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Significance of Combined Angiotensin Ⅱ Receptor Blocker andCarvedilol Therapy in Patients
With Congestive Heart Failure andArginine Variant
AtsushiIWATA, MD

Shin-ichiro

MIURA, MD

HiroakiNISHIKAWA, MD

Akira

KAWAMURA, MD

Yoshino

MATSUO, BS

Hideto

SAKO, MD

Koichiro

KUMAGAI, MD, FJCC

Kunihiro

MATSUO, MD

Keijiro

SAKU, MD, FJCC

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Objectives. Angiotensin Ⅱ receptor blockers（ARBs）and β-blockers have contributed to longer life
expectancies for patients with congestive heart failure. However, whether the use of ARBs is helpful for
introducing carvedilol（β-blocker）is unclear when patients with symptomatic congestive heart failure areadmitted to the hospital.
Methods. In this retrospective study, 27 patients with symptomatic congestive heart failure were given
carvedilol upon admission. Five patients received carvedilol monotherapy（group A）, and 22 were treatedwith a combination of carvedilol and ARBs
（group B）.
Results. There was no difference in medication between the groups except for ARBs. In addition, there
were no significant differences in the decrease in plasma brain natriuretic peptide, or the improvement ofleft ventricular ejection fraction upon carvedilol treatment between the groups. Although there was no significant difference in the maintenance dose of carvedilol between the groups, the gross dose of carvedilol
in group B was significantly lower than that in group A. In addition, the improvement of left ventricularejection fraction in group B was positively correlated with the maintenance dose of carvedilol in patients（arginine/arginine genotype）.
who had wild-type β1-adrenergic receptor at amino acid 389
Conclusions. These results suggest that ARBs are helpful for introducing carvedilol in patients with thewild-type β1-adrenergic receptor gene, and that treatment with combined treatment with ARB or analysisof the β1-adrenergic receptor genotype may offer advantages to control congestive heart failure in the shortterm.
──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2006 Jan ; 47（1）: 1−7

Key Words
Angiotensin Ⅱ
Heart failure

Beta-adrenergic receptor blockers

Genetics

──────────────────────────────────────────────
福岡大学病院 循環器科 : 〒 814−0180 福岡市城南区七隈 7−45−1
Department of Cardiology, Fukuoka University Hospital, Fukuoka
Address for correspondence : MIURA S, MD, Department of Cardiology, Fukuoka University Hospital, Nanakuma 7−45−1, Jonanku, Fukuoka 814−0180
Manuscript received June 6, 2005 ; revised August 23 and October 6, 2005 ; accepted October 6, 2005
BS ＝ bachelor of science1

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Iwata, Miura, Nishikawa et al

