Pulmonary arterial hypertension: evaluation and management.

Abstract: Pulmonary arterial hypertension (PAH), a rare disease involving the pulmonary vascular circuit, is defined as an elevation in pulmonary arterial pressures and is characterized by symptoms of dyspnea, chest pain, and syncope. If left untreated, the disease carries a high mortality rate, with the most common cause of death being decompensated right heart failure. Over the past 5 years, there have been significant advances in this field in regards to understanding the pathogenesis, diagnosis, and classification of PAH. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality. Ongoing research promises to lead to a more comprehensive understanding of the genetics, etiology, and pathogenesis of pulmonary arterial hypertension, which may ultimately translate into more effective therapeutic options.

Key Words: pulmonary hypertension, pulmonary vascular disease, prostacyclin, endothelin

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Pulmonary arterial hypertension (PAH) is a progressive disease which leads to narrowing and occlusion of the blood vessels in the lungs. The estimated median survival is approximately 2.8 years. (1) From the time of diagnosis, the 1-, 3-, and 5-year survival rates noted in the National Institute of Health Registry on Primary Pulmonary Hypertension were 77%, 41%, and 27%, respectively. (2) However, this data antedated current and evolving therapies. Despite the development of these newer medical therapies, therapeutic options remain limited. Treatment is aimed at improving quality of life and survival. In this review, we will discuss the presentation, the approach to diagnosis, and the treatment options for individuals with pulmonary arterial hypertension.

Definition

The first description of pulmonary arterial hypertension was published in 1951, and since that time there has been moderate progress in the categorization and management of PAH. (3) The National Institutes of Health Registry on Primary Pulmonary Hypertension defined it as a mean pulmonary arterial pressure greater than or equal to 25 mm Hg at rest, with a pulmonary capillary wedge pressure of less than or equal to 15 mm Hg. It is also thought to include a mean pulmonary arterial pressure greater than 30 mm Hg with exercise. (1) After the 2003 World Health Organization classification revision, pulmonary arterial hypertension is now subdivided into five categories: pulmonary arterial hypertension, pulmonary venous hypertension, pulmonary hypertension associated with hypoxemia, pulmonary hypertension due to chronic thrombotic or embolic disease, and miscellaneous (4) (Table 1). This classification is useful in describing causative factors and targeting treatment.

The disease affects twice as many females as males. In women, it presents during their 30s, while in men it tends to present in the 40s. (1) In the general population, the frequency of PAH is thought to be approximately 1 to 2 cases per million people. (5) Recent data from the Centers for Disease Control, however, has found an increase in the hospitalization rates and death rates for individuals with pulmonary arterial hypertension, suggesting a possible increase in this incidence. (6)

Pathophysiology

There is still a great deal that is unknown regarding the pathophysiology of pulmonary arterial hypertension; however, much has been learned over the past ten years regarding the basic molecular defects. These studies suggest that the disease results from an imbalance between regulators of vasodilation and proliferation. Although many agents, including serotonin, adrenomedullin, vasoactive intestinal peptide and vascular endothelial growth factor have been implicated in the pathogenesis of pulmonary arterial hypertension, prostaglandin, thromboxane, nitric oxide and endothelin have received the most attention. (7)

Nitric oxide, a potent vasodilator, antimitogen, and thrombosis inhibitor, has also been demonstrated to be affected in patients with pulmonary artery hypertension. Endothelial nitric oxide synthase levels are decreased in the pulmonary vessels of these patients. The vasodilator effects of nitric oxide are mediated via increasing intracellular levels of cyclic guanosine monophosphate (cGMP), ultimately reducing intracellular calcium and relaxing pulmonary vascular smooth muscle.

