Arne K. Andreassen, PhD a, *, Ragnhild Wergeland, MS b, Svein Simonsen, PhD a, Odd Geiran, PhD c, Cecilia Guevara, BSc a, and Thor Ueland, PhD d

Transcription

1 N-Terminal Pro-B-Type Natriuretic Peptide as an Indicator of Disease Severity in a Heterogeneous Group of Patients With Chronic Precapillary Pulmonary Hypertension Arne K. Andreassen, PhD a, *, Ragnhild Wergeland, MS b, Svein Simonsen, PhD a, Odd Geiran, PhD c, Cecilia Guevara, BSc a, and Thor Ueland, PhD d N-terminal pro-b-type natriuretic peptide (NT pro-bnp) is well established as a predictor of prognosis in patients with left ventricular dysfunction. Although a similar prognostic significance has been suggested in 1 study of right ventricular failure and idiopathic pulmonary arterial hypertension, NT pro-bnp has not been assessed as a marker of disease severity in a more heterogenous group of patients with chronic precapillary pulmonary hypertension (PH). Hence, this study assessed plasma NT pro-bnp and other clinical variables in 61 consecutively recruited patients with various forms of chronic precapillary PH. Right-sided cardiac catheterization and cardiopulmonary exercise testing were performed at baseline, and the prognostic significance of NT pro-bnp was investigated with a mean follow-up of 25 months. Compared with age-matched controls (n 10), plasma NT pro-bnp was significantly greater in those with idiopathic pulmonary arterial hypertension (n 16), chronic precapillary PH associated with other diseases (n 26), and chronic thromboembolic disease (n 19) and was correlated with hemodynamic variables and functional capacity. In 17 medically treated patients, the significant decrease in NT pro-bnp levels correlated with improved hemodynamics. During follow-up, 15 patients died from cardiopulmonary causes. Baseline NT pro-bnp was an independent predictor of mortality. Kaplan-Meier survival analysis according to the median value of NT pro-bnp (168 pmol/l) demonstrated a significantly higher mortality rate in those with supramedian values than in those with low plasma levels (p 0.010). In conclusion, these findings suggest that in a heterogenous group of patients with chronic precapillary PH, plasma NT pro-bnp can be used to determine the clinical severity of disease and is independently associated with long-term mortality Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98: ) B-type natriuretic peptide (BNP) is a cardiac hormone that is mainly synthesized, stored, and released in the ventricular myocardium. 1 BNP has been studied extensively in congestive heart failure. The stimuli for increased secretion of this peptide are ventricular wall stretching and volume overload, and elevated levels of BNP have been associated with reduced functional capacity and a poor prognosis. 2 Although more limited data are available for chronic precapillary pulmonary hypertension (PH) and right ventricular failure, 1 study in patients with idiopathic pulmonary arterial hypertension (IPAH) demonstrated a correlation between levels of BNP and survival. 3 However, it is unknown whether BNP is a parameter that can be applied as a prognostic marker in a more heterogenous group of patients with chronic precapillary PH. Thus, in the present study, we investigated the N- terminal part of its prohormone (NT pro-bnp) to determine Departments of a Cardiology, b Medical Biochemistry, and c Thoracic Surgery and d Research Institute for Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway. Manuscript received November 8, 2005; revised manuscript received and accepted February 16, * Corresponding author: Tel: ; fax: address: arne.andreassen@rikshospitalet.no (A.K. Andreassen). whether NT pro-bnp is an indicator of disease severity and survival in patients with various forms of chronic precapillary PH. Methods Patients: We consecutively recruited 61 patients referred to our center for the characterization of suspected chronic precapillary PH (Table 1). According to the revised clinical classification of PH, 40 patients had pulmonary arterial hypertension (PAH), 16 with IPAH (on the basis of the criteria of the National Institutes of Health Registry 4 ) and 24 associated with the following conditions: connective tissue disease (n 12; systemic sclerosis [n 4], systemic lupus erythematosus [n 4], mixed connective tissue disease [n 3], and dermatopolymyositis [n 1]), congenital systemic-to-pulmonary shunts (n 3; 2 with atrial