J Cardiol 2001; 37: 11 – 17

Impaired Ability to Secrete Atrial
Natriuretic Peptide in Response to
Isoproterenol Infusion in Patients
With Dilated Cardiomyopathy
Isao

NISHI, MD

Keiji

IIDA, MD

SatoruKAWANO, MD

TomokoMASUMI, MD

Iwao

YAMAGUCHI, MD, FJCC

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Objectives. The myocardium has 2 functions in vivo, that of pump and endocrine organ. Therefore,
simultaneous examinations of cardiac systolic reserve and endocrine reserve are important in evaluating
the activities of the myocardial cells. This study investigated the relationship between cardiac systolic
reserve and secretion of atrial natriuretic peptide（ANP）in response to isoproterenol infusion in patientswith dilated cardiomyopathy.
Methods. Isoproterenol was infused intravenously in 6 healthy individuals（control group）and 32
patients with dilated cardiomyopathy. The left ventricular systolic responses and plasma ANP concentrations were measured.
Results. Patients with dilated cardiomyopathy were classified into 2 groups : patients with a good
response（change in fractional shortening ＞ 7%, 17 patients）and those with a poor response（change in ＜−7%, 15 patients）. There was no significant difference in end-diastolic dimension, fractional shortening,heart rate, or systolic blood pressure between the 2 groups of patients with dilated cardiomyopathy at rest.
The resting plasma ANP concentration in the poor-response group（88.8 ± 59.0 pg/ml）was significantly
higher than that in the other 2 groups（good : 47.0 ± 35.9 pg/ml, p ＜ 0.05, control : 9.8 ± 4.1 pg/ml, p ＜0.01, respectively）. The percentage change in ANP after isoproterenol infusion in the poor-response group（− 7.1 ± 16.7%）was significantly less than that in the other 2 groups（good : 12.6 ± 27.3%, p ＜ 0.05,
control : 31.5 ± 24.6%, p ＜ 0.01, respectively）.
Conclusions. The resting plasma ANP concentration can be used to evaluate the cardiac systolic reservein patients with dilated cardiomyopathy. Decreased myocardial systolic reserve is also associated with
impaired ability to secrete ANP.
──────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2001; 37（1）: 11−17

Key Words■ Beta-adrenergic receptor agonists（isoproterenol）■ Cardiomyopathies, dilated■ Natriuretic peptide, atrial■ Stress echocardiography

INTRODUCTION
Plasma atrial natriuretic peptide（ANP）concentrations are increased in patients with congestive
heart failure1−5）. The atria and ventricles can syn-thesize substantial amounts of ANP in patients withdilated cardiomyopathy6−8）. The infusion of synthetic ANP significantly decreases the pulmonary
capillary wedge pressure and increases the strokevolume index in patients with congestive heart fail-──────────────────────────────────────────────
筑波大学臨床医学系 循環器内科 : 〒 305−8575 茨城県つくば市天王台 1−1−1
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki
Address for reprints : IIDA K, MD, Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine,
University of Tsukuba, Tennodai 1−1−1, Tsukuba, Ibaraki 305−8575
Manuscript received July 17, 2000 ; revised October 2, 2000 ; accepted October 12, 2000

11

12

Nishi, Iida, Kawano et alure9）. Therefore, increased plasma levels of ANP
may help to improve hemodynamic deterioration inchronic heart failure. ANP measurements may be
useful to evaluate the severity of symptoms andcardiac dysfunction in patients with chronic heart
failure. Evaluation of the left ventricular responses
to adrenergic stimulation is also useful in predicting
the course of dilated cardiomyopathy10−13）. The
myocardium has 2 functions in vivo, as a pump andan endocrine organ. Therefore, simultaneous examinations of cardiac systolic reserve and endocrine
reserve are important in evaluating the activities ofthe myocardial cells. However, there is no consensus about the relationship between changes in cardiac systolic function and changes in ANP secretion with adrenergic stimulation in patients withdilated cardiomyopathy.
We studied the relationship between cardiac systolic reserve and ANP secretion by determining thechanges in left ventricular systolic responses to isoproterenol and the ability to secrete ANP in
response to isoproterenol infusion in patients withdilated cardiomyopathy.
SUBJECTS AND METHODSPatients
Six healthy individuals（control group）and 32
patients with dilated cardiomyopathy admitted to
Tsukuba University Hospital or followed in the outpatient clinic were studied. Patients were aged from32 to 78 years（ mean age : 57 ± 12 years）andincluded 20 men and 12 women. The diagnosis ofdilated cardiomyopathy was based on findings
obtained at echocardiography or cardiac catheterization using the following criteria : left ventricular
dilation［left ventricular end-diastolic dimension
2＞ 55 mm or ＞ 36 mm/m（bodysurface area ＜−−2］; impaired systolic function defined as an
1.35 m ）M-mode fractional shortening ＜ 25% ; and absenceof coronary artery disease, severe valvular heartdisease, severe systemic hypertension, cor pulmonale, chronic systemic disease involving theheart muscle, and increased alcohol intake.
Coronary angiography was performed in 25 of 32
patients, and no significant coronary lesions weredetected. The remaining 7 patients had no clinicalhistory to suggest ischemic heart disease. Clinicalcharacteristics of the patients are summarized inTable 1. Five patients were in New York Heart
Association functional class Ⅰ, 20 in class Ⅱ, and7 in class Ⅲ. Among the 32 patients, 24 were in

