Pulmonary Hypertension

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Chapter 58 Pulmonary Hypertension

Kristin B. Highland, Andre Holmes

Pulmonary arterial hypertension (PAH) is a rare, pathologically complex disease characterized by a progressive increase in pulmonary arterial pressure associated with variable degrees of pulmonary vascular remodeling, vasoconstriction, and in situ thrombosis. These changes lead in turn to increased pulmonary vascular resistance (PVR) and eventual right-sided heart failure and death. PAH has a nonspecific clinical expression; therefore, the diagnosis often is established late in the disease course, making treatment problematic. Without treatment, the median survival after diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is only 2.8 years.

Definition

The current definition of pulmonary hypertension (PH) is a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg measured with the patient at rest. A systolic pulmonary artery pressure (sPAP) greater than 35 to 40 mm Hg on echocardiogram should prompt further workup for PH, but determination of sPAP is not adequate as a stand-alone test.

In an exhaustive systematic review of the literature that included data from 1887 healthy people enrolled in 47 studies from 13 countries, mPAP measured with the subject at rest was 14.0 ± 3.3 mm Hg; this finding was independent of sex and ethnicity and only slightly influenced by age (in subjects younger than 30 years, 12 ± 3.1 mm Hg; in those older than 50 years, 14.7 ± 4.0 mm Hg). Therefore, if the upper limit of normal is defined by the mean plus two times the standard deviation, the upper limit for mPAP determined at rest in a healthy person is 20.6 mm Hg; this value is considerably lower than the established definition for PH of greater than 25 mm Hg. This same systematic review showed that mPAP measured during exercise was dependent on age, exercise type, and exercise intensity, making it difficult to establish a threshold value that would accurately define exercise-induced PH. As a result, the former exercise criterion of greater than 30 mm Hg was abandoned during the Fourth World Symposium on Pulmonary Hypertension held in 2008 in Dana Point, California.

Although modestly elevated mPAP in the setting of chronic lung disease often is associated with a poor prognosis, the significance of a “borderline” mPAP (20 to 25 mm Hg) in subjects who are otherwise healthy remains unclear. This uncertainty highlights the importance of the clinical assessment and the need for early biomarkers, rather than a focus on hemodynamics alone, especially because these data suggest that the prevalence of mPAP values greater than 25 mm Hg will be substantially higher than that indicated by the known prevalence of PAH.

Classification

Pulmonary hypertension was previously classified as either primary or secondary, depending on the absence or the presence, respectively, of identifiable causes or risk factors. The diagnosis of primary pulmonary hypertension was one of exclusion after ruling out all other causes for PH. Subsequent classification schemes have attempted to create categories of PH that share pathologic and clinical features, as well as similar therapeutic options. These classification schemes have allowed investigators to conduct clinical trials in well-defined patient groups with a shared underlying pathogenesis for their PH, resulting in the development of new targeted drug therapies; consequently, improvements in both quality of life and survival can now be expected in this otherwise deadly disease. This more inclusive category of PAH also has afforded increased opportunities for treatment of some less common forms of the disorder that were previously too rare for individual treatment studies. The most recent classification scheme was the product of the aforementioned Fourth World Symposium on Pulmonary Hypertension (Box 58-1).

Box 58-1

Updated Clinical Classification of Pulmonary Hypertension

1. Pulmonary arterial hypertension (PAH)

1.1. Idiopathic PAH
1.2. Heritable:
1.2.1. BMPR2
1.2.2. ALK-1, endoglin
1.2.3. Unknown
1.3. Drug- or toxin-induced
1.4. Associated with:
1.4.1. Connective tissue diseases
1.4.2. Human immunodeficiency virus (HIV) infection
1.4.3. Portal hypertension
1.4.4. Congenital heart diseases
1.4.5. Schistosomiasis
1.4.6. Chronic hemolytic anemia
1.5. Persistent pulmonary hypertension of the newborn

1′ Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis

2. Pulmonary hypertension due to left-sided heart disease

3. Pulmonary hypertension due to lung disease and/or hypoxia

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with multifactorial mechanisms

Group 1: Pulmonary Arterial Hypertension

PAH is a subset of PH defined as a mPAP greater than 25 mm Hg determined with the patient at rest and a normal pulmonary capillary wedge pressure (PCWP) and/or left ventricular end-diastolic pressure (LVEDP) and a lesion localized to the pulmonary arteriole (Figure 58-1, A to C). Unfortunately, a limitation of these classification schemes is the fact that many of these patients have “multifactorial pulmonary hypertension.” The clinician is thus faced with treating PH in a variety of clinical scenarios that often include features from more than one of the World Health Organization (WHO) classification categories (i.e., groups 1 to 5, with an additional 1′ grouping as described later on). For example, the clinical presentation may include somewhat elevated pulmonary venous pressures, mild to moderate obstructive or restrictive lung disease, or a form of valvular heart disease that typically would not account for pulmonary hypertension severity. Patients with such “out of proportion” PH are not included in clinical trials; therefore, data pertaining to the safety and efficacy of conventional PAH therapies in this population are extremely limited.

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Figure 58-1 Histologic preparations (Von Giesen elastic stain) of normal lung and of specimens from patients with pulmonary arterial hypertension (PAH). A, Normal pulmonary arteriole flanked by a normal bronchiole (the latter at the 11 o’clock position). B, Concentric obliterative lesion characteristic of PAH. Intimal proliferation with encroachment on the lumen can be seen. A plexiform lesion is present to the left of the artery (at the 9 o’clock position). 40× objective. C, Plexiform lesions characteristic of PAH. 10× objective.

Idiopathic Pulmonary Arterial Hypertension

IPAH is a rare disease and remains a diagnosis of exclusion. Patients with this sporadic form of PAH do not have a family history of PAH or any identifiable risk factors. A female preponderance, with a gender ratio of 1.7 : 1, has been recognized, and the mean age at diagnosis is 37 years. The incidence of IPAH is approximately 1 to 2 cases per 1 million population, with a prevalence of approximately 6 per 1 million. Although IPAH originally was believed to be a disease of child-bearing women, cases of IPAH recently have been reported in a number of patients older than 70 years of age.

