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brain natriuretic peptide levels predict functional capacity in patients with chronic heart failure
Journal of the American College of Cardiology © 2002 by the American College of Cardiology Foundation Published by Elsevier Science Inc.
Vol. 40, No. 4, 2002 ISSN 0735-1097/02/$22.00 PII S0735-1097(02)02032-6
Diagnostics and Heart Failure
Brain Natriuretic Peptide Levels Predict Functional Capacity in Patients With Chronic Heart Failure Stefan Kru¨ger, MD,* Ju¨rgen Graf, MD,* Dagmar Kunz, MD,† Tina Stickel, CAND MED,* Peter Hanrath, MD, FESC, FACC,* Uwe Janssens, MD, FESC* Aachen, Germany The goal of this study was to determine if brain natriuretic peptide (BNP) levels are associated with exercise capacity in patients with chronic heart failure (HF). BACKGROUND Plasma levels of BNP are increased subject to the degree of systolic and diastolic left ventricular dysfunction in patients with chronic HF. Exercise testing is useful to assess functional capacity and prognosis in chronic HF. METHODS We prospectively studied 70 consecutive patients with chronic HF (60.3 ⫾ 10.4 years, 51 men) referred for cardiopulmonary exercise testing. Resting BNP was obtained after 10 min of supine rest before symptom-limited bicycle exercise testing. RESULTS In patients with chronic HF, BNP levels correlated with oxygen uptake (VO2), both at anaerobic threshold (VO2AT: r ⫽ ⫺0.54, p ⬍ 0.001) and peak exercise (peak VO2: r ⫽ ⫺0.56, p ⬍ 0.001). Impairment of ventilatory efficiency (EqCO2: r ⫽ 0.43, p ⬍ 0.001) and maximum exercise level (W % predicted: r ⫽ ⫺0.44, p ⬍ 0.05) correlated less well with BNP. There was a significant inverse correlation between left ventricular ejection fraction and BNP (r ⫽ ⫺0.50, p ⬍ 0.05). Brain natriuretic peptide discriminated well chronic HF patients with a peak VO2 ⬍10 ml/min/kg (area under the receiver operating characteristic [ROC] 0.93) or ⬍14 ml/min/kg (area under the ROC 0.72). A BNP ⬎316 pg/ml was associated with a risk ratio of 6.8 (95% confidence interval, 2.3 to 19.8) for a reduced exercise capacity with a peak VO2 ⬍14 ml/min/kg. CONCLUSIONS Brain natriuretic peptide is clearly associated with exercise capacity in chronic HF. Brain natriuretic peptide levels show a significant correlation with the impairment of VO2 at peak exercise and anaerobic threshold. Brain natriuretic peptide is able to differentiate between chronic HF patients with moderately and severely impaired exercise capacity. (J Am Coll Cardiol 2002;40:718 –22) © 2002 by the American College of Cardiology Foundation OBJECTIVES
Functional disability is one of the most common problems experienced by patients with chronic heart failure (HF). Therefore, one of the major goals of chronic HF management is to improve functional capacity. To accomplish this, reliable methods for detecting and monitoring the functional capacity of this population are warranted. Some clinicians use the clinical history to monitor the functional capacity of their patients. However, exertional symptoms frequently underestimate the severity of functional disability (1). Therefore, others prefer exercise testing to assess functional capacity in chronic HF. Previous studies have shown that peak exercise oxygen uptake (VO2) correlates with survival in chronic HF (2,3). Improvement in peak exercise VO2 over time is also accompanied by stable clinical status and fewer hospitalizations (4). Recently, brain natriuretic peptide (BNP)-guided therapy for chronic HF has been suggested. Troughton et al. (5) demonstrated that pharmacotherapy guided by BNP levels reduces cardiovascular events and delays time to first cardiovascular event compared with intensive clinically guided From the *Medical Clinic I and the †Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, University of Technology, Aachen, Germany. Guest Editor: Gottlieb Friesinger, II, MD. Manuscript received March 21, 2002; revised manuscript received April 29, 2002, accepted May 23, 2002.
therapy. Plasma concentrations of BNP are increased in patients with chronic HF and accurately predict left ventricular ejection fraction (LVEF) as well as morbidity and mortality in these patients (6 –13). The aim of this study was to further clarify the relation between BNP levels measured by a rapid bedside test and functional capacity as measured by cardiopulmonary exercise testing in patients with chronic HF.
