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Tex Heart Inst J. 2005; 32(3): 405–410.
PMCID: PMC1336721
Secondary Pulmonary Arterial Hypertension Treated with Endothelin Receptor Blockade
Sat Sharma, MD, FCCP, Tarek Kashour, MD, FRCPC, and Roger Philipp, MD, FRCPC
Sections of Pulmonary and Critical Care Medicine (Dr. Sharma) and Cardiology (Drs. Kashour and Phillipp), Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, R2H 2A6, Canada
Secondary pulmonary arterial hypertension (SPAH) is an adverse outcome of a variety of systemic disorders. These include collagen vascular diseases, chronic thromboembolism, human immunodeficiency virus, portopulmonary hypertension, and other diseases. Progression of SPAH may persist despite stabilization of the causative disease, thereby contributing to the poor quality of life and unfavorable survival in these patients. Treatment of the underlying cause and oxygen supplementation may alleviate symptoms, but no specific therapy to treat SPAH currently exists. Endothelin receptor blockade with bosentan has been shown to be beneficial in the treatment of primary pulmonary hypertension, but efficacy of this therapy in SPAH has not been established.
We describe a case series of 6 patients with disparate causes of SPAH, who benefited from endothelin receptor blockade therapy. The causes of SPAH included collagen vascular disease (scleroderma) (1); systemic lupus erythematosus (2); chronic thromboembolic disease (2); and granulomatous vasculitis from sarcoidosis (1). Therapy with bosentan led to improvements in symptoms, New York Heart Association functional class, and walking distance in all patients. Distance walked in 6 minutes increased from a mean of 151.67 ± 69.30 m at baseline to 314.83 ± 89.09 m after an average of 14 months of bosentan treatment. Pulmonary arterial pressure decreased in most but not all 6 patients on follow-up echocardiography. This case series suggests a role for endothelin receptor blockade therapy in SPAH and should generate further interest in pharmacologic management of SPAH. A prospective controlled clinical trial of bosentan in SPAH is urgently needed.
Key words: Bosentan, calcium channel blockers/administration & dosage, endothelin-1/antagonists and inhibitors, epoprostenol/therapeutic use, hypertension, pulmonary/drug therapy, liver/drug effects
Despite advances in the treatment of primary pulmonary hypertension (PPH), therapy for secondary pulmonary arterial hypertension (SPAH) remains unsatisfactory.1–6 Intravenous epoprostenol has been reported to be of benefit in patients who have pulmonary arterial hypertension associated with collagen vascular disease, human immunodeficiency virus, congenital heart disease, and portopulmonary hypertension.7–10 Some data suggest that endothelin receptor blockade with bosentan is possibly effective for patients with scleroderma.4 There have been no published reports of benefit of endothelin receptor blockade with bosentan in patients who developed pulmonary hypertension from other causes. We report a case series of 6 patients with SPAH in whom treatment with bosentan led to improvement in their clinical status, New York Heart association (NYHA) functional class, and 6-minute walking distance (see Table I).
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TABLE I. Summary of Clinical Aspects of Each Patient with SPAH
Patient 1
A 73-year-old woman presented with progressive dyspnea. She was known to have scleroderma of the CREST variety for the past 6 years. Her symptoms included Raynaud's phenomenon, arthralgias, and mild dysphagia. She was initially investigated with the aid of a spiral computed-tomographic (CT) scan and a ventilation-perfusion (V-Q) scan, to exclude the possibility of pulmonary thromboembolism. An echocardiogram showed normal left heart function and no valvular abnormalities, but evidence of pulmonary arterial hypertension. Subsequent right heart catheterization revealed pulmonary artery pressures at 42/15 mmHg and a mean of 33 mmHg. There was a positive response to vasodilator challenge with prostacyclin. On the basis of this information, she was placed on therapy with the calcium channel blocker nifedipine, and was also anticoagulated. While on therapy, she developed progressive exertional dyspnea compatible with New York Heart Association (NYHA) functional class III. A repeat echocardiogram showed a pulmonary arterial systolic pressure of 58 mmHg. At this point, bosentan 62.5 mg twice a day (increased to 125 mg twice a day, 1 month later) was added to the therapy. Walking oximetry had shown desaturation from 95% to 84%; she walked 252 meters in 6 minutes. While on bosentan 125 mg twice a day for 14 months, the patient significantly improved to NYHA functional class I. The distance walked in 6 minutes increased from 252 to 325 meters. Pulmonary arterial systolic (PA systolic) pressure had decreased to 48 mmHg as revealed on repeat echocardiography following bosentan therapy.