Heritable Pulmonary Arterial Hypertension

Several germline mutations have been associated with heritable PAH. These include mutations in the genes encoding bone morphogenetic protein receptor type II (i.e., BMPR2), active-like kinase type 1 (ALK-1), and endoglin.

Sporadic mutations in BMPR2 have been identified in approximately 11% to 40% of patients with presumably the idiopathic form of PAH and are seen in 70% to 80% of patients with familial PAH but are relatively uncommon in patients with so-called associated PAH (i.e., category 1.4 in Box 58-1). Although penetrance is low and only approximately 25% of carriers will go on to develop PAH, genetic anticipation also has been demonstrated (i.e., in affected families, each successive generation has more severe PAH developing at an earlier age). BMPR2 has been localized to chromosomal region 2q31-32, and inheritance occurs in an autosomal dominant fashion. Recently, it has been suggested that patients with PAH associated with BMPR2 mutations may represent a subgroup with more severe disease who are less likely to demonstrate vasoreactivity than those with IPAH. Because this mutation can occur sporadically in as many as 25% of patients with PAH and does not occur in all patients with so-called familial PAH, the term heritable is now favored over the designation familial.

Like BMPR-II, ALK-1 and endoglin also are members of the transforming growth factor-β (TGF-β) superfamily and are located on endothelial cells, and mutations can result in heritable PAH. Mutations in the ALK-1 gene and/or the endoglin gene also are associated with the autosomal dominant disorder hereditary hemorrhagic telangiectasia.

Drug- and Toxin-Induced Pulmonary Arterial Hypertension

A number of risk factors for the development of PAH have been identified (Box 58-2). Risk factors for PAH include “any factor or condition that is suspected to play a predisposing or facilitating role in the development of the disease.” Such risk factors have been categorized as “definite, very likely, possible, or unlikely, based on the strength of their association with [pulmonary hypertension] and their probable causal role.” As a result of the Dana Point symposium, methamphetamine use was reclassified as a very likely risk factor for the development of PAH.

Box 58-2

Risk Factors for Pulmonary Arterial Hypertension

Definite

Aminorex

Fenfluramine

Dexfenfluramine

Toxic rapeseed oil

Likely

Amphetamines

L-Tryptophan

Methamphetamines

Possible

Cocaine

Phenylpropanolamine

St. John’s wort

Chemotherapeutic agents

Selective serotonin reuptake inhibitors

Unlikely

Oral contraceptives

Estrogen

Cigarette smoking

Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases

PAH can occur in any of the connective tissue diseases but most commonly is seen in systemic sclerosis (scleroderma), mixed connective tissue disease, and systemic lupus erythematosus (SLE). The prevalence of PAH among patients with scleroderma is estimated to be between 7% and 12%. Although less well characterized, the prevalence among persons with SLE is thought to be between 1% and 4%. Of note, PAH is not the only cause of pulmonary hypertension in patients with connective tissue disease; these patients frequently have lung fibrosis and cardiac involvement. Experts recommend that all patients with systemic scleroderma have a yearly screening echocardiogram, because untreated PAH in patients with connective tissue disease is associated with a particularly poor prognosis.

Human Immunodeficiency Virus Infection

The prevalence of PAH in the human immunodeficiency virus (HIV)-infected population is approximately 1 per 200 persons. The mechanism for the development of PH remains unclear; it is thought to be a result of the indirect action of the virus through secondary messengers such as cytokines, growth factors, endothelin, or viral proteins. The occurrence of PAH is independent of the CD4+ count, but it seems to be related to the duration of HIV infection. PAH also is more common in those patients infected through intravenous drug abuse. PAH is an independent predictor of mortality in these patients; in a substantial number of cases, however, normalization of pulmonary vascular hemodynamics can be obtained with specific therapy for PAH.

Portal Hypertension

The development of PAH in association with elevated pressure in the portal circulation is known as portopulmonary hypertension (POPH). Portal hypertension, rather than the presence of underlying liver disease, is the main determining risk factor for the development of POPH. Approximately 2% to 6% of patients with portal hypertension will also have PH. The diagnosis of POPH usually is made within 4 to 7 years after the diagnosis of portal hypertension. Female sex and autoimmune hepatitis are risk factors for the development of POPH; as a point of interest, hepatitis C infection is associated with a decreased risk. The presence of PAH is a contraindication to liver transplantation, so all patients being referred for transplantation require a screening echocardiogram. Right-sided heart catheterization is absolutely mandatory for the definitive diagnosis of POPH, because several factors may increase PAP in the setting of advanced liver disease. For example, high flow and an elevated cardiac output are associated with the hyperdynamic circulatory state seen in advanced liver disease, and an increased PCWP secondary to fluid overload and/or diastolic dysfunction also will increase PAP. These conditions generally are associated with a normal PVR.

Congenital Heart Disease

Persistent exposure of the pulmonary vasculature to increased blood flow and pressure results in vascular remodeling, leading to an increased PVR and eventual shunt reversal. Eisenmenger syndrome is defined as congenital heart disease with an initial large and nonrestrictive systemic-to-pulmonary shunt that induces progressive pulmonary vascular disease and PAH, with resultant reversal of flow and cyanosis. This clinical entity represents the most advanced form of PAH associated with congenital heart disease. Although Eisenmenger syndrome occurs more frequently when blood flow is extremely high and the shunt exposes the pulmonary vasculature to systemic-level pressures, such as occurs with a ventricular septal defect, patent ductus arteriosus, or truncus arteriosis, PAH also may occur with low-pressure–high-flow abnormalities such as those seen with atrial septal defects.

Schistosomiasis

Previously, schistosomiasis was categorized in group 4 as PH due to chronic thrombotic and/or embolic disease secondary to embolic obstruction of pulmonary arteries by Schistosoma eggs. More recent publications, however, indicate that PH can be similar in presentation to IPAH, with similar histopathologic changes. The mechanism probably is multifactorial and related to POPH, a frequent complication of this disease, and to local vascular inflammation occurring as a result of impacted Schistosoma eggs. This is a common cause of PH worldwide: It is estimated that more than 200 million people are infected with schistosomiasis, and anywhere from 4% to 8% of these patients will develop hepatosplenic disease; 4.6% of these will then go on to develop PAH. Schistosomiasis also may cause postcapillary hypertension, reinforcing the need for diagnosis with right-sided heart catheterization.