Prostacyclin is a potent vasodilator, platelet inhibitor and antimitogen. There are less metabolites of prostacyclin in the urine of patients with pulmonary arterial hypertension. In addition, studies have shown a 50% reduction in prostacyclin synthase activity in the small pulmonary vessels of patients with pulmonary arterial hypertension. (8,9)

In contrast, thromboxane [A.sub.2], an arachidonic acid metabolite, vasoconstrictor and platelet activator is increased in patients with pulmonary arterial hypertension. Studies have also indicated that plasma levels of endothelin-1, a potent vasoconstrictor and pulmonary artery mitogen, are increased in the plasma and lung tissue in patients with pulmonary arterial hypertension. (10)

More recently, mutations in a protein receptor, bone morphogenetic protein receptor II (BMP R II) gene, have been found in familial and idiopathic types of PAH. These mutations have been seen to contribute to medial hypertrophy in blood vessels, plexiform lesion formation, and monoclonal endothelial cell proliferation. (11,12)

Our current understanding of the endothelial dysfunction found in pulmonary arterial hypertension includes a decrease in nitric oxide and prostacyclin synthesis, and an increase in thromboxane and enthothelin-1 synthesis. This disturbance of the normal balance results in the typical pathologic findings noted in this disease: small vessel smooth muscle hypertrophy, adventitial and intimal proliferation, and plexiform vascular lesions resulting in vascular thrombosis. The unraveling of these pathophysiological mechanisms provides the basis for the understanding of the pharmacological treatment of this disease and the disappointing responses to therapy found in more advanced disease states.

Clinical Assessment

The diagnosis of pulmonary arterial hypertension may be suspected based on a number of relatively nonspecific symptoms. Individuals often note slowly progressive dyspnea, exertional chest pain, a decrease in exercise tolerance, fatigue, and syncope. These nonspecific symptoms obviously require complete evaluation of more common cardiac and pulmonary disorders before proceeding to an evaluation of pulmonary arterial hypertension. Individuals with a history of certain other medical diseases, such as HIV and sickle cell anemia, are also at risk for pulmonary arterial hypertension. One should inquire about other possible medical issues and exposures which are associated with pulmonary arterial hypertension, including exposure to diet drugs, (13) amphetamines and other stimulants, toxic grapeseed oil, and a history or clinical signs of cirrhosis with portal hypertension and collagen vascular diseases. (14-19) Given the significant morbidity of PAH, a screening approach would be ideal; however, because of the rarity of the disease, the cost of screening would be prohibitive. Currently, family members and patients with diseases that predispose to the development of PAH should be evaluated with an echocardiogram.

In addition to symptoms, the physical examination can prompt an evaluation for pulmonary arterial hypertension. Individuals with PAH will often have an increased P2, ([S.sub.2]P) and paradoxical splitting of the second heart sound. The murmur of pulmonic regurgitation and tricuspid regurgitation may be heard, and a right ventricle heave may be appreciated. Patients with more advanced disease may demonstrate increased jugular venous pressure with prominent V waves, hepatomegaly with pulsations of the liver, and lower extremity edema associated with the right heart failure. Electrocardiographic changes may be present, including evidence of right ventricular hypertrophy, right atrial enlargement, and right axis deviation.

Pulmonary function testing can be utilized to aid in determining the etiology of dyspnea. One can identify obstructive or restrictive processes and demonstrate the gas exchange capabilities with evaluation of diffusing lung capacity for carbon monoxide. Patients with pulmonary arterial hypertension usually have normal pulmonary function in the early phase of disease. Over time and with progression, they demonstrate a decline in the DLCO with a mild to moderate decrease in lung volumes.

