Diagnostic Value of Plasma Levels of Brain Natriuretic Peptide in Arrhythmogenic Right Ventricular Dysplasia
From the Divisions of Cardiology (K.M., T.K., W.S., A.T., K.Suyama, N.A., S.K., K.Shimomura) and Hypertension (T.N.), Department of Internal Medicine, and Divisions of Pathology (C.Y.) and Radiology (M.T.), and Research Institute (K.K.), National Cardiovascular Center, Osaka, Japan.
Correspondence to Dr Toshio Nishikimi, Division of Hypertension, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail nishikim{at}jsc.ri.ncvc.go.jp
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Background—Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by local or diffuse wall motion abnormalities in the right ventricle (RV), associated with recurrent ventricular tachycardia (VT) of RV origin. Brain natriuretic peptide (BNP) was first isolated from a porcine brain extract. In humans, BNP is expressed predominantly in the ventricles of failing hearts, and its expression has been observed primarily in myocytes in the interstitial fibrous area in dilated cardiomyopathy. We hypothesized that BNP is increasingly secreted from the residual myocytes within the atrophic tissue in patients with ARVD.
Methods and Results—Plasma BNP levels were measured in 17 patients with ARVD, 12 patients with idiopathic RV outflow tract tachycardia (RVOT), and 120 control subjects. We performed cardiac catheterization, RV endomyocardial biopsy, electron- beam CT, and biventricular endomyocardial mapping in the ARVD patients. There was a significant increase in plasma BNP levels in the ARVD patients compared with the RVOT patients and control subjects (61.4±59.6 pg/mL versus 8.3±5.5 pg/mL and 9.3±5.8 pg/mL; P<0.0001, respectively). The plasma BNP levels had no correlation with any of the hemodynamic data, but they had a significant correlation with the RV ejection fraction (r=-0.588, P=0.025) and with the fractionated-area scores (r=0.705, P=0.005). Light microscopic immunohistochemistry showed strong BNP immunoreactivity in residual myocytes with fibrofatty replacement.
Conclusions—These results suggest that plasma BNP levels were not increased in RVOT patients but were increased in ARVD patients, and that the increased BNP levels indicate the severity of both the RV dysfunction and the arrhythmogenic substrate.
Key Words: tachyarrhythmias • cardiomyopathy • brain natriuretic peptide • electrophysiology
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Introduction |
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Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by local or diffuse wall motion abnormalities exclusively or predominantly affecting the right ventricle (RV), associated with recurrent monomorphic ventricular tachycardia (VT) originating from the RV.1 2 3 The diagnosis of ARVD is usually based on clinical, electrocardiographic, and morphological criteria.2 However, its diagnosis is difficult in the initial stage of the disease because the electrocardiographic findings at that time are almost normal.4 In addition, when wall motion abnormalities are localized in a small area of the RV, and VT originates from the RV outflow tract, it is difficult to assess the difference between ARVD and idiopathic right ventricular outflow tract tachycardia (RVOT).5
Brain natriuretic peptide (BNP) was first isolated from a porcine brain extract.6 In humans, BNP is expressed predominantly in the ventricles of failing hearts.7 Recent studies have demonstrated that BNP-expressing myocytes in the ventricle are located in the fibrous area in patients with dilated cardiomyopathy.8 9 ARVD is considered an "atrophic" cardiomyopathy with fibrofatty replacement.1 2 3 We hypothesized that BNP is increasingly secreted from the residual myocytes within the atrophic tissue in proportion to the severity of the disease in patients with ARVD.
The purpose of the present study was to assess (1) whether the plasma BNP level is increased in patients with ARVD and RVOT compared with control subjects, (2) the relation between the plasma BNP levels and the RV dysfunction, (3) the correlation between the plasma BNP levels and the arrhythmogenic substrate, and (4) the immunohistochemical expression of BNP in ARVD.
