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.

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.