Prostacyclin Therapy Before Pulmonary Thromboendarterectomy in Patients With Chronic Thromboembolic Pulmonary Hypertension*

clinical investigations Prostacyclin Therapy Before Pulmonary Thromboendarterectomy in Patients With Chronic Thromboembolic Pulmonary Hypertension* Noritoshi Nagaya, MD; Noriko Sasaki, MD; Motomi Ando, MD; Hitoshi Ogino, MD; Fumio Sakamaki, MD; Shingo Kyotani, MD; and Norifumi Nakanishi, MD

Objectives: The continuous IV administration of prostacyclin improves pulmonary hemodynamics and prognosis in patients with primary pulmonary hypertension. We investigated whether the administration of prostacyclin therapy to patients before they undergo pulmonary thromboendarterectomy ameliorates pulmonary hypertension in patients with the most severe form of chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Of the 33 patients with CTEPH who were candidates for pulmonary thromboendarterectomy, 12 patients with severe pulmonary hypertension (pulmonary vascular resistance, > 1,200 dyne 䡠 s 䡠 cmⴚ5) received IV prostacyclin prior to undergoing pulmonary thromboendarterectomy. Right heart catheterization and plasma brain natriuretic peptide (BNP) measurements were repeated at baseline, immediately before surgery, and 1 month after surgery. Results: During a mean (ⴞ SEM) follow-up period of 46 ⴞ 12 days, the IV administration of prostacyclin resulted in a 28% decrease in pulmonary vascular resistance (1,510 ⴞ 53 to 1,088 ⴞ 58 dyne 䡠 s 䡠 cmⴚ5; p < 0.001) before surgery. Prostacyclin therapy markedly decreased plasma BNP level (547 ⴞ 112 to 188 ⴞ 30 pg/mL; p < 0.01), suggesting improvement in right heart failure. Pulmonary thromboendarterectomy caused a further reduction of pulmonary vascular resistance (302 ⴞ 47 dyne 䡠 s 䡠 cmⴚ5) and plasma BNP levels (60 ⴞ 11 pg/mL) compared to each preoperative value (p < 0.05). Operative mortality rates were relatively low (8.3%) in patients with the most severe form of CTEPH. Conclusion: The IV administration of prostacyclin caused beneficial hemodynamic effects in patients with severe CTEPH and may serve as pretreatment for patients undergoing pulmonary thromboendarterectomy. (CHEST 2003; 123:338 –343) Key words: prostacyclin; pulmonary hypertension; pulmonary thromboendarterectomy; pulmonary thromboembolism Abbreviations: BNP ⫽ brain natriuretic peptide; CTEPH ⫽ chronic thromboembolic pulmonary hypertension; NYHA ⫽ New York Heart Association

thromboembolic pulmonary hypertenC hronic sion (CTEPH) is the result of chronic obstruction of the pulmonary arteries by thrombi.1 These *From the Departments of Internal Medicine (Drs. Nagaya, Sasaki, Sakamaki, Kyotani, and Nakanishi) and Cardiovascular Surgery (Drs. Ando and Ogino), National Cardiovascular Center, Osaka, Japan. This work was supported by Grant From Japan Cardiovascular Research Foundation and the Uehara Memorial Foundation. Manuscript received November 19, 2001; revision accepted May 16, 2002. Correspondence to: Noritoshi Nagaya, MD, Department of Internal Medicine, National Cardiovascular Center, 5–7-1 Fujishirodai, Suita, Osaka 565-8565, Japan; e-mail: [email protected] 338

obstructed pulmonary arteries contribute to the development of pulmonary hypertension, which ultimately leads to right heart failure and death. Earlier studies2– 4 have shown that pulmonary thromboendarterectomy strikingly decreases pulmonary vascular resistance and improves survival in patients with For editorial comment see page 319 major-vessel CTEPH. Nevertheless, operative mortality rates are relatively high in the most severe form of CTEPH.5,6 In fact, patients with severe pulmoClinical Investigations

