Review Provides Overview of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a rare form of pulmonary hypertension that poses diagnostic challenges and often comes with a delayed diagnosis.

Pulmonary hypertension (PH) is organized into 5 clinical groups, and a review published Wednesday in The New England Journal of Medicine discussed the pathophysiology of pulmonary arterial hypertension (PAH), a more-complicated and rare subset of PH.

The incidence of PH worldwide is about 1%, with many of those affected living in developing countries and thus without treatment. PH complicates other lung diseases such as chronic obstructive pulmonary disease, as well as blood diseases and viral infections.

PAH, in which right ventricular dysfunction leads to heart failure, affects 25 individuals per 1 million people in Western countries, according to the author. Most of them are women and the most severe cases happen in the elderly. PAH, belonging to group 1 of PH diseases, is marked by several shared features that result in luminal narrowing or the complete blockage of small vessels in the lungs:

  • Remodeling of the 3 layers of the distal pulmonary vasculature (intima, media, and adventitia), which involves uncontrolled growth of endothelial and smooth-muscle cells and fibroblasts;
  • Infiltration of inflammatory cells such as monocytes, B and T lymphocytes, and dendritic cells; and
  • Extension of the smooth-muscle cell layer to nonmuscularized distal capillaries

It is unclear what leads to the remodeling, “but endothelial dysfunction induced by shear stress, hypoxia, autoimmune phenomena, viral infections, drugs and toxins, or genetic alterations may initiate the process of excess vasoconstriction, inflammation, and uncontrolled cellular growth,” the author wrote. Inflammation may also play a role.

Another facet of PAH that also remains unclear is the process that creates remodeling of the right ventricle, the function of which is key to clinical outcomes and survival in PH. As pulmonary vascular pressure increases, the right ventricle undergoes hypertrophy, chamber dilatation, fat deposition, fibrosis, and metabolic shifts.

Remodeling may be adaptive or maladaptive. The current diagnostic standard for testing right ventricle function (pressure–volume loop technology with a high-fidelity conductance catheter) is invasive. Noninvasive measures, such as echocardiography or cardiac MRI, have not yet been formally validated but have predicted outcomes in some research.

PAH symptoms are nonspecific, including exertional dyspnea, fatigue, chest pain, fluid retention, and fainting. Risk factors include HIV, connective tissue disease, liver disease, pediatric PH, and a history of exposure to illicit drugs or toxins.

Transthoracic echocardiography (TTE) can not only measure the prevalence, cause, and severity of PAH but also identify left ventricular systolic or diastolic dysfunction and valvular abnormalities, which would indicate group 2 PH.

There are 3 signaling pathways targeted for PAH treatment: endothelin-1, prostacyclin (PGI2), and nitric acid. Three therapies are approved for the endothelin-1 pathway, including macitentan, bosentan, and ambrisentan; 4 therapies for the PGI2 pathway (selexipag, eporostenol, treprostinil, iloprost); and 3 for the nitricoxide pathway (riociguat, sildenafil, and taalfil).

The PAH field advanced more than 20 years ago with the discovery of a genetic predisposition through heterozygous mutations in the BMPR2 gene, a member of the transforming growth factor β (TGF-β) superfamily of receptors. At least 16 other genes have been identified in heritable PAH, including ACVRL1, SMAD1, SMAD4, SMAD9, CAV1, and others.


Hassoun PM. Pulmonary arterial hypertension. N Engl J Med. 2021;385:2361-2376. doi:10.1056/NEJMra2000348