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Endothelin Receptor Antagonism in Pulmonary Arterial Hypertension: Current Concepts, Clinical Experience, and New Horizons

Pathogenesis of PAH: General Overview

David B. Badesch, MD, FCCP, Professor of Medicine at the University of Colorado Health Sciences Center in Denver, reviewed the definition, classification, epidemiology, and pathogenesis of pulmonary arterial hypertension (PAH).

PAH can be classified as primary pulmonary hypertension (PPH), or pulmonary hypertension associated with a variety of underlying diseases (Rich S, ed. World Health Organization, 1998). Primary pulmonary hypertension can be of sporadic or familial etiology. Pulmonary hypertension can occur in association with the following conditions:

• Collagen vascular disease, particularly scleroderma and the CREST syndrome
• Portal hypertension or end-stage liver disease
• Congenital heart disease
• Drugs or toxins
• HIV infection
• Hypercoagulable states/thromboembolism
• Persistent pulmonary hypertension of the newborn.

Current thinking about PAH pathogenesis is as follows. When any of the aforementioned associated conditions occurs in a susceptible person and vascular injury occurs, that injury may be accompanied by endothelial dysfunction, decreased nitric oxide (NO) production, decreased prostacyclin production, increased thromboxane production (a vasoconstrictor and platelet aggregator), and/or increased endothelin production. Vascular injury can lead to disease progression. This is distinguished by loss of response to short-acting vasodilators, as well as smooth muscle cell hypertrophy and hyperplasia, intimal proliferation, in situ thrombosis, and development of a plexiform lesion (Gaine S. JAMA 2000;284:3160-3168).

Factors proposed to trigger PAH include appetite suppressant medications, amphetamines, altitude exposure, pregnancy, HIV infection, and (most recently identified) human herpes virus-8 (HHV-8) (Cool CD, et al. N Engl J Med 2003;349:1113-1122).

Expression of endothelin-1 is increased in the plexiform lesions associated with PAH (Giaid A, et al, N Engl J Med 1993;328:1732-1739). Endothelin has a number of acute and chronic detrimental effects, including acute vasoconstriction and inflammation; and chronic fibrosis, neurohormonal secretion, and cellular proliferation.

An exciting finding in the last several years has been the discovery of a gene associated with perhaps half the cases of familial primary pulmonary hypertension. This gene, bone morphogenetic protein receptor II (BMPR2), encodes a transforming growth factor beta (TGF-B) receptor that is thought to be involved in control of endothelial cell growth (Lane KB, et al. Nat Genet 2000;26:81-84; Deng Z, et al. Am J Hum Genet. 2000;67:737-744). It is thought that mutation of this receptor leads to endothelial cell proliferation without the usual controls, contributing to formation of a plexiform lesion obstructing the vascular lumen.

The Endothelin System in Pulmonary Disease: Pathogenic Mechanisms and Treatment Targets

Lewis J. Rubin, MD, FCCP, Professor of Medicine and Director of the Pulmonary Vascular Center at the University of California San Diego Medical Center in La Jolla, reviewed evidence detailing the detrimental role of endothelin in pulmonary disease.

Endothelin appears to mediate vasoconstriction as well as pathologic proliferation and growth in pulmonary vascular disease. There are two kinds of endothelin receptors: endothelin A (ET A) and endothelin B (ET B). Both are found in smooth muscle and fibroblasts. ET B receptors are also found in endothelial cells, macrophages, and the sympathetic nervous system. The ET A receptor mediates vasoconstriction in smooth muscle of normal vasculature, while the ET B receptor in the endothelial cell normally mediates vasodilation. In pathologic disease, the ET B receptor in pulmonary vasculature may also mediate vasoconstriction. Both receptor subtypes appear to be upregulated in pulmonary hypertensive states.

Endothelin is “probably one of the most potent mitogens, particularly of the human vascular smooth muscle cell,” he said. It is a strong promoter of growth and proliferation. (Yang Z, et al. Circulation 1999;100:5-8). It also is a potent inducer of fibrosis, he said. Endothelin could, in theory, mediate some of the inflammation that may be associated with viral infections (HIV, HHV-8) in pulmonary hypertension.

Although vasoconstriction is important in the pathogenesis of pulmonary hypertension, it is less important than growth and proliferation. “The vast
majority of patients with pulmonary hypertension do not have an active component of pulmonary vasoconstriction by the time we see them,” Dr. Rubin said. Hypertrophy, fibrosis, and perhaps inflammation are the key pathologic processes when patients come to medical attention.