Chronic Hemolytic Anemia

Increasing evidence suggests that PAH is a complication of chronic hereditary and acquired hemolytic anemias, including sickle cell disease, thalassemia, hereditary spherocytosis, stomatocytosis, and microangiopathic hemolytic anemia. The mechanism of PAH in hemolysis is uncertain but may involve high rates of nitric oxide consumption by free hemoglobin, resulting in a state of resistance to nitric oxide bioactivity.

Group 1′: Pulmonary Arterial Hypertension Associated with Pulmonary Venous or Capillary Abnormalities

Rarely, the typical findings in PAH also are associated with an occlusive venopathy—pulmonary venoocclusive disease (PVOD)—or a microvasculopathy—pulmonary capillary hemangiomatosis (PCH). Patients with these diseases exhibit features of both PAH and pulmonary venous hypertension, including pulmonary hemosiderosis, interstitial edema, and lymphatic dilatation. PVOD and PCH share similar risk factors including the scleroderma spectrum of disease, HIV infection, and the use of anorexigens. These entities should be suspected in the clinical setting of PAH associated with crackles on auscultation, digital clubbing, and pulmonary edema. Ground glass opacities, septal thickening, and mediastinal adenopathy may be seen on chest computed tomography scans. PVOD and PCH are set aside from the other members of group 1 because the management, response to medical therapy (patients with PVOD and PCH tend to develop pulmonary edema after the administration of PAH-specific therapies), and prognosis are quite different from that of PAH.

Group 2: Pulmonary Hypertension Due to Left-Sided Heart Disease

Pulmonary hypertension due to left-sided heart disease is defined as a mPAP greater than 25 mm Hg measured with the subject at rest with an elevated PCWP and/or LVEDP. It represents the most frequent cause of PH (accounting for more than 90% of the cases). Causes include systolic and diastolic heart failure as well as left-sided valvular disease. Guidelines have defined a PCWP and/or LVEDP less than 15 mm Hg as abnormal. In these patients, the PVR is normal or near normal (less than 3.0 Wood units), and no gradient significant is present between mPAP and pulmonary wedge pressure (i.e., the transpulmonary gradient is less than 12 mm Hg). In some patients with left-sided heart disease, the elevation of PAP is out of proportion to that expected from the elevation of the left atrial pressure, resulting in an increased PVR. This is due to either the increase in pulmonary artery vasomotor tone or pulmonary vascular remodeling, or both. No studies using medications approved for PAH have been performed in this patient population, and the efficacy and safety of PAH treatment medications remain unknown.

Group 3: Pulmonary Hypertension Due to Lung Disease And/or Hypoxia

Pulmonary hypertension associated with disorders of the respiratory system or hypoxemia is a category of PH that is caused mainly by inadequate oxygenation of pulmonary arterial blood as a result of either parenchymal lung disease (e.g., emphysema, interstitial lung disease), impaired control of breathing (e.g., obesity hypoventilation, obstructive sleep apnea), or residence at high altitude. As a rule, mPAP generally is modest (less than 35 mm Hg), and survival depends on the severity of the pulmonary disease, rather than on the severity of the associated hypertension. As with the category of PH out of proportion to left-sided heart disease, large randomized, controlled studies of medications approved for PAH are not available for PH out of proportion to parenchymal lung disease.

Group 4: Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important category of PH to exclude, because a proximal organized clot in the major pulmonary arteries may be surgically correctable by pulmonary endarterectomy. In all cases, life-long anticoagulation is indicated. The cumulative incidence of CTEPH after a first episode of pulmonary embolism approaches 4% at the 2-year follow-up examination.

Group 5: Pulmonary Hypertension of Unclear or Multifactorial Etiology

Group 5 consists of several forms of PH for which the etiology is unclear or multifactorial. Potential etiopathogenic disorders include chronic myeloproliferative disorders (polycythemia vera, essential thrombocythemia, chronic myeloid leukemia), systemic disorders (sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis type 1, antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis), metabolic disorders (type Ia glycogen storage disease, Gaucher disease, thyroid disease), and miscellaneous conditions (tumor obstruction, mediastinal fibrosis, end-stage renal disease).

Pathobiology

Normal pulmonary arteries have a thin medial layer of circular muscle whose thickness is less than 5% of the diameter of the vessel (see Figure 58-1, A). Consequently, under physiologic conditions, the pulmonary circulation is characterized by high flow, low pressure, and low vascular resistance. The histopathologic findings in PAH are characterized by variable intimal hyperplasia, medial hypertrophy, adventitial proliferation, and fibrosis culminating in concentric obliterative lesions (see Figure 58-1, B) that occur in close proximity to plexiform lesions (see Figure 58-1, C). The plexiform lesion results from neointimal proliferation and progresses from a cellular to a fibrotic lesion with advancing disease. It is made up of a predominance of endothelial cells in different stages of vascular organization, suggesting an abnormal form of angiogenesis. Pulmonary vascular remodeling also has been associated with in situ thrombosis and infiltration by inflammatory and progenitor cells.

As the vascular pathology progresses, the PVR increases and PAP rises in concert, in order to maintain cardiac output. So long as the right ventricle is able to compensate for the resistance, the pressure continues to increase as the PVR increases. When the contractile reserve of the right ventricle is exhausted, right ventricular systolic failure ensues. A varying degree of right ventricular diastolic dysfunction also is present in PH and is related to right ventricular muscle mass and afterload and correlates with parameters of disease severity. The combination of reduced right ventricular output and diastolic dysfunction enhances diastolic interdependence, severely impairing left ventricular filling and ultimately resulting in hemodynamic deterioration.

Unfortunately, what is known about the pathobiology of PAH largely stems from research in patients with IPAH or from animal models that are meant to represent IPAH. Nevertheless, the pathobiologic features of PAH are thought to result from a multiple-hit hypothesis involving the interaction of a predisposing state with an inciting stimulus (Figure 58-2). Consequently, the resulting imbalance favors vasoconstriction, thrombosis, and mitogenesis. Restoration of this balance by inhibition of endothelin and thromboxane or augmentation of nitric oxide and prostacyclin forms the basis of today’s current therapies.

image

Figure 58-2 Proposed pathogenesis of pulmonary arterial hypertension (PAH).