METHODS Patients. Seventy patients referred for the evaluation of chronic HF or consideration of heart transplantation were included in the analysis. All patients were in a clinically stable condition for at least six weeks and showed no signs of acute cardiac decompensation. All patients were on optimized medical chronic HF therapy including angiotensin-converting enzyme inhibitors and betablockers, which was unchanged for at least six weeks. Chronic HF was confirmed by left ventricular dysfunction (LVEF ⬍35%) and impairment of exercise capacity (maximal VO2 ⬍ 25 ml/min/kg). All patients had exertional dyspnea, fatigue, or both and were classified according to New York Heart Association functional class II to III. The etiology of HF was defined by cardiac catheterization in all
Kru¨ger et al. BNP and Exercise Capacity in HF
JACC Vol. 40, No. 4, 2002 August 21, 2002:718–22
Abbreviations and Acronyms AT ⫽ anaerobic threshold AUROC ⫽ area under the receiver operating characteristic curve BNP ⫽ brain natriuretic peptide CI ⫽ confidence interval EqCO2 ⫽ ventilatory efficiency HF ⫽ heart failure LVEF ⫽ left ventricular ejection fraction VO2 ⫽ oxygen uptake
patients. Left ventricular ejection fraction was evaluated with biplane transthoracic echocardiography by the modified Simpson rule using second harmonic imaging (14). Patients with renal failure (defined as a creatinine value ⬎2.0 mg/dl) were excluded from the study. Exercise test. A standard bicycle exercise protocol was used in the postabsorptive state. Exercise began with 10 W after a 2-min unload phase, followed by a ramp protocol with increments of 10 W/min. Oxygen uptake, CO2 production, and minute ventilation were measured using a breath-bybreath gas analysis (Ja¨ ger Oxycon Alpha, Wu¨ rzburg, Germany). A 12-lead electrocardiogram was continuously registered to exclude significant myocardial ischemia. Blood pressure was recorded every minute by a cuff sphygmomanometer. Peak VO2 was determined as the highest value in the terminal phase of exercise; the O2 uptake at the anaerobic threshold (VO2-AT) was determined by the V-slope method according to Beaver. Ventilatory efficiency (EqCO2) on exercise was defined as the slope of the VE versus VCO2 relation. Exclusion criteria were exerciselimiting diseases like peripheral vascular disease or degenerative joint disease, relevant primary pulmonary disease, and exercise tests that were not limited by dyspnea or fatigue. All patients reached the AT and a respiratory ratio ⱖ1.05. The physician that performed and analyzed the cardiopulmonary exercise test was unaware of the results of BNP testing. Measurement of BNP plasma levels. In all patients blood was sampled from an antecubital vein after 10 min of supine rest before symptom-limited bicycle exercise. We used a rapid bedside test for determination of BNP (Triage BNP, Biosite Diagnostics, San Diego, California). The Triage BNP test is an immunofluorometric assay for quantitative determination of BNP in ethylenediaminetetraacetic acidanticoagulated whole blood or plasma (9). The peripheral venous blood was collected into a sampling tube containing EDTA as the anticoagulant. Within 20 min after venipuncture, BNP concentrations were determined by the Triage system by analysts that were blinded to results of ergospirometry and the clinical status of the patients. Statistics. Values are presented as mean values ⫾ SD. All variables were tested for normal distribution by the Kolmogorov-Smirnov test. All data was found normally distributed. Correlations were performed using Pearson’s
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Table 1. General Patient Characteristics in 70 Patients With Chronic Heart Failure Characteristics
Patient Values
Age (yrs) Men Weight (kg) Height (cm) NYHA functional class I/II/III LVEF (%) Chronic HF etiology Idiopathic dilated CMP Coronary artery disease Valvular heart disease Medication ACE inhibitors Diuretics Digitalis Beta-blockers
60.3 ⫾ 10.4 51 (73%) 75 ⫾ 14 172 ⫾ 7 2 (3%)/44 (63%)/24 (34%) 26.4 ⫾ 6.0 41 (58.6%) 28 (40%) 1 (1.4%) 57 (81%) 60 (86%) 55 (79%) 57 (81%)
Values are mean ⫾ SD or number of patients (%). ACE ⫽ angiotensin-converting enzyme; CMP ⫽ cardiomyopathy; HF ⫽ heart failure; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association.
correlation. Results are presented as coefficient of correlation (r). The area under the receiver operating characteristic curve (AUROC) was utilized for discrimination. The AUROC provides a measure of overall accuracy that is independent of the decision criterion. The criterion value corresponding with the highest accuracy is the value with the minimum false negative and false positive results at the same time. Univariate logistic regression was performed with the BNP criterion value as the explanatory variable and peak VO2 ⬍14 or ⬍10 ml/min/kg as the response variable. All statistical tests were two-tailed, and a p value ⬍0.05 was considered statistically significant. Data were analyzed using SPSS 10.0 (SPSS Inc., Chicago, Illinois). The AUROC analysis was performed with MedCalc 6.12 (MedCalc software, Mariakerke, Belgium).