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Methods |
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Study Population
The study was conducted at the National Cardiovascular Center, Osaka, Japan, between January 1991 and December 1997; it included 17 consecutive patients with ARVD, 12 patients with RVOT, and 120 healthy control subjects. Informed consent was obtained from all of the ARVD and RVOT patients and control subjects, and the ARVD and RVOT patients underwent several tests including a physical examination, laboratory tests, chest X-ray, 12-lead ECG, signal-averaged ECG, echocardiography, electron- beam CT, MRI, and an electrophysiological study including catheter mapping. Cardiac catheterization including RV endomyocardial biopsy was performed in all 17 ARVD patients and 2 RVOT patients. In all patients and control subjects, befoe blood sampling, the heart rate and blood pressure were measured in the morning (8 to 9 AM) after they had fasted overnight and rested supine for 30 minutes. The blood was then withdrawn via the antecubital vein from all patients and control subjects during normal sinus rhythm. Blood was immediately transferred into a chilled glass tube containing aprotinin (500 U/mL) for the measurement of plasma BNP.
ARVD Group
This group consisted of 15 men and 2 women with ARVD (mean age,
47±11 years; range, 18 to 59 years). All 17 ARVD patients were class I
according to the New York Heart Association functional classification.
The diagnosis of ARVD was established on the basis of the criteria
proposed by the ARVD task force of the European Society of
Cardiology.2 According to the
criteria, 7 patients (patients 2, 4, 7 , 8, 9, 11, and 17) met 2 major
criteria, 8 patients (patients 1, 5, 6, 12, 13, 14, 15, and 16) met one
major plus 2 minor criteria, and the remaining 2 patients (patients 3
and 10) met 4 minor criteria. The characteristics of the patients with
ARVD are shown in Table 1
. Among these patients, 6
had been taking ß-blockers alone (n=2), or in combination with class
I antiarrhythmic agents (n=4). Three patients were taking both class I
and III antiarrhythmic agents, and one was receiving both
diuretic and an angiotensin-converting enzyme
inhibitor. The remaining 7 patients had not been taking any
drugs. No drugs were administered on the morning the blood sampling was
performed.
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RVOT Group
This group consisted of 6 men and 6 women (mean age, 35±13
years; range, 19 to 54 years) who had monomorphic VT with a left
bundle-branch block configuration and inferior axis. The 12
RVOT patients were not consecutive cases, but they were all patients
who underwent blood sampling as an RVOT patient between January 1996
and December 1997. All of their VTs originated from the RV outflow
tract and the VTs were sustained or nonsustained. The findings of all
diagnostic tests including 12-lead ECG, signal-averaged
ECG, echocardiography, and electron-beam CT were
normal; no fractionated electrograms were recorded. One of the 6
RVOT patients who underwent an MRI study had mild segmental dilatation
of the RV outflow tract. The ß-blockers being taken by 3 of the RVOT
patients were not administered in the morning before the blood
sampling. The other patients were not taking any medications.
Control Group
This group consisted of 120 healthy volunteers, 80 men and 40
women (mean age±SD, 49±11 years; range, 21 to 71 years). There was no
history of VT in this group. None of the control subjects were taking
any medications.
Assays of Plasma BNP
The plasma BNP levels were measured with a highly sensitive
immunoradiometric assay (Shiono RIA BNP assay kit, Shionogi Co), as
previously reported.10 This assay system uses 2
monoclonal antibodies against human BNP-32, one recognizing a
carboxy-terminal sequence and the other the ring structure of human
BNP; the assay measures human BNP by sandwiching it between the 2
antibodies without the extraction of plasma. The minimal detectable
quantity of human BNP in the assay is 2 pg/mL. Coefficients of
variation of the intra-assay, interassay, and repeated measurements
were 5.3%, 5.9%, and 5.2%, respectively. The recovery rate of 10 to
300 pg/mL of human BNP added to plasma was 105.7±5.4%. The
correlation between the plasma level of human BNP measured by this
method and that by the extraction method was highly significant, in the
range of 0 to 1500 pg/mL (r=0.98, P<0.001).