Radiographic imaging in patients with PAH can demonstrate a number of abnormalities. Oligemia may be present, with decreased vascularity seen peripherally on chest x-ray. The pulmonary arteries may be prominent and there can be evidence of right ventricular enlargement with loss of the retrosternal airspace on the lateral chest x-ray (Fig.). High resolution and contrast enhanced CT scanning can also assist in identifying enlarged pulmonary arteries, parenchymal lung disease contributing to the etiology, or may document embolic or thrombotic disease. Ventilation perfusion scans may demonstrate chronic or acute pulmonary vascular emboli or thrombosis and are an important screening tool for large central occlusive clots that may be amenable to thromboendarterectomy. Segmental or nonsegmental mismatched perfusion defects can suggest embolic or thrombotic phenomenon or venoocclusive disease. A pulmonary angiogram can assist in identifying distal vascular obstruction and aid in decisions regarding embolectomy or thromboendarterectomy. Pulmonary magnetic resonance angiogram can be used both to identify pulmonary artery hypertension, and acute and chronic pulmonary emboli. (20,21)

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Transthoracic echocardiography is a critical, noninvasive test in the differential diagnosis of pulmonary arterial hypertension. It can be used to assess left ventricle dysfunction, as well as aortic and mitral valve disease, which can all contribute to pulmonary arterial hypertension. PAH can lead to right atrial enlargement and right ventricular dysfunction. An echocardiogram can be used to evaluate tricuspid valve regurgitation, and from that measurement, an estimate of the right ventricular and pulmonary artery systolic pressure can be obtained. The right ventricular systolic pressure can be calculated from the tricuspid regurgitant velocity jet utilizing the modified Bernoulli Equation (RVSP = 4(velocity)[.sup.2] + right atrial pressure). A tricuspid valve regurgitant jet velocity of greater than 2.5 m/s is indicative of elevated pulmonary systolic pressure. Although several studies have shown an excellent correlation with the pulmonary artery systolic pressure measured at catheterization, it is possible to underestimate or overestimate the pulmonary artery systolic pressure utilizing this echocardiographic technique. (22-30)

Accordingly, right heart catheterization is the gold standard for the accurate determination of pulmonary artery pressure. It is the only way to accurately differentiate between pulmonary arterial hypertension and pulmonary venous hypertension via measurement of the pulmonary artery occlusion pressure. In addition to measuring pulmonary artery pressure, right heart catheterization can provide information for the calculation of pulmonary vascular resistance, cardiac output and the presence and extent of intracardiac shunts. During the course of right heart catheterization, it has become standard practice to assess the degree of vasoreactivity of the pulmonary circulation.

There is no serologic testing that is specific for pulmonary arterial hypertension; however, if clinical presentation is suggestive, complete liver function, thyroid function, HIV, and rheumatologic workup should be performed. Depending on the clinical presentation, testing might also include antinuclear antibodies, anticentromere antibody, anti-SCL-70 and RNP. These data will assist in determining the underlying etiology of the pulmonary arterial hypertension.

Functional classification becomes a useful way to assist in predicting mortality in patients with PAH. (32) Patients are classified according to their performance on cardiopulmonary exercise testing, but more commonly on their 6-minute walk performance. Miyamoto et al (31) demonstrated that individuals who are able to walk 332 m have a better prognosis than individuals who can walk less than that.

The World Health Organization's classification of functional status in patients with pulmonary arterial hypertension is customarily used as a way to describe the individual's limitation (Table 2).

Treatment

The treatment of pulmonary arterial hypertension has improved significantly over the past ten years (Table 3). The prior discussion of pathophysiology provides the basis for the current pharmacological approach to this disease. However, since the primary etiology of this disease remains unclear, the treatment has remained primarily palliative. Treatment options can be individualized based on the causative factors of the pulmonary arterial hypertension. Treatment options have expanded over the past ten years and include oral agents, inhaled agents, and IV agents. Treatment should be guided by a physician experienced in treating patients with pulmonary arterial hypertension. Currently available medications are prostanoids, phosphodiesterase-5 inhibitors, and endothelin receptor antagonists. Other treatments can also be individualized to address contributing factors. This would include using modalities such as positive airway pressure therapy for obstructive sleep apnea, or oxygen for hypoxemia. It is also advised that women with pulmonary artery hypertension not become pregnant, to avoid the hemodynamic changes and potential dangers during labor and delivery and the postpartum period. In addition, it is important for all patients to maintain an active lifestyle as much as possible, but individuals with severe PAH should be careful about overexertion, as life-threatening syncope is a risk.