septal defects and 1 with ventricular septal defect), portal hypertension due to liver cirrhosis (n 2), human immunodeficiency virus infection (n 3), and pulmonary veno-occlusive disease (n 4; clinical diagnosis verified by autopsy in 3 patients). In addition, 2 patients were in the miscellaneous group diagnosed as having sarcoidosis, and 19 patients had angiographically verified chronic thromboembolic PH, with /06/$ see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 526 The American Journal of Cardiology ( Table 1 Comparison of patient characteristics in various forms of chronic precapillary pulmonary hypertension according to survival Variable Survivors (n 46) Nonsurvivors (n 15) p Value Age (yrs) NS Men/women 15/31 4/11 NS NYHA functional class (n) II 3 0 NS III NS IV Exercise performance Peak oxygen uptake (ml/kg min 1 ) Hemodynamics Heart rate (beats/min) Systolic blood pressure (mm Hg) Right artrial pressure (mm Hg) Mean pulmonary artery pressure NS (mm Hg) Pulmonary capillary wedge pressure NS (mm Hg) Cardiac index (L/min/m 2 ) NS Pulmonary vascular resistance NS (Wood units) Blood gases Arterial oxygen saturation (%) NS Mixed venous oxygen saturation (%) Biochemical markers NT pro-bnp level (pmol/l) Uric acid level ( mol/l) Data are expressed as mean SD. obstructions of the proximal or distal pulmonary arteries. The median New York Heart Association (NYHA) functional class was III (3 patients in class II, 52 patients in class III, and 6 patients in class IV). Ten age- and gendermatched patients who underwent right-sided cardiac catheterization during electrophysiologic examinations served as controls. They had supraventricular arrhythmias in the form of Wolff-Parkinson-White syndrome (n 5) or atrioventricular nodal reentry tachycardia (n 5), with normal hemodynamic parameters. All patients gave informed consent. The study protocol was approved by the local ethics committee. Hemodynamics: Right-sided cardiac catheterization was performed with a thermodilution catheter through the right femoral vein, with a catheter inserted into the right femoral artery for the monitoring of arterial blood pressure and blood gases. Baseline hemodynamic variables included heart rate and right atrial, pulmonary arterial, and pulmonary capillary wedge pressures. Cardiac output was obtained using the thermodilution technique as the mean of 3 measurements. Pulmonary vascular resistance and cardiac index were calculated using standard formulas. Oxygen saturation was measured in blood samples from the femoral and pulmonary arteries. Acute vasoreactive testing was performed by inhalation of the aerosolized prostacyclin analogue iloprost. 5 Briefly, the inhalation of iloprost 10 g over 10 minutes was followed by renewed measurements of mean pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output after another 15 minutes. A reduction in mean pulmonary arterial pressure 10 mm Hg to an absolute value of mean PAH to 40 mm Hg, with parallel unchanged or improved cardiac output, was considered a positive acute vasoreactive response. Cardiopulmonary exercise testing: Within 24 to 48 hours of right-sided cardiac catheterization, a symptom-limited exercise test was performed using a cycle ergometer (ER900; Jäger, Wurzburg, Germany) started at 20 W, with the pedal rate kept constant at 60 rpm, and with stepwise increments of 5 W/min. Gas exchange measurements were obtained throughout the baseline rest, exercise, and early recovery periods. Peak oxygen uptake was defined as the greatest 30-second average of oxygen uptake during the last minute of exercise. Heart rate, 12-lead electrocardiogram, and cuff blood pressure were monitored and recorded. Of the 61 patients in the study, 12 did not undergo exercise testing because of clinical instability. Blood sampling and NT pro-bnp assay: During heart catheterization, blood samples were drawn from the pulmonary artery and immediately transferred into glass tubes and centrifuged at 4 C within 1 hour. All samples were stored at 80 C. NT pro-bnp in plasma was determined by an electrochemiluminescence immunoassay on a Modular platform (Roche Diagnostics, Basel, Switzerland). The interassay coefficient of variation was 5.7% at a concentration of 7.6 pmol/l and 3% at concentrations from 15.9 to 545 pmol/l. The lower detection limit was 0.6 pmol/l. Treatment and follow-up: After diagnostic assessment, all patients received long-term anticoagulation, unless