RESULTS Patients. Overall, 70 patients with chronic HF (Table 1) were included in this study. BNP levels and exercise parameters. Table 2 shows the correlation between BNP and exercise variables as well as LVEF. Brain natriuretic peptide levels correlated best with peak VO2 (Fig. 1a), VO2-AT and LVEF (Fig. 1b). Compared with BNP levels, LVEF correlated less with peak VO2 (r ⫽ 0.43) and VO2-AT (r ⫽ 0.29). The correlation of Table 2. Correlation Coefficients Between BNP Levels, Cardiopulmonary Exercise Variables and LVEF
BNP Correlation coefficient p value
Peak VO2
VO2-AT
EqCO2
W
LVEF
⫺0.56
⫺0.54
0.43
⫺0.44
⫺0.50
⬍0.001
⬍0.001
⬍0.001
⬍0.05
⬍0.05
BNP ⫽ brain natriuretic peptide; EqCO2 ⫽ ventilatory efficiency; LVEF ⫽ left ventricular ejection fraction; VO2 ⫽ oxygen uptake; VO2-AT ⫽ oxygen uptake at the anaerobic threshold; W ⫽ maximum exercise level in watts % predicted.
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JACC Vol. 40, No. 4, 2002 August 21, 2002:718–22
Figure 2. Receiver operating characteristic curve of brain natriuretic peptide for the determination of peak oxygen uptake (VO2) ⬍10 ml/ min/kg (a) and peak VO2 ⬍14 ml/min/kg (b). AUROC ⫽ area under the receiver operating characteristic curve. Figure 1. Scatter plots of brain natriuretic peptide (BNP) concentrations versus peak oxygen uptake (VO2) (a) and left ventricular ejection fraction (LVEF) (b).
BNP with peak VO2 was better in patients with dilated cardiomyopathy (r ⫽ ⫺0.64) compared with those with ischemic cardiomyopathy (r ⫽ ⫺0.41). The correlation of BNP with VO2-AT was equally good for both etiologies of chronic HF (r ⫽ ⫺0.53 vs. ⫺0.57). Receiver operating characteristic curves illustrate the sensitivity and specificity of BNP in discriminating patients to reach a peak VO2 ⬍10 or ⬍14 ml/min/kg. The AUROC was 0.93 (95% confidence interval [CI]: 0.85 to 1.0) for peak VO2 ⬍10 ml/min/kg (Fig. 2a), indicating very good discriminatory power. For peak VO2 ⬍14 ml/min/kg (Fig. 2b), the area under the curve was 0.72 (95% CI: 0.61 to 0.85), still demonstrating fair to good discriminatory power. The criterion value for BNP to predict a peak VO2 ⬍10 ml/min/kg was 532 pg/ml with a sensitivity of 100% and a
specificity of 78%. A peak VO2 ⬍14 ml/min/kg was predicted with a BNP criterion value of 316 pg/ml with a sensitivity of 76% and a specificity of 68%. Patients with chronic HF with BNP levels ⬎316 pg/ml had a 6.8-fold higher risk (95% CI: 2.3 to 19.8) to reach a peak VO2 ⬍14 ml/min/kg compared with patients with BNP levels below this cutoff value.
DISCUSSION Role of BNP in chronic HF. Brain natriuretic peptide is secreted predominantly from cardiac ventricles and is affected by the degree of myocardial stretch, damage, and ischemia in the ventricle (10). Brain natriuretic peptide levels are raised in patients with chronic HF and reflect severity of left ventricular and right ventricular dysfunction (11–13). Beyond these evidences the present study demonstrated a reliable correlation of BNP levels with exercise parameters
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such as peak VO2, VO2 at the AT, EqCO2, and with LVEF in chronic HF. To the best of our knowledge, this is the first study that systematically examines the correlation of a rapid bedside BNP test with cardiopulmonary exercise testing in patients with mild to severe symptoms of chronic HF. Brain natriuretic peptide is more useful than atrial natiuretic peptide, endothelin, or norepinephrine as an independent predictor of morbidity and mortality in patients with chronic HF and is independent of other clinical, hemodynamic, and neurohumoral risk factors in chronic HF (6). Endothelin and norepinephrine are closely correlated with exercise capacity in patients with chronic HF (15,16). However, the use of these markers, which give prognostic information in chronic HF, such as norepinephrine, renin, and endothelin, is difficult, impractical, and associated with long-lasting assays (17). For this reason BNP seems to be the most simple, reliable, readily available, and promising laboratory marker of cardiac dysfunction at present. Importance of point-of-care testing of BNP in chronic HF. A rapid bedside BNP test has several advantages compared with the formerly used assay systems to determine BNP (9). The major advantage is its rapid and accurate measurement of BNP from whole blood with 24-h availability in a routine laboratory or at the point-of-care. Additional time-consuming preparation, centrifugation, extraction, and incubation steps can be omitted. Thus, a fast BNP determination is possible, which makes the recently introduced BNP-guided therapy for chronic HF more feasible, especially in an ambulatory setting. Cardiopulmonary exercise testing as a gold standard is costly, time consuming and