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Correspondence
Letters Regarding Article by Bibbons-Domingo et
al, “B-Type Natriuretic Peptide and Ischemia in
Patients With Stable Coronary Disease: Data
From the Heart and Soul Study”
1. Bibbins-Domingo K, Ansari M, Schiller NB, et al. B-type natriuretic
peptide and ischemia in patients with stable coronary disease: data from
the Heart and Soul study. Circulation. 2003;108:2987–2992.
2. Gill JS, Prasad K, Stewart JT, et al. Acute changes in atrial natriuretic
peptide, insulin-like growth factor-1, and lactate levels during left anterior
descending coronary artery angioplasty. Am Heart J. 1995;130:717–722.
3. Malatino LS, Leonardi C, Stancanelli B, et al. Transient myocardial
ischemia stimulates atrial natriuretic factor release. Am Heart J. 1992;
123:693– 698.
4. Prachar H, Ogris E, Dittel M, et al. Rapid changes of atrial natriuretic
peptide concentration during percutaneous transluminal coronary angioplasty. Am Heart J. 1991;122:157–163.
5. Nishikimi T, Mori Y, Ishimura K, et al. Association of plasma atrial
natriuretic peptide, N-terminal proatrial natriuretic peptide, and brain
natriuretic peptide levels with coronary artery stenosis in patients with
normal left ventricular systolic function. Am J Med. 2004;116:517-523.
The following correspondence pertains to an original article
published in 2003 by Bibbons-Domingo et al (Circulation.
2003;108:2987–2992). The first letter, by Nishikimi et al, was
originally published in the June 29, 2004, issue of Circulation. It is reprinted here for readers’ convenience. Subsequently, a letter was received from Nielsen and Goetze,
published below. A final response from Nishikimi et al follows
the Nielsen/Goetze letter.
Downloaded from http://circ.ahajournals.org/ by guest on June 12, 2017
To the Editor:
We read with great interest the recent article by BibbinsDomingo et al1 on plasma brain natriuretic peptide (BNP) in
outpatients with stable coronary disease. They concluded that
elevated levels of BNP are independently associated with inducible ischemia in outpatients with stable coronary disease, particularly among those who have a history of myocardial infarction.
Previous studies have demonstrated that transient myocardial
ischemia stimulates the secretion of atrial natriuretic peptide
(ANP) and N-terminal ProANP (N-ANP); because of its longer
half-life, N-ANP may be a better marker than ANP for the
detection of high-grade coronary artery stenosis.2– 4 However,
whether plasma BNP levels are increased in patients with
coronary artery stenosis who have normal left ventricular function remains unknown. To examine whether coronary artery
stenosis affects plasma ANP, N-ANP, and BNP levels, we
recently measured these peptide levels in 104 patients with
normal left ventricular systolic function who had a suspected
diagnosis of angina pectoris.5
Plasma levels of all 3 of these natriuretic peptides were higher
in patients with coronary artery stenosis (major coronary artery
stenosis ⬎75%) (n⫽65) than in those without stenosis (n⫽39),
whereas hemodynamic variables were similar. Multiple logistic
regression analysis revealed that N-ANP (per 100 fmol/mL
increase; odds ratio⫽1.9 [95% CI⫽1.2 to 2.6], P⬍0.01), but not
ANP (per 10 pg/mL increase; odds ratio⫽0.9 [95% CI⫽0.5 to
1.2], P⫽0.41) or BNP (per 10 pg/mL increase; odds ratio⫽1.1
[95% CI⫽0.8 to 1.4], P⫽0.73), was independently associated
with coronary artery stenosis after adjusting for clinical and
demographic variables. Furthermore, we measured these natriuretic peptides before and 3 to 6 months after percutaneous
coronary intervention in patients with myocardial infarction of
recent onset (n⫽58). Plasma levels of ANP, N-ANP, and BNP
significantly decreased in patients without restenosis (n⫽46)
(ANP, 91⫾15 to 39⫾7 pg/mL; BNP, 134⫾28.9 to 41⫾9 pg/mL;
N-ANP, 688⫾81 to 407⫾52 fmol/mL; all P⬍0.05).