Patient 2
A 46-year-old woman developed progressive dyspnea on exertion. She had a history of myalgias and arthritis of the proximal interphalangeal joints of both hands. An immunologic workup had shown antinuclear antibody at 1:640 dilutions and a homogenous pattern. Skin-sensitizing antibody (SSA-RO), anti-DNA antibodies, and DNA-binding antibodies were strongly positive. Serum creatinine kinase and C3 and C4 levels were normal, and antineutrophil cytoplasmic antibodies were negative. Pulmonary function tests were normal except for reduction in DLCO (diffusing capacity) at 56% of predicted. Echocardiography showed a pulmonary artery systolic pressure of 88 mmHg, normal left ventricular size and function, and no evidence of valvular abnormalities. The diagnosis of pulmonary arterial hypertension was confirmed with right heart catheterization. Pulmonary artery pres-sures were as follows: systolic, 68 mmHg; diastolic, 26 mmHg; and mean, 42 mmHg. Oximetry upon walking showed desaturation from 96% to 81%, and the patient walked 154 meters in 6 minutes. Her symptoms were in keeping with NYHA functional class III. Because vasoreactivity was demonstrated on right heart catheterization, treatment was initiated with warfarin and the calcium channel blocking drug verapamil. Over the next 6 months, her dyspnea progressed; therefore, treatment with bosentan was initiated at 62.5 mg twice a day and increased to 125 mg twice a day after 1 month. After 12 months of therapy with bosentan 125 mg twice a day, her dyspnea improved remarkably, and she was then in NYHA functional class II. Furthermore, she walked a distance of 320 meters in 6 minutes, compared with 154 meters at baseline. Repeat echocardiography showed marked reduction in PA systolic pressure, to 44 mmHg.
Patient 3
A 71-year-old woman had been diagnosed with atrial septal defect in 1996. She had experienced exertional dyspnea for a few years before confirmation of the diagnosis. Repair of the atrial septal defect was undertaken the same year. Approximately 7 years later, she noted gradual worsening of the breathlessness on exertion. She could perform only minimal activities, developed peripheral edema, and upon physical examination showed elevated jugular venous pressure (JVP), a loud pulmonic component of the 2nd heart sound, and a grade 3/6 systolic murmur over the left sternal border. Her medical history included hyperthyroidism, for which radioactive iodine ablation had been performed several years earlier. Pulmonary function tests were normal except for markedly reduced DLCO: 48% of predicted. An echocardiogram confirmed severe pulmonary arterial hypertension and right ventricular failure. The PA systolic pressure was 68 mmHg on hemodynamic measurement made by pulmonary artery catheterization, and a normal pulmonary capillary wedge pressure was evident. A spiral computed tomographic (CT) scan confirmed bilateral large- and small-vessel thromboembolic disease. There was mosaic perfusion and organization of thrombi in keeping with the diagnosis of chronic thromboembolism-induced pulmonary arterial hypertension. The patient was offered thromboendarterectomy, but she declined the surgery. Therefore, therapy with warfarin, nifedipine extended-release 30 mg daily, and bosentan 62.5 mg twice a day (followed 1 month later by 125 mg twice a day) was initiated. A 6-minute walking test before the initiation of therapy had shown that she walked a distance of 62 meters. The patient had some difficulty tolerating bosentan because of an elevation in liver transaminases. However, she eventually could be placed on bosentan 125 mg twice a day. She was in NYHA functional class IV at presentation; 12 months after beginning medical therapy for SPAH, the patient improved to functional class III. A repeat spiral CT scan has shown persistent bilateral thromboembolic disease. The 6-minute walking distance significantly improved to 230 meters, although PA systolic pressure showed only a modest reduction, to 66 mmHg.
