Plasma Brain Natriuretic Peptide as a Noninvasive Marker for Efficacy of Pulmonary Thromboendarterectomy

Plasma Brain Natriuretic Peptide as a Noninvasive Marker for Efficacy of Pulmonary Thromboendarterectomy Noritoshi Nagaya, MD, Motomi Ando, MD, Hideo Oya, MD, Yutaka Ohkita, MD, Shingo Kyotani, MD, Fumio Sakamaki, MD, and Norifumi Nakanishi, MD Departments of Internal Medicine and Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan Background. Plasma brain natriuretic peptide (BNP), a cardiac hormone secreted mainly by the cardiac ventricles, has been shown to increase in proportion to the degree of cardiac overload. However, whether plasma BNP may serve as a marker for the efficacy of pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension remains unknown. Methods. Plasma BNP level was measured in 34 patients with chronic thromboembolic pulmonary hypertension before and 1 month after pulmonary thromboendarterectomy. Right heart catheterization was also performed before and 1 month after the operation. Results. Preoperative plasma BNP level was significantly elevated in patients with chronic thromboembolic pulmonary hypertension compared with control patients (246 40 vs 13 2 pg/ml; p < 0.001; n 34) and was positively correlated with total pulmonary resistance (r 0.57; p < 0.001). After pulmonary thromboendarterectomy, plasma BNP level in survivors markedly decreased (220 31 to 54 9 pg/ml; p < 0.001; n 32) in association with a reduction of total pulmonary resistance (15.6 1.0 to 4.5 0.3 Wood units; p < 0.001). The change in plasma BNP level was closely correlated with that in total pulmonary resistance (r 0.63; p < 0.001). Importantly, a sustained elevation of plasma BNP (> 50 pg/ml) indicated the presence of residual pulmonary hypertension (> 5 Wood units) after operation (sensitivity 73%; specificity 81%). Conclusions. Plasma BNP level was strongly associated with the severity of pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension and thereby may serve as a noninvasive marker for the efficacy of pulmonary thromboendarterectomy. (Ann Thorac Surg 2002;74:180 4) 2002 by The Society of Thoracic Surgeons Chronic thromboembolic pulmonary hypertension (CTEPH) is the result of chronic obstruction of the pulmonary arteries by thrombi [1]. These obstructed pulmonary arteries contribute to the development of pulmonary hypertension, which ultimately leads to right heart failure and death. Earlier studies have shown that pulmonary thromboendarterectomy strikingly decreases pulmonary vascular resistance and improves survival in patients with major-vessel CTEPH [2 4]. Nevertheless, operative mortality rates are relatively high, and inadequate hemodynamic improvement is observed in some patients with CTEPH [3 5]. Thus noninvasive assessment of the efficacy of pulmonary thromboendarterectomy would be desirable in the management of CTEPH patients after operation. Plasma brain natriuretic peptide (BNP), a cardiac hormone secreted mainly by the cardiac ventricles [6, 7], has been used as a noninvasive marker of left ventricular dysfunction and a prognostic indicator in a variety of Accepted for publication March 30, 2002. Address reprint requests to Dr Nagaya, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan; e-mail: nagayann@hsp.ncvc.go.jp. patients with left-sided heart failure [8, 9]. Recently we have shown that plasma BNP level increases in proportion to the degree of pulmonary hypertension and right ventricular dysfunction [10, 11]. However, whether plasma BNP may serve as a marker for the efficacy of pulmonary thromboendarterectomy in patients with CTEPH remains unknown. Thus in the present study, we measured plasma BNP levels before and 1 month after pulmonary thromboendarterectomy. The purposes of this study were investigate the following: (1) whether preoperative plasma BNP level is elevated in relation to disease severity in patients with CTEPH, (2) whether plasma BNP level decreases in association with hemodynamic improvement after pulmonary thromboendarterectomy, and (3) whether postoperative plasma BNP level can identify residual pulmonary hypertension after operation, thereby serving as a potential marker for the efficacy of thromboendarterectomy in patients with CTEPH. Material and Methods Study Patients This study included 34 patients with CTEPH (13 men and 21 women; mean age, 49 years; age range, 22 to 64 years) who underwent pulmonary thromboendarterectomy 2002 by The Society of Thoracic Surgeons 0003-4975/02/$22.00 Published by Elsevier Science Inc PII S0003-4975(02)03654-8 26