Cardiac Catheterization
With the use of a Swan-Ganz catheter inserted into the femoral
vein, hemodynamic measurements including
pulmonary arterial pressure, pulmonary
capillary wedge pressure, RV pressure, right atrial pressure, and
cardiac output were measured. Cardiac output was determined by the
thermodilution technique. A pigtail catheter was inserted into the
femoral artery and advanced to the left ventricle (LV) to measure the
LV pressure.
Electron-Beam CT
Electron-beam CT was performed in all of the ARVD patients with
a C-100 scanner (Imatron), as described
previously.11 Volume-mode scanning (scanning
time, 100 ms for 512 matrix images) was performed in all of the
patients after the administration of nonionic contrast medium
(Iopamidol 370, Nippon Schering). Eight levels (covering 8 cm) near the
short-axis cine-mode scans (10 contiguous images per level) were
obtained to examine the function of both the RV and LV. We used a
modified version of Simpson's method to obtain these multisection
cine-mode scans; we then calculated the biventricular
end-diastolic and end-systolic volume indexes and
the biventricular ejection fraction.
Electrophysiological Study
A 6F or 7F quadripolar diagnostic pacing and sensing
catheter (EP Technologies) was introduced through the femoral vein and
artery and advanced into the RV and LV under fluoroscopic guidance to
record the local electrograms.12 13 The 12
sites of each ventricle were the segmental areas assessed (Figure 1). The local electrograms were
recorded with the use of a 2.5-mm interelectrode distance during
sinus rhythm. Intracardiac electrograms (filtered at a frequency of 30
to 400 Hz), surface ECG leads, and the radial artery pressure were
recorded using a computerized multichannel system (EP Laboratory,
Quinton Inc). Fractionated abnormal electrograms were defined as those
having a duration 
100 ms and multiple rapid low-amplitude (
0.5 mV)
deflections (Figure 2). Fractionated-area
scores were determined as the sum of the segmental areas in which
fractionated electrograms could be recorded during sinus
mapping.
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Histological Evaluation
RV endomyocardial biopsy specimens were
obtained from the RV septum in 15 ARVD patients and 2 RVOT patients at
cardiac catheterization. The specimens were fixed in
10% formalin and embedded in paraffin for hematoxylin-eosin staining.
The severity of the histopathological findings was classified into 4
grades; none=0, mild=1, moderate=2, and severe=3, as previously
described.14 The findings of
interstitial fibrosis and fatty replacement were divided by
the point-counting method in which 375 (25x15) points in 2 or 3 fields
were observed at a magnification of x200. The gradings of
interstitial fibrosis were then determined as follows:
none, <10%; mild, <10% to 30%; moderate, <30% to 50%; and
severe, >50%, and those of fatty replacement as follows: none, <2%;
mild, <2% to 10%; moderate, <10% to 30%; and severe, >30%.
Light Microscopic Immunohistochemistry
The 2 monoclonal antibodies against human BNP-32 which
constitute the radioimmunoassay system used in this study were
prepared. These monoclonal antibodies belong to the IgG1 subclass.
Immunohistochemical reactions using an indirect immunoperoxidase method
were obtained as described previously.8 9 15
Serial 4-µm-thick sections of paraffin-embedded specimens were
dewaxed and immunostained by the streptavidin-biotin method
using a DAKO LSAB, according to the manufacturer's instruction, as
reported previously.16 Briefly, the first step
involved the inhibition of intrinsic peroxidase activity by the
addition of 0.3% hydrogen peroxidase in phosphate-buffered saline.
Nonspecific binding was blocked with normal goat serum. As a primary
antibody, the monoclonal antibody described above was incubated with
the sections for 48 hours at 4°C. Diaminobenzidine (Sigma Chemical
Co) was used as the chromogen. The presence of immunoreactive BNP was
assessed by light microscopy.