has limited availability, so that, with respect to the good correlation of BNP with exercise variables, BNP may be a cost-effective, generally available and reliable tool for the guidance of chronic HF therapy. Role of exercise testing in chronic HF. Exercise testing with gas-exchange analysis has become a routine clinical tool for the evaluation of patients with chronic HF and is predictive of mortality (2,18 –22). Therefore, current guidelines recommend exercise testing to select appropriate candidates for heart transplantation (23). Peak VO2 is less valuable in patients with mild symptoms of CHF, although their annual mortality is still high with rates of 8% to 10% (24). In this subset of patients, enhanced ventilatory response to exercise (EqCO2) predicts poor prognosis, whereas peak VO2 is not associated with outcome (25). A significant number of patients with severe chronic HF do not reach maximal exertion. Therefore, some authors assessed the prognostic significance of respiratory data during submaximal exercise. Pardaens et al. (20) found that respiratory data during submaximal exercise are significant predictors of outcome in chronic HF, but inferior to that of peak VO2. Thus, this study examined not only oxygen kinetics at exercise, but also EqCO2. Many authors concluded that peak VO2 provides superior prognostic information in chronic HF (20). Various cutoff values have been proposed for decision making. Mancini et
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al. (2) observed that cardiac transplantation could be safely deferred in ambulatory patients with left ventricular dysfunction and peak exercise VO2 of ⱖ14 ml/min/kg. The highest mortality rate is seen in patients with chronic HF with a peak VO2 of ⬍10 ml/min/kg (21,22). In our study a criterion value for BNP of 532 pg/ml exhibits a very good discriminative power for the prediction of a severely reduced peak VO2 of ⬍10 ml/min/kg, and a criterion value of 316 pg/ml also has good discriminatory power for the prediction of a peak VO2 of ⬍14 ml/min/kg. A BNP concentration ⬎316 pg/ml constitutes a 6.8-fold higher risk for a reduced exercise capacity with a peak VO2 ⬍14 ml/min/kg. However, peak VO2 is a continuous, rather than a discrete variable, and the evidence of an optimal cutoff point seems questionable (22). Our data underline the importance of peak VO2. The best correlation with BNP as a marker of neuroendocrine activation in chronic HF was seen for peak VO2 and, to a comparable degree, also for VO2-AT. Maximum exercise level, EqCO2 and also LVEF correlated less with BNP. Because there is a good correlation of BNP and exercise capacity, the determination of resting BNP might be a simple and cost-saving alternative in the future to select patients for heart transplantation compared with the more expensive and time-consuming exercise testing, which is not without risk in patients with chronic HF. Moreover, the prognostic power of plasma BNP assessing the mortality in patients with chronic HF has already been shown by Tsutamoto et al. (26). Study limitations. There are several limitations of our study. First, we did not perform invasive hemodynamic tests to evaluate the relation between hemodynamics and BNP. Previous studies have already shown that there is a close correlation between BNP levels and left ventricular enddiastolic pressure. Secondly, we did not study the influence of medications on BNP. All patients were treated according to chronic HF guidelines. Previous studies demonstrated that BNP levels are reduced after treatment with betablockers (27), whereas they are increased after treatment with angiotensin-converting enzyme inhibitors (28) or digitalis (29). Finally, patients with renal failure were excluded from the study because of potentially marked elevation of plasma BNP (30,31). Thus, it remains unknown whether plasma BNP levels can also be used to predict functional capacity in these patients. Conclusions. Brain natriuretic peptide testing may be an effective way to improve monitoring and therapy of patients with chronic HF, including in-hospital and outpatient management. Brain natriuretic peptide is clearly associated with exercise capacity and LVEF in chronic HF. Brain natriuretic peptide is able to differentiate between patients with chronic HF with moderately and severely impaired exercise capacity. Further studies are needed to compare the prognostic value, outcome, and cost-effectiveness of BNPguided versus exercise-testing-guided therapy in chronic HF.
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Reprint requests and correspondence: Dr. Stefan Kru¨ ger, Medizinische Klinik I, Universita¨ tsklinikum, Rheinisch Westfa¨ lische Technische Hochschule, Pauwelsstraße 30, 52057 Aachen, Germany. E-mail: [email protected].
