Pulmonary Arterial Hypertension (PAH)


Pulmonary arterial hypertension (PAH) is a type of pulmonary hypertension characterized by remodeling (thickening and narrowing) of the small pulmonary arteries, which results in increased pulmonary vascular resistance and right-sided heart failure. It is classified by the World Health Organization as Pulmonary Hypertension Group 1.1

PAH can be categorized into 4 types according to the cause: idiopathic PAH, heritable PAH, drug- or toxin-induced PAH, and PAH associated with other conditions (connective tissue disorders, HIV infection, portal hypertension, congenital heart disease, and schistosomiasis).1

Idiopathic PAH

Idiopathic PAH occurs spontaneously, with no apparent or known cause. Idiopathic PAH is a rare, progressive, and fatal condition in which, as a result of elevated pulmonary arterial pressure, the right side of the heart must exert additional force to push blood into the lungs. This ultimately leads to heart failure if left untreated. Most individuals with idiopathic PAH are women aged 20 to 39 years.2

Heritable PAH

Heritable PAH is associated with mutations in several genes, including: bone morphogenetic protein receptor type 2 (BMPR2), activin receptor-like kinase 1 (ALK1), mothers against decapentaplegic homolog 9 (SMAD9), endoglin 1 (ENG), caveolin-1 (CAV1), potassium channel subfamily K member 3 (KCNK3), bone morphogenetic protein receptor type 1B (BMPR1B), kinase insert domain receptor (KDR), T-box transcription factor 4 (TBX4), and tet-methylcytosine-dioxygenase-2 (TET2). The genes BMPR2, ALK1, SMAD9, BMPR1B, and ENG encode proteins belonging to the transforming growth factor β (TGF-β) receptor superfamily. 

Approximately 70% of patients with heritable PAH and 10% to 40% of those with idiopathic PAH have mutations in the BMPR2 gene. About 5% of individuals with heritable PAH have mutations in the remaining PAH-associated genes of the TGF-β superfamily: ALK1, SMAD9, and ENG. In almost 20% of cases, no mutation can be identified.3 Heritable PAH is inherited in an autosomal dominant pattern; however, penetrance is incomplete, which complicates the diagnosis.1

Studies in animals have shown that reduced BMPR2 activity in pulmonary vascular endothelial cells promotes cell death, resulting in vascular remodeling and subsequently PAH.1

Drug- or Toxin-Induced PAH

As the name indicates, drug- or toxin-induced PAH is caused by exposure to a drug or toxin. Several drugs and toxins associated with PAH have been identified and classified as “possible” or “definite” risk factors. They belong to various classes, including appetite suppressants (eg, aminorex fumarate), illicit drugs (eg, methamphetamine), industrial chemicals (eg, toxic rapeseed oil), and therapeutic drugs approved by the US Food and Drug Administration (eg, dasatinib and interferon).4

According to the 6th World Symposium on Pulmonary Hypertension (WSPH), definite risk factors for PAH include aminorex fumarate, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil. Possible risk factors for PAH include cocaine, L-tryptophan, St. John’s wort, phenylpropanolamine, amphetamines, bosutinib, interferons-α and -β, alkylating agents, direct-acting antiviral agents used to treat hepatitis C, leflunomide, and indirubin.4

The exact mechanisms that are responsible for the development of PAH following exposure to drugs and toxins are unknown. However, research has identified some of the underlying molecular mechanisms, such as increased serotonin levels, interaction with serotonin receptors, proliferation of pulmonary artery smooth-muscle cells, and potassium channel inhibition leading to vasoconstriction.5

PAH Associated With Other Conditions

pulmonaty arterial hypertension etiology
PAH prognosis affected by damage caused by
connective tissue disease

Connective Tissue Disease

Connective tissue diseases are frequently associated with PAH. The incidence of PAH is highest in patients with systemic sclerosis (8%-12%), followed by those with systemic lupus erythematosus (1%-5%) or mixed connective tissue disease (3%-4%). The underlying mechanisms that lead to vascular remodeling and the development of PAH include increased production of vasoconstrictors and proliferative mediators (eg, endothelin 1) and impaired production of vasoactive mediators (eg, nitric oxide, prostacyclin). Recent studies suggest that inflammation and autoimmunity may also contribute to the progression of PAH associated with connective tissue disease, particularly in patients with systemic lupus erythematosus or mixed connective tissue disease.6