(From Reed AK, Evans TW, Wort SJ: Pulmonary hypertension. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

Prostacyclin (i.e., prostaglandin I2 [PGI2]) is a product of endothelial cells generated by the action of prostacyclin synthase on arachidonic acid. Prostacyclin relaxes smooth muscle by increasing intracellular cyclic adenosine monophosphate (cAMP). It also is an inhibitor of platelet aggregation and smooth muscle cell proliferation. Patients with PAH exhibit increased excretion of urinary metabolites of thromboxane and decreased excretion of urinary metabolites of prostacyclin in comparison with normal control subjects. Likewise, prostacyclin synthase activity is reduced in patients with PAH.

Endothelin-1 is synthesized and secreted by endothelial cells and is metabolized in the normal lung. It is a potent acute vasodilator and chronically stimulates cellular proliferation and fibrosis. Patients with PAH exhibit increased plasma levels of endothelin-1 and decreased clearance in comparison with normal control subjects.

Nitric oxide is a potent vasodilator that is produced by endothelial cells from arginine by nitric oxide synthase and acts on the vascular smooth muscle cells via cyclic guanosine monophosphate (cGMP). Phosphodiesterase-5 degrades cGMP, thus counteracting this vasodilatory pathway. Patients with PAH have decreased plasma levels of nitric oxide metabolites; likewise, endothelial nitric oxide synthase (eNOS) expression is reduced in the pulmonary arteries.

Ongoing research on other mediators and pathways (Table 58-1) promises new targets for novel therapies.

Table 58-1 Mediators and Pathways in Pulmonary Arterial Hypertension

Increased Activity Decreased Activity

Endothelin-1

Serotonin

Thromboxane A2

Angiopoietin-1

Plasminogen activator inhibitor-1

Growth factors

Oxidant stress

Inflammation

Prostacyclin synthase

Nitric oxide

Nitric oxide synthase

Vasoactive intestinal peptide

Voltage-gated potassium channels

Fibrinolysis

Diagnostic Approach

The diagnosis of PH is complex and should involve early referral to a provider with expertise in the diagnosis and treatment of the condition. Patients may present because they are concerned about symptoms, because they require further investigation of an incidental finding during previous testing, or because they belong to a high-risk population (e.g., systemic sclerosis, congenital heart disease, liver transplantation evaluation).

Signs and Symptoms

There are no early signs or symptoms of PH. Therefore, annual screening should be performed in high-risk populations (Table 58-2). A diagnosis of PH should be considered in any patient who presents with breathlessness in the absence of specific cardiac or pulmonary disease, or in patients who have underlying cardiac or pulmonary disease and present with increasing breathlessness that is not explained by the underlying disease itself. The initial symptoms and signs are nonspecific and may include fatigue, progressive dyspnea on exertion, palpitations, chest pain, dizziness, and cough. Unfortunately, the mean duration of symptoms before diagnosis reported in most registries approaches 2 years. Exertional dizziness and syncope are suggestive of an inadequate cardiac output and should raise clinical suspicion for PH. As PH progresses, patients go on to develop symptoms and signs of right-sided heart failure including jugular venous distention, right ventricular heave, tricuspid regurgitation, right ventricular gallops, ascites, and edema. Establishing an accurate diagnosis has important implications for therapy.

Table 58-2 Recommendation for Screening for Pulmonary Arterial Hypertension

Risk Factor Recommendation
Family history of PAH Yes
Connective tissue disease  
Scleroderma Yes
Other No
Congenital heart disease  
Large ASD, nonoperated Yes
Large VSD, nonoperated Yes
HIV infection No
Portal hypertension No
Consideration for liver transplantation Yes
Use of appetite-suppressant drugs No
Previous pulmonary embolism No
Increasing dyspnea Yes
Massive/submassive PE Yes

ASD, atrial septal defect; HIV, human immunodeficiency virus; PE, pulmonary embolism; VSD, ventricular septal defect.

Electrocardiogram

The electrocardiogram shows abnormalities in 85% of patients with established PH but is not adequately sensitive as a screen for PH. Typical changes include right axis deviation with evidence of right ventricular or right atrial hypertrophy and right ventricular strain (Figure 58-3). The degree of these changes does not always reflect the severity of disease, and a normal ECG appearance does not eliminate the diagnosis of PH. Nevertheless, the following ECG findings have negative prognostic implications: (1) right axis deviation, (2) a tall R wave and small S wave with R/S ratio greater than 1 in lead V1, (3) qR complex in lead V1, (4) rSR′ pattern in lead V1, (5) a large S wave and small R wave with R/S ratio less than 1 in lead V5 or V6, or (6) S1-S2-S3 pattern (see Figure 58-3).

image

Figure 58-3 Electrocardiogram (ECG) demonstrating right atrial enlargement and right ventricular enlargement with strain in a patient with pulmonary arterial hypertension (PAH).

Chest Radiograph

The chest radiograph also is not particularly sensitive for detecting PH. However, incidental findings of enlarged main and hilar pulmonary arterial shadows (right descending greater than 1.6 cm, left greater than 1.8 cm), with concomitant attenuation of peripheral pulmonary vascular markings (“pruning”), and right ventricular hypertrophy as evidenced by a reduced retrosternal clear space on the lateral projection should prompt a workup for PH. Chest radiographic findings also may lead to the diagnosis of an underlying pulmonary process (Figure 58-4).

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Figure 58-4 Chest radiograph obtained in a patient with pulmonary arterial hypertension (PAH). Note the massively enlarged pulmonary arteries and peripheral “pruning.”

Pulmonary Function Testing

Pulmonary function testing is a necessary part of the initial evaluation of all patients with PH, to exclude or characterize the contribution of underlying airway or parenchymal lung disease. On such testing, patients with IPAH and CTEPH typically exhibit a mild to moderate restrictive ventilatory defect and evidence of small airways dysfunction with a reduction in diffusion capacity. No correlation has been observed between the severity of PH and the reduction in diffusion; however, an isolated reduction in diffusion should alert the physician to the possibility of underlying PH. Arterial blood gas analysis typically shows hypoxemia, hypocapnia secondary to alveolar hyperventilation, and an increased alveolar-arterial oxygen gradient. Severe hypoxemia usually is the result of intracardiac shunting.

