Pulmonary arterial hypertension: rare and PHighting for air
“Pulmonary Hypertension Association of Canada estimates that 2,000 to 10,000 Canadians currently live with PAH with about 250 to 500 new patients diagnosed each year.”
Pulmonary arterial hypertension (PAH) is a rare and incurable disease defined by high blood pressure in the lungs and progressive narrowing of the pulmonary arteries1. The pulmonary arteries carry blood from the right side of the heart to the lungs for oxygenation. Researchers currently believe that the high blood pressure damages the cells lining the pulmonary arteries leading to increased cell growth, scarring, and narrowing1. This makes it difficult for the heart to pump blood through the lungs and eventually causes heart failure1.
Although there is no official PAH patient registry in Canada, PAH mainly affects young to middle-aged women2, and the Pulmonary Hypertension Association of Canada estimates that 2,000 to 10,000 Canadians currently live with PAH with about 250 to 500 new patients diagnosed each year. There are 20 pulmonary hypertension treatment centers across Canada.
There are several subtypes of PAH grouped according to the cause of the disease including heart defects, connective tissue diseases, exposure to and use of certain drugs or toxins, and HIV infection. About 6%–10% of cases are caused by inherited genetic mutations, known as familial PAH (FPAH), but the vast majority of cases are idiopathic (IPAH), meaning there is no identifiable cause3. To determine the exact cause of PAH, researchers from all over the world have examined the genomes of FPAH and IPAH patients4. Indeed, in 2000, scientists discovered that genetic mutations (permanent mistakes in DNA) that code for a protein expressed by cells lining the arteries of the lungs, called BMPR-II, were associated with PAH5. Since then, BMPR-II mutations have been found to account for approximately 80% of FPAH and 20% of IPAH cases4. Recent genetic studies have also identified several rare mutations in PAH patients, many of which are related to the BMPR-II gene and affect blood vessel growth6. Because of this genetic link, newly diagnosed patients with PAH should consider genetic testing for themselves and their family members, as they too can carry the mutation even though they do not have the disease6. Canadians with PAH can ask their doctor for a referral to a genetic counsellor or visit the Canadian Association of Genetic Counsellors’ website to find the nearest clinic.
Despite advances in understanding and treating PAH over the past 20 years, there is still no cure; however, there are treatments to slow progression of the disease, help improve patient quality of life, and increase survival rates7. Untreated, patients only live about 3 years after diagnosis8, but with treatments, about 50% of patients live for 7 years after diagnosis9. Thus, a timely and correct diagnosis is crucial in extending a patient’s life.
For most patients, their symptoms progress from fatigue, dizziness, and mild shortness of breath during exercise to frequent fainting episodes, chest pain, and hypoxia, where a person’s lips, fingers, or toes develop a blue hue due to poor blood circulation. These symptoms are similar to the symptoms of other common conditions, such as anxiety and asthma, thus doctors unfamiliar with PAH will often misdiagnose patients, delaying their access to life-extending treatments.
To determine if someone has PAH, doctors start with a heart ultrasound. A heart ultrasound is a safe and non-invasive way to roughly calculate the blood pressure inside the pulmonary arteries10. If the ultrasound shows high pulmonary pressures, patients next undergo right-heart catheterization. During this procedure, doctors thread a thin wire through a large vein into the heart and pulmonary arteries to measure the mean pulmonary artery pressure (mPAP)10. Although a right-heart catheterization is more invasive and has more risks associated with it, it provides the most accurate measurement of the mPAP. A healthy person has an mPAP of less than 21 mm Hg11, while an mPAP greater or equal to 25 mm Hg is considered PAH10,12.
In Canada, patients have access to 4 types of PAH drugs: endothelin receptor antagonists (ERAs), which are used to prevent the pulmonary vessels from narrowing, and medications which relax the blood vessels to increase blood flow and decrease blood pressure13 such as phosphodiesterase-5 inhibitors (PDE5is), prostacyclin agonists (PROs), and soluble guanylate cyclase (SGC) stimulators. Often, patients are prescribed both ERAs and PDE5is at the same time, as combination therapy has been shown to be more effective than using a single drug14. After patients begin treatment, doctors track their progress using the 6-minute walk test. The 6-minute walk test measures how far a patient can walk in a 6-minute period while simultaneously monitoring their blood oxygen levels15. In general, the further a patient can walk, the better their prognosis10. In addition, patients whose oxygen levels fall below 90% red blood cell saturation during the walk test are prescribed supplemental oxygen therapy to help oxygenate the blood13—chronically low oxygen levels can damage the body’s vital organs. PAH treatments are powerful drugs and may have side effects such as headaches, nausea, and muscle cramps. ERAs also cause serious birth defects16, and female patients prescribed these medications are required to take contraceptives. Some female patients decide to forego their ERAs in pregnancy, but pregnancy associated with PAH involves a considerable risk of death and is not recommended17.
The cost of PAH treatments is high in Canada and differs from province to province. Costs can range $10,000–$40,000 per patient per year for ERAs and PDE5is, and up to $80,000–$100,000 per patient per year for PROs. A 2016 study conducted in Ontario reported that the average cost of single drug therapy for PAH was about $2,800 per month; dual therapy, about $4,600 per month2. Even with clear evidence that combination therapy allows patients to live longer14, the cost of PAH drugs can make it difficult for patients to get approval for combination therapy from public provincial drug coverage or private insurance2. Coverage varies by province but the cost of most PAH drugs is covered by provincial plans; for example, most PAH drugs are covered under the Alberta Health Care Insurance Plan, and in Ontario, patients that do not have private insurance may qualify for the Trillium Drug Program.