nary hypertension (ie, mean pulmonary arterial pressure, ⬎ 50 mm Hg; pulmonary vascular resistance, ⬎ 1,100 dyne 䡠 s 䡠 cm⫺5) have been shown to experience sixfold higher operative mortality compared to those with mild pulmonary hypertension.5 Thus, a reduction in pulmonary vascular resistance would be desirable prior to patients undergoing pulmonary thromboendarterectomy. Prostacyclin produces strong vasodilation and inhibition of platelet aggregation and vascular smooth muscle cell proliferation.7,8 Some studies have shown that the continuous IV infusion of prostacyclin markedly lowers pulmonary vascular resistance and improves survival in patients with precapillary pulmonary hypertension conditions such as primary pulmonary hypertension9,10 and collagen vascular diseases.11 As a result, prostacyclin therapy has become recognized as a therapeutic breakthrough in patients with severe pulmonary hypertension. However, whether IV prostacyclin therapy may attenuate pulmonary hypertension in patients with majorvessel CTEPH remains unknown. The preoperative improvement in pulmonary hemodynamics would result in a beneficial surgical outcome in CTEPH patients after they undergo pulmonary thromboendarterectomy. Thus, the purpose of this study was to investigate whether the IV administration of prostacyclin ameliorates pulmonary hypertension in patients with the most severe form of CTEPH before they undergo pulmonary thromboendarterectomy.

Materials and Methods Study Patients This study included 33 consecutive patients with CTEPH (11 men and 22 women; mean age, 54 years; age range, 22 to 76 years) who had undergone pulmonary thromboendarterectomy from December 1998 to October 2001. The preoperative condition was New York Heart Association (NYHA) functional class III or IV. Twelve patients who had a pulmonary vascular resistance of ⬎ 1,200 dyne 䡠 s 䡠 cm⫺5 at diagnostic catheterization received IV prostacyclin before undergoing pulmonary thromboendarterectomy (prostacyclin group). The remaining 21 patients with a pulmonary vascular resistance of ⱕ 1,200 dyne 䡠 s 䡠 cm⫺5 were treated with conventional therapy alone (conventional group). 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/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 precapillary pulmonary hypertension (mean pulmonary arterial pressure, ⬎ 30 mm Hg; pulmonary capillary wedge pressure, ⬍ 12 mm Hg). All subjects gave written informed consent. www.chestjournal.org

Prostacyclin Therapy and Other Medication Prostacyclin therapy was begun at a dose of 2 ng/kg/min and was increased with increments of 1 ng/kg/min over 1 week prior to patients undergoing pulmonary thromboendarterectomy (mean [⫾ SEM] dose, 6 ⫾ 1 ng/kg/min; dose range, 2 to 11 ng/kg/min). The mean duration of prostacyclin therapy immediately before pulmonary thromboendarterectomy was 46 ⫾ 12 days. Pulmonary thromboendarterectomy was performed through two separate arteriotomies on both main intrapericardial pulmonary arteries following the standard technique, which has been described previously.3,14 The infusion of prostacyclin was discontinued while patients were receiving cardiopulmonary bypass. Prostacyclin therapy was restarted at the preoperative dose immediately after the patient was weaned from cardiopulmonary bypass. After surgery, the dose of prostacyclin was gradually reduced, and it was discontinued within 1 week after surgery. Anticoagulation therapy was continued in all patients before and after surgery. Other medications such as digitalis and diuretics were not significantly changed before and after surgery. Hemodynamic Studies Baseline right heart catheterization was performed in all patients (33 patients) during hospitalization. Immediately before and 1 month after patients underwent pulmonary thromboendarterectomy, right heart catheterization was repeated in 31 patients (prostacyclin group, 11 patients; conventional group, 20 patients). Hemodynamic variables, including mean pulmonary artery pressure, mean right atrial pressure, and mean pulmonary wedge pressure, were measured. Cardiac output was determined by the Fick method.15 Pulmonary vascular resistance was calculated using the standard formulas. Blood Sampling and Assay Blood samples were taken from the antecubital vein in all patients at baseline, immediately before undergoing surgery, and 1 month after undergoing pulmonary thromboendarterectomy. Blood was immediately transferred into a chilled glass tube containing disodium ethylenediaminetetraacetic acid (1 mg/mL) and aprotinin (500 U/mL), and was centrifuged immediately at 4°C. The plasma was frozen and stored at ⫺80°C until assay. For the noninvasive assessment of right ventricular function, the plasma brain natriuretic peptide (BNP) level was measured directly with a specific immunoradiometric assay kit (Shiono RIA BNP assay kit; Shionogi Co, Ltd; Osaka, Japan).16,17 The investigators collecting the BNP data were blinded to treatment. Data Analysis All data were expressed as the mean ⫾ SEM. Comparisons of parameters between two groups were made by Fisher exact test or unpaired Student t test. Changes in clinical and hemodynamic parameters during prostacyclin therapy were compared by paired Student t test. Comparisons of the time course of pulmonary vascular resistance and plasma BNP level between the two groups were made by two-way analysis of variance for repeated measures, followed by a Scheffe multiple comparison test. A p value of ⬍ 0.05 was considered to be statistically significant.

