Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a rare disease in which high blood pressure in the pulmonary arteries leads to increased pulmonary vascular resistance, resulting in heart failure and ultimately death.^1,2 

Several factors have been identified that potentially increase the risk of PAH development.³ These include sex and family history of the condition, underlying diseases, and certain medications. 

Sex and Family History

PAH can develop at all ages, including in children. Its incidence increases with age; however, PAH is more common in people over 75 years of age.⁴ The disease is more frequently identified in non-Hispanic black people, and both idiopathic and heritable PAH are more common in female patients.^4,5

The risk of developing PAH is increased when there are 2 or more family members with PAH or when a family member has a gene linked to PAH.^5,6 The presence of the BMPR2 mutation significantly increases the risk of PAH development.⁷ Genetic counseling and testing should therefore be provided to the families of patients with idiopathic and heritable PAH.³

Obesity and Sleep Apnea

Excessive bodyweight has been established as an independent risk factor in cardiovascular disease development and death.² It has also been associated with PAH, but obesity by itself is not a risk factor and different data points toward lower long-term mortality in obese patients.^5,8 If combined with obstructive sleep apnea, however, PAH can develop.⁵

Pregnancy

Registries and experts suggest that pregnancy can be a possible risk factor for PAH.⁵ Pregnancy causes several hemodynamic and anatomic changes during gestation and through the delivery and postpartum periods that can affect women with diagnosed PAH.⁹ Female PAH patients who become pregnant have an increased risk of morbidity and mortality. Contraception is therefore recommended.^5,10 

Drugs and Toxins

Certain drugs and toxins have been established as possible or definite risk factors for PAH development.¹¹ These include appetite suppressants such as fenfluramine and dexfenfluramine, methamphetamines, and dasatinib.¹² The risk of PAH in patients taking appetite suppressants for at least 3 months was shown to be increased by about 9 times compared to that of nonusers.¹

Other drugs such as amphetamines, cocaine, interferon alfa, interferon beta, alkylating agents, and antiviral drugs for treating hepatitis C virus are likely to predispose patients to PAH. Drugs used to treat depression and anxiety that may be prescribed to pregnant women, such as selective serotonin reuptake inhibitors, can increase the risk of the newborn developing persistent pulmonary hypertension.¹² 

Altitude

Living at high altitudes for years, typically above 2500 meters, can increase the risk of PAH development.^5,13 At such high altitudes, the barometric pressure is lower, which results in a decrease in the partial pressure of oxygen in the air. Less oxygen reaches the lungs in these conditions than at sea level. The development of hypoxia leads to pulmonary vasoconstriction and an increase in pulmonary arterial pressure.¹³ Patients with PAH may also experience worsening symptoms while traveling by air due to the higher altitude.⁵

Other Diseases

In many patients, other diseases can be identified in association with PAH. These include connective tissue diseases such as scleroderma, lupus, liver disease, congenital heart disease, chronic obstructive pulmonary disease, sleep apnea, and hereditary hemorrhagic telangiectasia.^1,14 Approximately 30% of scleroderma patients and about 1 in 200 HIV patients develop at least mild disease.¹⁴ 

Blood disorders such as hemolytic anemia and sickle cell disease can also increase the risk of developing PAH. The release of hemoglobin into the plasma that occurs in these conditions results in the formation of reactive oxygen species that impact the hemostatic system.¹² About 20% to 40% of patients with sickle cell disease will develop a mild form of the PAH.¹⁴ Additionally, patients with sickle cell disease may experience other conditions, such as liver disease and thrombotic events, that may promote PAH.¹² Blood clots can result in chronic thromboembolic pulmonary hypertension as the obstruction of blood flow into the pulmonary arteries leads to pressure increases.¹

References

1. Pulmonary arterial hypertension. National Organization for Rare Disorders (NORD). Accessed March 10, 2022.

2. McLean LL, Pellino K, Brewis M, Peacock A, Johnson M, Church AC. The obesity paradox in pulmonary arterial hypertension: the Scottish perspective. ERJ Open Res. 2019;5(4):00241-2019. doi:10.1183/23120541.00241-2019

3. Galiè N, Humbert M, Vachiery JL, et al; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. doi:10.1093/eurheartj/ehv317

4. Pulmonary hypertension. Centers for Disease Control and Prevention (CDC). Accessed March 10, 2022.

5. Risk factors. Pulmonary Hypertension Association. Accessed March 10, 2022.

6. Genetic testing and counseling for idiopathic and familial pulmonary arterial hypertension (PAH). Pulmonary Hypertension Association. Accessed March 10, 2022.

7. Levine DJ. Pulmonary arterial hypertension: updates in epidemiology and evaluation of patients. Am J Manag Care. 2021;27(3 Suppl):S35-S41. doi:10.37765/ajmc.2021.88609

8. Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309(1):71-82. doi:10.1001/jama.2012.113905

9. Sun X, Feng J, Shi J. Pregnancy and pulmonary hypertension: an exploratory analysis of risk factors and outcomes. Medicine (Baltimore). 2018;97(44):e13035. doi:10.1097/MD.0000000000013035

10. Corbach N, Berlier C, Lichtblau M, et al. Favorable pregnancy outcomes in women with well-controlled pulmonary arterial hypertension. Front Med (Lausanne). 2021;8:689764. doi:10.3389/fmed.2021.689764

11. Ramirez RL III, Pienkos SM, de Jesus Perez V, Zamanian RT. Pulmonary arterial hypertension secondary to drugs and toxins. Clin Chest Med. 2021;42(1):19-38. doi:10.1016/j.ccm.2020.11.008

12. Gladwin MT, Levine AR. Pulmonary hypertension. MSD Manual Professional Version. Updated September 2020. Accessed March 10, 2022.

13. Ulloa NA, Cook J. Altitude induced pulmonary hypertension. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Accessed March 10, 2022.

14. Associated conditions. Pulmonary Hypertension Association. Accessed March 10, 2022.

Reviewed by Hasan Avcu, MD, on 3/21/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.