PAH patients that progress to heart failure can also expect to be treated with diuretics13 (often referred to as “water pills” by patients), which help get rid of excess fluid that can put a strain on the heart. Also, anticoagulation therapy helps reduce the number of blood clots in the small arteries of the lungs13. Patients with severe PAH that do not respond well to drug therapies can be referred to undergo assessment for a double lung transplant or dual heart-lung transplant13,18.
The Pulmonary Hypertension Association of Canada (PHA Canada) is a non-profit charity that supports patients and caregivers through education and advocacy, and strives to increase awareness of pulmonary hypertension and fund research for a cure. In 2013, PHA Canada conducted a nationwide survey and found that patients struggle most with social isolation and lack of disease awareness among physicians and the public. A PAH diagnosis impacts quality of life and can put patients at risk of developing mental health disorders19,20. Counselling and support are crucial for patients dealing with this life-altering and incurable disease. PHA Canada encourages all patients to reach out to local support groups, and participate in the PHA Canada annual national conference. The organization also publishes Connections magazine, as well as the The Pulse monthly e-newsletter, both free for PAH patients.
Download This Article
Works Cited:
1. Humbert M, Sitbon O, Simonneau G. Treatment of Pulmonary Arterial Hyperntesion. N Engl J Med 2004;351:1425-36. doi: 10.1056/NEJMra040291
2. Vaid HM, Camacho X, Granton JT, et al. The Characteristics of Treated Pulmonary Arterial Hypertension Patients in Ontario. Can Respir J. 2016;2016:6279250. doi:10.1155/2016/6279250
3. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013:24;62(25 Suppl):D34-41. doi: 10.1016/j.jacc.2013.10.029
4. Condon DF, Nickel NP, Anderson R, Mirza S, de Jesus Perez VA. The 6th World Symposium on Pulmonary Hypertension: what's old is new. F1000Res. 2019;8:F1000 Faculty Rev-888. Published 2019 Jun 19. doi:10.12688/f1000research.18811.1
5. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000;37(10):741–745. doi:10.1136/jmg.37.10.741
6. Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J. 2019;53(1):1801899. doi:10.1183/13993003.01899-2018
7. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394–403. doi:10.1093/eurheartj/ehp022
8. Gatzoulis M. A. Pulmonary Arterial Hypertension. Oxford, UK: Oxford University Press; 2012.
9. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 2012;142(2):448-456.
10. Badesch DB, Champion HC, Sanchez MAG, et al. Diagnosis and Assessment of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology 2009;54(1):S55-66.
11. Kovacs G1, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J. 2009 Oct;34(4):888-94. doi: 10.1183/09031936.00145608.
12. Prins KW, Thenappan T. World Health Organization Group I Pulmonary Hypertension: Epidemiology and Pathophysiology. Cardiol Clin. 2016;34(3):363–374. doi:10.1016/j.ccl.2016.04.001
13. Provencher S, Granton JT. Current treatment approaches to pulmonary arterial hypertension. Canadian Journal of Cardiology. 2015:31(4):460–477 doi: 10.1016/j.cjca.2014.10.024
14. Galiè N1, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, Peacock AJ, Simonneau G, Vachiery JL, Grünig E, Oudiz RJ, Vonk-Noordegraaf A, White RJ, Blair C, Gillies H, Miller KL, Harris JH, Langley J, Rubin LJ; AMBITION Investigators. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27;373(9):834-44. doi: 10.1056/NEJMoa1413687.
15. Torbicki A, Kurzyna M. Pulmonary Arterial Hypertension: Evaluation of the Newly Diagnosed Patient. Semin Respir Crit Care Med. 2005 Aug;26(4):372-8.
16. de Raaf MA1, Beekhuijzen M2, Guignabert C3, Vonk Noordegraaf A1, Bogaard HJ4. Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension. Reprod Toxicol. 2015 Aug 15;56:45-51. doi: 10.1016/j.reprotox.2015.06.048. Epub 2015 Jun 22.
17. Jaïs X, Olsson KM, Barbera JA, Blanco I, Torbicki A, Peacock A, Vizza CD, Macdonald P, Humbert M, Hoeper MM. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. Eur Respir J. 2012 Oct;40(4):881-5. Epub 2012 Jan 26.
18. de Perrot M1, Granton JT, McRae K, Pierre AF, Singer LG, Waddell TK, Keshavjee S. Outcome of patients with pulmonary arterial hypertension referred for lung transplantation: a 14-year single-center experience. J Thorac Cardiovasc Surg. 2012 Apr;143(4):910-8. doi: 10.1016/j.jtcvs.2011.08.055. Epub 2012 Feb 4.
19. Bussotti M, Sommaruga M. Anxiety and depression in patients with pulmonary hypertension: impact and management challenges. Vasc Health Risk Manag. 2018;14:349–360. Published 2018 Nov 8. doi:10.2147/VHRM.S147173
20. Taichman DB, Shin J, Hud L, et al. Health-related quality of life in patients with pulmonary arterial hypertension. Respir Res. 2005;6(1):92. Published 2005 Aug 10. doi:10.1186/1465-9921-6-92
Cite This Article:
Bergeret M. Pulmonary arterial hypertension: rare and PHighting for air. Illustrated by J. Chen. Rare Disease Review. November 2019. DOI:10.13140/RG.2.2.33650.04807.