contraindicated. Patients with fluid retention received diuretics. Long-term oxygen therapy was introduced in 2 patients with hypoxemia at rest. A calcium channel blocker in the form of nifedipine was given to 3 patients considered responders after vasoreactivity testing. The remaining patients in NYHA functional class III or IV were treated with inhaled or intravenous prostanoids, endothelin antagonists, or sildenafil. Also, 4 patients were placed on the transplantation waiting list, and 3 were referred for thromboendarterectomy. We particularly examined 17 patients with IPAH (n 12) or PAH associated with other conditions (n 5) treated with either epoprostenol (n 14) or nifedipine (n 3). Levels of NT pro-bnp, right-sided cardiac catheterization, and functional capacity were reassessed in these patients 3 and 12 months after the initiation of therapy. Survival: Survival was estimated from the date of the first blood sampling to April 15, 2005, or cardiopulmonary death. None were lost to follow-up. Statistical analysis: Data are given as mean SD unless otherwise stated. For comparisons between 2 groups of patients, the Mann-Whitney U-statistic test was used. When comparing 2 groups, 1-way analysis of variance was fol-

3 Miscellaneous/NT Pro-BNP in Chronic Precapillary Pulmonary Hypertension 527 Figure 1. Plasma NT pro-bnp levels in patients with IPAH (n 16), chronic precapillary PH associated with other diseases (aph; n 26), and PH due to chronic thromboembolic disease (CTEPH; n 19) compared with controls (n 10). *p 0.05 versus IPAH. lowed by Scheffe s post hoc test for statistical significance. For comparisons within the same patients, Wilcoxon s matched-pairs test was applied. The correlations of NT pro- BNP plasma levels with hemodynamic and clinical parameters were tested using Spearman s correlation coefficient. Logistic regression analysis was applied to identify the predictive value of each variable, and with the use of forward conditional multivariate Cox regression, the prognostic power of plasma NT pro-bnp was compared with that of other significant predictors. Survival curves were derived using the Kaplan-Meier method and compared by means of the log-rank test. Statistical significance was accepted at p Results Plasma NT pro-bnp: Plasma levels of NT pro-bnp were significantly elevated in 61 patients with chronic precapillary PH compared with 10 controls ( vs 7 6 pmol/l, p 0.001). When dividing patients into groups according to cause, the highest levels of NT pro-bnp were found in those with IPAH ( pmol/l) and chronic precapillary PH associated with other diseases ( pmol/l), with significantly higher levels also in the group with chronic thromboembolic PH ( pmol/l) compared with controls (p 0.001; Figure 1). Correlation analysis of NT pro-bnp and functional class, exercise, and hemodynamic parameters: Plasma NT pro-bnp increased significantly with the severity of NYHA functional class (r 0.27, p 0.047), and an inverse correlation was found between peak oxygen uptake and NT pro-bnp (r 0.42, p 0.003). Furthermore, NT pro-bnp was correlated positively with right atrial pressure (r 0.47, p 0.001), mean PAH (r 0.47, p 0.001), pulmonary vascular resistance (r 0.66, p 0.001), and heart rate (r 0.31, p 0.020), whereas negative associations were found with cardiac index (r 0.58, p 0.001), mixed venous oxygen saturation (r 0.53, p 0.001), and systolic arterial pressure (r 0.29, p 0.028). Figure 2. Plasma NT pro-bnp levels at baseline, 3 months, and 12 months in 17 patients initiating treatment with epoprostenol (n 14) or nifedipine (n 3). Table 2 Multivariate analysis of variables associated with mortality in patients with various forms of chronic precapillary pulmonary hypertension Variable Odds Ratio 95% Confidence Interval p Value Peak oxygen uptake Heart rate Systolic blood pressure Right atrial pressure Mixed venous oxygen saturation NT pro-bnp Treatment with epoprostenol or nifedipine: Among the 17 patients with IPAH or PAH associated with other diseases treated with epoprostenol or nifedipine, 2 patients died before reaching their 3-month control. Between the 3- and 12-month controls, 1 patient received a liver transplant after acceptable reduction of portal PAH with epoprostenol and postoperative withdrawal. Epoprostenol was also tapered and withdrawn postoperatively in 1 patient after the successful closure of an atrial septal defect with an