A normal pulmonary artery is characterized by “a very fine endothelin, a very small amount of smooth muscle, an internal and external elastic lamina, and minimal amount of interstitial or matrix around the vessel,” he said. The pulmonary artery in a patient with PAH is characterized by a thickened media, a widened space between the internal and external lamina, endothelial proliferation and growth, endothelial injury, a smaller lumen, and adventitial proliferation. In PAH, growth and proliferation of the entire vessel wall then occurs, with concentric hypertrophy, and loss of endothelial definition and function. “You have fibrosis and narrowing of the vascular lumen, fibrointimal proliferation, growth and proliferation of the entire vascular wall,” he said.

At least some of these processes may be governed by excess production or activity of endothelin. Endothelin is overproduced in the plexiform lesion of pulmonary arterial hypertension (Giaid A, et al. N Engl J Med. 1993;328:1732-1739). Plasma levels of endothelin are correlated “reasonably well” with severity of primary pulmonary hypertension (Rubena C, et al. Chest 2001;120:1562-1569).

Endothelin level in circulating plasma also is correlated with survival (Galie N, et al. Eur J Clin Invest. 1996; 26[Suppl 1]:273). “The higher your
level of endothelin in the circulating plasma, the poorer your survival with primary pulmonary hypertension,” Dr. Rubin said.


Pulmonary Arterial Hypertension Today: Contemporary Approaches to Screening and Diagnosis

Adaani E. Frost, MD, FCCP, Professor of Medicine, Baylor College of Medicine, Houston, Texas, outlined evaluation and management of patients at risk for PAH. Patients may need to be screened for pulmonary hypertension because of symptoms or incidental findings on tests (chest x-rays, electrocardiograms). Screening also is needed for patients with certain conditions that place them at elevated risk for developing pulmonary hypertension.

Patients with scleroderma should undergo echocardiographic screening for PAH, she said. This is based in part on recommendations from a large (N = 930) retrospective study of patients at a central tertiary referral center for scleroderma in the UK, she said (MacGregor AJ, et al. Rheumatology 2001;40:453-459). This study, along other data, supports a cumulative prevalence for PAH of 10% to 15% in scleroderma patients, she said. Those with limited scleroderma have a much higher risk of rapid progression to severe pulmonary hyper- tension than those with diffuse scleroderma (odds ratio: 18.1) (MacGregor AJ, et al. Rheumatology 2001;40:453-459).

Patients with a single measure of 30 mm Hg in pulmonary arterial systolic pressure had a 20% risk of death in 20 months—“a rather daunting mortality,” she said (MacGregor AJ, et al. Rheumatology 2001;40:453-459). “This is a high-risk patient population,” Dr. Frost said. “You can certainly improve quality of life by readily addressing and diagnosing their pulmonary hypertension.”

Congenital heart disease
Risk of PAH in persons with congenital heart disease depends upon the type of defect, said Dr. Frost. Roughly 4% to 6% of patients with atrial septal defects go on to develop pulmonary hypertension (Friedman WF, ed. Proceedings of the National Heart, Lung and Blood Institute Pediatric Cardiology Workshop 1986; 20:811-824; Besterman E. Br Heart J 1961;23:587-598). As many as 10% of patients with ventricular septal defects that are uncorrected before 2 years old, and 4% of those with ostium secundum, develop PAH (Hoffman J, et al. Am J Cardiol 1985;16:634-653; Ammash NM, et al. Ann Int Med. 2001; 135:812-824). The congenital defect often will be diagnosed only during the evaluation for PAH, she said.

Incidence of PAH in HIV-infected persons is about 1 to 5 per 1,000, compared to 1 or 2 cases per 1 million in the general population, she said (Himelman RB, et al. Am J Cardiol 1989, 64:1396-1399; Barbarini G, et al. AIDS 2003;17[Sup-pl 1]: S46-50). The reasons why viral inflammation of HIV is associated with PAH is unclear. Dr. Frost recommended having a low threshold for suspecting PAH in persons with HIV. A retrospective study (N = 80) reported a 3-year survival rate of 47% for HIV patients with PAH (Nunes H, et al. Am J Respir Crit Care Med 2003;167:1433-1439). Such sobering numbers demonstrate that PAH in HIV is “a very mortal disease in a patient population that now has a pretty good survival,” she said.

Epoprostenol plus highly active antiretroviral therapy [HAART] therapy substantially improves overall survival compared to conventional therapy (eg, calcium channel blockers if appropriate, digoxin, warfarin) plus HAART therapy (Nunes H, et al. Am J Respir Crit Care Med 2003;167:1433-1439). In her experience, said Dr. Frost, “HIV patients do not tolerate calcium channel blockers very well.”

