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 Toshio Nishikimi, MD, PhD, Yosuke Mori, MD, PhD, Kimihiko Ishimura, MD, Kazuyoshi Tadokoro, MD, Hiroshi Yagi, MD, Akihisa Yabe, MD, PhD, Shigeo Horinaka, MD, PhD, Hiroaki Matsuoka, MD, PhD PURPOSE: To examine whether coronary artery stenosis af- fects plasma levels of atrial natriuretic peptide (ANP), N-termi- nal proatrial natriuretic peptide (proANP), and brain natri- uretic peptide (BNP) in patients with normal left ventricular systolic function. METHODS: We studied 104 consecutive patients with normal left ventricular function and suspected coronary artery stenosis. Plasma natriuretic peptide levels were measured by immunora- diometric assays. RESULTS: Plasma levels of ANP, N-terminal proANP, and BNP were higher in patients with (n = 65) than in those without (n = 39) coronary artery stenosis, whereas hemodynamic vari- ables were similar. Patients who had coronary artery stenosis with only distal lesions (n = 36) had higher levels of all three natriuretic peptides than did patients with no coronary artery stenosis. N-terminal proANP levels were significantly higher in patients who had coronary artery stenosis with proximal lesions (n = 29) than in patients who had coronary artery stenosis with only distal lesions and those with no coronary artery stenosis. Multiple logistic regression analysis revealed that N-terminal proANP, but not ANP or BNP, was independently associated with coronary artery stenosis after adjusting for clinical and demographic variables (odds ratio per 100 fmol/mL increase = 1.9; 95% confidence interval: 1.9 to 2.6; P = 0.01). However, the sensitivity, specificity, and positive and negative predictive val- ues of each peptide were not sufficiently high to be used for prediction. CONCLUSION: N-terminal proANP may be associated with clinically important coronary artery stenosis in patients with normal left ventricular systolic function, but its clinical useful- ness may be limited. Am J Med. 2004;116:517–523. ©2004 by Excerpta Medica Inc. M any studies have shown that plasma levels of atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide (proANP), and brain natriuretic peptide (BNP) are elevated in patients with heart failure (1– 4), acute myocardial infarction (5– 8), and hypertension (9 –11). These circulating cardiac peptides reflect cardiac function, remodeling, and hyper- trophy (12–14) and can be used to predict outcomes in cardiovascular diseases (15–18). Recently, these peptides have received considerable attention for their use in screening tests in clinical trials and population-based studies (19 –21). Atrial natriuretic peptide is stored as proANP in atrial myocytes (22). On secretion, proANP is cleaved to bio- logically active -ANP and N-terminal proANP in equimolar amounts (23). Atrial natriuretic peptide is cleared rapidly (half-life of 2.5 minutes) from plasma by specifically binding to peripheral receptors and, to some extent, by enzymatic degradation. In contrast, N-termi- nal proANP is not cleared by binding to receptors and therefore has a longer half-life. Findings from several studies (24 –26) suggest that N-terminal proANP may be a better marker for the detection of high-grade coronary artery stenosis. Brain natriuretic peptide, a cardiac hormone secreted mainly by the cardiac ventricles, has been used as a non- invasive marker and a prognostic indicator of right or left ventricular dysfunction (14 –18). Studies assessing its di- agnostic usefulness in coronary artery disease have re- ported that plasma BNP levels are increased in unstable angina and acute coronary artery syndromes, perhaps re- lated to left ventricular function (18,27,28). To date, however, whether plasma BNP levels are increased in pa- tients with coronary artery stenosis who have normal left ventricular function remains unknown. From the Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Tochigi, Japan. This work was supported in part by Scientific Research Grants-in-Aid 1167073 and 14570692 from the Ministry of Education, Culture, Sports, Science and Technology and by the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan. Requests for reprints should be addressed to Toshio Nishikimi, MD, PhD, Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321– 0293, Japan, or nishikim@dokkyomed.ac.jp. Manuscript submitted June 3, 2003, and accepted in revised form December 9, 2003. © 2004 by Excerpta Medica Inc. 0002-9343/04/$–see front matter 517 All rights reserved. doi:10.1016/j.amjmed.2003.12.022