Pulmonary Hypertension

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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.

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).

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.