Atrial natriuretic peptide (ANP) and brain natriuretic

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1 Exertional Changes in Circulating Cardiac Natriuretic Peptides in Patients with Suggested Coronary Artery Disease Sébastien Bergeron, MD, Jacob E. Møller, MD, PhD, Kent R. Bailey, PhD, Horng H. Chen, MD, John C. Burnett, MD, and Patricia A. Pellikka, MD, Rochester, Minnesota Background: We measured plasma brain natriuretic peptide (BNP) and N-terminal atrial natriuretic peptide (ANP) levels before and after exercise stress testing and correlated results with echocardiographic evidence of ischemia. Methods: Sixty patients with left ventricular ejection fraction greater than 50% referred for clinically indicated exercise echocardiogram were studied. Peptides were measured at rest and 5 minutes after symptom-limited exercise. Results: Echocardiography was positive for ischemia in 19 (32%). With exercise, ANP level increased in all 60 patients (median at rest 2501 [ ] [ ] pg/ml after exercise [P <.0001]). BNP increased in 54 patients (90%) (19 [< ]-30 [< ] pg/ml [P <.0001]). In multivariable analysis, both exercise BNP level and exertional change in BNP were closely associated with rest BNP (P <.0001); both were also significantly associated with change in wall-motion score index and workload (P.001 and P.01, respectively). Exercise ANP was strongly related to rest level (P <.0001); change in ANP was related to workload (P <.0001). Conclusion: In patients with suggested coronary artery disease, exertional levels of BNP are influenced not only by development of stress-induced ischemia, but also by resting levels. diogr 2006;19: ) (J Am Soc Echocar- these cardiac peptides. 5-7 Based on this, we hypothesized that impaired contractility during acute myocardial ischemia is associated with increased re- Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are released from the atria and assessed by examining plasma BNP and N-terminal leased amounts of natriuretic peptides. This was ventricles in response to dynamic changes in ventricular function. 1 ANP is stored in the atrial myocytes i n and correlating the results with exercise echocardio- ANP levels before and after exercise stress testing the form of a propeptide that is rapidly released in graphic changes in regional wall motion. response to increased atrial stretch, whereas BNP is secreted from the atria and ventricles in response to 1 increased wall stress and pressure overload. In the normal heart ANP is usually predominant. Under METHODS pathologic conditions, production of both peptides increases rapidly although the concentration of BNP Patients becomes dominant. In addition to patients with 2-4 predominantly systolic and diastolic heart failure, patients along the entire spectrum of symptomatic ischemic heart disease from stable angina to acute coronary syndromes can manifest elevated levels of From the Division of Cardiovascular Diseases and Department of Biostatistics (K.R.B.), Mayo Clinic. Supported by grants from Laval University, Québec, Canada (Dr Bergeron), Danish Heart Foundation (Dr Møller), Mayo Foundation, and American Heart Association, Northland Affiliate. Reprint requests: Patricia A. Pellikka, MD, Mayo Clinic, 200 First St SW, Rochester, MN ( pellikka.patricia@mayo.edu) /$32.00 Copyright 2006 by the American Society of Echocardiography. doi: /j.echo Our institutional review board approved this study. From March to October 2002, 60 patients referred for clinically indicated exercise echocardiography were studied. All patients were at least 40 years of age and provided informed consent. We excluded patients with ejection fraction of 50% or less, acute or chronic renal failure, severe congestive heart failure (New York Heart Association class III or IV), poor acoustic window, and atrial fibrillation. Pretest probability of coronary artery disease (CAD) was assessed according to age and symptoms combined with assessment of risk factors. The risk factors considered were hypertension, diabetes mellitus, hypercholesterolemia, smoking, and ST-T segment changes on resting electrocardiogram (ECG). Chest pain was classified as typical or atypical. To be classified as typical, chest pain met the 3 following criteria: (1) substernal location; (2) precipitated by exercise or emotion; and (3) relieved by rest or nitroglycerin. 772