INTRODUCTION
Congestive heart failure is associated with highmortality and morbidity. Many trials have demonstrated significant improvements with regard to survival and reduced hospitalization for patients who
received angiotensin-converting enzyme inhibitors（ACEIs）and β-blockers, and these results haveguided the recommendations of national andinternational guidelines for the management ofheart failure. In patients with congestive heart failure and reduced left ventricular ejection fraction（LVEF）, the results of clinical randomized trials
have shown that ACEIs can provide life-saving andsymptomatic benefits 1−3）. Furthermore, several
double-blind, placebo-controlled, randomized studies performed in the United States and Europe haveshown that β-blockers have beneficial effects on
mortality and mobility in patients with congestive
heart failure4−8）. In addition,β-blocker carvedilol
treatment for congestive heart failure patients is ahighly cost-effective method of therapy in theJapanese medical environment9）.
However, as the prevalence of heart failure rises,
its impact on morbidity, mortality, and healthcare
costs exerts a heavy toll worldwide. A previous
study10） demonstrated that angiotensin Ⅱ receptor
blockers（ARBs）
prevented patients with heart failure from worsening. A recent result showed thattreatment with combinations of β-blockers and
ACEIs reduced the mortality rate of patients withcongestive heart failure 7）. Another study also
demonstrated that the addition of ARBs to ACEIs
and β-blockers and other conventional treatments
leads to a further clinically important reduction in
relevant cardiovascular death and hospital admissions for heart failure in patients with congestive
heart failure and improves LVEF10−13）. In addition,
carvedilol and losartan alone and in combination
prevent ventricular remodeling after acute myocardial infarction in rats, with almost equivalenteffect14）. Several genetic polymorphisms have been
identified in the β1-adrenergic receptor（AR）gene,and the genetic heterogeneity of β1-AR correlateswith a pathophysiological role in patients with congestive heart failure. A recent investigation suggested that heart failure patients with the aminoacid residue arginine（ Arg）389 β1 -AR variant
showed improved left ventricular function whentreated with carvedilol, a third-generation β-blocker with vasodilatory and antioxidant actions, whencompared with glycine（Gly）389 patients15）.
It would be worthwhile to determine whether
treatment with ARBs is useful for introducing βblockers in patients with congestive heart failure.
Therefore, we tested the hypothesis that the ARBs
is useful for introducing carvedilol in patients withsymptomatic congestive heart failure. We also
examined the association between genetic variancesof Arg389 in β1-AR and the results of carvedilol
treatment in congestive heart failure.
SUBJECTS AND METHODS
Subjects
The subjects consisted of 27 patients with symptomatic congestive heart failure who were admitted
to Fukuoka University Hospital. Patients had
ischemic or non-ischemic cardiomyopathy withsymptoms［New York Heart Association（NYHA）
functional class Ⅱ−Ⅳ］. Patients with the following
conditions were excluded : valvular heart disease,
hypertrophic obstructive cardiomyopathy, cardiogenic shock, systolic blood pressure ＜ 90 mmHg,
bradycardia（＜ 60/min）, grade Ⅱ or Ⅲ atrioventricular block, life-threatening arrhythmia, unstableangina, resting angina, cor-pulmonale, asthma,
Raynaud phenomenon, and intermittent claudication. Hypertensive heart disease was defined bypressure of hypertension and left ventricular hypertrophy as assessed by echocardiography.
All patients were given carvedilol upon admission : 5 received carvedilol monotherapy（groupA）, and 22 were treated with combined carvedilol
and ARBs（ group B）. In group B, 27%（n ＝ 6）
received 5 ± 1 mg/day of candesartan, 46%（n＝10）
received 52 ± 13 mg/day of valsartan and 27%（n ＝ 6）received 33 ± 5 mg/day of losartan. All
patients in group B were introduced to carvedilol
after ARB administration on admission to a hospital. ARB on admission and diuretics, digitalis, calcium channel blockers, vasodilators, and antiarrhythmic agents could be used concomitantly ifnecessary for treatment of congestive heart failure.
We investigated blood pressure, heart rate, echocardiography, plasma brain natriuretic peptide（BNP）
level, and the maintenance and total doses ofcarvedilol at two points（on admission before treatment and when the patients left the hospital）. The
ethics committee of Fukuoka University Hospital
approved this study.

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ARB and Carvedilol Therapy in Congestive Heart Failure

Table 1

3

Baseline patient characteristics
Group A
（n＝5）

Group B
（n＝22）

Age（yr）

56±4

66±2

Body mass index（m2/kg）

22±2

23±1

Male（%）

60

65

Alcohol use（%）

40

36

Current smoker（%）

8041Ischemic heart disease

044＊

Idiopathic cardiomyopathy

40

36

Hypertensive heart disease40

16

Others20

4Hypertension

40

45

Diabetes mellitus

20

18

Hyperlipidemia

20

32

Diuretics

80

82

Digitalis20

23

20/80/0

0/74/26

24±5

37±3

Heart disease cause（%）

Concomitant disease（%）

Medical treatment（%）

NYHA class（%）
Ⅱ/Ⅲ/Ⅳ
LVEF
（%）
LVDd（mm）

60±6

57±2

Systolic BP（mmHg）

110±11122±4

Diastolic BP（mmHg）

75±12

77±4

Heart rate（beats/min）

91±9

81±4

BNP level（pg/ml）

789±209584±112

Continuous values are mean±SE. ＊p＜0.05 vs group A.
Group A : Patients treated with carvediol. Group B : Patientstreated with combined carvediol and angiotensionⅡreceptor
blockers.
NYHA＝New York Heart Association ; LVEF＝left ventricularejection fraction ; LVDd＝left ventricular diastolic dimension ;BP＝blood pressure ; BNP＝brain natriuretic peptide.