Results Characteristics of Patients With and Without Prostacyclin Therapy There was no significant difference in age or sex between the prostacyclin group and the conventional CHEST / 123 / 2 / FEBRUARY, 2003

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Table 1—Characteristics of Patients With and Without Prostacyclin*

Characteristics Age, yr Sex Male Female NYHA functional class III IV Hemodynamics Heart rate, beats/min mSAP, mm Hg mPAP, mm Hg CO, L/min PVR, dyne 䡠 s 䡠 cm⫺5 RAP, mm Hg PCWP, mm Hg Pulmonary function SaO2, % Sv៮ o2, % FVC, % predicted FEV1, % predicted Medication Anticoagulant agents Digitalis Diuretics

Prostacyclin Group (n ⫽ 12)

Conventional Group (n ⫽ 21)

p Value

55 ⫾ 4

53 ⫾ 3

NS

5 7

6 15

NS

5 7

20 1

⬍ 0.05 ⬍ 0.05

85 ⫾ 3 88 ⫾ 3 53 ⫾ 2 2.3 ⫾ 0.1 1631 ⫾ 136 7⫾1 7⫾1

76 ⫾ 2 87 ⫾ 2 44 ⫾ 2 3.5 ⫾ 0.2 893 ⫾ 49 4⫾1 6⫾1

⬍ 0.05 NS ⬍ 0.05 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 NS

88 ⫾ 1 51 ⫾ 2 93 ⫾ 5 72 ⫾ 4

92 ⫾ 1 64 ⫾ 1 94 ⫾ 3 75 ⫾ 2

⬍ 0.05 ⬍ 0.001 NS NS

12 4 9

21 9 5

NS NS ⬍ 0.05

*Values given as No. or mean ⫾ SEM. CO ⫽ cardiac output; mSAP ⫽ mean systemic arterial pressure; mPAP ⫽ mean pulmonary arterial pressure; PVR ⫽ pulmonary vascular resistance; RAP ⫽ right atrial pressure; PCWP ⫽ pulmonary capillary wedge pressure; Sao2 ⫽ arterial oxygen saturation; Sv៮ o2 ⫽ mixed venous oxygen saturation; NS ⫽ not significant.

Hemodynamic Effects of Prostacyclin Therapy Before Pulmonary Thromboendarterectomy The IV administration of prostacyclin tended to decrease the mean pulmonary arterial pressure (before administration, 51 ⫾ 2 mm Hg; after administration, 47 ⫾ 2 mm Hg; difference not significant) [Fig 1] and significantly increased cardiac output (before administration, 2.3 ⫾ 0.1 L/min; after administration, 3.1 ⫾ 0.2 L/min; p ⬍ 0.01). Thus, prostacyclin therapy resulted in a 28% decrease in pulmonary vascular resistance (before therapy, 1,510 ⫾ 53 dyne 䡠 s 䡠 cm⫺5; after therapy, 1,088 ⫾ 58 dyne 䡠 s 䡠 cm⫺5; p ⬍ 0.001) before pulmonary thromboendarterectomy. In addition, IV prostacyclin therapy significantly decreased mean right atrial pressure (before therapy, 7 ⫾ 1 mm Hg; after therapy, 4 ⫾ 1 mm Hg; p ⬍ 0.05). There was no significant change in heart rate (before therapy, 85 ⫾ 3 beats/min; after therapy, 82 ⫾ 2 beats/min), mean systemic arterial pressure (before therapy, 88 ⫾ 3; after therapy, 87 ⫾ 3 mm Hg), or pulmonary capillary wedge pressure (before therapy, 7 ⫾ 1 mm Hg; after therapy, 6 ⫾ 1 mm Hg). Pulmonary arterial oxygen saturation significantly increased during prostacyclin therapy (before therapy, 51 ⫾ 2%; after therapy, 56 ⫾ 1%; p ⬍ 0.01), although systemic arterial oxygen saturation was not significantly altered (before therapy, 88 ⫾ 1%; after therapy, 88 ⫾ 1%). These parameters remained unchanged in the conventional group. Time Course of Plasma BNP Level in Patients With and Without Prostacyclin Therapy