In contrast, these natriuretic peptide levels did not change after
coronary intervention in patients with restenosis (n⫽12) (ANP,
57⫾19 to 50⫾20; BNP, 102⫾35 to 57⫾13; N-ANP, 567⫾178
to 508⫾126; all NS). Our results support the findings of
Bibbins-Domingo et al1; however, we propose that N-ANP may
be more useful for the discrimination of clinically significant
coronary artery stenosis than BNP because of its different sites of
production, mechanisms of release, and metabolic
characteristics.
To the Editor:
We read the correspondence1 about the article by BibbinsDomingo et al2 with great interest. The report by BibbinsDomingo et al2 demonstrated elevated plasma concentrations of
B-type natriuretic peptide (BNP) associated with inducible ischemia in patients with stable coronary artery disease. In
contrast, Nishikimi and Matsuoka1 suggested that N-terminal
proANP (atrial natriuretic peptide) might be a more sensitive
plasma marker of stable coronary artery disease than are ANP
and BNP. We recently measured the plasma concentrations of
BNP as well as its biosynthetic precursor, proBNP, in patients
with coronary artery disease and normal left ventricular systolic
function.3 Both BNP and proBNP were markedly elevated (5and 10-fold, respectively) in those patients as compared with
individuals without coronary artery disease. Moreover, the BNP
and proBNP plasma concentrations were closely associated.
Interestingly, within a group of patients undergoing coronary
artery bypass surgery, the extent of elevation of both plasma
BNP and proBNP concentrations in each patient was positively
associated with the ventricular BNP mRNA content.3 These data
suggest that both BNP and proBNP are sensitive markers of
chronic cardiac ischemia and that the elevated plasma concentrations reflect an increased BNP gene transcription. In studies of
pigs, we recently found that even acute cardiac hypoxia induces
BNP gene expression in the ventricular myocardium and an
increase of the plasma proBNP concentration.4 Moreover, only
proBNP (not BNP) was rapidly released from ventricular myocytes when subjected to hypoxia in vitro.4 These experimental
data are in accord with another recent clinical observation that
coronary arteriography results in a rapid but transient rise in the
plasma proBNP but not BNP concentrations.5
We suggest that plasma measurement of both BNP and
proBNP is useful in detecting chronic ischemia associated with
coronary artery disease, whereas proBNP may be a more
sensitive marker of acute cardiac ischemia.
Lars B. Nielsen, MD, PhD, DMSc
Jens P. Goetze, MD
Department of Clinical Biochemistry
Rigshospitalet, University of Copenhagen
Copenhagen, Denmark
1. Nishikimi T, Matsuoka H. Are plasma levels of atrial natriuretic peptide,
N-terminal ProANP, and brain natriuretic peptide affected by the
presence of coronary artery disease? Circulation. 2004;109:e331.
2. Bibbins-Domingo K, Ansari M, Schiller NB, Massie B, Whooley MA.
B-type natriuretic peptide and ischemia in patients with stable coronary
disease: data from the Heart and Soul study. Circulation. 2003;108:
2987–2992.
3. Goetze JP, Christoffersen C, Perko M, Arendrup H, Rehfeld JF, Kastrup
J, Nielsen LB. Increased cardiac BNP expression associated with myocardial ischemia. FASEB J. 2003;17:1105–1107.
Toshio Nishikimi, MD, PhD
Hiroaki Matsuoka, MD, PhD
Department of Hypertension and Cardiorenal Medicine
Dokkyo University Medical School
Mibu, Tochigi, Japan
e15
16
Correspondence
4. Goetze JP, Gore A, Møller CH, Steinbrüchel DA, Rehfeld JF, Nielsen
LB. Acute myocardial hypoxia increases BNP gene expression. FASEB J.
2004;18:1928 –1930.
5. Goetze JP, Yongzhong W, Rehfeld JF, Jorgensen E, Kastrup J. Coronary
angiography transiently increases plasma pro-B-type natriuretic peptide.