Statistical Analysis
Data are expressed as the mean±SD. Comparisons between groups
were performed by 1-way ANOVA. The significance of differences between
the mean values in the control group, RVOT group, and ARVD group was
tested with Fisher's multiple comparison test. The correlation
coefficients between plasma BNP levels and hemodynamic
and volumetric data were calculated by linear regression
analysis. Spearman's rank correlation test was used to
evaluate the correlation coefficients between the plasma BNP levels and
the fractionated-area scores. A P value <0.05 was regarded
as significant.
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Plasma BNP Levels in ARVD and RVOT Patients and Control Subjects
There were no significant differences in the plasma BNP levels between the RVOT patients (8.3±5.5 pg/mL; range, 4 to 19 pg/mL) and control subjects (9.3±5.8 pg/mL; range, 2 to 28 pg/mL), whereas there was a significant increase in plasma BNP levels in the ARVD patients (61.4±59.6 pg/mL; range, 15 to 200 pg/mL) (Figure 3
). The plasma BNP levels of all but 3 of
the 17 ARVD patients were20 pg/mL, whereas those of all 12 RVOT
patients were <20 pg/mL. In addition, the plasma BNP levels of 12 of
the 17 ARVD patients were25 pg/mL (71% sensitivity), whereas those
of all but one of the 120 control subjects were <25 pg/mL (99%
specificity).
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Hemodynamic Parameters and Plasma BNP
Levels in ARVD
Hemodynamic data of the 17 ARVD patients were
obtained from cardiac catheterization. Table 2 shows the correlations
between the hemodynamic parameters and the
plasma BNP levels. The mean values of the pressure data were all
normal. The mean value of the cardiac index was also normal. The plasma
BNP levels had no correlation with any of the
hemodynamic parameters.
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Volumetric Parameters and Plasma BNP Levels in
ARVD
Volumetric data of the 17 ARVD patients were obtained by
electron-beam CT. Table 3
shows the correlations between the volumetric parameters
and the plasma BNP levels. The mean values of the LV
end-diastolic and end-systolic volume indexes and
the LV ejection fraction were normal. The plasma BNP levels had no
significant correlation with the LV volumetric parameters.
In contrast, the mean RV values (RV end-diastolic and
end-systolic volume indexes) and the RV ejection fraction were
abnormal. An increased RV end-diastolic volume index (90
mL/m2) and an increased end-systolic
volume index (40 mL/m2) were recognized in
13 and all 17 ARVD patients, respectively, and a decreased RV
ejection fraction (45%) was found in 16 ARVD patients. The plasma
BNP levels had no significant correlation with the RV
end-diastolic or end-systolic volume indexes.
However, there was a significant negative correlation between the
plasma BNP levels and the RV ejection fraction (Figure 4).
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Fractionated-Area Scores and Plasma BNP Levels in ARVD
The fractionated-area scores of the 17 ARVD patients were obtained
by sinus mapping (range, 1 to 5 areas; mean±SD, 2.8±1.2). All of the
ARVD patients had fractionated electrograms in the RV. In 2 of the ARVD
patients (patients 8 and 10), fractionated electrograms were also
obtained from the LV. The most frequently affected site was the
inferior wall of the RV inflow tract (RV area 6); in 12 of
the 17 patients, fractionated electrograms were recorded at this
site. Six of the patients had fractionated electrograms at the free
wall of the RV outflow tract (RV area 12) including the anterior
infundibulum. Only one had such an electrogram at the RV apex (RV area
8). The plasma BNP levels had a significant positive correlation with
the fractionated-area scores in the patients with ARVD (Figure 5).
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Light Microscopic Examination and Immunohistochemical Expression
of BNP
In the light microscopic examination, varying degrees of
interstitial fibrosis and fatty replacement were found in
13 of the 15 ARVD patients on whom this study was performed (Table 1
).