Amplatzer device (AGA Medical Corporation, Golden Valley, Minnesota). For the remaining patients, peak oxygen uptake improved to 56 15% and pulmonary vascular resistance was reduced by 58 12% after 12 months. As shown in Figure 2, levels of NT pro-bnp were significantly reduced between baseline and 3 months, with sustained effects also seen after 12 months of treatment. The reduction in natriuretic peptide levels was correlated with the reduction of pulmonary vascular resistance (r 0.55, p 0.041). The 3 patients whose NT pro-bnp levels normalized were those using nifedipine because of adequate responses to acute vasoreactivity testing at right-sided cardiac catheterization. Patient characteristics in survivors and nonsurvivors: During a mean follow-up of months (range 1 to 60), 15 patients died, all from cardiopulmonary causes (3 with IPAH, 9 with associated forms of chronic precap-

4 528 The American Journal of Cardiology ( A receiver-operating characteristic analysis indicated that NT pro-bnp had reasonable accuracy for predicting mortality in patients with chronic precapillary PH, with comparable values for peak oxygen uptake (Figure 3). Combining these 2 risk factors did not provide additional prognostic information. The Kaplan-Meier survival curves grouped according to the median value of NT pro-bnp demonstrated that patients with supramedian values had significantly lower survival than those with lower levels of NT pro-bnp (Figure 4). Three patients were bilateral lung transplant (n 1) or liver transplant (n 2) recipients. Defining urgent transplantation as an end point did not statistically alter the results of our survival analysis. Figure 3. Receiver-operating characteristic curves of NT pro-bnp and peak oxygen uptake predicting mortality in patients with various forms of chronic precapillary PH. The area under the curve (AUC) was 0.75 (95% confidence interval 0.62 to 0.88, p 0.004) for NT pro-bnp and 0.77 (95% confidence interval 0.59 to 0.95, p 0.012) for peak oxygen uptake. Figure 4. Kaplan-Meier cumulative survival curves according to the median value of NT pro-bnp for 61 patients with various forms of chronic precapillary PH. illary PH, and 3 with chronic thromboembolic PH). In addition to the observed differences in levels of NT pro- BNP between the 2 groups, a significantly more advanced NYHA functional class and significantly smaller peak oxygen uptake were observed in nonsurvivors compared with survivors (Table 1). Furthermore, a significantly higher heart rate and right atrial pressure, together with significantly lower mixed venous oxygen saturation and systolic systemic blood pressure, were evident in the former group. Of significant univariate variables of survival, only plasma NT pro-bnp and peak oxygen uptake were independent predictors of mortality in patients with various forms of chronic precapillary PH by multivariate analysis (Table 2). Discussion In the present study, we included patients with various forms of chronic precapillary PH and demonstrated that NT pro-bnp is (1) enhanced across the spectrum of symptomatic patient groups, (2) closely related to hemodynamics and functional capacity, (3) an independent predictor of mortality on multivariate analysis, and (4) decreased in survivors treated medically. These results suggest that plasma NT pro-bnp levels increase in proportion to the clinical severity of chronic precapillary PH and have a strong, independent association with long-term mortality in a heterogenous group of these patients. Previous studies have shown increased levels of BNP or NT pro-bnp in symptomatic patients with PH of the idiopathic form of the disease, 3 associated with acute and chronic thromboembolism, 6,7 scleroderma, 8 and lung fibrosis. 9 Assessing patients with different backgrounds of rightsided cardiac strain, these same studies were able to demonstrate relations between levels of natriuretic peptides and the degree of right ventricular dysfunction. Only the investigation by Nagaya et al 3 included data on survival and established BNP as a possible prognostic indicator in IPAH. With a follow-up period comparable with ours, the group with supramedian levels of BNP had a significantly lower survival rate than those with low plasma levels. Because of co-morbid factors and various backgrounds of disease, it has been warned against the extrapolation of recommendations on assessing prognosis in patients with IPAH to those with chronic precapillary PH due to various conditions. 