Overnight Oximetry/Polysomnography

Nocturnal desaturation in PH is related primarily to gas exchange abnormalities. Although the clinical consequence of nocturnal desaturation is not well understood, it is likely that hypoxia-induced pulmonary vasoconstriction exacerbates the preexistent pulmonary hypertensive state. Nocturnal desaturation cannot be predicted by exercise desaturation; therefore, overnight oximetry is recommended in all patients with PH. Use of standard oxygen-prescribing guidelines, such as those derived from the Nocturnal Oxygen Treatment Trial, are recommended for hypoxemic patients with PH to maintain an oxygen saturation greater than 90% in adults.

The literature examining the relationship between obstructive sleep apnea and PH is difficult to interpret. In general, pulmonary hypertension associated with obstructive sleep apnea is mild with an average mPAP less than 30 mm Hg. It is recommended that all patients with PH be assessed for sleep-disordered breathing, and polysomnography should be performed if the clinical presentation is highly suggestive of obstructive sleep apnea. Although these patients are at higher risk for other cardiovascular morbidity, routine screening for PH with echocardiography is not recommended in patients with obstructive sleep apnea. In patients with concomitant obstructive sleep apnea and PH, treatment of the sleep apnea with positive-pressure therapy should be provided, with the expectation that pulmonary pressures will decrease, although they may not normalize, particularly when PH is more severe.

Ventilation-Perfusion Scan

PH caused by chronic thromboembolic disease is a potentially surgically curable condition that should be considered in all patients with unexplained PH. A ventilation-perfusion scan is essential to rule out chronic thromboembolic disease in all patients with unexplained pulmonary hypertension; a normal scan effectively excludes a diagnosis of chronic thromboembolic disease. In patients with PAH, the ventilation-perfusion scan typically is normal or displays only minor, patchy perfusion defects, whereas in patients with CTEPH, at least one but often several major segmental or subsegmental mismatches in ventilation and perfusion will be evident (Figure 58-5, A and B). Unmatched perfusion defects also may be seen in PVOD. The “gold standard” diagnostic modality remains contrast angiography performed at the time of catheterization, which is able to characterize the nature and extent of any thromboembolic disease.

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Figure 58-5 A, Patchy subsegmental defects on perfusion scan obtained in a patient with pulmonary arterial hypertension (PAH). B, Multiple segmental (or larger) defects on perfusion scan obtained in a patient with chronic thromboembolic pulmonary hypertension (CTEPH).

(From Reed AK, Evans TW, Wort SJ: Pulmonary hypertension. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

Chest Computed Tomography

A wide spectrum of abnormalities on computed tomography (CT) scanning has been described in patients with chronic thromboembolic disease. Such abnormalities may include right ventricular enlargement, dilated central pulmonary arteries, presence of persistent thromboembolic material within central pulmonary arteries, increased bronchial artery collateral flow, variability in the size and distribution of pulmonary arteries, parenchymal abnormalities consistent with previous infarcts, or mosaic attenuation of the pulmonary parenchyma (Figure 58-6). These are nonspecific findings, however, and their absence does not exclude the presence of surgically accessible disease, because only sixth- or seventh-generation pulmonary arteries can be visualized with confidence. Therefore, contrast-enhanced CT should not be used to exclude the diagnosis of chronic thromboembolic disease.

image

Figure 58-6 Computed tomography angiogram obtained in a patient with chronic thromboembolic pulmonary hypertension (CTEPH). Note the mosaic pattern of perfusion.

High-resolution CT (HRCT) scanning, however, is required to exclude parenchymal lung disease as the cause of PH and may be particularly useful in helping to make the diagnosis of PVOD.

Echocardiogram

In patients in whom the clinical picture is suggestive of PH or in asymptomatic patients at high risk for the condition, Doppler echocardiography should be performed as a noninvasive screening test to detect elevated sPAP. It provides a noninvasive estimation of right ventricular function and sPAP and can reveal other underlying cardiac abnormalities.

Signs indicative of PH on echocardiogram include increased sPAP or tricuspid regurgitant jet, right atrial and ventricular hypertrophy, flattening of the intraventricular septum, small left ventricular dimension, and a dilated pulmonary artery (Figure 58-7, A and B). A pericardial effusion in the setting of PH carries a poor prognosis. Although echocardiography has been found to correlate with right-sided heart catheterization, Doppler echocardiography generally underestimates systolic PAP in patients with severe PH and overestimates systolic PAP in populations consisting mostly of subjects with normal pressures. Furthermore, the systolic PAP may fall in decompensated right ventricular heart failure (Figure 58-8). Echocardiography also is particularly inaccurate in persons with advanced lung disease and both underestimates and overestimates the degree of PH in these patients. With echocardiographic evidence of significant PH, a right-sided heart catheterization should always be undertaken at least once to provide an accurate baseline assessment of the pulmonary hemodynamics and to permit reversibility studies. Echocardiography is, however, useful in following disease progression, removing the need for repeated pulmonary artery catheterizations.

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Figure 58-7 A, Echocardiogram, four-chamber view, obtained in a normal subject. B, Echocardiogram, four-chamber view, obtained in a patient with pulmonary arterial hypertension (PAH). Note the enlarged right atrium, right ventricle with intraventricular septal flattening, and small dimension of the left ventricle.

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Figure 58-8 Pathophysiology of pulmonary arterial hypertension. In the early stages, cardiac output remains normal at rest but fails to increase appropriately with exercise. With disease progression, cardiac output falls and is subnormal even when the patient is at rest. PAP, pulmonary artery pressure.

(From Reed AK, Evans TW, Wort SJ: Pulmonary hypertension. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

Contrast echocardiography can be useful to assess for intracardiac shunting suggesting the possibility of a congenital heart defect or patent foramen ovale. Agitated saline contrast or commercially available encapsulated microbubble contrast agents also can be used to enhance the spectral tricuspid regurgitant signal. As a general rule, a right ventricular systolic pressure greater than 40 mm Hg generally warrants further evaluation in the patient with unexplained dyspnea. An abnormal right-sided morphology or function also should trigger further evaluation.