Table 1 Clinical characteristics of control and dilated
cardiomyopathy groups
Control group（n＝6）

DCM group（n＝32）

p value

38±12

57±12

＜0.01

Sex
（males/females）

4/2

20/12

NS

Atrial fibrillation

0/6

8/24

NS

Dd
（mm）

47±9

63±6

＜0.01

Ds（mm）

31±8

55±6

＜0.01

FS
（%）

36±7

14±5

＜0.01

Age（yr）

Continuous values are mean±SD.
DCM＝dilated cardiomyopathy ; Dd＝end-diastolic dimension ;Ds＝end-systolic dimension ; FS＝fractional shortening.

sinus rhythm and 8 had atrial fibrillation.
Concerning concurrent agents, diuretics were prescribed for 23 patients, angiotensin-converting
enzyme inhibitors for 16, digitalis for 9, and calcium channel blockers for 2. The patients did notreceive β-blockers before the isoproterenol stresstest. The study was explained to each patient andinformed consent was obtained.
Echocardiographic studies
All 6 healthy individuals and 32 patients underwent real-time two-dimensional and M-mode
echocardiographic examination. M-mode andcross-sectional echocardiograms were obtainedwith a Toshiba SSH-160A, SSA-380A or SSA390A ultrasonoscope（Toshiba Co.）equipped with a
2.5- or 3.75-MHz transducer and a Toshiba line
scan recorder, LSR-100A. The paper speed was
50 mm/sec. Left ventricular echocardiograms wereobtained at the level of the chordae tendineae justbelow the tips of the mitral leaflets using twodimensional echocardiographic guidance.
Electrocardiograms and phonocardiograms wererecorded simultaneously with the echocardiograms.
Fractional shortening was calculated as［left ventricular end-diastolic dimension（mm）− left ventricular end-systolic dimension（mm）］/left ventricular end-diastolic dimension（mm）× 100（%）.
Isoproterenol stress echocardiography
The isoproterenol test was performed in theafternoon in all 6 healthy individuals and32 patients using a previously described technique10, 14−16）. Briefly, the patient lay in the supine
position in a darkened room and isoproterenol was
J Cardiol 2001; 37: 11 – 17

13

Response to Isoproterenol Infusion in Dilated Cardiomyopathy

infused intravenously for 5 min through an antecubital vein at doses of 0.01 and 0.02μg/kg/min
using a calibrated infusion pump. During isoproterenol infusion, electrocardiogram monitoring was
performed continuously. Blood pressure was alsomeasured with a mercury column sphygmomanometer at rest and during isoproterenol infusion
every one minute. M-mode echocardiography was
performed before and immediately after isoproterenol infusion using a line scan recorder at
50 mm/sec. The change in the fractional shortening
with isoproterenol infusion was determined as fractional shortening immediately after isoproterenol
infusion at a doses of 0.02μg/kg/min（%）− fractional shortening at rest（%）.
Plasma atrial natriuretic peptide concentration
Venous blood samples were obtained from theantecubital vein via an indwelling butterfly needle
after the patients had rested in the supine position
for 20 min and again at the end of the protocol tomeasure plasma ANP concentrations. Plasma ANP
concentrations were determined by immunoradiometric assay. The minimal detectable level of ANP
was 5 pg/ml.
Statistical analysis
Data were presented as mean ± standard deviation. Significant differences were determined withthe paired or unpaired t-test as appropriate.
Differences in frequencies were analyzed with theFisher s exact probability test or the chi-square statistic test. Statistical calculations were performed
using Statview software. A p value of ＜ 0.05 wasconsidered statistically significant.
RESULTS
Isoproterenol stress echocardiography
In the control group, the change in fractional
shortening with isoproterenol ranged from 14% to20%（mean : 17 ± 2%）. In patients with dilated
cardiomyopathy, the change in fractional shortening with isoproterenol infusion ranged from − 3%
to 15%（mean : 7 ± 4%）. In this study, the criterion
for a good response to isoproterenol was defined asa ＞ 7% increase in fractional shortening（the meanvalue in patients with dilated cardiomyopathy）.
The patients with dilated cardiomyopathy weredivided into 2 groups : patients with a good
response（change in fractional shortening ＞ 7% ;good-response group）and those with a poor
J Cardiol 2001; 37: 11 – 17