As discussed previously, prostaglandins, nitric oxide and endothelins are all important mediators of pulmonary vascular homeostasis, and have been shown to be affected by this disease. The resultant effects lead to vasoconstriction, adverse vascular proliferation, and in situ thrombosis. Current therapies attempt to forestall or inhibit these adverse effects.

Prostanoids

Prostacyclin analogues, iloprost, treprostinil and epoprostenol, have been utilized to repair the imbalance between [PGI.sub.2] and [TBXA.sub.2]. These agents act as vasodilators and anti-platelet agents. They have been shown to decrease mean pulmonary artery pressure and increase the cardiac index in patients with PAH. (32) Studies also have demonstrated an improvement in the six-minute walk test as well as prolonged survival. (33) IV epoprostenol appears to have the best effects in this regard. Epoprostenol is administered via continuous IV infusion pump through a tunneled Hickman catheter. It has a brief half-life of three to five minutes. Headache, flushing, and transient jaw pain are among the most important side effects. Risks include infection of the indwelling vascular catheter, thrombosis, and rebound pulmonary arterial hypertension and even death if medication is reduced or withdrawn. Studies have shown a significant improvement in long term survival, quality of life, pulmonary pressures, and sixminute walk. (33,34)

Treprostinil. Treprostinil has a half-life of four and a half hours and can be delivered subcutaneously or intravenously. With subcutaneous administration, there can be significant injection site pain. If given IV, it appears to have all of the same benefits of subcutaneous administration, including improvement in the six-minute walk test and functional class. (35) When given IV, the side effects and benefits are similar to those seen with epoprostenol, and there is no injection site pain. The longer half life and drug stability at room temperature may provide significant safety advantages over epoprostenol.

Beraprost. Beraprost is used in Japan, but has not yet been approved in the United States. It can be taken orally and is fast acting with a peak concentration achieved in 30 minutes. A study conducted by Barst et al (36) was not able to demonstrate symptomatic improvement in dyspnea, or improvement in the 6-minute walk at 9 or 12 months. These findings, along with the side effect profile, including possible significant diarrhea and nausea, may prevent its approval in the United States.

Iloprost. Iloprost can be delivered orally, intravenously, or via aerosolized. In the United States, it is approved for aerosolized use and is administered six to nine times a day. The half-life is 20 to 24 minutes. Improvements in the six-minute walk and quality of life have been demonstrated. (37)

Phosphodiesterase Inhibitors

The most commonly used agents to enhance nitric oxide effects in this condition are the phosphodiesterase ([PDE.sub.5]) inhibitors. Specifically, [PDE.sub.5] inhibitors decrease the breakdown of cyclic GMP, thereby increasing intracellular levels of this vasorelaxing agent. [PDE.sub.5] inhibitors are most prominent in tissues with increased expression of [PDE.sub.5] isoenzymes such as the lungs, lower esophageal sphincter and the corpus cavernosum. Sildenafil is the only agent in this category approved for use in PAH. In a recently completed clinical trial, treatment with sildenafil resulted in significant improvement in the 6-minute walk and functional class. (38) The most important side effect during the study was headache. Follow-up data suggests that these effects are sustained.

Endothelin Receptor Blockers

Another class of agents used in the treatment of pulmonary artery hypertension are the endothelin-1 receptor antagonists. The most commonly utilized agent at this time is bosentan, an oral nonselective A and B receptor blocker. This agent also has produced a decrease in pulmonary vascular resistance and an improvement in the six-minute walk test. In addition, oral bosentan treatment has resulted in a significant survival benefit at 24-month follow-up. (39) Both the III and IV WHO consensus recommend bosentan for all patients not responding to calcium channel blockers. Important side effects of bosentan include elevation of liver function abnormalities in up to 11% of patients, and lower extremity edema.