However, no abnormal findings were observed in the 2 RVOT patients who
underwent RV biopsy. No obvious inflammatory infiltration was detected
in any specimens.
In the immunohistochemical study of the
endomyocardial biopsy specimens, none of the
control specimens obtained from the RVOT patients showed BNP
immunoreactivity (Figure 6A and 6B). In
contrast, BNP immunoreactivity was found in all of the ARVD patients,
showing a fine granular pattern in residual myocytes with fibrofatty
replacement. The immunoreactivity was similar between the 2 monoclonal
antibodies. No immunopositive products were seen in the endocardium
or in any of the connective or adipose tissues. In the 2 ARVD patients
whose biopsy specimens showed no apparent fibrofatty replacement, BNP
immunoreactivity was relatively weak (Figure 6C and 6D), whereas strong
BNP immunoreactivity was found in the other ARVD patients whose biopsy
specimens showed fibrofatty replacement (Figure 6E and 6F).
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Diagnostic Tools in the Discrimination Between ARVD and RVOT
The electrocardiographic diagnosis of ARVD is difficult in the initial stage of the disease.4 During sinus rhythm, 5 of 17 the present ARVD patients had almost normal findings in a 12-lead ECG. Although echocardiography is considered the most convenient noninvasive tool for detecting diffuse or localized abnormalities of the RV, it has several limitations.17 MRI is useful for the diagnosis of ARVD.18 However, mild wall motion and structural abnormalities have been detected by MRI even in patients with RVOT.19 A signal-averaged ECG has demonstrated high sensitivity and specificity in previous studies.17 20 In the present study, a late potential was found in all 17 of the ARVD patients but not in any of the 12 RVOT patients. However, the relation between signal-averaged ECG variables and RV function has not been established. The plasma BNP levels were found to be a specific and sensitive indicator for the distinction of patients with ARVD from those with RVOT. Compared with these conventional diagnostic methods, the measurement of the plasma BNP level is also useful as a simple, noninvasive, and reliable tool for the discrimination between ARVD and RVOT. In addition, the plasma BNP levels had a significant correlation with the RV ejection fraction and the fractionated-area scores.
Clinical Significance of Plasma BNP Levels in ARVD
In previous clinical studies, the plasma BNP levels demonstrated a
significant correlation with the LV end-diastolic pressure,
cardiac index, and end-diastolic and end-systolic
volume indexes of the LV in patients with dilated or hypertrophic
cardiomyopathy.7 15 In the
present study, the plasma BNP levels had no significant
relationship with those parameters related to the RV as
well as the LV. These results may be responsible for the absence of
biventricular heart failure in the present ARVD
patients. However, the plasma BNP levels were particularly increased in
proportion to the deterioration of the RV ejection fraction. Nagaya et
al21 recently reported that the plasma BNP levels
were significantly correlated with the RV ejection fraction but not
with the RV end-diastolic volume index in patients with
primary or thromboembolic pulmonary hypertension or atrial
septal defects, which is consistent with the present
results. Fractionated electrograms during sinus rhythm are considered a
substrate of reentrant VT in patients with organic heart
disease.13 Tada et al12
recently reported that the endocardial fat-infiltrated areas detected
by electron-beam CT tended to encompass the fractionated areas
demonstrated by the endocardial mapping in patients with ARVD. In the
present study, we found several grades of
electrophysiologically abnormal areas in
which fractionated abnormal electrograms were recorded. Thus,
plasma BNP levels might be increased in proportion to the expansion of
electrophysiological disorder based on the
histopathological abnormalities. The plasma BNP levels in the ARVD
patients showed values in a significantly wide range (from 15 to 200
pg/mL), suggesting that the present study included ARVD patients at
several stages of the disease; ie, from the early clinically concealed
phase to overt electrical heart disorder with severe RV
dysfunction.