Ann Thorac Surg NAGAYA ET AL 2002;74:180 4 PLASMA BNP AND PULMONARY THROMBOENDARTERECTOMY 181 from January 1996 to October 2000. The preoperative condition was New York Heart Association functional class III (n 27) or IV (n 7). The diagnosis of CTEPH was made on the basis of the previously reported procedure [12]. In brief, patients with clinical symptoms suggesting CTEPH underwent ventilation and perfusion lung scanning to detect pulmonary perfusion defects. The diagnosis was confirmed by pulmonary angiography. All patients had occlusion and stenosis from the lobar to segmental arteries [13]. Cardiac catheterization was performed to confirm pre-capillary pulmonary hypertension (mean pulmonary arterial pressure 30 mm Hg with pulmonary capillary wedge pressure 12 mm Hg). All patients received anticoagulation therapy before and after pulmonary thromboendarterectomy. Vasodilators such as prostacyclin or its analogue and calcium antagonists were used in 22 patients. Medications were not significantly changed before and after operation, except vasodilators, which were discontinued because of significant improvement in pulmonary hypertension. The study included 12 age-matched control patients (5 men and 7 women; mean age, 50; age range, 29 to 67 years). All patients gave written informed consent. Hemodynamic Studies Right heart catheterization was performed in all 34 patients before pulmonary thromboendarterectomy. In addition, catheterization was repeated in 32 patients 1 month after operation because of 2 operative deaths. Hemodynamic variables including mean pulmonary arterial pressure, mean right atrial pressure, and mean pulmonary wedge pressure were measured. Cardiac output was determined by Fick s method [14]. Total pulmonary resistance was calculated by dividing mean pulmonary arterial pressure by cardiac output. Right ventricular and left ventricular ejection fraction at base line was determined in 30 patients using electron-beam computed tomography, as reported previously [10]. Blood Sampling and Assay Blood samples for base line measurements were drawn from a peripheral vein in all 34 patients at diagnostic catheterization when the patient was in a stable hemodynamic state. Blood sampling was repeated in 32 patients 1 month after pulmonary thromboendarterectomy. Blood was immediately transferred into a chilled glass tube containing disodium ethylenediaminete-traacetic acid (1 mg/ml) and aprotinin (500 U/mL) and centrifuged immediately at 4 C, and then the plasma was frozen and stored at 80 C until assay. Plasma BNP level was measured directly with a specific immunoradiometric assay kit (Shiono RIA BNP Assay Kit; Shionogi Co, Ltd, Osaka, Japan) [8]. Pulmonary Thromboendarterectomy Pulmonary thromboendarterectomy was performed through two separate arteriotomies on both main intrapericardial pulmonary arteries following the standard technique described previously [3, 15]. Table 1. Clinical and Hemodynamic Parameters Before and After Pulmonary Thromboendarterectomy Before After p Value a New York Heart 3.2 0.1 1.8 0.1 0.001 Association functional class No. of deaths NA 2 NA Hemodynamics Heart rate, bpm 77 2 76 2 NS Mean systemic arterial 86 1 85 2 NS pressure (mm Hg) Mean pulmonary 46 2 19 1 0.001 artery pressure (mm Hg) Cardiac output (L/min) 3.2 0.1 4.5 0.2 0.001 Total pulmonary 15.6 1.0 4.4 0.3 0.001 resistance (Wood units) Pulmonary capillary 8 1 7 1 NS wedge pressure (mm Hg) Mean right arterial 5 1 3 1 0.01 pressure (mm Hg) Gas exchange SaO 2 (%) 90 1 95 1 0.001 SvO 2 (%) 58 2 69 1 0.001 Medication use Anticoagulant agents 34 32 NS Digitalis 14 14 NS Diuretics 17 15 NS Prostacyclin or its 18 5 0.001 analogue Calcium antagonists 4 2 NS a p 0.05 versus before operation. NA not applicable; NS not significant; SaO 2 arterial oxygen pressure; SvO 2 mixed venous oxygen saturation. Statistical Analysis All data were expressed as mean value standard error of the mean. Log transformation was used to normalize the distribution of plasma BNP level unless otherwise indicated. Comparisons of measurements between two groups were made by unpaired Student s t test. Comparisons of measurements among three groups were made by one-way analysis of variance, followed by the Scheffe s multiple comparison test. Changes in clinical and hemodynamic measurements by thromboendarterectomy were compared by paired Student s t test (Table 1). Correlation coefficients between hemodynamic measurements and plasma BNP level were determined by linear regression analysis. A p value less than 0.05 was considered statistically significant. Results Elevation of Preoperative Plasma BNP Level in Patients With CTEPH Preoperative plasma BNP level was significantly elevated in patients with CTEPH compared with control patients

