Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.
The 6th World Symposium on Pulmonary Hypertension (WSPH) in 2019 revised the classification of pulmonary arterial hypertension (PAH), called Group 1, to categorize it into 7 classes based on similar pathological mechanisms, causes, clinical signs and symptoms, hemodynamic features, and therapies. These classes are idiopathic PAH (IPAH), heritable PAH (HPAH), drug- and toxin-induced PAH, PAH associated with other conditions (such as connective tissue diseases, portal hypertension, and congenital heart disease), PAH in long-term responders to calcium channel blockers (CCBs), PAH with overt features of venous/capillaries involvement, and persistent PH of the newborn syndrome. The majority of cases of PAH are idiopathic, followed by PAH associated with connective tissue diseases (CTD) and congenital heart disease (CHD).1
1.1 Idiopathic PAH (IPAH)
IPAH, the most common type of PAH, occurs spontaneously without any family history or identifiable risk factor. It is characterized by increased pulmonary vascular resistance leading to, or likely caused by, vascular remodeling, which leads to increased pulmonary blood pressure and increased workload in the right ventricle of the heart. If the increased blood pressure persists and is not treated, it may lead to heart failure.
1.2 Heritable PAH (HPAH)
HPAH is inherited in an autosomal dominant manner, ie, one mutated copy of the gene can cause it. To date, mutations have been found in 10 genes, namely the bone morphogenetic protein receptor 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).
HPAH mutations can be diagnosed using genetic testing. However, diagnosis is complicated by the incomplete penetrance of the BMPR2 mutations, with 80% of individuals carrying the PAH-associated mutations not developing the condition. In addition, variable expressivity and female dominance of the gene mutations suggest that a combination of genetic and environmental factors are involved in developing PAH.2
1.3 Drug- and Toxin-Induced PAH
Several drugs and toxins have been found to increase the risk of developing PAH. The first drug found to induce PAH was aminorex fumarate, an appetite suppressant that led to the epidemic of PAH in Europe in the 1960s.
According to the 6th WSPH, drugs and toxins are categorized as either definite or possible risk factors. The definite risk factors for PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.
The possible risk factors of PAH include cocaine, phenylpropanolamine, L-tryptophan, St. John’s wort, amphetamines, interferon-α and -β, alkylating agents, bosutinib, direct-acting antiviral agents against hepatitis C virus, leflunomide, and indirubin.3
1.4 PAH Associated With Other Conditions
PAH Associated With Connective Tissue Diseases (CTD-PAH)
Connective tissue diseases (CTD) are the second most common causes of PAH. CTDs that have been found to cause PAH include systemic sclerosis (SSc), mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE), Sjörgen syndrome, inflammatory idiopathic myopathies, and rheumatoid arthritis. SSc (74% of CTD-PAH cases) is the most common cause of CTD-PAH, followed by SLE and MCTD (8% of CTD-PAH cases each).4
PAH Associated With HIV infection
PAH associated with human immunodeficiency virus (HIV) is a severe and fatal complication, with an estimated prevalence of 0.5% in HIV-infected patients, which is 2000 times greater than in the general population. The underlying mechanisms are not clear, but studies suggest that HIV proteins (such as negative factor or Nef, glycoprotein or Gp120, and transactivator of transcription or Tat), chronic immune activation, coinfections, or other risk factors may play important roles in the pathogenesis of PAH associated with HIV.5,6
PAH Associated With Portal Hypertension
PAH associated with portal hypertension (PoH), also called portopulmonary hypertension, is a fatal complication in patients with PoH, which is characterized by increased blood pressure in the portal vein caused by liver disease or other conditions that lead to mechanical obstruction in the vein. The survival of the patients is poor as compared to other forms of PAH.7
PAH Associated With Congenital Heart Disease (CHD)
PAH is a frequent complication of CHD, with the prevalence ranging between 4.2% and 28% among adult CHD patients. Patients with PAH associated with CHD are classified into 4 clinical groups, Groups A, B, C, and D. Group A includes patients with a large congenital left-to-right shunt that leads to increased blood flow and pressure, resulting in the development of pulmonary vasculopathy. This leads to increased pulmonary vascular resistance (PVR) and subsequently partial or complete shunt reversal (to right-to-left) causing cyanosis and erythrocytosis, a condition called Eisenmenger’s syndrome. Group B includes patients with moderate-to-large left-to-right shunts and is characterized by mild to moderately increased PVR. There is no cyanosis observed at rest in such patients. Group C patients are characterized by increased PVR in the presence of small defects, atrial septal defect＜2cm or ventricular septal defect＜1cm diameter. Group D consists of patients in which PAH develops or recurs or persists even after the repair of a defect.8