Table 2 Patient characteristics
Good-response Poor-response
p valuegroup（n＝17） group（n＝15）
Age（yr）

55±13

59±10

NS

Sex
（males/females）

13/4

7/8

NS

NYHA class（Ⅰ/Ⅱ/Ⅲ） 3/12/2

2/8/5

NS

In-/outpatients

12/5

12/3

NS

Atrial fibrillation

5

3

NS

Dd
（mm）

63±7

64±5

NS

Ds（mm）

54±8

55±4

NS

FS
（%）

14±5

13±5

NS

（%）
ΔFS

10±2

4±3

＜0.01

Diuretics

13

10

NS

ACE inhibitors

9

7

NS

Digitalis

6

3

NS

Ca channel blockers

2

0

NS

Continuous values are mean±SD.
NYHA＝New York Heart Association ; ΔFS＝change infractional shortening with isoproterenol infusion ; ACE＝angiotensin-converting enzyme ; Ca＝calcium. Other abbreviations as in Table 1.

response（change in fractional shortening ＜− 7% ;
poor-response group）. Fifteen of the 32 patientswith dilated cardiomyopathy had a poor response
and 17 had a good response（Table 2）. There wasno significant difference in the left ventricular resting end-diastolic dimension, the left ventricularresting end-systolic dimension, resting fractional
shortening, New York Heart Association functionalclass, the number of outpatients or inpatients, andincidence of atrial fibrillation between the 2 groupsof patients with dilated cardiomyopathy（Table 2）.
Diuretics were prescribed to 13 of 17 patients in the
good-response group and to 10 of 15 patients in thepoor-response group. Angiotensin-converting
enzyme inhibitors were used in 9 of 17 patients in
the good-response group and in 7 of 15 patients inthe poor-response group. Digitalis was prescribedfor 6 good-response patients and 3 poor-response
patients. Calcium channel blockers were prescribedfor 2 good-response patients. There were no differences in medication between the 2 groups ofpatients with dilated cardiomyopathy（Table 2）. In
addition, there was no difference in heart rate orsystolic blood pressure either at rest or immediately
after isoproterenol infusion between the 3 groups（Table 3）. In response to isoproterenol infusion,
the heart rate increased significantly（p ＜ 0.01）,

14

Nishi, Iida, Kawano et al

Table 3

Heart rate and systolic blood pressure at rest and immediately after isoproterenol infusionin 3 groups
Control group
BeforeAfter ISP＊

Good-response group

Poor-response group

BeforeAfter ISP

BeforeAfter ISP＊

Heart rate（beats/min）

67±9

104±1771±12107±2570±16

110±36＊SBP（mmHg）

117±10128±19117±19125±38109±21

108±24＊p＜0.01 vs before ISP.
ISP＝isoproterenol ; SBP＝systolic blood pressure.

Fig. 2 Percentage change in atrial natriuretic peptide
after isoproterenol infusion（%ΔANP）
Abbreviation as in Fig. 1.