2 Volume 19 Number 6 Bergeron et al 773 Exercise Stress Echocardiography A symptom-limited treadmill exercise echocardiogram 8,9 was performed according to the Bruce protocol. Medications were not interrupted. Three-channel ECG monitoring was performed continuously during the stress test, and a 12-lead ECG and vital signs were recorded at each stage. End points for termination of exercise test included a decrease in systolic blood pressure greater than 10 mm Hg from baseline blood pressure, moderate or severe angina, ventricular tachycardia, S-T segment elevation greater than 1 mm in leads without Q waves, or inability to continue exercise. 8,9 Standard echocardiographic images (parasternal long- and short-axis and apical 4- and 2-chamber) were obtained at rest and immediately after exercise. Images were stored digitally for measurement after completion of the test without knowledge of peptide levels. Left ventricular (LV) wall motion was assessed using a segment model of the LV. Each segment was scored at rest and after exercise based on myocardial motion and systolic thickening (1 normal, 2 hypokinetic, 3 akinetic, 4 dyskinetic). The wall-motion score index was calculated by dividing the wall-motion score by the number of segments analyzed. The echocardiogram was considered positive for myocardial ischemia if new or worsening regional wall-motion abnormality developed, and abnormal in the presence of ischemia or resting wall-motion abnormalities unchanged with exercise. From apical views, LV end-systolic and end-diastolic volumes were measured at rest and after exercise and LV ejection fraction was calculated according to Simpson s modified biplane method. 10 Cardiac Peptide Measurements Venous blood samples were drawn from a catheter inserted in the right antecubital vein. The first sample was drawn after 30 minutes of rest. Samples were collected in prechilled tubes containing EDTA and aprotinin, placed immediately on ice and centrifuged within 30 minutes. Plasma N-terminal ANP concentration was measured with a double antibody radioimmunoassay using a commercial kit (Phoenix, Belmont, CA). Interassay coefficient of variation is between 13.6% and 15.2%. Plasma BNP concentration was measured with a specific immunoradiometric assay for human BNP using a commercial kit (Shinioria, Osaka, Japan). The minimal detectable quantity in our test was 3.9 pg/ml. The intra-assay and interassay coefficients of variation were 5.2% and 6.1%, respectively. To determine the optimal timing of measurement of postexercise BNP and ANP levels, we performed a pilot study in 10 patients. In this group, BNP and ANP were measured immediately after exercise and at 5, 15, and 30 minutes postexercise. Median BNP was 9 pg/ml at rest, 23 pg/ml at peak and 5 minutes, 22 pg/ml at 15 minutes, and 14 pg/ml at 30 minutes. Median ANP was 2666 pg/ml at rest, 3069 pg/ml at peak, 3230 pg/ml at 5 minutes, 3417 pg/ml at 15 minutes, and 3280 pg/ml at 30 minutes. Based on these data, postexercise peptide measurements were obtained at 5 minutes after exercise in the subsequent 50 patients and measurements at this time were used for analysis in all patients. Statistical Analyses Continuous data are expressed as medians with 25th and 75th percentiles unless otherwise specified. Rank sum tests were used for comparisons of continuous variables and the 2 test for categorical variables. Nonparametric Wilcoxon paired sample test was used for assessment of within subject changes in cardiac peptides. Multivariable linear regression analysis was used to assess predictors of exertional changes in BNP. A P value less than.05 was considered significant. RESULTS Patients Clinical characteristics and exercise echocardiography parameters of the 60 patients are presented in Table 1. Indications for the stress test included evaluation of chest pain or dyspnea in 14 patients (23%), screening for CAD because of risk factors in 15 (25%), and evaluation of known CAD in 31 (52%). Among those patients without known CAD, pretest probability of disease was low in 13 patients (22%), moderate in 7 (12%), and high in 14 (23%). Workload achieved was 10 (8-11) metabolic equivalents. Echocardiography was positive for ischemia in 19 patients (32%) and abnormal in 26 (43%). The exercise ECG was