10 However, our findings suggest that BNP and NT pro-bnp may serve as markers of prognosis also in a more heterogenous cohort of such patients, broadening the potential use of natriuretic peptides in chronic precapillary PH. Although hemodynamic variables known to be of prognostic value in patients with IPAH also demonstrated such relevance in univariate analysis in our patients, exercise capacity was the only other parameter that independently predicted survival in multivariate analysis. Thus, although right-sided cardiac catheterization data at rest gave prognostic information in the present study, these invasive mea-

5 Miscellaneous/NT Pro-BNP in Chronic Precapillary Pulmonary Hypertension 529 surements did not add to the prognostic accuracy obtained by levels of NT pro-bnp and peak oxygen uptake. Exercise testing has previously been shown to be an excellent predictor of survival in patients with IPAH. 11 We were unable to show that combining the information obtained from measuring NT pro-bnp levels and peak oxygen uptake improved the prediction of survival compared with just 1 of either parameter. However, because we could not assess functional capacity in the sickest and most unstable patients, we cannot rule out that such a strategy would be superior in risk stratification. The reduction of NT pro-bnp levels on long-term treatment with epoprostenol or calcium channel blockers indicates natriuretic peptides potential in the monitoring of therapy. The number of patients treated with vasodilators in our group was too small to demonstrate sustained predictive value of NT pro-bnp levels after the initiation of treatment. However, renewed analysis of BNP was previously performed in 53 patients with IPAH receiving prostacyclin, with improved prediction of survival compared with pretreatment evaluation. 3 Consistent with that study, changes in NT pro-bnp in our treated patients were correlated with changes in pulmonary vascular resistance. Thus, reducing resistance using drugs with vasodilatory and/or antiproliferative properties, with lowering of NT pro-bnp levels because of improved right ventricular function, is in line with the view of BNP as a biochemical marker of ventricular overload. Interestingly, patients with the most pronounced response to acute vasoreactivity testing before the introduction of medical treatment demonstrated the normalization of NT pro-bnp levels at 3- and 12-month followup. This supports the view of our 3 users of nifedipine as true responders and is in accordance with their described good prognoses Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature 1988;332: de Lemomos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular medicine. Lancet 2003;362: Nagaya N, Nishikimi T, Uematsu E, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K, Okano Y, Nakanishi N, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000;102: Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107: Olschewski H, Walmrath D, Schermuly, Ghofrani A, Grimminger E, Seeger W. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med 1996;124: Tulevski II, Hirsch A, Sanson B-J, Romkes H, van der Wall EE, van Veldhuisen DJ, Büller HR, Mulder BJM. Increased brain natriuretic peptide as a marker for right ventricular dysfunction in acute pulmonary embolism. Thromb Haemost 2001;86: Nagaya N, Ando M, Oya H, Nakanishi N. Plasma brain natriuretic peptide as a non-invasive marker for efficacy of pulmonary thromboendarterectomy. Ann Thorac Surg 2002;74: Mukerjee D, Yap LB, Holmes AM, Nair D, Ayrton P, Black CM, Coghlan JG. Significance of plasma N-terminal pro-brain natriuretic peptide in patients with systemic sclerosis-related pulmonary arterial hypertension. Respir Med 2003;97: Leuchte NN, Neurohr C, Baumgartner RA, Holzapfel M, Giehrl W, Vogeser M, Behr J. Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2004;170: McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahern G. Prognosis of pulmonary arterial hypertension. ACCP evidence-based clinical practice guidelines. Chest 2004;126: 78S 92S. 11. Wensel R, Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, Sharma R, Hummel M, Hetzer R, Ewert R. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation 2002;106: Rich S, Kaufmann E, Levy PS. The effect of high doses of calciumchannel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76 81.