Fig. 1 Plasma atrial natriuretic peptide concentrations
both at rest and immediately after isoproterenol
infusion
ANP ＝ atrial natriuretic peptide. Other abbreviation asin Table 3.

although the systolic blood pressure did not change
in all 3 groups（Table 3）.
Plasma atrial natriuretic peptide concentrations
and changes in response to isoproterenol
Our data indicate that cardiac systolic reserve asassessed by isoproterenol stress echocardiography
is related to resting plasma ANP concentrations andpercentage change in ANP after isoproterenol infusion［｛（Plasma ANP immediately after isoproterenol infusion − plasma ANP before isoproterenol infusion）/plasma ANP before isoproterenol
infusion｝× 100（%）］.
Fig. 1 summarizes the plasma ANP concentra-

tions before and immediately after isoproterenol
infusion in the poor-response, good-response, andcontrol groups. At rest, the plasma concentration of
ANP in the poor-response group（88.8 ± 59.0
pg/ml）was significantly higher than in both goodresponse（47.0 ± 35.9 pg/ml, p ＜ 0.05）and control（9.8 ± 4.1 pg/ml, p ＜ 0.01）groups. Immediately
after isoproterenol infusion, the plasma concentration of ANP in the poor-response group（83.5 ±58.4 pg/ml）was significantly（p ＜ 0.01）higher thanin the control group（12.4 ± 4.6 pg/ml）and tended
to be higher than in the good-response group（49.9 ± 35.8 pg/ ml, p ＝ 0.056 ; Fig. 1）. Plasma
concentration of ANP in the good-response groupwas significantly（p ＜ 0.05）
higher than in the control group before and after isoproterenol infusion.
The plasma ANP concentration after isoproterenol
infusion tended to be higher than that before theinfusion in the control group（p ＝ 0.059 ; Fig. 1）.
The percentage change in ANP after isoproterenol infusion in the poor-response group（− 7.1 ± 16.7%）was lower than in the control
group（31.5 ± 24.6%, p ＜ 0.01）and in the goodJ Cardiol 2001; 37: 11 – 17

Response to Isoproterenol Infusion in Dilated Cardiomyopathy

response group（12.6 ± 27.3%, p ＜ 0.05 ; Fig. 2）.
The change in ANP secretion with isoproterenol
infusion was not associated with aging in the control group（data not shown）.
DISCUSSION
Our results indicate that cardiac systolic reserve
is inversely related to resting plasma ANP concentration in patients with dilated cardiomyopathy.
Resting plasma ANP concentration in patients withdilated cardiomyopathy is correlated inversely withthe percentage increase in the cardiac index in
response to adrenergic stimulation17）, but heart rate,systolic blood pressure, left ventricular end-diastolic volume, and incidence of atrial fibrillation
were not determined17）. In contrast, our study foundthat these factors did not differ between the poorresponse group and the good-response group.
Infusion of ANP improves left ventricular function
in patients with congestive heart failure 9）. We
thought that increases in ANP secretion reduce preload and afterload in patients with a poor response,
and, as a result, the left ventricular end-diastolicdimension and fractional shortening at rest would
be similar in the 2 groups.
Our results also demonstrate the relationshipbetween the cardiac systolic reserve and the ability
to increase the rate of ANP secretion. Patients witha poor response to isoproterenol infusion also failed
to augment ANP secretion. These results indicatethat not only cardiac systolic reserve but also ability to secrete ANP was impaired in patients with apoor response. We thought that in patients with apoor response, a high level of ANP contributed to
the regulation of fluid volume and blood pressure at
rest, whereas the increase in the rate of ANP secretion under strenous conditions was impaired andthe supply of ANP could not meet the demand for
ANP under stress.
Previous studies have shown that plasma ANP
concentration in patients with heart disease is generally related to the magnitude of increases in rightatrial pressure or pulmonary artery wedge pressure.
Cardioacceleration with increased atrial pressure
has been shown to further elevate plasma ANP concentration. In our study, the heart rate increased significantly in the 3 groups in response to isoproterenol infusion. However, there was no differencein heart rate either at rest or immediately after isoproterenol infusion between the 3 groups. We did
not measure the right atrial pressure and pulmonary
J Cardiol 2001; 37: 11 – 1715artery wedge pressure in this noninvasive study.
However, the change in fractional shortening withisoproterenol in the poor-response group was
smaller than in both good-response and control
groups. We thought that the improvement in cardiac hemodynamics with isoproterenol in the poorresponse group was less than in both the goodresponse and control groups.
Some studies have demonstrated that isoproterenol induces the release of ANP18−20）. In experimental models, isoproterenol induces the release of
ANP by directly stimulating β-adrenoreceptors.
However, in rats with congestive heart failure
which received chronic infusion of isoproterenol,
isoproterenol failed to increase the plasma ANP
concentration18）. These results suggest that downregulation of β-adrenoreceptors diminished the
myocardial systolic reserve and ANP secretion. In
our study, isoproterenol increased the rate of ANP
secretion in the healthy individuals, but failed toincrease the rate of ANP secretion in the poorresponse group. We think that fibrotic changes andeither degeneration or down-regulation of βadrenoreceptors in the patients with a poor response
were responsible for the decreased cardiac systolic
reserve and the blunted changes in the plasma ANP
concentration during isoproterenol infusion. The
healthy individuals were significantly younger thanthe patients with dilated cardiomyopathy. The
inotropic response of catecholamines in the aged
myocardium diminishes in healthy individuals21）.
Plasma ANP concentration is not associated withaging in healthy individuals22）. Therefore, the age
differences between healthy individuals and thepatients with dilated cardiomyopathy might influence the differences in response to isoproterenol,
but the differences in age did not greatly affect thecorrelation between cardiac systolic reserve andresting plasma ANP concentration in the 3 groups.
In our study, the change in ANP secretion with isoproterenol infusion was not associated with aging
in healthy individuals（data not shown）. So the differences in age did not extremely influence the correlation between cardiac systolic reserve and thechanges in ANP secretion with isoproterenol infusion in the 3 groups.
Study limitations
We did not measure the pulmonary artery wedge
pressure, right atrial pressure, and left ventricular
end-diastolic pressure in this noninvasive study.