positive in 10 (17%); in each of these, the exercise echocardiogram was also positive. Peptide Results All patients increased ANP level with exercise. The median levels were 2501 pg/ml ( ) at rest and 3167 pg/ml ( ) after exercise (P.0001). Comparing the 19 with ischemia to the 41 without, median rest ANP levels were 2745 pg/ml (25th and 75th percentiles ) and 2386 pg/ml ( ), respectively, P.06; exercise levels were 4231 pg/ml ( ) and 3061 pg/ml ( ), respectively, P.02. BNP increased with exercise in 54 patients (90%). Median rest level increased from 19 ( ) to 30 ( ) pg/ml (P.0001). Comparing the results in patients with and without ischemia, median rest BNP levels were 24 (25th and 75th percentiles 10-69) and 15 (8.1-24) pg/ml, respectively, P.05; exercise levels were 50 (30-94) and 29 pg/ml (13-40), respectively, P.004. Of the 6 patients who did not increase BNP concentration with exercise, 5 had undetectable ( 3.9) values at rest and with exercise and one patient had identical values before and after exercise (20 pg/ml). In univariate analysis, exercise ANP concentration or change in ANP were significantly associated with

3 774 Bergeron et al June 2006 Table 1 Clinical, echocardiographic, and neurohormonal variables Variable N 60 Clinical characteristics Age, y 66 (61-74) Male 49 (81%) Body mass index, kg/m ( ) Medication Beta-blocker 24 (40%) Calcium channel blocker 13 (22%) Angiotensin inhibitor 13 (30%) Prior myocardial infarction 14 (22%) Prior coronary revascularization 23 (38%) Diabetes mellitus 8 (13%) Current smoking 5 (8%) Hypertension 36 (60%) Hypercholesterolemia 51 (85%) Hemodynamic parameters Rest heart rate, beat/min 69 (59-81) Change in heart rate, beat/min 73 (54-88) Rest systolic blood pressure, 130 ( ) mm Hg Change in systolic blood pressure, 38 (26-56) mm Hg Rate pressure product, mm 24,436 (21,053-27,414) Hg/min Echocardiographic parameters Ejection fraction at rest, % 63 (60-68) Ejection fraction with exercise, % 69 (62-74) LV mass index, g/m 2 87 (68-100) Rest wall-motion score index 1.0 ( ) Exercise wall-motion score index 1.0 ( ) % Abnormal segments at peak* 34 (13-53) Neurohormonal variables Rest BNP, pg/ml 18.7 ( ) Exercise BNP, pg/ml 30.4 ( ) Change in BNP, pg/ml 12.6 ( ) Rest ANP, pg/ml 2501 ( ) Exercise ANP, pg/ml 3167 ( ) Change in ANP, pg/ml 598 ( ) ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide; LV, left ventricular. *Only calculated for patients with wall-motion abnormalities at peak stress. Data are expressed as median (25th and 75th percentiles), or number (percent). resting concentration of natriuretic peptides, age, wall-motion score index, known history of CAD, rate pressure product, and metabolic equivalents (Table 2). Exercise BNP and change in BNP with exercise were associated with resting concentration of cardiac peptides, history of CAD, exercise wall-motion score index, and rate pressure product. In multivariable analysis, both the exercise concentration of BNP and the exertional change in BNP were closely associated with the BNP concentration at rest (Table 3). In addition, both were associated with the change in wall-motion score index and the workload in metabolic equivalents. Peak concentration of ANP was strongly related to rest concentration of ANP, whereas the change in ANP was mainly related to exercise capacity. DISCUSSION In this group of patients with known or suggested CAD and preserved LV systolic function, exercise resulted in an increase in plasma N-terminal ANP level in all patients whereas 90% increased their BNP level. The increase of BNP was especially related to resting BNP concentration and, to a lesser degree, to development of regional wall-motion abnormalities with exercise. In contrast, increase in ANP concentration with exercise was best related to resting ANP level and workload. Natriuretic Peptides and Myocardial Ischemia Prolonged myocardial ischemia will cause an increase in LV end-diastolic pressure, which is a major stimulus for cardiac peptide secretion. In addition, experimental studies have demonstrated that hypoxemia may trigger BNP release, even in the 11,12 absence of an increase in end-diastolic pressure (increased wall stress). 