PAH Associated With Schistosomiasis
Schistosomiasis is the most dominant cause of PAH worldwide. PAH associated with schistosomiasis is a fatal complication of chronic schistosomiasis infection, particularly hepatosplenic schistosomiasis caused by the parasite Schistosoma mansoni. Pathological mechanisms are local inflammation in the pulmonary vessels by embolization of eggs into the lungs, ultimately causing vessel remodeling and PAH.9
1.5 PAH in Long-Term Responders to CCBs
Less than 10% of patients with PAH are those who show a sustained hemodynamic improvement in response to at least 1 year of treatment with calcium channel blockers (CCBs), which lower the pulmonary blood pressure through vasodilation. These patients are identified through a positive response to vasoreactivity testing using vasodilators such as inhaled nitric oxide (preferred), intravenous epoprostenol, intravenous adenosine, or inhaled iloprost. Patients who show an acute vasodilator response, identified as a reduction of mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg, have improved survival when treated with long-term CCBs in comparison to patients with no acute response.10
1.6 PAH With Overt Features of Venous/Capillaries Involvement
PAH with overt features of venous or capillaries involvement includes pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). In both PVOD and PCH, there are marked similarities in the clinical symptoms, hemodynamic profile, histological features, and pathological mechanisms. Further, heritable forms of both PVOD and PCH have been found to be caused by mutations in both copies of the eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) gene. Exposure to organic solvents, especially trichloroethylene, has been linked to the development of PVOD/PCH. Of note, PAH-targeted therapies have been found to be ineffective in the treatment of PVOD/PCH and may result in pulmonary edema.11
Pulmonary Veno-Occlusive Disease (PVOD)
Pulmonary veno-occlusive disease (PVOD) is a fatal type of PAH that is characterized by occlusion or narrowing of the pulmonary veins by fibrous tissue. Almost 3%-12% of patients described as having ‘idiopathic PAH’ actually have PVOD. The prognosis is poor due to a high incidence of negative response to vasodilators.12
Pulmonary Capillary Hemangiomatosis (PCH)
PCH is a form of PAH characterized by abnormal proliferation of pulmonary capillaries within alveolar septae. Clinical symptoms include dyspnea, cough, chest pain, and fatigue.11
1.6 Persistent PH of the Newborn Syndrome
Persistent PH of the newborn syndrome is a fatal syndrome among neonates (with a mortality rate of 4% to 33%) in which the pulmonary vasculature fails to adapt to the circulation outside the uterus that normally occurs just after delivery. The underlying mechanisms are not clearly understood but increased pulmonary vasoconstriction and vascular remodeling cause the right-to-left shunting to persist and prevent the flow of blood through the lungs to allow normal breathing.13
- 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
- Lan N, Massam B, Kulkarni S, Lang C. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6(2):38. doi:10.3390/diseases6020038
- Orcholski ME, Yuan K, Rajasingh C, et al. Drug-induced pulmonary arterial hypertension: A primer for clinicians and scientists. Am J Physiol Lung Cell Mol Physiol. 2018;314(6):L967-L983. doi:10.1152/ajplung.00553.2017
- 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
- Barnett CF, Hsue PY. Human immunodeficiency virus-associated pulmonary arterial hypertension. Clin Chest Med. 2013;34(2):283-292. doi:10.1016/j.ccm.2013.01.009
- Simenauer A, Nozik-Grayck E, Cota-Gomez A. The DNA damage response and HIV-associated pulmonary arterial hypertension. Int J Mol Sci. 2020;21(9). doi:10.3390/ijms21093305
- 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
- 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
- Sibomana JP, Campeche A, Carvalho-Filho RJ, et al. Schistosomiasis pulmonary arterial hypertension. Front Immunol. 2020;11:1. doi:10.3389/fimmu.2020.608883
- Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. doi:10.1183/13993003.01913-2018
- Weatherald J, Dorfmüller P, Perros F, et al. Pulmonary capillary haemangiomatosis: a distinct entity? Eur Respir Rev. 2020;29(156). doi:10.1183/16000617.0168-2019
- Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med. 2000;162(5):1964-1973. doi:10.1164/ajrccm.162.5.9912045
- Martinho S, Adão R, Leite-Moreira AF, Brás-Silva C. Persistent pulmonary hypertension of the newborn: pathophysiological mechanisms and novel therapeutic approaches. Front Pediatr. 2020;8:342. doi:10.3389/fped.2020.00342
Reviewed by Kyle Habet, MD, on 7/1/2021.