Newer selective endothelin-A receptor antagonists, namely ambrisentan and sitaxsentan, are currently being studied. Prior data has demonstrated an improvement in the 6-minute walk, functional class and hemodynamics with sitaxsentan. (40) A phase 3 trial looking at ambrisentan has demonstrated an improvement in the 6-minute walk distance at week 12, compared with a baseline of 30 to 51 m. (41)

Other Medical Options

Other agents such as serotonin 2b receptor blockers have also been entertained. Serotonin has been found to contribute to smooth muscle cell hypertrophy, proliferation, and likely remodeling. (42) Vasoactive intestinal peptide (VIP) agonists are also being examined. VIP-containing nerve fibers are found in the airway. They have been seen to have pulmonary vasodilator properties. Aviptadil is a synthetically made inhalational form of vasoactive intestinal peptide currently in phase II clinical trials.

Future therapeutic agents also include SSRI inhibitors, anti-VEGF agents, potassium channel openers, immunosuppressant agents, statins, gene therapy, and tyrosine kinase inhibitors, to mention a few. Studies are underway with a number of these agents.

Combinations

In view of the above results, various combination therapy protocols have been introduced. Wilkens et al (43) stated that the combination of iloprost and sildenafil produced an additive effect on pulmonary artery measures. Further studies are ongoing in this area. The use of prostaglandin analogs is based on clinical considerations, and transition from these agents can be performed with careful monitoring and overlap therapies. Epoprostenol and iloprost are two agents commonly used in this setting.

Anticoagulation

Warfarin anticoagulation is recommended due to the fact that thrombosis in situ is found in 25 to 50% of these patients. Also, the pathophysiology of this disease provides a thrombotic medium in the pulmonary vessels in this setting. Prior studies addressing the use of oral anticoagulation looked at individuals with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with anorexigen use. These were nonrandomized studies. (44-46) In addition, the 1992 study by Rich et al, looking at calcium channel blockers and pulmonary arterial hypertension, noted an association of warfarin use with improved survival. (45) This was not a primary outcome being studied, however.

Additional Agents

The use of oxygen, diuretics and digitalis is not well defined, although maintenance of adequate Sa[O.sub.2] levels is obviously essential. Diuretics may be used for individuals with evidence of right heart failure. (47)

Calcium Channel Blockers

Oral calcium channel blockers may be effective in a small (5%) percentage of patients. Utilization of these agents should be based on evidence of dynamic pulmonary circulation vasoreactivity and sustained drug response. Survival is prolonged in individuals with a response to vasodilatory challenge. The challenge is conducted using agents such as adenosine, inhaled nitric oxide, or IV prostacyclin. A pulmonary artery catheter is placed and baseline readings are recorded on room air. The medication is then administered while catheter readings are observed. A positive response is one which causes a drop in pulmonary vascular resistance, or mean pulmonary artery pressure by 20%, or a mean pulmonary artery pressure drop to 40 mm Hg or less. Once a positive response is achieved with short-acting medication, oral calcium channel blockers can be used.

Surgical Options

Surgical options should also be considered. Atrial septostomy may be helpful by decompressing the right heart. These effects are variable and careful patient selection is critical. This can also be said for lung transplant selection. Individuals with New York Heart Association functional class III and IV should be referred for lung transplant evaluation. In patients with chronic thromboembolic disease and large central clots, pulmonary endarterectomy can prevent further propagation of changes in patent vessels, improve ventilation-perfusion mismatch, and limit right ventricular dysfunction, tricuspid regurgitation and extension of clot. (48,49)

The prognosis of pulmonary artery hypertension remains guarded despite recent advances. These patients present with complicated issues and their care is best provided in a center with clinicians experienced in the complex management of individuals with pulmonary artery hypertension. New treatments have improved both the lifespan and lifestyle of these patients. Further research will provide us with more information regarding etiologic mechanisms and more effective therapies. The large volume of research being done in the field of pulmonary hypertension continues to open many new avenues to the understanding and the management of this disease. Special efforts are being focused on the development of new pulmonary vasodilators, trying to make available more efficient and less cumbersome means of delivery.