12 Thus, it is conceivable that exercise-induced myocardial ischemia could trigger release of ANP and BNP. Recently, two studies have suggested increased release of BNP in response to transient myocardial ischemia assessed with exercise nuclear perfusion imaging. Foote et al 13 13,14 studied 74 patients with known CAD and demonstrated that assessment of exercise-induced changes in cardiac peptides greatly improved the sensitivity of the test compared with conventional exercise 14 ECG analysis. Furthermore, Sabatine et aldemon- strated in a larger, more heterogeneous population that circulating BNP levels increased in response to exercise stress testing, and the magnitude of that increase was proportional to the degree of inducible ischemia, and remained an independent predictor of transient ischemia on multivariable analysis (no adjustment for baseline BNP concentration was done). Based on those studies, a recent review proposed BNP to be a biomarker for myocardial ischemia with the potential of distinguishing patients with and without ischemia with a high degree of accuracy. However, other studies using nuclear imaging and dobutamine echocardiography have been less convincing and failed to detect an association of peak exercise BNP concentration and transient myocardial ischemia. 16,17 This is the first study to evaluate exertional changes in natriuretic peptides using exercise echocardiography. In our population we found the most important predictor of peak exercise BNP and change in BNP was baseline BNP and, to a much lesser degree, exertional impairment in regional wall motion. This is not surprising as the amount of BNP stored in secretory granules is at 15

4 Volume 19 Number 6 Bergeron et al 775 Table 2 Univariable Spearman correlation analysis peak exertional concentrations and change with exercise in N-terminal atrial and brain natriuretic peptides ANP BNP Variable Exercise Change Exercise Change r s P r s P r s P r s P Rest ANP Rest BNP Age Known coronary artery disease Rate pressure product Metabolic equivalents Rest ejection fraction Rest wall-motion score index Exercise wall-motion score index Change in wall-motion score index with exercise ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide. Table 3 Multivariable linear regression analysis of predictors of exertional concentrations and change with exercise in N-terminal atrial and brain natriuretic peptides ANP BNP Exercise r Change r Exercise r Change r Variable P P P P Rest ANP Rest BNP Age Known coronary artery disease Rate pressure product Metabolic equivalents Rest ejection fraction Rest wall-motion score index Exercise wall-motion score index ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide. least partly determined by the blood BNP concentration. Furthermore, previous studies have suggested that resting levels of BNP are predictive of severity of CAD, 5 and several studies have demon - strated BNP to be increased in acute coronary syndromes. 6,7 Although speculative, it seems possi - ble that repetitive episodes of myocardial ischemia are associated with increased resting BNP but also increased ability to release BNP during transient ischemia. Furthermore, the current study suggests that even in the absence of ischemia, a greater increase in BNP occurs with exercise if the resting level is increased. This can potentially lead to falsepositive test results if diagnosis is based on the change in BNP. This may limit the applicability of exertional changes of BNP for detection of ischemia. Natriuretic Peptides and Intensity of Exercise Workload was independently associated with the postexercise level and exertional change of both peptides. The greater increase may be related to a longer stimulus, which permitted more synthesis and secretion of peptides; with prolonged exercise, atrial stretch may have been more extensive. Thus, a greater increase of both cardiac peptides was seen in those who exercised longest. Limitations Our relatively small population was heterogeneous. In some patients, resting wall-motion abnormalities may be responsible for elevation of resting peptide concentrations. Coronary angiography was not obtained and it is possible that ischemia occurred in some patients who did not manifest wall-motion abnormalities. However, the excellent diagnostic performance of exercise echocardiography is well known. By using this method, we were able to assess the effect of ischemia on ventricular function.