End-stage liver disease
One-year survival after liver transplantation is 96%. However, pulmonary hypertension significantly impacts postoperative survival. An analysis (N = 43) found that all patients with mean pulmonary arterial pressure (4cmPAP) 50 mm Hg died (Krowka MJ, et al. Liver Transpl 2000;6:443-450). Conversely, all those with 4cmPAP < 35 mm Hg survived the transplant. Survival for those with pressures between 35 and 50 mm Hg was 50%, which Dr. Frost characterized as “still very daunting.” Surgical portosystemic shunts appear to increase risk of pulmonary hypertension, she said.

Because of the impact of PAH on transplantation survival, screening echocardiography is recommended as part of evaluation for liver transplantation. If the findings suggest the presence of PAH, then right heart catheterization should be performed to confirm the diagnosis. If right heart catheterization is negative for PAH, then repeat echocardiography should be performed to ensure that the patient is still a candidate for transplantation.

Familial PAH
About 60% of persons with familial pulmonary hypertension have mutations within the BMPR2 gene, as do about 25% of so-called sporadic cases, Dr. Frost said (Newman JH, et al. N Engl J Med 2001;345:319-324). The gene is autosomal dominant. However, about 20% of family members with the gene do not develop pulmonary hypertension. “You can have the gene and not have the disease,” she said. The role of genetic screening is uncertain, she said. Some families seek genetic information prior to conceiving children. Others wish to “put their mind at ease,” she said. Current recommendation supports predominantly clinical screening for patients with a familial history of PPH, she said.

PAH may be suspected in patients because of symptoms such as shortness of breath, fatigue, lightheadedness, and peripheral edema. It is important to remember that “pulmonary hypertension is not the most common cause of many of the symptoms” of PAH, Dr. Frost said.

Algorithm for evaluating possible PAH
Patients whose history or physical exam findings suggest PAH should undergo a chest x-ray, electrocardiography, and echocardiography. This recommendation comes from the Third World Symposium on Pulmonary Arterial Hypertension in Venice (June 23-25, 2003).

A person with no symptoms and negative findings from the three studies mentioned above “doesn’t have to worry about pulmonary hypertension,” she said. If studies are equivocal and symptoms are mild and early, then the physician should evaluate the patient for connective tissue disease. If studies are equivocal but symptoms are “more substantial,” then further evaluation for PAH is needed. This includes pulmonary function testing and measuring diffusion capacity. “If diffusion capacity is less than 40%, then I do a high resolution computed tomography (CT) scan,” she said. She recommends ventilation/perfusion scanning over CT angiography. Dr. Frost runs HIV tests on all patients, she said. “Then I don’t have to explain why I do it in some,” she explained.

An echocardiogram that is positive for PAH mandates right heart catheterization to confirm the diagnosis. “The diagnostic test is still a right heart catheterization,” she stressed. Echocardiography is a highly sensitive screening test but is nonspecific for PAH, she said. “The echocardiogram…will tell you when to do a (right heart) catheterization,” she said.

Dr. Frost also uses the 6-minute walk test during evaluation for PAH as an indicator of “just how functional a patient is,” she said. Ability to walk less than 250 meters is a negative prognostic indicator, she said.

The purpose of vasodilator testing is to determine the safety of calcium channel blocker therapy and likelihood of a response to it, said Dr. Frost. Response to inhaled nitric oxide safely predicts response to calcium channel blocker therapy, she said. In two studies, nonresponse to nitric oxide was associated with the risk of serious adverse reactions to calcium channel blocker therapy (Sitbon O, et al. Eur Respir J 1998;12:265-270). No nonresponders to nitric oxide responded to calcium channel blockers, and some had serious adverse reactions (eg, death, shock, severe hypotension). Therefore, vasodilator testing should be performed with nitric oxide rather than a calcium channel blocker.


Endothelin Receptor Antagonism in Pulmonary Hypertension: State-of-the-Art Therapy and New Horizons

Dr. Lewis J. Rubin spoke about current management of PAH and endothelin receptor antagonists. His presentation drew on as-yet-unpublished guidelines from the Third World Symposium on Pulmonary Arterial Hypertension in Venice (June 23-25, 2003), and the ACCP Evidence-Based Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. Acute response to vasodilator therapy in PAH is defined as a reduction in MPAP of at least 10%, to less than 40 mm Hg, with a normal or increased cardiac output, he said.