HIV Infection

HIV infection is a known risk factor for PAH. The underlying pathological mechanisms are not known, but viral proteins (eg, negative factor, or Nef; glycoprotein, or Gp120) have been found in the pulmonary endothelial wall. These antigens may stimulate processes required for the development of PAH, such as abnormal apoptosis, growth, and proliferation. Other mechanisms may also contribute to the development of PAH, such as an HIV-induced chronic inflammatory state and persistent activation of the immune system, coinfections, and other risk factors.7

PAH portal hypertension
Portal hypertension and hepatosplenic schistosomiasis

Portal Hypertension

PAH develops in approximately 2% to 10% of patients with portal hypertension, or elevated pressure in the portal vein with or without liver disease. The underlying mechanisms are poorly understood. The imbalance in vasoactive substances caused by defective liver metabolism or mechanical obstruction of the portal vein has been found to result in pulmonary vessel constriction and an increase in pulmonary vascular resistance.8

Increased pressure in the portal vein leads to splanchnic vasodilation and the formation of portosystemic shunts. These changes, in addition to shear stress due to persistent high flow, cause an imbalance of vasodilators and vasoconstrictors in the pulmonary vasculature, resulting in vasoconstriction and increased pulmonary vascular resistance.8

Congenital Heart Disease

PAH can be a complication of congenital heart disease, especially in patients with a left-to-right cardiac shunt. It is believed that persistent exposure of the pulmonary vasculature to increased blood flow due to the shunt may result in vascular remodeling and dysfunction. Pulmonary vascular resistance then increases, ultimately with reversal of the shunt and the development of Eisenmenger syndrome.9 It is estimated that approximately 4% to 28%10 of adults with congenital heart disease may have PAH.

Schistosomiasis

PAH develops in approximately 5% to 10% of patients with hepatosplenic schistosomiasis as a long-term complication. PAH associated with schistosomiasis is one of the main causes of PAH-related death.

The pathological mechanisms include a combination of several factors. As a result of egg embolization in the portal vessels and the subsequent portal hypertension caused by vessel occlusion, portosystemic shunts open around the liver, which increases blood flow through the lungs and causes shear stress. In addition, portosystemic shunts allow eggs to pass from the liver to the lungs. Egg embolization into the lungs results in either direct mechanical obstruction of the lung vasculature or localized type 2 inflammation, which leads to vascular remodeling. Moreover, a generalized systemic type 2 immunity may contribute to the development of PAH.11,12

References

  1. Lan N, Massam B, Kulkarni S, Lang C. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6(2):38. doi:10.3390/diseases6020038
  2. Hoendermis ES. Pulmonary arterial hypertension: an update. Netherlands Heart J. 2011;19(12):514-522. doi:10.1007/s12471-011-0222-1
  3. Pulmonary arterial hypertension. National Organization for Rare Disorders. Accessed June 21, 2021.
  4. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53:180193. doi:10.1183/13993003.01913-2018
  5. Ramirez III RL, Thomas CA, Anderson RJ, et al. Drug- and toxin-induced pulmonary arterial hypertension: current state of the literature. Glob Cardiol Sci Pract. 2020;2019(3). doi:10.21542/gcsp.2019.19
  6. Zanatta E, Polito P, Famoso G, et al. Pulmonary arterial hypertension in connective tissue disorders: pathophysiology and treatment. Exp Biol Med. 2019;244(2):120-131. doi:10.1177/1535370218824101
  7. Barnett CF, Hsue PY. HIV-associated pulmonary hypertension: a global perspective. Adv Pulm Hypertens. 2017;15(3):138-143. doi:10.21693/1933-088x-15.3.138
  8. Thomas C, Glinskii V, de Jesus Perez V, Sahay S. Portopulmonary hypertension: from bench to bedside. Front Med. 2020;7:569413. doi:10.3389/fmed.2020.569413
  9. D’Alto M, Mahadevan VS. Pulmonary arterial hypertension associated with congenital heart disease. Eur Respir Rev. 2012;21(126):328-337. doi:10.1183/09059180.00004712
  10. Condliffe R. Pulmonary arterial hypertension associated with congenital heart disease: classification and pathophysiology. J Congenit Cardiol. 2020;4(S1):1-7. doi:10.1186/s40949-020-00040-0

Reviewed by Michael Sapko, MD, on 7/1/2021.

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