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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online April 22, 2003 as doi:10.1096/fj.02-0796fje. |
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Department of
* Clinical Biochemistry,
Medical Department B, Cardiac Catheterization Laboratory, and
Thoracic Surgery, Rigshospitalet, University of Copenhagen, Denmark
2Correspondence: Department of Clinical Biochemistry, KB 3011, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. E-mail: larsbo{at}rh.dk
SPECIFIC AIMS
Congestive heart failure is accompanied by increased cardiac BNP gene expression and augmented plasma concentrations of BNP and its precursor, proBNP. Recent studies have shown that plasma concentrations of BNP and proBNP are elevated in patients presenting with unstable coronary syndrome or myocardial infarction. In this study, we investigated whether myocardial ischemia in the absence of overt heart failure may be another mechanism for increased cardiac BNP gene expression and elevated plasma BNP and proBNP concentrations.
PRINCIPAL FINDINGS
1. Cardiac BNP secretion was examined in plasma obtained from coronary artery disease patients undergoing coronary bypass grafting surgery or percutaneous transluminal intervention therapy
Ventricular function was assessed by ventriculography and was not significantly decreased in ischemic patients compared with a group of normal individuals (Fig. 1
A). However, the plasma BNP and proBNP concentrations in the coronary artery bypass grafting surgery patients were markedly increased (BNP, fivefold, P<0.01, proBNP, eightfold, P<0.01) compared with a control group without coronary artery disease (Fig. 1B
). Similar to the coronary artery bypass grafting surgery patients, another group of patients undergoing percutaneous intervention therapy had normal left ventricular ejection fraction (Fig. 1A
) and markedly increased plasma BNP and proBNP concentrations (BNP, 5-fold, P<0.01, proBNP, 10-fold, P<0.01) compared with the control group (Fig. 1B
). Plasma BNP and proBNP concentrations in the coronary artery disease patients did not significantly differ from those found in a group of congestive heart failure patients with severely reduced left ventricular ejection fraction (Fig. 1B
).
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2. Quantitative analysis of cardiac BNP mRNA in atrial and hypoxic ventricular biopsies from coronary artery disease patients undergoing coronary artery bypass grafting surgery revealed a positive association between ventricular BNP mRNA expression and plasma BNP concentration (r=0.83, P<0.001, Fig. 2A
) and plasma proBNP concentration (r=0.78, P<0.001)
In contrast, plasma BNP and proBNP concentrations were not associated with the atrial BNP mRNA expression (Fig. 2B
) even though the atrial BNP mRNA expression was almost sixfold higher in atrial than in ventricular biopsies.
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CONCLUSION AND SIGNIFICANCE
It is known that cardiac BNP gene expression is increased in failing hearts and that plasma measurements of BNP and proBNP are markers of impaired function of the left ventricle. Recently it was shown that plasma BNP and proBNP concentrations provide prognostic information of later development of heart failure during an acute myocardial infarction and are prognostic markers of morbidity and death in patients presenting with acute coronary syndrome. Until now, it has been an enigma as to precisely how an elevated plasma concentration of BNP or proBNP is a marker of manifest heart failure and, in some studies, precedes and even predicts subsequent cardiac dysfunction. Our study suggests that myocardial ischemia per se causes the increase in plasma BNP and proBNP concentrations. This mechanism most likely reflects an increased cardiac BNP gene expression in the ischemic left ventricle, since plasma BNP and proBNP concentrations were closely associated with ventricular BNP mRNA expression. In contrast, we found no association between plasma BNP and proBNP concentrations with atrial BNP mRNA expression despite a markedly higher BNP mRNA content in the atrial than the ventricular biopsies. This may reflect different processing and storage of proBNP peptides in atrial and ventricular myocytes as well as the smaller atrial mass than the ventricular myocardium. Our data suggest that ventricular BNP gene expression is up-regulated by myocardial hypoxia, resulting in augmented plasma concentrations of BNP and proBNP. Thus, elevated BNP and proBNP concentrations do not necessarily reflect heart failure, but may also result from cardiac ischemia.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0796fje; to cite this article, use FASEB J. (April 22, 2003) 10.1096/fj.02-0796fje 
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