle in haemodialysis patients also
remain to be determined. Elevated cardiac output secondary to an arteriovenous fistula may be one important
cause of cardiac failure in patients on long-term haemodialysis, and β-blocker treatment may attenuate the high
output associated with haemodialysis. In view of the
results of the present study, β-blocker treatment may be
one of several important strategies that could be employed in the treatment of haemodialysis patients with
a dilated left ventricle.
The major limitations of the present study are that it
was open-labelled, uncontrolled and had a small sample
size. We are aware that a randomized study with a larger
number of subjects could have improved the impact of
our results. However, we believe that β-blocker treatment
may improve left ventricular function in haemodialysis
patients with a dilated left ventricle. To confirm the effect
of β-blockers in haemodialysis patients, it will be necessary to repeat the present study using a much larger group
of patients undergoing haemodialysis. In addition, it will
also be necessary to assess the longer-term effects of
β-blocker treatment in haemodialysis patients.
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Received 10 January 2001/12 March 2001; accepted 27 April 2001
# 2001 The Biochemical Society and the Medical Research Society
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