Exercise echocardiography is challenging both to perform and to interpret and may not be able to discern the extent to which elevated left-sided heart filling pressure may contribute to “exercise-induced pulmonary hypertension.” Therefore, no treatment decisions can be made on the basis of exercise-induced pulmonary hypertension alone.

Right-Sided Heart Catheterization

In patients with suspected PH, right-sided heart catheterization is required to confirm the presence of PH, to establish the specific diagnosis, and to determine the severity and prognosis of PH. In particular, an elevated right atrial pressure and a depressed cardiac output are associated with worse prognosis and decreased survival. The PCWP is, by definition, normal in PAH. An elevated PCWP in the absence of left-sided heart disease should raise clinical suspicion for PVOD, although the PCWP also is commonly normal, in keeping with the patchy nature of this disease. The transpulmonary gradient (i.e., mPAP – PCWP) is significantly elevated in patients with PAH, but not in patients whose PH is due to increased cardiac output or left-sided heart myocardial or valvular disease. In other words, by definition, both PAP and PVR are elevated in patients with PAH.

Right-sided heart catheterization also can be used to evaluate for vasoreactivity and to guide therapy; a favorable acute response to a vasodilator (intravenous epoprostenol, adenosine, or inhaled nitric oxide) is defined as a fall in mPAP of at least 10 mm Hg to 40 mm Hg or less, with an increased or unchanged cardiac output. These “responders” have an improved survival when treated with calcium channel blockers (a 95% 5-year survival rate has been reported). Of note, patients with suspected PVOD should not be subjected to vasoreactivity studies, because such testing may precipitate life-threatening pulmonary edema.

Functional Assessment

In patients with PAH, serial determinations of functional class and exercise capacity assessed by the 6-minute walk test provide benchmarks for disease severity, response to therapy, progression, and survival. WHO functional classification of patients with PAH is based on a modification of the New York Heart Association (NYHA) system for heart failure and takes syncope into account as a marker of functional status.

The 6-minute walk test is simple and reproducible and has been used as the primary end point in a number of clinical trials for PAH. The 6-minute walk distance correlates inversely with functional class and PVR and directly with baseline cardiac output, peak exercise oxygen consumption, and survival. This test, however, gives no indication of the source of exercise impairment and is less discriminatory for walk distances greater than 450 m (“plateau effect”). Consequently, it is less useful for patients with systemic disease and those assigned to functional class I or II.

Although CPET is used less frequently in PAH clinical trials, owing to a lack of methodologic consistency among different centers, maximal oxygen consumption (peak VO2) determined by progressive exercise testing with cycle ergometry was found to be an independent predictor of survival in a study in patients with IPAH. In this study, a peak VO2 greater than 10.4 mL/kg/minute was associated with significantly better 1-year survival than lower peak VO2 values. Patients with a peak systemic blood pressure higher than 120 mm Hg also enjoyed a better 1-year survival than those patients who did not achieve this systemic blood pressure.

Biomarkers

Brain natriuretic peptide (BNP) is released from cardiac myocytes in response to increased ventricular wall tension. ProBNP (the prohormone) is cleaved into active BNP and the more stable amino-terminal (N-terminal) fragment (NT) proBNP. Studies in patients with PAH have demonstrated that plasma BNP and/or proBNP levels are raised in proportion to the extent of right ventricular dysfunction. Growing evidence suggests that BNP may be a potential biomarker for PAH in screening for occult disease, diagnostic evaluation, gauging prognosis, and predicting response to therapy. Baseline and serial changes in BNP correlate well with mortality and other markers such as pulmonary hemodynamics, WHO functional class, and 6-minute walk test. Of note, however, because plasma BNP levels rise in a variety of cardiopulmonary conditions and are affected by several physiologic factors, interpretation of BNP assay results requires experience and good clinical judgment; NT proBNP may have an advantage over BNP, because it is less affected by renal function and age.

Other biomarkers of interest include uric acid and troponin levels. In IPAH, uric acid levels may reflect impaired oxidative metabolism and have been shown to be increased with worsening severity of functional class and hemodynamics and correlated with mortality. Detectable cardiac troponin T also confers a poor prognosis, potentially as a consequence of the effect of right ventricular ischemia.

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging (MRI) is now the most accurate means for examination of the structure and function of the right ventricle and is able to accurately assess the size and function of the right ventricle with a high degree of reproducibility. Right ventricular function is an important prognostic indicator in PAH and cardiac MRI of poor right ventricular function, including stroke volume of 25 mL/m2 or less, right ventricular end-diastolic volume of 84 mL/m2 or greater, and left ventricular end-diastolic volume of 40 mL/m2 or less, were found to be independent predictors of mortality and treatment failure, and pulmonary artery stiffness, as measured by relative cross-sectional area change, was predictive of survival in a cohort of 86 patients with PAH studied with MRI. Those with a relative cross-sectional area change of less than 16% had a greater mortality than those with values greater than 16%. The use of noninvasive imaging, such as cardiac MRI, to monitor disease-targeted therapy currently is being evaluated.

Other Blood Tests

All patients should have routine hematology, biochemistry, and thyroid function tests. Antinuclear antibody testing frequently gives a positive result in patients with PAH despite absence of connective tissue disease (29% in the National Institutes of Health [NIH] registry) despite the absence of connective tissue disease. These usually are of a nonspecific pattern and are present in low titers. Strongly positive results on serologic testing should lead to further, more specific investigations to exclude PAH related to connective tissue disease. HIV testing should be considered in all patients presenting with apparent PAH.

Approach to Therapy

Treatment goals for patients with PAH include reduction in clinical signs and symptoms and improvement in exercise tolerance, functional class, hemodynamics, and quality of life, along with decreased need for hospitalization or lung transplantation (or both) and longer survival. The recommended approach to treatment can be divided into two categories: general care and PAH-specific therapy.