5 776 Bergeron et al June 2006 Conclusion In patients with suggested CAD, exertional changes in BNP are influenced not only by development of stress-induced ischemia, but also by resting levels. Thus, caution is indicated when considering exertional levels as a marker of ischemia. REFERENCES 1. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougaski M, et al. Localization and mechanism of secretion of B-type natruretic peptide in comparison with those of A-type natruretic peptide in normal subjects and patients with heart failure. Circulation 1994;90: Lubien E, DeMaria A, Krishnaswamy P, Clopton P, Koon J, Kazanegra R, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105: Maisel A. B-type natriuretic peptide levels: a potential novel white count for congestive heart failure. J Card Fail 2001; 7: Troughton R, Frampton C, Yandle T, Espiner E, Nicholls M, Richards A. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355: Bibbins-Domingo K, Ansari M, Schiller N, Massie B, Whooley M. B-type natriuretic peptide and ischemia in patients with stable coronary disease: data from the heart and soul study. Circulation 2003;108: de Lemos J, Morrow D, Bentley J, Omland T, Sabatine M, McCabe C, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345: Richards A, Nicholls M, Espiner E, Lainchbury J, Troughton R, Elliott J, et al. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation 2003;107: Armstrong W, Pellikka P, Ryan T, Crouse L, Zoghbi W. Stress echocardiography, recommendations for performance and interpretation of stress echocardiography: stress echocardiography task force of the nomenclature and standards committee of the American Society of Echocardiography. J Am Soc Echocardiogr 1998;11: Roger V, Pellikka P, Oh J, Miller FJ, Seward J, Tajik A. Stress echocardiography, part I: exercise echocardiography techniques, implementation, clinical applications, and correlations [see comments]. Mayo Clin Proc 1995;70: Schiller N, Shah P, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography committee on standards, subcommittee on quantitation of two-dimensional echocardiograms. J Am Soc Echocardiogr 1989;2: Toth M, Vuorinen K, Vuolteenaho O. Hypoxia stimulates release of ANP and BNP from perfused rate ventricular myocardium. Am J Physiol 1994;266:H D Souza S, Yellon D, Martin C. B-type natriuretic peptide limits infarct size in rate isolated hearts via KATP channel opening. Am J Physiol Heart Circ Physiol 2003;284:H Foote R, Pearlman J, Siegel A, Yeo K. Detection of exerciseinduced ischemia by changes in B-type natriuretic peptides. J Am Coll Cardiol 2004;44: Sabatine M, Morrow D, de Lemos J, Omland T, Desai T, Tanasijevic M, et al. Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia. J Am Coll Cardiol 2004;44: Yeo K, Lee H, Wong K, Foote R. Can exercise-induced changes in B-type natriuretic peptides be used to detect cardiac ischemia? J Card Fail 2005;11:S Asada J, Tsuji H, Iwasaka T, Thomas J, Lauer M. Usefulness of plasma brain natriuretic peptide levels in predicting dobutamine-induced myocardial ischemia. Am J Cardiol 2004;93: Marie P, Mertes P, Hassan-Sebbag N, de Talence N, Djaballah K, Djaballah W, et al. Exercise release of cardiac natriuretic peptides is markedly enhanced when patients with coronary artery disease are treated medically by beta-blockers. J Am Coll Cardiol 2004;43:353-9.

Effect of Short-term Maximal Exercise on BNP Plasma Levels in. Healthy Individuals

1 Effect of Short-term Maximal Exercise on BNP Plasma Levels in Healthy Individuals Jan Krupicka, MD, Tomas Janota, MD, Zdislava Kasalova, MD, Jaromir Hradec, MD 3rd Department of Internal Medicine, 1st