Patient 4
A 57-year-old woman was evaluated for secondary pulmonary hypertension. She had a history of systemic lupus erythematosus, which was in remission at the time of presentation. The lupus manifestations had been polyserositis, malar rash, and elevation of antinuclear antibodies. Approximately 5 years before current presentation, she had been diagnosed with mitral valve stenosis, and the valve was later replaced with a mechanical valve. At the time of mitral valve surgery, she was known to have pulmonary arterial hypertension; right heart catheterization had shown pulmonary artery systolic pressure at 48 mmHg. At her current hospitalization, transesophageal echocardiography was performed because of progressive exertional dyspnea and signs of right heart failure. The echocardiogram showed evidence of worsening pulmonary arterial hypertension: the PA systolic pressure was calculated at 70 mmHg. Elevated PA pressures were confirmed on right heart catheterization, but pulmonary capillary wedge pressure was normal. A spiral CT scan excluded chronic thromboembolic disease, and an evaluation of the systemic lupus erythematosus did not confirm disease activity. Because the patient's mitral valve prosthesis had been functioning properly, she was thought to have SPAH due to previous systemic lupus erythematosus, with a contribution from her prior mitral valve disease. She had already been on calcium channel blocking therapy with diltiazem 90 mg 4 times a day and on systemic anticoagulation for the prosthetic valve. Therapy with bosentan 62.5 mg twice a day was initiated and increased to 125 mg twice a day. A 6-minute walking test at baseline showed a distance of 92 meters. At first, the patient had some difficulty tolerating bosentan therapy because of an elevation in liver transaminases, which likely reflected passive liver congestion rather than bosentan toxicity. However, she subsequently could be placed on bosentan 125 mg twice a day. The patient's symptoms gradually improved, and she is currently in NYHA functional class III, compared with functional class IV at presentation. A 6-minute walking test 16 months later showed considerable improvement, as she now walked 224 meters. A modest reduction in pulmonary arterial pressures (PA systolic pressure, 58 mmHg) was demonstrated on follow-up echocardiography.
Patient 5
A 46-year-old man had developed hydrocephalus following a head injury approximately 22 years before his current presentation. The hydrocephalus had been treated with the creation of a ventriculoatrial shunt. Approximately 5 years after surgery, the shunt was associated with multiple pulmonary emboli. There also occurred concomitant thrombosis of the internal jugular vein, right subclavian vein, and superior vena cava. Cardiac catheterization around that time had shown the PA systolic pressure to be 40 mmHg. The ventriculoatrial shunt was removed and replaced with a ventriculoperitoneal shunt. Approximately 5 years before this current presentation, the patient developed gradually worsening exertional dyspnea. Over the last 6 months, he developed signs and symptoms of cor pulmonale. A spiral CT scan showed signs of chronic thromboembolic disease, although large intraluminal filling defects were not identified. Echocardiography revealed severe pulmonary arterial hypertension, severe right ventricular dysfunction, and tricuspid regurgitation. These findings were confirmed on right heart catheterization, and the PA systolic pressure was measured at 80 mmHg. After undergoing initial temporizing measures (diuresis, oxygen supplementation, and anticoagulation), the patient was referred for consideration of thromboendarterectomy. However, because organized thrombi were located distally, this procedure was not considered appropriate. Medical therapy for SPAH—a calcium channel blocker and bosentan at 125 mg twice a day—was administered. His 6-minute walking distance at the beginning of the therapy was 150 meters. With medication, the patient gradually improved; over a period of 18 months, the NYHA functional class improved from class IV to class II. The walking distance increased to 470 meters, and the PA systolic pressure decreased to 68 mmHg.
Patient 6
A 72-year-old black man had been diagnosed with stage III pulmonary sarcoidosis approximately 30 years before. After initial treatment with oral corticosteroids for 5 years, he was considered stable and therapy was withdrawn. Approximately 5 years before his current presentation, he developed worsening dyspnea on exertion. His breathlessness had been progressive over the past year, and at initial evaluation he was breathless after minimal activity. The results of physical examination were in keeping with severe pulmonary arterial hypertension. A high-resolution CT scan showed volume loss and infiltration in both upper lung zones. There were also nodular opacities along the bronchovascular bundles, which was in keeping with sarcoidosis. Mild uptake in the perihilar regions was seen on gallium scan. An echocardiogram showed a normal left atrium, a competent mitral valve, and a normal left ventricle. There was dilatation of the right ventricle, with severe hypokinesis and mild tricuspid regurgitation; the right ventricular systolic pressure was calculated at 78 mmHg. Severe pulmonary arterial hypertension was confirmed on right heart catheterization. Arterial blood gases showed a pH of 7.40, PaCO2 of 52 mmHg, PaO2 of 61 mmHg, and HCO3 of 32 mmol/L. Pulmonary function test results were in keeping with moderate restrictive disease: total lung capacity was 62% of predicted, vital capacity was 40% of predicted, and DLCO 46% of predicted. The patient could walk only 30 meters before stopping. He was started on treatment for sarcoidosis with prednisone 1 mg/kg. The pulmonary arterial hypertension was thought to be secondary to granulomatous vasculitis; treatment was initiated with warfarin, the calcium channel blocker nifedipine extended-release 60 mg once daily, and bosentan 125 mg twice a day. Four months after therapy, his 6-minute walking distance increased to 200 meters. One year after beginning therapy for his sarcoidosis and pulmonary hypertension, pulmonary function tests did not show appreciable change. However, the patient's walking distance had increased to 320 meters and his repeat echocardiogram showed a PA systolic pressure at 72 mmHg. His clinical status improved from NYHA functional class IV to class II. The patient is currently leading an active lifestyle; he works out in a gymnasium 5 times a week.