General Therapy

It is expert opinion that all patients with PAH and documented hypoxemia should be on supplemental oxygen to maintain oxygen saturation above 90%. A sodium-restricted diet also is indicated in patients with PH to help maintain volume status and is particularly important in patients with right ventricular failure. Careful diuresis is indicated in patients with evidence of right ventricular failure. Caution must be exercised to avoid overdiuresis, however, because right ventricular performance is highly dependent on preload for maintenance of adequate cardiac output and systemic blood pressure.

Digoxin may produce a modest increase in cardiac output in patients with PH and right ventricular failure, along with a significant reduction in circulating norepinephrine, although the use of cardiac glycosides in treating right-sided heart dysfunction is controversial owing to the lack of prospective randomized, double-blind, placebo-controlled trials.

Improved survival has been reported with oral anticoagulation in patients with idiopathic PAH, and anticoagulation is recommended for all patients with PAH after analysis of the risk-benefit ratio for bleeding complications.

Arrhythmias, particularly atrial flutter and other tachyarrhythmias, are very poorly tolerated and often result in worsening right ventricular function. Prognosis is improved if sinus rhythm is restored. Cardioversion may be performed electrically or chemically with amiodarone, but ablation therapy may be a better option. Right ventricular failure may worsen with the addition of therapeutic agents that are strong negative inotropes.

Pregnancy and the postpartum period are associated with greater than 50% mortality in patients with PH. Therefore, the WHO recommends adequate birth control and advises discussion of termination of any pregnancy.

Patients should be immunized annually against influenza and pneumococcal pneumonia. They also should be instructed to seek the advice of their PAH treatment center for appropriate management before undergoing any form of elective surgery.

Exposure to high altitudes may contribute to hypoxic pulmonary vasoconstriction. Therefore, patients with an oxygen saturation of less than 92% should receive supplemental oxygen during air travel and when participating in sports and other activities at higher altitudes.

Calcium Channel Blockers

Calcium channel blockers may precipitate right-sided heart failure because of the negative inotropic properties of these agents and should be used only in the rare patient who has a documented vasoreactive response during right-sided heart catheterization. If the functional status of a patient who meets the definition of an acute responder does not improve to class I or II, an alternative or additional PAH therapy should be instituted. Owing to its potential negative inotropic effects, verapamil should be avoided. The main limitations to therapy in responders are systemic hypotension, peripheral edema, and hypoxia caused by increased ventilation-perfusion mismatch. More severe adverse reactions, including arrhythmias, cardiogenic shock, and death, have been reported.

Disease-Targeted Therapies

In general, oral therapies are considered first-line treatment for PAH in patients of functional classes II and III, whereas parenteral therapy should be considered in patients of functional class IV. Clinical trials using combination therapy currently are under way. Although currently no consensus has been reached on how to monitor patients for PAH, a clear survival benefit has been recognized for goal-directed therapy. Most experts reevaluate patients every 3 to 4 months by functional class, 6-minute walk testing, and BNP assay. Follow-up echocardiography and right-sided heart catheterization also are done on a routine basis.

Phosphodiesterase Type-5 Inhibitors

The pulmonary vasodilating effects of nitric oxide are mediated through cGMP. Nitric oxide activates guanylate cyclase, which increases cGMP production. Cyclic GMP causes vasorelaxation, but its effects are attenuated by the rapid degradation of cGMP by phosphodiesterase. Sildenafil and tadalafil inhibit phosphodiesterase type 5, thus enhancing relaxation and growth inhibition of vascular smooth muscle cells. Both have demonstrated improvement in exercise capacity and functional class. In its pivotal trial, sildenafil also effected improvement in hemodynamics but did not meet the end point “time to clinical worsening,” which was met in the pivotal trail for tadalafil. Side effects include headache, flushing, dyspepsia, and epistaxis. These drugs are contraindicated in patients on nitrates because of the potential for an unsafe drop in blood pressure.

Endothelin Receptor Antagonists

Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen that is overexpressed in the plasma and lung tissue of patients with PAH. Bosentan is an oral nonselective endothelin receptor antagonist, whereas ambrisentan is an oral selective endothelin type A receptor antagonist. Both of these agents have been shown to improve exercise capacity, functional class, and time to clinical worsening. In one of its pivotal trials, bosentan also was shown to improve hemodynamics. Abnormal hepatic function, defined as elevation of hepatic transaminases to three times the upper limit of normal or higher, is seen in approximately 10% of patients on bosentan and approximately 2% of patients on ambrisentan. Consequently, the U.S. Food and Drug Administration (FDA) mandates monthly liver function testing in those patients on bosentan.

In addition to potential hepatotoxicity, other side effects include anemia and the development of edema. The endothelin receptor antagonists (ERAs) are classified as pregnancy category X, so monthly pregnancy tests are required in women of child-bearing potential.

Prostanoids

Prostacyclin is a potent vasodilator and inhibitor of platelet activation and smooth muscle proliferation. Three prostanoids that have been shown to improve exercise capacity, quality of life, functional class, and hemodynamics are epoprostenol, treprostinil, and iloprost. Regimens proven effective include continuous intravenous epoprostenol therapy; inhaled, subcutaneous, and intravenous treprostinil therapy; and inhaled iloprost. Epoprostenol also has been shown to improve survival. Their respective delivery systems are complex and require collaboration with a clinical center with appropriate expertise.

Expert consensus recommends intravenous epoprostenol therapy as first-line treatment for patients with WHO class IV disease and those with class III disease in whom treatment with other disease-targeting therapies has failed to effect improvement. The main drawbacks to intravenous therapy with epoprostenol are its short half-life (approximately 2 to 5 minutes), invasive mode of delivery, expense, and side effects, which include jaw pain, flushing, diarrhea, headache, backache, leg pain, and hypotension. Catheter-related adverse effects include infection, thrombosis, pump failure, and rebound PAH.

Compared with epoprostenol, treprostinil has a longer half-life (approximately 4 hours), so it can be administered by continuous subcutaneous infusion or intravenously. Treprostinil has a side effect profile similar to that for epoprostenol, with two notable differences: The subcutaneous route is associated with significant pain at the infusion site, often resulting in discontinuation of therapy, and the intravenous route is associated with an increased risk of bloodstream infections, particularly gram-negative infections.