182 NAGAYA ET AL Ann Thorac Surg PLASMA BNP AND PULMONARY THROMBOENDARTERECTOMY 2002;74:180 4 Fig 1. Preoperative plasma brain natriuretic peptide (BNP) level in patients with chronic thromboembolic pulmonary hypertension according to New York Heart Association (NYHA) functional classes. *p less than 0.05 versus controls; p less than 0.05 versus NYHA functional class III. Fig 3. Change in plasma brain natriuretic peptide (BNP) level by pulmonary thromboendarterectomy. (Post postoperative; Pre preoperative.) Fig 2. Relationship between preoperative plasma brain natriuretic peptide (BNP) level and total pulmonary resistance in patients with chronic thromboembolic pulmonary hypertension. (246 40 vs 13 2 pg/ml, p 0.001). Plasma BNP level increased significantly with the severity of New York Heart Association functional class (Fig 1). Preoperative pulmonary arterial pressure (r 0.37; p 0.05) and negatively with cardiac output (r 0.57; p 0.001), thus showing a strong positive correlation with total pulmonary resistance (r 0.57; p 0.001) (Fig 2). Preoperative right atrial pressure (r 0.40; p 0.05) but not with pulmonary capillary wedge pressure (r 0.28; p NS). Preoperative right ventricular ejection fraction was markedly decreased (30% 2%), whereas left ventricular ejection fraction was preserved (63% 2%). Plasma BNP level was inversely correlated with right ventricular ejection fraction (r 0.53; p 0.01), although it was not significantly correlated with left ventricular ejection fraction (r 0.21; p not significant). Reduction of Plasma BNP Level After Pulmonary Thromboendarterectomy Pulmonary thromboendarterectomy markedly decreased total pulmonary resistance in patients with CTEPH (15.6 1.0 to 4.5 0.3 Wood units, p 0.001). Plasma BNP level also markedly decreased after operation (220 31 to 54 9 pg/ml; p 0.001) (Fig 3). The decrease in plasma BNP level was closely correlated with the decrease in total pulmonary resistance after thromboendarterectomy (r 0.63, p 0.001) (Fig 4). Postoperative pulmonary arterial pressure (r 0.33, p 0.05), total pulmonary resistance (r 0.45, p 0.01), and mean right atrial pressure (r 0.43, p 0.01), although it was not significantly correlated with cardiac output (r 0.27; p not significant) or pulmonary capillary wedge pressure (r 0.26, p not significant). Interestingly, 1 patient had an increase in his levels between preoperative and postoperative examination. He had severe pericardial effusion and high right atrial pressure (14 mm Hg) after operation.

Ann Thorac Surg NAGAYA ET AL 2002;74:180 4 PLASMA BNP AND PULMONARY THROMBOENDARTERECTOMY 183 Fig 4. Relationship between change in plasma brain natriuretic peptide (BNP) level and change in total pulmonary resistance by pulmonary thromboendarterectomy. Sustained Elevation of Plasma BNP Level in Patients With Residual Pulmonary Hypertension After One month after pulmonary thromboendarterectomy, residual pulmonary hypertension ( 5 Wood units) was observed in 11 patients with CTEPH. Postoperative plasma BNP level was significantly higher in these patients with residual pulmonary hypertension than in those without (92 20 vs 32 4 pg/ml; p 0.001). Interestingly, a sustained elevation of plasma BNP ( 50 pg/ml) indicated the presence of residual pulmonary hypertension with sensitivity of 73% and specificity of 81%. Comment In the present study, we demonstrated that (1) preoperative plasma BNP level increased with disease severity of CTEPH, (2) plasma BNP level decreased in association with a reduction of total pulmonary resistance by pulmonary thromboendarterectomy, and (3) a sustained elevation of postoperative BNP level indicated the presence of residual pulmonary hypertension after operation. Pulmonary thromboendarterectomy has been shown to improve hemodynamic status and survival in patients with CTEPH [2 4]. However, this procedure does not always result in normalized pulmonary vascular resistance, most likely caused by superimposed peripheral thromboembolic disease. Inadequate reduction of pulmonary vascular resistance may limit the quality of life and prognosis of patients after operation. Thus it is important to assess the degree of hemodynamic improvement by pulmonary thromboendarterectomy in patients with CTEPH. In the present study, preoperative plasma BNP level was markedly elevated in patients with CTEPH (19 times the controls). In addition, plasma BNP level was positively correlated with total pulmonary resistance. These results suggest that plasma BNP level reflects the disease severity in patients with CTEPH. Considering that BNP is secreted predominantly from the cardiac ventricles through a constitutive pathway in association with the degree of myocardial stretch, damage, and ischemia [6, 7, 16], increased secretion of BNP may be attributable to right ventricular overload caused by pulmonary hypertension. To investigate whether plasma BNP level can be used as a noninvasive marker for the efficacy of thromboendarterectomy, we measured preoperative and postoperative BNP levels in patients with CTEPH. Expectedly, successful pulmonary thromboendarterectomy markedly decreased total pulmonary resistance. Plasma BNP level also decreased 1 month after operation. Furthermore, the decrease in plasma BNP level was closely correlated with the reduction of total pulmonary resistance by pulmonary thromboendarterectomy. It is possible that a decrease in pulmonary vascular resistance may attenuate increased wall stress in the right ventricle, resulting in the reduction of BNP secretion in patients with CTEPH. Thus