Conclusion

Pulmonary arterial hypertension is a vascular disease, which may be primary or may stem from diverse etiologies. The common end result of these processes is elevation of pulmonary artery pressures and vascular resistance, with resultant right-sided heart failure. Progressive dyspnea is almost a cardinal feature of pulmonary arterial hypertension and may be accompanied by fatigue, syncope, or chest pain. Conventionally treated with vasodilators and anticoagulants, the concept of management of this disease has continued to evolve at a rapid pace. Apart from conferring symptomatic as well as hemodynamic improvement to patients with pulmonary arterial hypertension, pulmonary vasodilator use has been shown to delay or even set aside the need for lung transplantation in many patients. Research oriented toward a better understanding of the disease promises a much better prognosis in the near future.

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Anne V. LaRaia, MD, and Aaron B. Waxman, MD, PhD

From the Pulmonary Critical Care Unit and the Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Reprint requests to Dr. Aaron B. Waxman, Pulmonary Vascular Disease Program, Pulmonary Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 148, Boston, MA 02114. Email: [e-mail]

Dr. Waxman is an investigator in ongoing clinical trials with Pfizer, Encysive, Cotherix, and Myogen. He has no financial interest in any of these companies.

Accepted September 6, 2006.

RELATED ARTICLE: Key Points

* The typical signs and symptoms of patients presenting with unexplained dyspnea and suspected pulmonary hypertension are reviewed.

* The components of the clinical evaluation for patients with suspected pulmonary arterial hypertension are reviewed.

* The current therapeutic options in treating pulmonary arterial hypertension are reviewed.

Table 1. 2003 Revised Pulmonary Hypertension Classification

Group 1 -- Pulmonary arterial hypertension (PAH)
  1.1 Idiopathic pulmonary artery hypertension (IPAH)
  1.2 Familial pulmonary artery hypertension (FPAH)
  1.3 Disease associated with:
    Collagen vascular disease
    Congenital systemic to pulmonary shunts
    Portal hypertension
    HIV infection
    Drugs and toxins
    Other (glycogen storage disease, Gaucher disease, hereditary
      hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative
      disorders, splenectomy)
  1.4 Associated with significant venous or capillary involvement
    Pulmonary veno-occlusive disease (PVO)
    Pulmonary capillary hemangiomatosis (PCH)
  1.5 Persistent pulmonary hypertension
Group 2 -- Pulmonary venous hypertension associated with left heart
  disease
  2.1 Left-sided atrial or ventricular heart disease
  2.2 Left-sided valvular heart disease
Group 3 -- Pulmonary hypertension associated with hypoxemia
  3.1 COPD
  3.2 Interstitial lung disease
  3.3 Sleep-disordered breathing
  3.4 Alveolar hypoventilation disorders
  3.5 Chronic exposure to high altitude
  3.6 Developmental abnormalities
Group 4 -- Pulmonary hypertension due to chronic thrombotic and/or
  embolic disease
  4.1 Thromboembolic obstruction of proximal pulmonary arteries
  4.2 Thromboembolic obstruction of distal pulmonary arteries
  4.3 Pulmonary embolism (tumor, parasites, foreign material)
Group 5 -- Miscellaneous
  5.1 Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of
    pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

Table 2. World Health Organization

Functional Classes

I: Symptoms only at levels that would limit a normal individual
II: Symptoms with ordinary exertion
III: Symptoms with less than ordinary exertion
IV: Symptoms at rest

Table 3. Treatment

Prostacyclin deficiency
  Prostanoids
    Epoprostenol
    Treprostinil
    Iloprost
Nitric oxide deficiency
  Phosphodiesterase-5 inhibitors
    Sildenafil
Endothelin excess
  Endothelin receptor blockers
    Bosentan
Vasoreactive group
  Calcium channel blockers
All groups
  Oxygen
  Warfarin anticoagulation
  Diuretics
  Digitalis