Iloprost is a stable prostacyclin analogue that can be given by inhalation but has a relatively short duration of action and must be inhaled between six and nine times per day, whereas treprostinil can be inhaled four times daily. Both inhaled prostanoids require unique devices for drug delivery and are associated with cough.

Rehabilitation

Data on which to base recommendations regarding exercise are limited; nevertheless, experts recommend low-level aerobic exercise and supervised pulmonary rehabilitation. Patients should be advised to avoid heavy physical exertion or isometric exercise, because such effort may evoke exertional syncope.

Surgical Options

Atrial Septostomy

The use of atrial septostomy should be limited to patients who have signs of right-sided heart failure and syncope and who are on maximal medical therapy. It often is viewed as a bridge to transplantation. Atrial septostomy creates a left-to-right intracardiac shunt that decompresses the right side of the heart, increases left ventricular preload, and augments systemic cardiac output. Thus, despite significant arterial oxygen desaturation, oxygen delivery to the tissues can be improved. The procedure is associated with significant mortality and should be performed only in specialized centers.

Lung Transplantation

Lung transplantation should be considered for patients who fail to improve on prostanoid therapy and those who remain in functional class III or IV. Little difference in efficacy between single lung, bilateral sequential lung, and heart-lung transplantation has been noted, with survival rates of 70% to 80% at 1 year and 50% to 60% at 4 years regardless of the procedure performed. Single-lung transplantation is more complicated in the immediate postoperative period because of reperfusion edema in the transplanted lung. Because of the limited availability of organ transplants, heart-lung blocks are reserved for patients with left-sided heart disease or congenital heart disease coexistent with Eisenmenger syndrome.

Pulmonary Thromboendarterectomy

Pulmonary thromboendarterectomy (PTE) is the treatment of choice for patients with proximal CTEPH and offers a potential cure in carefully selected patients. This procedure is performed in just a few specialized centers. During PTE, organized thromboembolic material is carefully removed from the affected pulmonary arteries under hypothermic circulatory arrest, attempting to restore pulmonary hemodynamics to normal or near normal levels. Those patients with a disproportionately higher PVR than would be expected from the segmental obstruction seen on imaging have a higher mortality and benefit less from PTE. With advances in both surgical technique and postoperative intensive care, the procedure-associated mortality rate has progressively diminished to approximately 6% to 8%. More than 90% of survivors return to functional class I or II. Patients with CTEPH caused by distal disease are not amenable to such treatment, and evidence is emerging for PAH-specific mediations in this group.

Survival and Outlook

The natural history of IPAH has been well characterized, with an estimated mean survival period of 2.8 years and 1-, 3-, and 5-year survival rates of 68%, 48%, and 34%. Prognostic indicators generally are related to right ventricular function and include clinical and echocardiographic evidence of right ventricular failure or dysfunction, poor exercise tolerance, advanced functional class, elevated serum concentrations of BNP, and poor hemodynamics (elevated right atrial pressure, decreased cardiac index). Patients with these risk factors should be considered for early initiation of prostanoid therapy.

Different survival curves have emerged for the different types of PAH. For example, survival typically is better in patients with congenital heart disease than in patients with IPAH, but worse in patients with connective tissue disease (reported rate of 40% at 2 years). This difference highlights another limitation of the classification scheme: Although the different types of PAH share similar pathobiologic features, key differences are recognized: different responses of the right ventricle (congenital heart disease), differences in the pathologic lesions (absence or reduced presence of the plexiform lesion seen in the connective tissue diseases), presence or absence of concomitant left ventricular diastolic dysfunction and/or pulmonary fibrosis (commonly seen in scleroderma), and differing responses to vasodilatation, hyperdynamic or high-flow states (congenital heart disease, portopulmonary hypertension, and chronic hemolysis), and other comorbid conditions seen in all of the “associated” forms of PAH. Fortunately, data suggest that mortality is decreasing in today’s era of expanding PAH therapy.

The past decade has brought a more thorough understanding of the pathogenesis of PAH, improved methods of detection, and better treatment options, which together have resulted in improved exercise tolerance and quality of life along with increased time to clinical worsening and survival.

Controversies and Pitfalls

• Combination therapy: Combination therapy that uses drugs with different therapeutic mechanisms is an attractive option for patients who fail to improve or deteriorate with first-line treatment (monotherapy), but trials to confirm the value of this approach are ongoing and may be limited by the expense of these therapies. Many experts are interested in the concept of induction therapy followed by tailoring to a maintenance regimen.

• Out-of-proportion magnitude of pulmonary hypertension: Most patients present with features of more than one WHO group. Unfortunately, clinical trials are lacking in patients with PH that is out of proportion to their parenchymal lung disease or left heart dysfunction. Decisions on how to treat these patients are limited to anecdotal reports and the clinician’s own experience.

• Peripheral/nonoperable CTEPH: Data on use of PAH therapies for patients with peripheral or nonoperable CTEPH are evolving, but large clinical trials showing a benefit in this population also are lacking

• Exercise-induced pulmonary hypertension: Convincing data show that patients should be treated early for their PH; however the exercise definition (greater than 30 mm Hg) for PH was removed at the most recent symposium in Dana Point. Further studies regarding exercise hemodynamics are sorely needed to allow for earlier detection and treatment, with consequent better prognosis.

• Associated PAH: Most of what is known about PAH comes from IPAH; likewise, clinical trials largely comprise patients with IPAH, with a minority of patients with scleroderma spectrum of disease and occasionally diet drugs–related PAH or congenital heart disease. Caution should be taken before applying these data to all forms of PAH.

Web Resource

Pulmonary Hypertension Association. www.phassociation.org.

Suggested Readings

Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S56–S66.

Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S78–S84.

Hoeper MM, Barberà JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S85–S96.

Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J. 2009;34:888–894.

McLaughlin VV, Archer SL, Badesh DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. J Am Coll Cardiol. 2009;53:1573–1619.

McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417–1431.

McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(1 Suppl):78S–92S.

Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S43–S54.

Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med. 2009;30:376–385.

Tuder RM, Abman SH, Braun T, et al. Development and pathology of pulmonary hypertension. J Am Coll Cardiol. 2009;54:S3–S9.

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