Ventricular Expression of BNP in ARVD
The specimens of endomyocardial biopsy are
usually obtained from the right or left side of the
interventricular septum, which is unlikely to be an
affected region in ARVD. Therefore, an
endomyocardial biopsy specimen may be unlikely to
demonstrate evidence of the synthesis of BNP. However, the positive
finding of fibrofatty replacement of myocytes on biopsy can be a
valuable diagnostic indicator.2
Strong BNP immunoreactivity was found in the present RV
endomyocardial biopsy specimens showing fibrofatty
replacement, whereas its immunoreactivity was relatively weak in the
tissue not indicating fibrofatty replacement. In addition, the
present finding that BNP-positive myocytes were always present
in the specimens obtained from the interventricular septum
of ARVD patients suggests that BNP may be produced from the relatively
wide region including atrophic area in the RV. The exact relationship
between BNP secretion and the grading of atrophy in the most affected
site of the RV free wall remains unclear. It was also reported that
BNP-positive myocytes are noted in the chronic
myocarditis.22 In addition, inflammation is
thought to be one of the main pathological findings in
ARVD.3 In the present ARVD patients, although
obvious inflammatory infiltrates could not be found, it may be
responsible for our endomyocardial biopsy specimens
obtained from the right side of the interventricular septum
which is rarely involved in ARVD.3 Further
histopathological investigations, eg, using surgically resected
specimens and necropsy specimens is needed to identify the genesis of
BNP in patients with ARVD.
Mechanisms of the Synthesis and Secretion of BNP in ARVD
Although the etiology and pathogenesis of ARVD are still obscure,
two possible mechanisms are considered for the synthesis and secretion
of BNP in ARVD. One is local wall stress on myocytes around the
atrophic area. Because the fibrofatty area may be relatively
resistant to contraction, residual myocytes around this area
may undergo more stretching.8 Such regional
mechanical stress may stimulate the synthesis and secretion of
BNP.23 However, the mean values of plasma BNP in
the present patients with ARVD (mean values, 61.4 pg/mL) are much
less than those in patients with RV hypertrophy due to
pulmonary artery hypertension (mean values, 250
pg/mL).21 The differences of plasma BNP levels
between the two groups may be due to the grading of wall stress; ie,
regional wall stress in ARVD versus generalized wall stress in
pulmonary artery hypertension. The other possible explanation
concerns the effect of the vasoactive substances and growth factors
which are synthesized and secreted by the fibroblasts, adipocytes, and
vascular endothelial cells.24 25 26
The synthesis and secretion of BNP are also stimulated by endothelin-1
and angiotensin II in vivo and in
vitro.27 Under these circumstances, BNP may be
secreted increasingly from the residual myocytes in the atrophic tissue
with fibrofatty replacement.
Study Limitations
ARVD is often familial (about 30%), with an autosomal dominant
inheritance.2 Rampazzo et
al28 recently reported that a gene defect was
localized on chromosome 14q23-q24. Because we could not perform a
linkage analysis, the diagnosis for ARVD was defined according
to the diagnostic criteria by the ARVD task force of the
European Society of Cardiology.2
Further studies using genetic diagnosis with ARVD patient series that
are more homogenous are needed to determine the true
diagnostic value of the plasma BNP level in ARVD.
The medical treatments differed among the 3 groups. Although all medications were stopped on the day of the blood sampling, their influences cannot be completely excluded. Because the effects of drugs, including antiarrhythmic agents, on BNP in humans have not been reported, further studies are necessary.
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Acknowledgments |
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This work was supported in part by Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) from the Science and Technology Agency of Japan, grants from the Ministry of Health and Welfare, and the Human Science Foundation of Japan, and Scientific Research grant-in-aid 09670776 from the Ministry of Education, Science and Culture of Japan. We thank Dr Masashi Inagaki for his encouragement and advice, Kazuyoshi Masuda for his technical assistance with immunohistochemistry, and Yoko Saito for her technical assistance with the assays of plasma BNP.
Received April 13, 1998; revision received July 27, 1998; accepted July 30, 1998.
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