Chapter 58 Pulmonary Hypertension
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.
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.
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).
Updated Clinical Classification of Pulmonary Hypertension
1. Pulmonary arterial hypertension (PAH)
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)
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.
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.
Risk Factors for Pulmonary Arterial Hypertension
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.
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.
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).