Patients who develop pulmonary arterial hypertension (PAH) secondary to an underlying systemic disease often have a poor chance of survival. Although treatment of the underlying disorder, anticoagulation, and long-term oxygen therapy may offer some benefit, no specific therapy is currently available for patients with SPAH. Whether endothelin receptor blockade with antagonists such as bosentan is effective in SPAH has not been well established. Because no controlled data are currently available, this case series of 6 patients with a variety of causes leading to PAH suggests a benefit of endothelin receptor blockade with bosentan. All of these patients were treated with calcium channel blocking agents, anticoagulation with warfarin, and bosentan. Calcium channel blockers and warfarin are known to have a modest benefit in patients with PPH, although this benefit has been limited to patients in early stages of the disease (NYHA I and II).11,12 The remarkable clinical and physiologic improvement seen in the patients described in this case series is likely secondary to endothelin receptor blockade.
Normal pulmonary circulation is characterized by a high-flow, low-resistance vascular bed; the pathophysiology of PAH encompasses a combination of vasoconstriction, vascular wall remodeling, and thrombosis in situ.1,13 Injury to the vascular endothelium, regardless of the cause, will activate endothelin and lead to proliferative changes in the vascular wall and ultimately to the development of pulmonary arterial hypertension. The histopathologic changes in the pulmonary vasculature of patients who have SPAH are similar to the changes that occur with PPH: thickening of the adventitia, medial hypertrophy, and eventually plexiform arteriopathy.13 In health, there is a balance between endothelium-derived relaxing factors (nitric oxide and prostacyclin) and constricting factors (endothelin-1 and thromboxane). Tilting the balance in favor of constrictive factors elevates vasomotor tone, promotes smooth muscle cell proliferation, induces vascular remodeling, and provokes thrombosis. At present, PAH is considered to be a vasoproliferative rather than a vasoconstrictive disorder. Therefore, a paradigm shift in the treatment of PAH has occurred, as the current standard places emphasis on antiproliferative agents, rather than vasodilators.1,14
Vasodilator therapy with calcium channel blockers and hydralazine has produced a decrease in pulmonary vascular resistance in patients with SPAH, but the hemodynamic responses are variable.15,16 Moreover, the combination of cardiac output augmentation and sustained elevations in pulmonary artery pressure may lead to deleterious effects on right ventricular function. Other untoward effects of vasodilator use in patients with SPAH are worsening of the ventilation–perfusion mismatch and hypoxemia.17 Consequently, it appears that only a very small group of patients with SPAH may actually benefit from vasodilator therapy.
Prostacyclin analogs and bosentan have been shown to be efficacious in primary pulmonary hypertension. Prostacyclin possesses several properties other than vasodilation; these include antiproliferative activity (which affects vascular remodeling) and inhibition of platelet aggregation.7 Case reports and case series have reported a benefit from epoprostenol in cases of SPAH that are caused by connective tissue diseases (scleroderma), human immunodeficiency virus (HIV) infection, congenital heart disease, and portopulmonary hypertension.8,9 In 1 large case series, 33 patients with SPAH as a result of congenital heart disease, collagen vascular disease, sarcoidosis, chronic thromboembolic disease, portopulmonary hypertension, and congenital heart disease were treated with continuous epoprostenol therapy.10 After an average of 12.7 months, significant improvements were demonstrated in treadmill exercise time, pulmonary arterial pressure, and pulmonary vascular resistance.10 Despite the benefits of epoprostenol having been shown in measurements of hemodynamic values and functional capacity, its effects on survival in SPAH have not been studied.
