Pulmonary Arterial Hypertension (PAH)


Pulmonary Hypertension

What Is Pulmonary Arterial Hypertension?

Pulmonary arterial hypertension (PAH) is a rare and progressive type of pulmonary hypertension (PH), which is a general term used to describe increased blood pressure in the pulmonary arteries.1

PAH is characterized by narrowing and thickening of the pulmonary arteries, which causes increased resistance to the flow of blood. To overcome the increased resistance, blood pressure increases in the pulmonary arteries and in the right ventricle of the heart. Over time this may lead to right ventricular failure and eventual death if left untreated.2

PAH History

The first case of PAH was reported in 1891 by German physician Ernst von Romberg, who was puzzled by a patient autopsy when he discovered the thickening of the pulmonary artery, which he called “pulmonary vascular sclerosis,” without the presence of heart or lung disease.3

In 1951, David T. Dresdale, MD, defined the concept of PAH and reported clinical and hemodynamic features in 3 cases.4 In 1952, Paul Wood, OBE, MD, FRCP, described the clinical features of PAH for the first time.5

In the late 1960s, an epidemic of PAH was caused by the ingestion of aminorex fumarate, which was sold as an appetite suppressant to promote weight loss. Prompted by the outbreak, the World Health Organization (WHO) held its first meeting in Geneva in 1973 to discuss PH. It was there that the first pathology-based classification system for PH was defined.6

The meeting was followed by great interest in studying the underlying mechanisms that led to the development of PAH associated with aminorex fumarate, and the number of clinical trials on the topic increased in the 1980s.

Norm Shumway, MD, PhD, et al introduced heart-lung transplantation as the first treatment for PAH in 1982. In 1995, epoprostenol (synthetic prostacyclin injected intravenously) was approved by the US Food and Drug Administration (FDA) as the first medical therapy for the treatment of idiopathic PAH (IPAH). The first oral therapy approved for the treatment of PAH was bosentan, an endothelin receptor antagonist.7

Recent advancements in the medical field have led to the identification of 14 drugs that have been approved for the treatment of PAH, including treprostinil (subcutaneous/intravenous/inhaled/oral), iloprost (inhaled), sildenafil (oral), ambrisentan (oral), tadalafil (oral), riociguat (oral), macitentan (oral), and selexipag (oral).

WHO Classification of PH

The WHO defined a classification for PH in 1973, based on the cause of the disease. However, with the advancement in the understanding of the disease, this classification has undergone multiple revisions, with the most recent presented in early 2019 at the 6th World Symposium on Pulmonary Hypertension (WSPH).1  Presently PH is classified into 5 groups based on similar etiologies, pathophysiology, clinical signs/symptoms, hemodynamic features, and therapeutic options.

Group 1: Pulmonary Arterial Hypertension (PAH)

The first group comprises diseases that cause similar pathological changes in the pulmonary vasculature.

Group 2: PH Due to Left-Sided Heart Disease

The second group includes PH that is secondary to the diseases of the left side of the heart such as systolic or diastolic heart failure, left-sided valvular diseases, congenital/acquired cardiovascular conditions leading to postcapillary PH, and others.

Group 3: PH Due to Lung Diseases and/or Hypoxia

The third group includes PH caused by diseases of lung parenchyma or hypoxia-related diseases such as obstructive lung disease, restrictive lung disease, developmental lung disorders, and others.

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Other Pulmonary Artery Obstructions

The fourth group includes pulmonary artery obstructive conditions such as chronic thromboembolic pulmonary hypertension (CTEPH), sarcoma or angiosarcoma, other malignant tumors (renal carcinoma, uterine carcinoma, germ cell tumors of the testis, and other tumors), nonmalignant tumors (uterine leiomyoma), arteritis without connective tissue disease, congenital pulmonary artery stenoses, and parasites.

Group 5: PH With Unclear or Multifactorial Etiologies

The fifth group includes:

  • hematologic disorders such as chronic hemolytic anemia and myeloproliferative disorders;
  • systemic disorders and metabolic disorders such as pulmonary Langerhans cell histiocytosis, Gaucher disease, glycogen storage disease, neurofibromatosis, and sarcoidosis;
  • other conditions like chronic renal failure with or without hemodialysis, and fibrosing mediastinitis; and
  • complex congenital heart disease such as segmental pulmonary hypertension (isolated pulmonary artery of ductal origin, absent pulmonary artery, pulmonary atresia with ventricular septal defect and major aorto-pulmonary collateral arteries, hemitruncus, and others), single ventricle (unoperated, operated), and scimitar syndrome.

Read more about Pulmonary Hypertension types.

Group 1 Pulmonary Arterial Hypertension

According to the 6th WSPH, PAH is now defined by specific hemodynamic criteria that includes mean pulmonary artery pressure or mPAP of 20 mm Hg or greater, pulmonary artery wedge pressure (PAWP) of 15 mm Hg or less, and pulmonary vascular resistance (PVR) 3 Wood units or greater without the presence of other causes of PH.8

Based on the etiology, Group 1 PAH is further divided into the following categories1

1.1 IPAH

1.2 Heritable PAH (HPAH)

1.3 Drug- and toxin-induced PAH

1.4 PAH-associated with other conditions (such as connective tissue diseases, portal hypertension, congenital heart disease, human immunodeficiency virus infection, and schistosomiasis)

1.5 PAH in patients who are long-term responders to calcium channel blockers

1.6 PAH with overt features of venous/capillaries involvement including pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis

1.7 Persistent PH of the newborn syndrome

References

  1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1). doi:10.1183/13993003.01913-2018
  2. Lan N, Massam B, Kulkarni S, Lang C. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6(2):38. doi:10.3390/diseases6020038
  3. Romberg E. [Ueber Sklerose der Lungen arterie]. Dtsch Archiv Klin Med 1891;48:197–206.
  4. Dresdale DT, Schultz M, Michtom RJ. Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med. 1951;11(6):686-705. doi:10.1016/0002-9343(51)90020-4
  5. Wood P. Pulmonary hypertension. Br Med Bull. 1952;8(4):348-353. doi:10.1093/oxfordjournals.bmb.a074201
  6. Fishman AP. Primary pulmonary arterial hypertension: a look back. J Am Coll Cardiol. 2004;43(12):S2-S4. doi:10.1016/j.jacc.2004.03.019
  7. Yaghi S, Novikov A, Trandafirescu T. Clinical update on pulmonary hypertension. J Investig Med. 2020;68(4):821-827. doi:10.1136/jim-2020-001291
  8. Sahay S. Evaluation and classification of pulmonary arterial hypertension. J Thorac Dis. 2019;11(Suppl 14):S1789-S1799. doi:10.21037/jtd.2019.08.54

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