Gene analysis
Genomic DNA was extracted from peripheral
whole blood using the Genomix kit. For genotypingof the Arg389Gly polymorphism of the β1-AR
gene, the polymerase chain reaction and restriction
enzyme digestion were performed as described previously16）.
Statistical analysis
Data are shown as the mean ± standard error.
Categorical variables were compared between
groups by chi-square analysis. Differences in individual variables were analyzed by the unpaired ttest. Correlation between variables was examined
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Fig. 1 Comparison of parameters in heart failure
patients in groups A and B
No significant differences in the decrease in the BNP
level（ΔBNP, Δ values after carvedilol treatment minus
those before treatment ; A）or the increase in LVEF
（ΔLVEF ; B）were observed between the groups.
Explanation of the groups and abbreviations as in Table
1.

by the Pearson correlation. A value of p ＜ 0.05 wasregarded as significant. Data were analyzed using
commercially available statistical software（Statview-J 5.0 ; Abacus Concepts Inc.）.
RESULTS
Baseline patient characteristics are shown in
Table 1. There were no significant differences inbaseline characteristics between the two groups,
except for the etiology of heart failure. None and
44% of the patients in groups A and B, respectively, had ischemic heart disease（p ＜ 0.05）.
There were no significant differences in thedecrease in the BNP level or the increase in LVEF
（measured by M-mode echocardiography）during
carvedilol treatment between groups A and B（Fig.
1）. Since cardiac function in the groups recovered
similarly, we did further statistical analysis. In addition, all patients in both groups became NYHA
class Ⅰ after treatment.
The gross and maintenance doses of carvedilol
before and after treatment for introducing
carvedilol are shown in Fig. 2. The gross dose indicates total amount of carvedilol during hospitalization for patients. Although there was no significant
difference in the maintenance dose of carvedilol（group A : 7.5 ± 1.6 mg/day, group B : 9.3 ±1.1 mg/day）, the gross dose of carvedilol in group
B（125 ± 12 mg）was significantly lower than thatin group A（204 ± 63 mg）（ p ＜ 0.05）. Group B

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Iwata, Miura, Nishikawa et al

Fig. 2 Gross and maintenance doses of carvedilol for introducing carvedilol in groups
A and B
Although there was no significant difference in the maintenance dose of carvedilol（B）, thegross dose of carvedilol in group B was significantly lower than that in group A（A ; p ＜0.05）. Total days of carvedilol administration is shown in（C）.
Gross dose of carvedilol ＝ dose of carvedilol × total days of administration. Explanationof the groups as in Table 1.

tended to have a shorter total period of carvedilol
administration compared to group A（group A :32 ± 7 days, group B : 23 ± 2 days, p ＜ 0.10）.
Fig. 3 compares the gross and maintenance dosesof carvedilol before and after treatment for introducing carvedilol between the Arg/Arg（n ＝14）
and Arg/Gly（n ＝ 8）groups in all patients. Five
patients were excluded because of no approval toanalyze DNA. There were no differences between
the groups in baseline patient characteristics of age,body mass index, sex, drinking, smoking, heart disease cause, concomitant disease, medical treatment,
NYHA class, LVEF, blood pressure, heart rate and
BNP.
There were no significant differences in the grossor maintenance dose of carvedilol between thegroups. Although there was no difference in the
improvement of LVEF（ΔLVEF ＝ value aftercarvedilol treatment minus that before treatment）
between the Arg/Arg and Arg/Gly groups（Fig. 4−A）in all patients, ΔLVEF was positively correlatedwith the maintenance dose of carvedilol in group B
patients who had the Arg/Arg genotype（Fig. 4−
B）. In the Arg/Gly group, there was no correlation
between LVEF and the maintenance dose of
carvedilol（p ＞ 0.10）. If a patient with congestive
heart failure and the wild-type β1-AR gene（position 389 is Arg/Arg）receives combination therapy
with ARBs for the introduction of carvedilol, ahigher maintenance dose of carvedilol may more

