Pulmonary Arterial Hypertension

Updated: Apr 25, 2018
  • Author: Kristin E Schwab, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

Background

Pulmonary hypertension, defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise, is often characterized by a progressive and sustained increase in pulmonary vascular resistance that eventually may lead to right ventricular failure. It can be a life-threatening condition if untreated. Therapy for pulmonary hypertension is targeted at the underlying cause and its effects on the cardiovascular system, with success rates varying according to the etiology. Novel therapeutic agents, such as prostacyclin and others undergoing clinical trials, have led to the possibility of specific therapies for these once untreatable disorders.

The World Health Organization (WHO) has divided pulmonary hypertension into five groups on the basis of similarities in pathophysiology, clinical presentation, and therapeutic options. [1] These groups include the following:

  • Group 1 - Pulmonary arterial hypertension (PAH)
  • Group 2 - Pulmonary hypertension due to left-sided heart disease
  • Group 3 - Pulmonary hypertension due to lung diseases and/or hypoxia
  • Group 4 - Chronic thromboembolic pulmonary hypertension (CTEPH)
  • Group 5 - Pulmonary hypertension with unclear or multifactorial etiologies, including hematologic disorders (eg, myeloproliferative disorders), systemic disorders (eg, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis), metabolic disorders (eg, glycogen storage disease, Gaucher disease, thyroid disorders), and miscellaneous conditions (eg, tumor obstruction, mediastinal fibrosis, chronic renal failure on dialysis)

Recognition of fetal causes and developmental abnormalities has also led to a pediatric-specific classification. [2]

This review focuses on group 1 pulmonary hypertension, which is also referred to as pulmonary arterial hypertension.

Note the gross pathology images of PAH below.

Gross pathology on patient who died of severe pulm Gross pathology on patient who died of severe pulmonary arterial hypertension secondary to persistent patent ductus arteriosus.
Close-up view of gross pathology on patient who di Close-up view of gross pathology on patient who died of severe arterial pulmonary hypertension secondary to persistent patent ductus arteriosus.

For patient education resources, see the Lung and Airway Center.

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Pathophysiology

Increased pulmonary vascular resistance is the main pathogenic mechanism in pulmonary arterial hypertension (PAH). This is typically due to vasoconstriction, remodeling, and thrombosis of the small pulmonary arteries and arterioles. [3]  

On pathology, patients with PAH are found to have hyperplasia and hypertrophy of the intima, media, and adventitia of the pulmonary arterial vasculature. On the molecular level, this is related to endothelial dysfunction, which leads to disorganized endothelial cell proliferation, decreased production of vasodilators such as prostacyclin and nitric oxide, and overexpression of vasoconstrictors like endothelin. These pathophysiologic mechanisms are particularly important as they guide the therapeutic targets of pharmacotherapies for advanced PAH disease.

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Etiology

Pulmonary arterial hypertension (PAH) can be further divided into the following subgroups:

  • Subgroup 1 - Idiopathic PAH (IPAH)
  • Subgroup 2 - Heritable PAH, including those with BMPR2 and ALK2 gene mutations
  • Subgroup 3 - Drug- and toxin-induced PAH (Aminorex, fenfluramine derivatives, and toxic rapeseed oil have been identified as definite risk factors for PAH. [1] Other drugs implicated as possible risk factors for PAH include amphetamine and amphetamine derivatives, cocaine, L-tryptophan, phenylpropanolamine, St. John’s wort, leflunomide, phentermine, mazindol, dasatinib, and interferon.)
  • Subgroup 4 - Conditions with known localization of lesions in the small pulmonary arterioles, which include (1) collagen-vascular disease (scleroderma/ CREST syndrome), (2) congenital left-to-right shunts, (3) portopulmonary hypertension, (4) HIV-associated pulmonary hypertension, and (5) schistosomiasis

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis have been designated as 1’ to reflect the fact that although related, they are clinicopathologically and therapeutically distinct entities from PAH (ref 62)

Of note, while persistent pulmonary hypertension of the newborn was previously classified under group 1 PAH, the 2013 classification schema removed this from group 1 to better reflect the differences between this and other PAH subgroups. The updated schema also moved chronic hemolytic anemia from group 1 to group 5 pulmonary hypertension. [4]

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Epidemiology

The overall prevalence of pulmonary arterial hypertension (PAH) is difficult to determine given the disease’s heterogeneity and likely underdiagnosis.

Worldwide, schistosomiasis is likely the most prevalent cause of PAH, [5] with studies suggesting that over 7% of patients with hepatosplenic schistosomiasis have pulmonary hypertension. [6, 7] However, data registries in countries most burdened by schistosomiasis-related PAH are limited. [5]

Data registries in areas without endemic schistosomiasis such as the United States and Europe report a PAH prevalence ranging from 6.6-26 cases per million adults. [8] The majority of these cases are idiopathic. While approximately 10% are classified as heritable, it is likely that this number will increase with time as genetic testing becomes more widespread.

Studies have also estimated the prevalence of specific subgroups of PAH. An observational study of 277 patients with HIV infection found that 0.46% of patients had pulmonary hypertension. [9] In comparison with prior studies, [10] no change in prevalence rate was seen with modern highly active antiretroviral treatment (HAART). In scleroderma patients, the incidence has been estimated to be 6-60% of all patients, with the variance based on the extent of disease. [11]

Women are more likely to have PAH, with registries reporting a 65-80% female predominance of the disease. [8] Interestingly, while prior studies suggested a mean age of diagnosis in the thirties, current registries suggest a mean age of diagnosis in the fifties. [8] Although PAH can affect all races, data from the US REVEAL registry suggest a white predominance (73% white vs 12% African American, 9% Latino, and 3% Asian). [12]  

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Prognosis

The prognosis of patients with pulmonary arterial hypertension (PAH) is variable and depends on the etiology, severity, and treatment.

US registry data suggest a 5-year survival rate of 57% without treatment (from the time of diagnostic right-sided heart catheterization). [13] Risk score calculators for patients with newly diagnosed PAH are available and validated. [13, 14] In general, male sex, age older than 50 years, worse WHO functional status, and right ventricular dysfunction confer a worse prognosis. For example, patients with right-sided heart failure survive approximately 1 year without treatment.

Important to note is that longitudinal trends suggest that survival in patients with PAH has improved. Since the introduction of advanced pharmacotherapies, scleroderma-associated PAH, for example, has seen an improved prognosis. [15] Overall, although, etiology remains important for prognostication, patients with PAH secondary to connective-tissue disease, portal hypertension, and familial causes tend to have worse survival than patients with other etiologies of PAH.

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