group (Table 1). NYHA functional class was significantly higher in the prostacyclin group than in the conventional group. Baseline heart rate, mean pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure were significantly higher in the prostacyclin group than in the conventional group. Cardiac output, arterial oxygen saturation, and mixed venous oxygen saturation were significantly lower in the prostacyclin group than in the conventional group. There was no significant difference between the two groups in the use of the medications except for diuretics and prostacyclin.

The baseline plasma BNP level was markedly higher in the prostacyclin group than in the conventional group (547 ⫾ 112 vs 153 ⫾ 42 pg/mL, respectively; p ⬍ 0.05) [Fig 2]. The IV administration of prostacyclin significantly decreased plasma BNP levels in patients with CTEPH (before administration, 547 ⫾ 112 pg/mL; after administration, 188 ⫾ 30 pg/mL; p ⬍ 0.01). In contrast, plasma BNP levels remained unchanged in the conventional group (before administration, 153 ⫾ 42 pg/mL; after administration, 136 ⫾ 38 pg/mL; difference not significant). Consequently, the preoperative plasma BNP level did not significantly differ between the two groups.

Adverse Effects of Prostacyclin Therapy

Postoperative Outcome in Patients With and Without Prostacyclin Therapy

The following minor complications related to prostacyclin therapy occurred in nine patients (75%): flushing; jaw pain; headaches; and loose stools. Nevertheless, no clinically significant adverse effects, including hypotension and desaturation, were observed during prostacyclin therapy. 340

Pulmonary thromboendarterectomy caused further improvement in pulmonary hemodynamics in the prostacyclin group (mean pulmonary arterial pressure, 18 ⫾ 2 mm Hg; cardiac output, 4.0 ⫾ 0.2 L/min; pulmonary vascular resistance 302 ⫾ 47 Clinical Investigations

Figure 1. The effects of prostacyclin therapy on mean pulmonary arterial pressure (mPAP; left), cardiac output (CO; middle), and pulmonary vascular resistance (PVR; right) in patients with the most severe form of CTEPH (n ⫽ 11). Preop ⫽ preoperative.

dyne 䡠 s 䡠 cm⫺5; p ⬍ 0.001 vs each preoperative value) [Fig 3], as observed in the conventional group. Consequently, postoperative pulmonary vascular resistance did not significantly differ between the prostacyclin group and conventional group (302 ⫾ 47 vs 320 ⫾ 66 dyne 䡠 s 䡠 cm⫺5, respectively; difference not significant). Pulmonary thromboendarterectomy markedly decreased plasma BNP level

in both groups (Fig 3). Postoperative plasma BNP levels did not significantly differ between the two groups. One patient of the 12 patients in the prostacyclin group died during the first 30 days after undergoing the operation. This was due to persistent postoperative pulmonary hypertension (mean pulmonary arterial pressure, 47 mm Hg; cardiac output, 2.7 L/min; pulmonary vascular resistance, 1,300 dyne 䡠 s 䡠 cm⫺5). Perioperative mortality rates were 8.3% in patients with the most severe form of CTEPH. No perioperative death was observed in patients with the milder form of CTEPH (ie, the conventional group). Therefore, the mortality rate for all patients was 3.0% (n ⫽ 33). Discussion