effectively improve cardiac function.
DISCUSSION
Our results support the hypothesis that ARBs
and β-blockers have beneficial effects for patientswith heart failure. Previous studies have demonstrated that ARBs have long-term benefits andreduce cardiovascular death and hospital admissions for heart failure. Our results suggest that
ARBs also have a short-term benefit, i.e., additional
treatment with ARBs can reduce the gross dose of
carvedilol. Therefore, the use of carvedilol combined with ARBs may be useful for introducing
carvedilol in patients with heart failure.
Once the onset of heart failure has occurred, avicious cycle is initiated. After a sizable myocardial
loss to precipitate heart failure, neurohormonal activation, especially of the sympathetic nerve systemand the renin-angiotensin system, results in further
losses of cardiac myocytes through apoptosis andnecrosis. A primary objective of treatment is to prevent the further loss of cardiac myocytes 17）, by
reducing the recurrence of myocardial infarctions,myocarditis, or cardiomyopathic processes. The
former can be effectively achieved by inhibiting therenin-angiotensin system or the sympathetic system. The latter can also be partly achieved by treatment with angiotensin converting enzyme
inhibitors and possibly ARBs18,19）. Administrationof β -blocker normalized the abundance of
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ARB and Carvedilol Therapy in Congestive Heart Failure

5Fig. 4 ΔLVEF in the Arg/Arg and Arg/Gly groups（A）,
and ΔLVEF was positively correlated with themaintenance dose of carvedilol in group B
patients who had the Arg/Arg genotype（y ＝3.222 ＋ 0.801x, r ＝ 0.674, p ＜ 0.05; B）.
Explanation of group B and abbreviation as in Table 1,
Fig. 3.

Fig. 3 Representative genetic variances in three individuals, gross and maintenance doses of carvediol
A : Representative genetic variances of β1-AR at aminoacid 389 in three individuals. Polymerase chain reaction
fragments were digested with the restriction endonuclease Bcg Ⅰ, which did not digest the Arg-389 productbecause of the guanine to cytosine transition.
B,C : Gross（B）and maintenance（C）doses of carvedilolin the Arg/Arg（n ＝ 14）and Arg/Gly groups（n ＝ 8）areshown. None of the subjects in this study were Gly/Gly.
There were no significant differences in the gross andmaintenance doses of carvedilol between the groups.
Arg ＝ arginine ; Gly ＝ glycine ; bp ＝ base paire.

myocyte Ca2 ＋ regulatory proteins and improved
Ca2 ＋ handling20）. In addition,β-blockers can effectively suppress the sympathetic system, thus interrupting the downward spiral caused by the vicious
cycle in patients with heart failure, and prevent further losses of cardiac myocytes. Accordingly, theaccelerated deterioration of cardiac pumping capability can be ameliorated by therapy aimed at
inhibiting angiotensin and/or β-adrenergic effects
using ARBs and/or β-blockers. The combination
therapy with carvedilol and ARBs may be morepotent than individual treatments through the combined beneficial mechanisms for controlling heart
failure as seen in this study.
Over the past decade, increasing evidence has
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accumulated to indicate that angiotensin Ⅱ is
involved in the development of atherosclerosis,
myocardial infarction, vascular and myocardial
remodeling, and heart failure21,22）. In the case ofheart failure, angiotension Ⅱ type 1（AT1）receptors
expressed in myocardial cells are activated, whichcauses consequent cellular hypertrophy, proliferation, and apoptosis. ARBs strongly block AT 1
receptors, and reduce cardiovascular death and hospital admissions for heart failure. Up-regulation ofangiotension Ⅱ caused by ARBs stimulates AT 2
receptor. Other mechanisms of action, such as AT2
receptor effects, and the anti-oxidant 23） or antifibrotic effects of ARBs24）, may also contribute to
the improvement of heart failure.
According to a previous epidemiological study,
the β1-AR Ser49Gly variant might be associatedwith a decreased risk of morbidity and mortality inpatients with congestive heart failure25）. Also, alack of polymorphic α2c-AR（α2c Del322−325）andabnormality of β1-AR（Arg389Gly）act synergistically to increase the risk of heart failure inblacks 26）. A recent study demonstrated that thehuman Arg389 variant predisposes patients to heart
failure by instigating hyperactive signaling programs which lead to depressed receptor coupling
and ventricular dysfunction, and influences thetherapeutic response to β1-AR blockade. Heart failure patients with Arg 389 homozygosis showed
improved left ventricular function during long-termcarvedilol treatment compared to Gly389 patients.