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JACC Vol. 40, No. 4, 2002 August 21, 2002:718–22 15. Krum H, Goldsmith R, Wilshire-Clement M, Miller M, Packer M. Role of endothelin in the exercise intolerance of chronic heart failure. Am J Cardiol 1995;75:1282–3. 16. Kraemer MD, Kubo SH, Rector TS, Brunsvold N, Bank AJ. Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure. J Am Coll Cardiol 1993;21:641–8. 17. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of left ventricular dysfunction (SOLVD). Circulation 1990;82:1724 –9. 18. Myers J, Gullestad L, Vagelos R, et al. Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure. Ann Intern Med 1998;129: 286 –93. 19. Opaasich C, Pinna GD, Bobbio M, et al. Peak exercise oxygen consumption in chronic heart failure: toward efficient use in the individual patient. J Am Coll Cardiol 1998;31:766 –75. 20. Pardaens K, van Cleemput J, Vanhaecke J, Fagard RH. Peak oxygen uptake better predicts outcome than submaximal respiratory data in heart transplant candidates. Circulation 2000;101:1152–7. 21. Myers J, Gullestad L, Vagelos R, et al. Cardiopulmonary exercise testing and prognosis in severe heart failure: 14 ml/kg/min revisited. Am Heart J 2000;139:78 –84. 22. Mancini D, LeJemtel T, Aaronson K. Peak VO2: a simple yet enduring standard. Circulation 2000;101:1080 –2. 23. ACC/AHA Task Force. Guidelines for the evaluation and management of heart failure. Circulation 1995;92:2764 –84. 24. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med 1992;327:685–91. 25. Ponikowski P, Francis DP, Piepoli MF, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation 2001;103:967–72. 26. Tsutamoto T, Wada A, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96:509 –16. 27. Kawai K, Hata K, Takaoka H, Kawai H, Yokoyama M. Plasma brain natriuretic peptide as a novel therapeutic indicator in idiopathic dilated cardiomyopathy during -blocker therapy: a potential of hormoneguided treatment. Am Heart J 2001;141:925–32. 28. Talwar S, Squire IB, Downie PF, et al. Profile of plasma N-terminal proBNP following acute myocardial infarction: correlation with left ventricular systolic dysfunction. Eur Heart J 2000;21:1514 –21. 29. Tsutamoto T, Wada A, Maeda K, et al. Digitalis increases brain natriuretic peptide in patients with severe congestive heart failure. Am Heart J 1997;134:910 –6. 30. Haug C, Metzele A, Steffgen J, Kochs M, Hombach V, Grunert A. Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure. Clin Invest 1994;72:430 –4. 31. Ishizaka Y, Yamamoto Y, Fukunaga T, et al. Plasma concentration of human brain natriuretic peptide in patients on hemodialysis. Am J Kidney Dis 1994;24:461–72.
Vol. 40, No. 4, 2002 ISSN 0735-1097/02/$22.00 PII S0735-1097(02)02032-6
Diagnostics and Heart Failure
Brain Natriuretic Peptide Levels Predict Functional Capacity in Patients With Chronic Heart Failure Stefan Kru¨ger, MD,* Ju¨rgen Graf, MD,* Dagmar Kunz, MD,† Tina Stickel, CAND MED,* Peter Hanrath, MD, FESC, FACC,* Uwe Janssens, MD, FESC* Aachen, Germany The goal of this study was to determine if brain natriuretic peptide (BNP) levels are associated with exercise capacity in patients with chronic heart failure (HF). BACKGROUND Plasma levels of BNP are increased subject to the degree of systolic and diastolic left ventricular dysfunction in patients with chronic HF. Exercise testing is useful to assess functional capacity and prognosis in chronic HF. METHODS We prospectively studied 70 consecutive patients with chronic HF (60.3 ⫾ 10.4 years, 51 men) referred for cardiopulmonary exercise testing. Resting BNP was obtained after 10 min of supine rest before symptom-limited bicycle exercise testing. RESULTS In patients with chronic HF, BNP levels correlated with oxygen uptake (VO2), both at anaerobic threshold (VO2AT: r ⫽ ⫺0.54, p ⬍ 0.001) and peak exercise (peak VO2: r ⫽ ⫺0.56, p ⬍ 0.001). Impairment of ventilatory efficiency (EqCO2: r ⫽ 0.43, p ⬍ 0.001) and maximum exercise level (W % predicted: r ⫽ ⫺0.44, p ⬍ 0.05) correlated less well with BNP. There was a significant inverse correlation between left ventricular ejection fraction and BNP (r ⫽ ⫺0.50, p ⬍ 0.05). Brain natriuretic peptide discriminated well chronic HF patients with a peak VO2 ⬍10 ml/min/kg (area under the receiver operating characteristic [ROC] 0.93) or ⬍14 ml/min/kg (area under the ROC 0.72). A BNP ⬎316 pg/ml was associated with a risk ratio of 6.8 (95% confidence interval, 2.3 to 19.8) for a reduced exercise capacity with a peak VO2 ⬍14 ml/min/kg. CONCLUSIONS Brain natriuretic peptide is clearly associated with exercise capacity in chronic HF. Brain natriuretic peptide levels show a significant correlation with the impairment of VO2 at peak exercise and anaerobic threshold. Brain natriuretic peptide is able to differentiate between chronic HF patients with moderately and severely impaired exercise capacity. (J Am Coll Cardiol 2002;40:718 –22) © 2002 by the American College of Cardiology Foundation OBJECTIVES
Functional disability is one of the most common problems experienced by patients with chronic heart failure (HF). Therefore, one of the major goals of chronic HF management is to improve functional capacity. To accomplish this, reliable methods for detecting and monitoring the functional capacity of this population are warranted. Some clinicians use the clinical history to monitor the functional capacity of their patients. However, exertional symptoms frequently underestimate the severity of functional disability (1). Therefore, others prefer exercise testing to assess functional capacity in chronic HF. Previous studies have shown that peak exercise oxygen uptake (VO2) correlates with survival in chronic HF (2,3). Improvement in peak exercise VO2 over time is also accompanied by stable clinical status and fewer hospitalizations (4). Recently, brain natriuretic peptide (BNP)-guided therapy for chronic HF has been suggested. Troughton et al. (5) demonstrated that pharmacotherapy guided by BNP levels reduces cardiovascular events and delays time to first cardiovascular event compared with intensive clinically guided From the *Medical Clinic I and the †Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, University of Technology, Aachen, Germany. Guest Editor: Gottlieb Friesinger, II, MD. Manuscript received March 21, 2002; revised manuscript received April 29, 2002, accepted May 23, 2002.
therapy. Plasma concentrations of BNP are increased in patients with chronic HF and accurately predict left ventricular ejection fraction (LVEF) as well as morbidity and mortality in these patients (6 –13). The aim of this study was to further clarify the relation between BNP levels measured by a rapid bedside test and functional capacity as measured by cardiopulmonary exercise testing in patients with chronic HF.