Figure 2. The effect of prostacyclin therapy on plasma BNP levels in patients with the most severe form of CTEPH (n ⫽ 12). See legend of Figure 1 for abbreviations not used in the text. www.chestjournal.org

In the present study, prostacyclin therapy was performed as pretreatment before pulmonary thromboendarterectomy for patients with the most severe form of CTEPH. We demonstrated the following: (1) that IV administration of prostacyclin markedly decreased pulmonary vascular resistance in patients with CTEPH; (2) that IV prostacyclin also decreased plasma BNP levels before surgery; and (3) that the surgical mortality rate of patients with severe CTEPH who had received prostacyclin were relatively low (8.3%). The IV administration of prostacyclin has been established as the most effective treatment for precapillary pulmonary hypertension conditions such as primary pulmonary hypertension9,10 and collagen CHEST / 123 / 2 / FEBRUARY, 2003

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Figure 3. Time course of pulmonary vascular resistance (left) and plasma BNP levels (right) in CTEPH patients who have received prostacyclin (prostacyclin group [n ⫽ 11], F) and in those patients who have not received prostacyclin therapy (conventional group [n ⫽ 20], E). * ⫽ p ⬍ 0.05 vs conventional group; † ⫽ p ⬍ 0.05 vs baseline; ‡ ⫽ p ⬍ 0.05 vs Preop. Postop ⫽ postoperative condition. See the legend of Figure 1 for abbreviations not used in the text.

vascular diseases.11 However, it is not known whether prostacyclin therapy could serve as an effective pretreatment in patients with major-vessel CTEPH before they undergo pulmonary thromboendarterectomy. Thus, in the present study, prostacyclin was administered IV in patients with the most severe form of CTEPH (pulmonary vascular resistance, ⬎ 1,200 dyne 䡠 s 䡠 cm⫺5). Prostacyclin therapy could be performed in all patients without clinically significant adverse effects such as hypotension and desaturation, although minor complications occurred in several patients. The dosage of prostacyclin used in the present study was relatively low (2 to 11 ng/kg/min) compared with those used in earlier studies9,10 for the treatment of patients with primary pulmonary hypertension. Nevertheless, the continuous administration of prostacyclin markedly increased cardiac output (by 35%) and decreased pulmonary vascular resistance (by 28%) in patients with CTEPH. As a result, preoperative pulmonary vascular resistance did not significantly differ between the prostacyclin group and the conventional group. Considering that prostacyclin produces strong vasodilation, and inhibition of platelet aggregation and vascular smooth muscle proliferation,7,8 it is interesting to speculate that the infusion of prostacyclin may be effective not only by dilating the pulmonary vasculature, but also by inhibiting medial hypertrophy, intimal fibrosis, and thrombotic lesions of the pulmonary arteries. Further studies are necessary to examine the potential mechanisms that are responsible for the beneficial effects of prostacyclin in patients with CTEPH. BNP is secreted predominantly from the cardiac ventricles via a constitutive pathway in association with the degree of myocardial stretch and damage.18,19 Thus, the increased plasma BNP levels in patients with pulmonary hypertension is considered 342

to reflect the degree of right ventricular dysfunction.16,17 In the present study, the baseline plasma BNP level was markedly higher in the prostacyclin group than in the conventional group, suggesting the presence of right heart failure in the prostacyclin group. However, prostacyclin therapy markedly decreased plasma BNP levels immediately before surgery. Consequently, preoperative plasma BNP levels did not significantly differ between the two groups. These results suggest that the decrease in pulmonary vascular resistance by prostacyclin therapy may ameliorate increased wall stress in the right ventricle and may improve right ventricular dysfunction in patients with CTEPH. Earlier studies5,6 have shown that high pulmonary vascular resistance before surgery is associated with perioperative mortality. In the present study, patients in the prostacyclin group had markedly high pulmonary vascular resistance (1,631 ⫾ 136 dyne 䡠 s 䡠 cm⫺5) compared with patients in the conventional group (893 ⫾ 49 dyne 䡠 s 䡠 cm⫺5) and those patients included in earlier studies (937 to 988 dyne 䡠 s 䡠 cm⫺5).3,6,20,21 Nevertheless, the surgical mortality rate of patients who had received prostacyclin was relatively low (8.3%) and was comparable to those reported in earlier studies (6.4 to 10.1%).3,6,20,21 As a result, the mortality rate for all patients in the present study was 3.0% (33 patients). These results may be attributable to the preoperative improvement in pulmonary hemodynamics that was accomplished by prostacyclin therapy. The consecutive pulmonary thromboendarterectomy caused further improvement in pulmonary hemodynamics and plasma BNP levels in such patients. Thus, combined therapy with preoperative prostacyclin administration and pulmonary thromboendarterectomy may have beneficial effects in patients with the most severe form of CTEPH. Clinical Investigations