Therapies for PAH target pathologic changes such as increased endothelin, and reduced nitric oxide and prostacyclin. Treatments include:

• Bosentan and other endothelin antagonists
• Nitric oxide or its precursor, L-arginine
• Phosphodiesterase 5 (PDE-5) inhib-itors (eg, sildenafil), which inhibit cyclic GMP breakdown and enhance the vasodilatory effect of nitric oxide.
• Prostenoids (eg, epoprostenol)

There is little evidence that calcium channel blockers address any pathogenic pathway in PAH, he said. Most patients, even most PPH patients, do not respond to them. “My own opinion is, they have absolutely no role in any disease other than PPH,” Dr. Rubin said.

This was the first drug demonstrated to have efficacy regardless of vasodilator response. “It’s complex, it has to be given by a continuous infusion in a central venous catheter, it’s expensive, it has major side effects and toxicities,” said Dr. Rubin. However, he added, “It is a lifesaving drug in patients with severe advanced pulmonary hypertension.” Epoprostenol has significantly improved survival in PPH compared to historical controls (Sitbon O, et al. J Am Coll Cardiol 2002;40:780-788). It requires close monitoring and careful dose adjustment. “You can make a patient worse with (epoprostenol) therapy,” he cautioned. It is reserved for the “sickest, most complex patients,” Dr. Rubin said.

The prostacyclin analogue aero-solized iloprost, is given by nebulizer directly to the lung. It is approved in the European Union for treatment of PPH. It improved the 6-minute walk test and functional class compared to placebo in a randomized clinical trial (N = 203) (Olschewski H, et al. N Engl J Med. 2002;347:322-329).

Bosentan (dual endothelin receptor antagonist), an oral medication, is approved in the US for class III and IV PAH. Two randomized clinical trials demonstrate its efficacy. Both a pilot trial (N = 32, 12 weeks) (Channick RN, et al. Lancet 2001;358:1119-1123) and the larger BREATHE-1 study (N = 213, 12 weeks) (Rubin LJ, et al. N Engl J Med 2002;346: 896-903) reported significant benefits in the 6-minute walk test with bosentan compared to placebo. In the pilot trial, bosentan also decreased pulmonary vascular resistance and improved hemodynamics. In BREATHE-1, bosentan therapy increased time to clinical worsening. This suggests that “this drug does slow the progression of pulmonary hypertensive disease,” said Dr. Rubin.

Long-term follow-up indicates that nearly half of the patients in the initial pilot study showed improved functional class after 6 months of bosentan therapy, from Class III to Class II or I (Sitbon O, et al. Chest 2003;124:247-254). Most maintained that improvement at 12 months of therapy. Data presented at last year’s American Thoracic Society meeting reported an apparent event-free survival benefit with bosentan therapy at 36 months compared to historical controls (NIH registry). A BREATHE-1 echocardiographic substudy has demonstrated evidence that right ventricular hypertrophy regresses with bosentan therapy (Galie N, et al. JACC 2003;41: 1380-1386).

The dose-related risk of liver toxicity requires monthly monitoring of liver enzymes, he said. Mild enzyme elevation is relatively common and requires close monitoring. Elevations exceeding 5 times upper limits of normal dictate dose reduction or discontinuation. “You may consider re-challenging (with bosentan),” he said. More severe elevations (8 times upper limits of normal, occurring in about 5% of patients) require discontinuation of the drug, then monitoring to be sure that liver enzymes reduce and normalize. “Don’t rechallenge,” he said (Tracleer® package insert). Liver function normalizes when the drug is stopped, he said. “There has not been a case of progressive liver injury when this algorithm is followed,” he said.

The treatment algorithm for pulmonary hypertension, Class III and IV patients, follows:

• Anticoagulation for all patients
• Vasoreactivity testing; for the few responders (roughly 10% of PPH patients), consider calcium channel blocker therapy.
• Bosentan or prostanoid analogues for the large majority of patients who are nonresponsive to vasodilation or who lose that response. “Bosentan received a level A recommendation based on evidence,” he said.
• Prostanoid analogues (level B recommendation) include iloprost by inhalation, treprostinil, subcutaneous prostacyclin analogue for selected patients, orally active prostacyclin with “relatively modest efficacy”
• Epoprostenol IV is the treatment of choice for the sickest Class IV patients. Treprostinil also may be considered.
• If there is no improvement or if deterioration occurs, consider combination therapy. This approach is investigational.
• Lung transplantation “is the court of last appeal,” he said.

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