METHODS Patients. Seventy patients referred for the evaluation of chronic HF or consideration of heart transplantation were included in the analysis. All patients were in a clinically stable condition for at least six weeks and showed no signs of acute cardiac decompensation. All patients were on optimized medical chronic HF therapy including angiotensin-converting enzyme inhibitors and betablockers, which was unchanged for at least six weeks. Chronic HF was confirmed by left ventricular dysfunction (LVEF ⬍35%) and impairment of exercise capacity (maximal VO2 ⬍ 25 ml/min/kg). All patients had exertional dyspnea, fatigue, or both and were classified according to New York Heart Association functional class II to III. The etiology of HF was defined by cardiac catheterization in all
Kru¨ger et al. BNP and Exercise Capacity in HF
JACC Vol. 40, No. 4, 2002 August 21, 2002:718–22
Abbreviations and Acronyms AT ⫽ anaerobic threshold AUROC ⫽ area under the receiver operating characteristic curve BNP ⫽ brain natriuretic peptide CI ⫽ confidence interval EqCO2 ⫽ ventilatory efficiency HF ⫽ heart failure LVEF ⫽ left ventricular ejection fraction VO2 ⫽ oxygen uptake
patients. Left ventricular ejection fraction was evaluated with biplane transthoracic echocardiography by the modified Simpson rule using second harmonic imaging (14). Patients with renal failure (defined as a creatinine value ⬎2.0 mg/dl) were excluded from the study. Exercise test. A standard bicycle exercise protocol was used in the postabsorptive state. Exercise began with 10 W after a 2-min unload phase, followed by a ramp protocol with increments of 10 W/min. Oxygen uptake, CO2 production, and minute ventilation were measured using a breath-bybreath gas analysis (Ja¨ ger Oxycon Alpha, Wu¨ rzburg, Germany). A 12-lead electrocardiogram was continuously registered to exclude significant myocardial ischemia. Blood pressure was recorded every minute by a cuff sphygmomanometer. Peak VO2 was determined as the highest value in the terminal phase of exercise; the O2 uptake at the anaerobic threshold (VO2-AT) was determined by the V-slope method according to Beaver. Ventilatory efficiency (EqCO2) on exercise was defined as the slope of the VE versus VCO2 relation. Exclusion criteria were exerciselimiting diseases like peripheral vascular disease or degenerative joint disease, relevant primary pulmonary disease, and exercise tests that were not limited by dyspnea or fatigue. All patients reached the AT and a respiratory ratio ⱖ1.05. The physician that performed and analyzed the cardiopulmonary exercise test was unaware of the results of BNP testing. Measurement of BNP plasma levels. In all patients blood was sampled from an antecubital vein after 10 min of supine rest before symptom-limited bicycle exercise. We used a rapid bedside test for determination of BNP (Triage BNP, Biosite Diagnostics, San Diego, California). The Triage BNP test is an immunofluorometric assay for quantitative determination of BNP in ethylenediaminetetraacetic acidanticoagulated whole blood or plasma (9). The peripheral venous blood was collected into a sampling tube containing EDTA as the anticoagulant. Within 20 min after venipuncture, BNP concentrations were determined by the Triage system by analysts that were blinded to results of ergospirometry and the clinical status of the patients. Statistics. Values are presented as mean values ⫾ SD. All variables were tested for normal distribution by the Kolmogorov-Smirnov test. All data was found normally distributed. Correlations were performed using Pearson’s
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Table 1. General Patient Characteristics in 70 Patients With Chronic Heart Failure Characteristics
Patient Values
Age (yrs) Men Weight (kg) Height (cm) NYHA functional class I/II/III LVEF (%) Chronic HF etiology Idiopathic dilated CMP Coronary artery disease Valvular heart disease Medication ACE inhibitors Diuretics Digitalis Beta-blockers
60.3 ⫾ 10.4 51 (73%) 75 ⫾ 14 172 ⫾ 7 2 (3%)/44 (63%)/24 (34%) 26.4 ⫾ 6.0 41 (58.6%) 28 (40%) 1 (1.4%) 57 (81%) 60 (86%) 55 (79%) 57 (81%)
Values are mean ⫾ SD or number of patients (%). ACE ⫽ angiotensin-converting enzyme; CMP ⫽ cardiomyopathy; HF ⫽ heart failure; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association.