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Iwata, Miura, Nishikawa et al

Although we did not note any differences in the
improvement of left ventricular function for introducing carvedilol between the Arg/Arg and
Arg/Gly groups, this may have been due to theshort duration of this study. This study found that
the Arg389 variant in β1-AR may be useful for introducing carvedilol in heart failure patients because ahigher maintenance dose of carvedilol was more
effective for improving cardiac function in patientswith the wild-type β1-AR gene（Arg/Arg at position389）. If heart failure patients who have theArg/Arg genotype and receive combination therapy
with ARBs for introducing carvedilol, a higher
maintenance dose of carvedilol might be recommended.
Study limitations
This study has several important limitations.
要First, there was a difference in the etiology of heart
failure between groups A and B. However, this difference did not affect our main conclusion that
ARBs are helpful for introducing carvedilol inpatients with the wild-type β1-AR gene. Second,
the sample size is small, which limited our ability
to determine significance. Our study was a nonrandomized, retrospective, observational study. A large
randomized controlled trial of statins in patientswith coronary artery disease is warranted to evaluate the potential benefits of these agents.
CONCLUSIONS
Additional treatment with ARBs and the analysis
of Arg389 variant in β1-AR in patients with congestive heart failure may be helpful for introducing
carvedilol, and treatment with the combination ofcarvedilol and ARBs may have advantages over約

うっ血性心不全患者のアンジオテンシンⅡ受容体遮断薬併用によるカルべジロール
導入とβ1 アドレナジック受容体アルギニン 389 バリアントの意義
岩 田

目

敦

三浦伸一郎

西川

宏明

河 村

彰

松尾

佐光

英人

熊谷浩一郎

松尾

邦浩

朔

啓二郎

佳野

的 : アンジオテンシンⅡ受容体遮断薬（ARB）とβ遮断薬は，うっ血性心不全患者の予後を改善する．しかし，カルベジロール（β遮断薬）の導入に ARB の併用が有効であるかについては明らかでない．
方法 : 入院後，カルベジロールを導入された症状を有する 27 例のうっ血性心不全患者を後ろ向きに検討した．2 群に分け，5 例をカルベジロール投与群，22 例をカルベジロール＋ ARB 投与群とした．
結果 : 投薬内容は，ARB 投与を除いて両群間に有意差はなかった．また，脳性 Na 利尿ペプチ

ド，左室駆出率にも有意差はなかった．カルベジロールの維持量は，両群間に有意差はなかったが，カルベジロール＋ ARB 投与群では，カルベジロール投与群に比べて有意にカルベジロールの総投与量が減少していた．さらに，カルベジロール＋ ARB 投与群における左室駆出率の改善度は，β1
アドレナジック受容体の 389 番のアミノ酸が Arg/Arg 遺伝子型（野生型）を有する患者においてカル
ベジロールの維持量と正相関していた．
結論 : ARB は，β1 アドレナジック受容体の 389 番のアミノ酸が Arg/Arg 遺伝子型を有する心不全患者のカルベジロール導入を容易にし，ARB の併用療法およびβ1 受容体の遺伝子解析は，短期に心不全患者に対してカルベジロールを導入する場合に有用であることが示唆された．

J Cardiol 2006 Jan; 47（1）: 1−7

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