Eur Heart J. 2004;25:759 –764.
Response
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We thank Drs Nielsen and Goetze for their interest in our
recently published correspondence.1 In our study, we measured
levels of N-terminal proatrial natriuretic peptide (N-ANP), atrial
natriuretic peptide (ANP), and brain natriuretic peptide (BNP) in
patients with normal left ventricular function (ejection fraction
ⱖ60%) who were suspected of having coronary artery disease
(CAD).1,2 Our main objective was to determine whether coronary artery stenosis affects plasma natriuretic peptide levels. Our
findings suggested that N-ANP is associated with the presence of
coronary artery stenosis in patients with normal left ventricular
systolic function because transient myocardial ischemia stimulates the secretion of ANP and N-ANP3 and increased plasma
N-ANP levels may last for a longer time than ANP because the
former has a longer half-life.
Goetze et al4 showed that plasma BNP and proBNP levels are
higher than controls in patients who have CAD with normal
systolic function. Although left ventricular ejection fraction
(LVEF) was similar in the CAD and the control groups in their
study, the CAD group included patients with an LVEF of ⱕ50 (5
of 13 patients undergoing CABG and 5 of 10 undergoing
percutaneous coronary intervention). The figures seem to indicate that patients with good systolic function (LVEF ⱖ60%) had
normal BNP levels and low BNP mRNA levels. Thus, plasma
BNP and proBNP levels may increase in patients with minimal
degrees of impaired systolic function, wall motion abnormality,
or both. In these patients, hypoxia may be an important stimulus
for BNP mRNA expression, as Goetze et al suggest.
Thus, ANP, N-ANP, BNP, and proBNP all are useful biochemical markers for cardiovascular diseases, including CAD,
but their clinical implications differ slightly because they have
different sites of production, mechanisms of release, and metabolic characteristics.
Finally, we would like to comment on the plasma BNP levels
measured by Goetze et al4 using a Shionoria BNP kit (Shionogi
Inc). This kit uses 2 monoclonal antibodies, which recognize the
ring structure and carboxyterminal sequence. Therefore, BNP
levels measured with this kit indicate the sum of BNP (77–108)
plus proBNP(1–108,) not BNP (77–108) alone.
Toshio Nishikimi, MD, PhD
Hiroaki Matsuoka, MD, PhD
Department of Hypertension and Cardiorenal Medicine
Dokkyo University School of Medicine
Tochigi, Japan
1. Nishikimi T, Matsuoka H. Are plasma levels of atrial natriuretic peptide,
N-terminal ProANP, and brain natriuretic peptide affected by the
presence of coronary artery disease? Circulation. 2004;109:e331.
2. Nishikimi T, Mori Y, Ishimura K, Tadokoro K, Yagi H, Yabe A,
Horinaka S, Matsuoka H. Association of plasma atrial natriuretic peptide,
N-terminal proatrial natriuretic peptide, and brain natriuretic peptide
levels with coronary artery stenosis in patients with normal left ventricular systolic function. Am J Med. 2004;116:517–523.
3. Malatino LS, Leonardi C, Stancanelli B, Polizzi G, Grassi R, Tamburino
C, Tamburino G. Transient myocardial ischemia stimulates atrial natriuretic factor release. Am Heart J. 1992;123:693– 698.
4. Goetze JP, Christoffersen C, Perko M, Arendrup H, Rehfeld JF, Kastrup
J, Nielsen LB. Increased cardiac BNP expression associated with myocardial ischemia. FASEB J. 2003;17:1105–1107.
Letters Regarding Article by Bibbons-Domingo et al, ''B-Type Natriuretic Peptide and
Ischemia in Patients With Stable Coronary Disease: Data From the Heart and Soul Study''
Toshio Nishikimi and Hiroaki Matsuoka
Downloaded from http://circ.ahajournals.org/ by guest on June 12, 2017
Circulation. 2005;111:e15
doi: 10.1161/01.CIR.0000152484.15271.A8
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2005 American Heart Association, Inc. All rights reserved.
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