correlation. Results are presented as coefficient of correlation (r). The area under the receiver operating characteristic curve (AUROC) was utilized for discrimination. The AUROC provides a measure of overall accuracy that is independent of the decision criterion. The criterion value corresponding with the highest accuracy is the value with the minimum false negative and false positive results at the same time. Univariate logistic regression was performed with the BNP criterion value as the explanatory variable and peak VO2 ⬍14 or ⬍10 ml/min/kg as the response variable. All statistical tests were two-tailed, and a p value ⬍0.05 was considered statistically significant. Data were analyzed using SPSS 10.0 (SPSS Inc., Chicago, Illinois). The AUROC analysis was performed with MedCalc 6.12 (MedCalc software, Mariakerke, Belgium).
RESULTS Patients. Overall, 70 patients with chronic HF (Table 1) were included in this study. BNP levels and exercise parameters. Table 2 shows the correlation between BNP and exercise variables as well as LVEF. Brain natriuretic peptide levels correlated best with peak VO2 (Fig. 1a), VO2-AT and LVEF (Fig. 1b). Compared with BNP levels, LVEF correlated less with peak VO2 (r ⫽ 0.43) and VO2-AT (r ⫽ 0.29). The correlation of Table 2. Correlation Coefficients Between BNP Levels, Cardiopulmonary Exercise Variables and LVEF
BNP Correlation coefficient p value
Peak VO2
VO2-AT
EqCO2
W
LVEF
⫺0.56
⫺0.54
0.43
⫺0.44
⫺0.50
⬍0.001
⬍0.001
⬍0.001
⬍0.05
⬍0.05
BNP ⫽ brain natriuretic peptide; EqCO2 ⫽ ventilatory efficiency; LVEF ⫽ left ventricular ejection fraction; VO2 ⫽ oxygen uptake; VO2-AT ⫽ oxygen uptake at the anaerobic threshold; W ⫽ maximum exercise level in watts % predicted.
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Figure 2. Receiver operating characteristic curve of brain natriuretic peptide for the determination of peak oxygen uptake (VO2) ⬍10 ml/ min/kg (a) and peak VO2 ⬍14 ml/min/kg (b). AUROC ⫽ area under the receiver operating characteristic curve. Figure 1. Scatter plots of brain natriuretic peptide (BNP) concentrations versus peak oxygen uptake (VO2) (a) and left ventricular ejection fraction (LVEF) (b).
BNP with peak VO2 was better in patients with dilated cardiomyopathy (r ⫽ ⫺0.64) compared with those with ischemic cardiomyopathy (r ⫽ ⫺0.41). The correlation of BNP with VO2-AT was equally good for both etiologies of chronic HF (r ⫽ ⫺0.53 vs. ⫺0.57). Receiver operating characteristic curves illustrate the sensitivity and specificity of BNP in discriminating patients to reach a peak VO2 ⬍10 or ⬍14 ml/min/kg. The AUROC was 0.93 (95% confidence interval [CI]: 0.85 to 1.0) for peak VO2 ⬍10 ml/min/kg (Fig. 2a), indicating very good discriminatory power. For peak VO2 ⬍14 ml/min/kg (Fig. 2b), the area under the curve was 0.72 (95% CI: 0.61 to 0.85), still demonstrating fair to good discriminatory power. The criterion value for BNP to predict a peak VO2 ⬍10 ml/min/kg was 532 pg/ml with a sensitivity of 100% and a
specificity of 78%. A peak VO2 ⬍14 ml/min/kg was predicted with a BNP criterion value of 316 pg/ml with a sensitivity of 76% and a specificity of 68%. Patients with chronic HF with BNP levels ⬎316 pg/ml had a 6.8-fold higher risk (95% CI: 2.3 to 19.8) to reach a peak VO2 ⬍14 ml/min/kg compared with patients with BNP levels below this cutoff value.