Aberration in the regulation of nitric oxide or of nitric oxide-mediated cyclic guanosine monophosphate (cGMP) production in the pulmonary vasculature has been shown to contribute to the development of PAH.18 Nitric oxide inhalation can ameliorate PAH but is an impractical therapy because of its short half-life. Sildenafil is a selective phosphodiesterase type-5 inhibitor that prevents the degradation of cGMP and thereby selectively dilates pulmonary arteries by nitric oxide-dependent mechanisms.19 Several small studies have shown improvement of pulmonary hemodynamics in patients with PPH.20–22 In a recent randomized, double-blind crossover study, 22 sildenafil was compared with placebo in patients with PPH over a 6-week period. In the 22 patients who completed the study, sildenafil significantly improved exercise tolerance, cardiac index, and quality of life. When compared with epoprostenol in patients with SPAH due to pulmonary fibrosis, sildenafil reduced shunt fraction and improved oxygenation.23 Notwithstanding these encouraging data on sildenafil use in patients with PPH, further research is required to define the role of phosphodiesterase inhibitor therapy with sildenafil in PPH and SPAH.
Before the publication of this present report, no comparable data existed on the use of endothelin receptor antagonists in the treatment of SPAH. Bosentan, a competitive antagonist of endothelin receptors ETA and ETB, has been shown to arrest vascular remodeling and reverse established pulmonary hypertension. Patients with PPH attain improvement in dyspnea, NYHA functional class, and 6-minute walking distance.4–6 In a prospective trial of bosentan in PPH, Sitbon and colleagues6 enrolled some patients who had SPAH attributable to scleroderma. Although endothelin receptor therapy was effective in the group as a whole, its benefit to patients with SPAH is unknown.6
Bosentan is eliminated primarily by the liver and is known to induce liver injury, mainly at the higher doses. Data from clinical trials have shown an 11% incidence of a greater-than-three-fold rise in aminotransferases. These elevations can occur either early or late during treatment and are often asymptomatic. The liver injury generally resolves with dose reduction or cessation of therapy. Reintroduction of bosetan at a lower dose may be tolerated and has not resulted in recurrent elevation of liver enzymes. Measurements of the liver enzymes alanine aminotransferase and aspartate aminotransferase before therapy and monthly thereafter are imperative in patients undergoing therapy with bosetan. Patients with abnormal liver function should not receive bosetan unless the cause is liver congestion from cor pulmonale that could effectively be treated with diuretic therapy.
In our case series, all patients with SPAH developed significant improvement in exercise capacity, as documented by the 6-minute walking test. This case series included SPAH due to collagen vascular disease (scleroderma in 1; systemic lupus erythematosis in 2; chronic thromboembolic disease in 2; and granulomatous vasculitis from sarcoidosis in 1). The mean 6-minute walking distance in 6 patients increased from 151.67 ± 69.30 meters at baseline to 314 ± 89.09 meters (P<0.05), after an average duration of 14 months of bosentan therapy. These 6 patients displayed a mean increase in walking distance of 163 ± 17.79 meters over the baseline. The NYHA functional class improved from class IV to class III in 4 patients, from class III to class II in 1, and from class III to class I in another. Our case series does not record repeat hemodynamic measurements, but clinical improvement in conjunction with improvement on the 6-minute walking test has been shown to be an acceptable outcome measure.24 These patients were treated with multiple therapies, including calcium channel blockers and anticoagulation. Although calcium channel blockers and anticoagulation may have contributed to the therapeutic effect seen in these patients, those agents have not been shown to improve exercise capacity or functional class in cases of advanced pulmonary hypertension. The patients in this series very likely improved secondary to the antiproliferative effects of bosentan on the pulmonary vasculature. This case series makes a compelling argument for a systematic, controlled study of endothelin receptor antagonists in patients with secondary pulmonary arterial hypertension.
Address for reprints: Sat Sharma, MD, FRCPC, Respiratory Medicine, St. Boniface General Hospital, BG034, 409 Tache Avenue, Winnipeg, MB, R2H 2A6, Canada
Email: Ssharma/at/
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