plasma BNP may serve as a noninvasive marker for the efficacy of pulmonary thromboendarterectomy. Residual pulmonary hypertension is one of the most important risk factors for death in patients with CTEPH. In the present study, a sustained elevation of plasma BNP level was observed in 10 patients with residual pulmonary hypertension after operation. Interestingly, a sustained elevation of plasma BNP ( 50 pg/ml) indicated the presence of residual pulmonary hypertension ( 5 Wood units) with high sensitivity and specificity. These results suggest that postoperative plasma BNP level may be helpful to detect inadequate hemodynamic improvement after operation. Measurement of plasma BNP is simple, noninvasive, and relatively inexpensive. Preoperative plasma BNP level may be a marker for disease severity in patients with CTEPH. The difference between preoperative and postoperative BNP levels may reflect improvement in pulmonary hemodynamics. A second measurement of plasma BNP level may identify residual pulmonary hypertension. Thus repeated measurements of plasma BNP level may complement invasive hemodynamic markers in evaluation of the efficacy of pulmonary thromboendarterectomy in patients with CTEPH. In conclusion, plasma BNP level was strongly associated with the severity of pulmonary hypertension in patients with CTEPH and thereby may serve as a noninvasive marker for the efficacy of pulmonary thromboendarterectomy. This work was supported in part by the research grant for cardiovascular disease (12C-2) from the Ministry of Health, Labor and Welfare, Osaka, Japan, the Uehara Memorial Foundation, Tokyo, Japan, and a grant from the Japan Cardiovascular Research Foundation, Osaka, Japan.

184 NAGAYA ET AL Ann Thorac Surg PLASMA BNP AND PULMONARY THROMBOENDARTERECTOMY 2002;74:180 4 References 1. Benotti JR, Dalen JE. The natural history of pulmonary embolism. Clin Chest Med 1984;5:403 10. 2. Moser KM, Auger WR, Fedullo PF. Chronic major vessel thrombo-embolic pulmonary hypertension. Circulation 1990;81:1735 43. 3. Jamieson SW, Auger WR, Fedullo PF, et al. Experienced results with 150 pulmonary thromboendarterectomy operations over a 29-month period. J Thorac Cardiovasc Surg 1993; 106:116 27. 4. Archibald CJ, Auger WR, Fedullo RN, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999;160:523 8. 5. Tscholl D, Langer F, Wendler O, et al. Pulmonary thromboendarterectomy risk factors for early survival, and hemodynamic improvement. Eur J Cardiothorac Surg 2001;19: 771 6. 6. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature 1988;332:78 81. 7. Mukoyama M, Nakao K, Saito Y, et al. 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Circulation 1995; 92:1558 64. INVITED COMMENTARY Pulmonary thromboendarterectomy has been shown to be a very effective treatment option for patients with thromboembolic pulmonary hypertension. It drastically reduces pulmonary vascular resistance and markedly improves right ventricular function and exercise ability. Despite increasing experience, a number of questions remain in conjunction with this operation. Patient selection for this treatment as opposed to lung transplantation still involves subjective decision criteria. The early postoperative course is characterized by marked hemodynamic instability and increased vasopressor support, indicating the action of systemic factors such as cytokines that in this disease appear to have a more pronounced effect than in other areas of cardiac surgery. The exact pathomechanism still needs to be elucidated. While PTE has obvious advantages over lung transplantation, only limited long-term data have been published after surgical desobliteration of the pulmonary arterial tree. The information that is available is mostly limited to survival and NYHA stage which are very crude parameters. In the process of generating hemodynamic follow-up data, we have in some patients found a marked discrepancy between persistent pulmonary hypertension and their (subjective) NYHA class. Thus, more objective (and possibly non-invasive parameters) are needed. The current investigation by Nagaya and coworkers is one step in this direction. It still leaves a number of questions. In view of the correlation between BNP and pulmonary artery pressure and resistance, could it be used as a prognostic indicator in preoperative decisionmaking? What are the reasons for the limited sensitivity and specificity of BNP as a predictor for persistent PHT? How marked would the effect of concomitant left heart failure be? Much more information will be needed until we understand the physiology of the disease better, which will hopefully aid us in choosing our treatment options better and refine them further. Hans-Joachim Schäfers, MD Department of Thoracic and Cardiovascular Surgery University of Saarland Kirrberger Str. Homburg/Saar D-66421, Germany 2002 by The Society of Thoracic Surgeons 0003-4975/02/$22.00 Published by Elsevier Science Inc PII S0003-4975(02)03750-526