DISCUSSION Role of BNP in chronic HF. Brain natriuretic peptide is secreted predominantly from cardiac ventricles and is affected by the degree of myocardial stretch, damage, and ischemia in the ventricle (10). Brain natriuretic peptide levels are raised in patients with chronic HF and reflect severity of left ventricular and right ventricular dysfunction (11–13). Beyond these evidences the present study demonstrated a reliable correlation of BNP levels with exercise parameters
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such as peak VO2, VO2 at the AT, EqCO2, and with LVEF in chronic HF. To the best of our knowledge, this is the first study that systematically examines the correlation of a rapid bedside BNP test with cardiopulmonary exercise testing in patients with mild to severe symptoms of chronic HF. Brain natriuretic peptide is more useful than atrial natiuretic peptide, endothelin, or norepinephrine as an independent predictor of morbidity and mortality in patients with chronic HF and is independent of other clinical, hemodynamic, and neurohumoral risk factors in chronic HF (6). Endothelin and norepinephrine are closely correlated with exercise capacity in patients with chronic HF (15,16). However, the use of these markers, which give prognostic information in chronic HF, such as norepinephrine, renin, and endothelin, is difficult, impractical, and associated with long-lasting assays (17). For this reason BNP seems to be the most simple, reliable, readily available, and promising laboratory marker of cardiac dysfunction at present. Importance of point-of-care testing of BNP in chronic HF. A rapid bedside BNP test has several advantages compared with the formerly used assay systems to determine BNP (9). The major advantage is its rapid and accurate measurement of BNP from whole blood with 24-h availability in a routine laboratory or at the point-of-care. Additional time-consuming preparation, centrifugation, extraction, and incubation steps can be omitted. Thus, a fast BNP determination is possible, which makes the recently introduced BNP-guided therapy for chronic HF more feasible, especially in an ambulatory setting. Cardiopulmonary exercise testing as a gold standard is costly, time consuming and has limited availability, so that, with respect to the good correlation of BNP with exercise variables, BNP may be a cost-effective, generally available and reliable tool for the guidance of chronic HF therapy. Role of exercise testing in chronic HF. Exercise testing with gas-exchange analysis has become a routine clinical tool for the evaluation of patients with chronic HF and is predictive of mortality (2,18 –22). Therefore, current guidelines recommend exercise testing to select appropriate candidates for heart transplantation (23). Peak VO2 is less valuable in patients with mild symptoms of CHF, although their annual mortality is still high with rates of 8% to 10% (24). In this subset of patients, enhanced ventilatory response to exercise (EqCO2) predicts poor prognosis, whereas peak VO2 is not associated with outcome (25). A significant number of patients with severe chronic HF do not reach maximal exertion. Therefore, some authors assessed the prognostic significance of respiratory data during submaximal exercise. Pardaens et al. (20) found that respiratory data during submaximal exercise are significant predictors of outcome in chronic HF, but inferior to that of peak VO2. Thus, this study examined not only oxygen kinetics at exercise, but also EqCO2. Many authors concluded that peak VO2 provides superior prognostic information in chronic HF (20). Various cutoff values have been proposed for decision making. Mancini et
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al. (2) observed that cardiac transplantation could be safely deferred in ambulatory patients with left ventricular dysfunction and peak exercise VO2 of ⱖ14 ml/min/kg. The highest mortality rate is seen in patients with chronic HF with a peak VO2 of ⬍10 ml/min/kg (21,22). In our study a criterion value for BNP of 532 pg/ml exhibits a very good discriminative power for the prediction of a severely reduced peak VO2 of ⬍10 ml/min/kg, and a criterion value of 316 pg/ml also has good discriminatory power for the prediction of a peak VO2 of ⬍14 ml/min/kg. A BNP concentration ⬎316 pg/ml constitutes a 6.8-fold higher risk for a reduced exercise capacity with a peak VO2 ⬍14 ml/min/kg. However, peak VO2 is a continuous, rather than a discrete variable, and the evidence of an optimal cutoff point seems questionable (22). Our data underline the importance of peak VO2. The best correlation with BNP as a marker of neuroendocrine activation in chronic HF was seen for peak VO2 and, to a comparable degree, also for VO2-AT. Maximum exercise level, EqCO2 and also LVEF correlated less with BNP. Because there is a good correlation of BNP and exercise capacity, the determination of resting BNP might be a simple and cost-saving alternative in the future to select patients for heart transplantation compared with the more expensive and time-consuming exercise testing, which is not without risk in patients with chronic HF. Moreover, the prognostic power of plasma BNP assessing the mortality in patients with chronic HF has already been shown by Tsutamoto et al. (26). Study limitations. There are several limitations of our study. First, we did not perform invasive hemodynamic tests to evaluate the relation between hemodynamics and BNP. Previous studies have already shown that there is a close correlation between BNP levels and left ventricular enddiastolic pressure. Secondly, we did not study the influence of medications on BNP. All patients were treated according to chronic HF guidelines. Previous studies demonstrated that BNP levels are reduced after treatment with betablockers (27), whereas they are increased after treatment with angiotensin-converting enzyme inhibitors (28) or digitalis (29). Finally, patients with renal failure were excluded from the study because of potentially marked elevation of plasma BNP (30,31). Thus, it remains unknown whether plasma BNP levels can also be used to predict functional capacity in these patients. Conclusions. Brain natriuretic peptide testing may be an effective way to improve monitoring and therapy of patients with chronic HF, including in-hospital and outpatient management. Brain natriuretic peptide is clearly associated with exercise capacity and LVEF in chronic HF. Brain natriuretic peptide is able to differentiate between patients with chronic HF with moderately and severely impaired exercise capacity. Further studies are needed to compare the prognostic value, outcome, and cost-effectiveness of BNPguided versus exercise-testing-guided therapy in chronic HF.
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Reprint requests and correspondence: Dr. Stefan Kru¨ ger, Medizinische Klinik I, Universita¨ tsklinikum, Rheinisch Westfa¨ lische Technische Hochschule, Pauwelsstraße 30, 52057 Aachen, Germany. E-mail: [email protected].
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