16

Nishi, Iida, Kawano et al

The possibility remains that these indices are higher
in patients with a poor response than in patientswith a good response.
CONCLUSIONS
Our results indicate that resting plasma ANP
concentration can be used to evaluate cardiac systolic reserve in patients with dilated cardiomyopa要

thy. Decreased myocardial systolic reserve is also
associated with reduced increase in the rate of ANP
secretion in response to isoproterenol.
This work was supported by grants for the study of idiopathic cardiomyopathy from the Japanese Ministry of Health and Welfare,Tokyo, Japan.

約

拡張型心筋症のイソプロテレノール静注に対する
心房性ナトリウム利尿ペプチド分泌予備能の検討
西
目

功

飯田

啓治

河 野

了

増見

智子

山 口

巖

的 : 心臓はポンプおよび内分泌器官の役割を持っている．それゆえ，ポンプ器官としての予備能（心収縮予備能）と内分泌器官としての予備能［心房性 Na 利尿ペプチド（ANP）分泌予備能］を同時に知ることは，心筋細胞の活性度を評価するうえで重要と考えられる．本研究では，拡張型心筋症患者にイソプロテレノール負荷心エコー図法を行い，薬物負荷による心収縮予備能と血漿 ANP
濃度の動態との関連を検討した．
方

法 : 拡張型心筋症患者 32 例と正常対照者 6 例を対象にイソプロテレノールを静注した．安静

時と負荷直後にそれぞれ心エコー図を記録し，血漿 ANP 濃度を測定した．
結果 : イソプロテレノール負荷前後の左室内径短縮率（FS）の変化分（ΔFS : 負荷直後 FS −安静時 FS）
により，負荷反応良好群（ΔFS ＞ 7% : 17 例）に分類した．
と負荷反応低下群（ΔFS ＜− 7% : 15 例）
反応良好群と反応低下群の間において安静時の左室拡張末期径，FS，心拍数，収縮期血圧には有意差はなかった．安静時血漿 ANP 濃度は，反応低下群（88.8 ± 59.0 pg/ml）で反応良好群（47.0 ±35.9 pg/ml，p ＜ 0.05），対照群（9.8 ± 4.1 pg/ml，p ＜ 0.01）よりいずれも有意に高値であった．また，反応低下群（− 7.1 ± 16.7%）の［（後 ANP 濃度−前 ANP 濃度）/前 ANP 濃度× 100（%）］の式により求められた血漿 ANP 濃度の変化率では，反応良好群（12.6 ± 27.3%，p ＜ 0.05）および対照群（31.5 ±
24.6%，p ＜ 0.01）と比較して有意に小であった．
結論 : 拡張型心筋症において安静時血漿 ANP 濃度は，心収縮予備能を評価するのに有用と考えられた．心収縮予備能の減少は ANP 分泌予備能の低下と関連していた.

J Cardiol 2001; 37（1）: 11−17

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