Study Limitations The present study was neither randomized nor placebo-controlled. Prostacyclin therapy was performed in 12 consecutive patients who had a pulmonary vascular resistance ⬎ 1,200 dyne 䡠 s 䡠 cm⫺5 at diagnostic catheterization. Thus, the severity of disease differed between patients in the prostacyclin group and the conventional group, which may bias the comparison. A prospective, randomized, multicenter trial should be planned based on the results of this study. Conclusion These preliminary results suggest that the IV administration of prostacyclin may have beneficial hemodynamic effects in patients with severe CTEPH and may serve as pretreatment before they undergo pulmonary thromboendarterectomy. References 1 Benotti JR, Dalen JE. The natural history of pulmonary embolism. Clin Chest Med 1984; 5:403– 410 2 Moser KM, Auger WR, Fedullo PF. Chronic major vessel thrombo-embolic pulmonary hypertension. Circulation 1990; 81:1735–1743 3 Jamieson SW, Auger WR, Fedullo PF, et al. Experienced results with 150 pulmonary thromboendarterectomy operations over a 29-month period. Thorac Cardiovasc Surg 1993; 106:116 –127 4 Archibald CJ, Auger WR, Fedullo PF, et al. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999; 160:523–528 5 Hartz RS, Byrne JG, Levitsky S, et al. Predictors of mortality in pulmonary thromboendarterectomy. Ann Thorac Surg 1996; 62:1255–1260 6 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– 776 7 Moncada S, Gryglewski RJ, Bunting S, et al. An enzyme isolated from arteries transforms prostaglandin endoperox-

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8

9

10

11

12 13 14 15

16

17

18 19

20 21

ides to an unstable substance that inhibits platelet aggregation. Nature 1976; 263:663– 665 Moncada S, Vane JR. Archidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Engl J Med 1979; 300:1142–1147 Higenbottam TW, Wheeldon D, Wells FC, et al. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1984; 1:1046 –1047 McLaughlin VV, Genthner DE, Panella MM, et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338:273–277 Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 2000; 132:425– 434 Viner SM, Bagg BR, Auger WR, et al. The management of pulmonary hypertension secondary to chronic thromboembolic disease. Prog Cardiovasc Dis 1994; 37:79 –92 Auger WR, Fedullo PF, Moser KM, et al. Chronic majorvessel thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology 1992; 182:393–398 Ando M, Takamoto S, Okita Y, et al. Operation for chronic pulmonary thromboembolism accompanied by thrombophilia in 8 patients. Ann Thorac Surg 1998; 66:1919 –1924 Antman EM, Marsh JD, Green LH, et al. Blood oxygen measurements in the assessment of intracardiac left to right shunts: a critical appraisal of methodology. Am J Cardiol 1980; 46:265–271 Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998; 31:202–208 Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000; 102:865– 870 Sudoh T, Kangawa K, Minamino N, et al. A new natriuretic peptide in porcine brain. Nature 1988; 332:78 – 81 Mukoyama M, Nakao K, Saito Y, et al. Brain natriuretic peptide (BNP) as a novel cardiac hormone in humans: evidence for an exquisite dual natriuretic peptide system, ANP and BNP. J Clin Invest 1991; 87:1402–1412 Jamieson SW. Pulmonary thromboendarterectomy. Heart 1998; 79:118 –120 Daily PO, Dembitsky WP, Jamieson SW. The evolution and the current state of the art of pulmonary thromboendarterectomy. Semin Thorac Cardiovasc Surg 1999; 11:152–163

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