What is pulmonary arterial hypertension

Pulmonary hypertension (PH) is the inappropriate elevation of pressure in the pulmonary vascular system. PH is diagnosed by cardiac catheterization, and defined as an increase in mean pulmonary arterial pressure of 25 mmHg or higher at rest. PH can be a difficult diagnosis to make, as it may present at any age with symptoms that are not uncommonly non-specific in nature. While the most common symptom is shortness of breath with activity, it may also present with syncope, chest pain, palpitations, and other non-specific signs and symptoms. Unfortunately, PH is a potentially lethal disease left untreated, and often lethal despite aggressive therapy. While most frequently associated with lung or heart diseases, it may also be associated with a diverse group of other diseases such as connective tissue diseases.

Pulmonary arterial hypertension (PAH) is one type of PH. PAH is a progressive form of pulmonary hypertension characterized by pulmonary vascular remodeling of the distal pulmonary vasculature, ultimately leading to destruction and loss of the smallest pulmonary arteries (1). The ensuing syndrome of PAH is clinically characterized by reduced pulmonary arterial circulatory flow, resulting in increased pulmonary vascular resistance, which ultimately results in failure of the right heart (2). In both children and adults, PAH presents as a primary disease or in association with a diverse range of diseases such as connective tissue diseases, portal hypertension and congenital heart disease (3). Nearly all forms of World Health Organization Group 1 PAH demonstrate a skewed gender ratio with significantly more females diagnosed with PAH than males (4-6).

A conservative estimate of the prevalence of isolated PAH is 15 cases per million which represents more than 4800 patients in the United States (6); however, the true impact of PAH is more extensive because it also occurs in association with multiple common systemic diseases, such as connective tissue diseases (3). For example, ~15% of all patients with a connective tissue disease develop PAH (7). PAH has a very high annual mortality despite recent progress and a surge of data generation with regard to the molecular understanding, such that a third of all patients still die within 3 years of diagnosis (8, 9). As a result, improved understanding of the genetic and molecular risk factors in the pathogenesis of PAH represents a critical opportunity for the development of effective treatments in the future. Because PAH represents one subtype of a larger syndrome of pulmonary vascular disease (3), and molecular advances in the field of PAH are often more widely applicable to other forms of pulmonary vascular disease, progress in the PAH research field often benefits PH understanding more broadly.

As shown in the Figure below, the pathology of PAH involves multiple processes/factors which influence vascular remodeling. These factors include vasoactive factor imbalance, growth factors, exuberant inflammatory cell recruitment, endothelial cell resistance to apoptosis, and vascular smooth muscle cell growth & proliferation.

Germline bone morphogenetic protein receptor type 2 (BMPR2) gene mutations are responsible for HPAH in 80-85% of families with a family history of PAH, while 5-25% of patients diagnosed as having idiopathic PAH (IPAH) actually have a detectable germline mutation in BMPR2 as well (10-16). BMPR2 mutations constitute the largest known risk for developing PAH. However, recent studies have uncovered additional rare and common variants relevant to disease pathogenesis. However, subjects who are BMPR2 mutation carriers have only a 26% chance of developing disease (17). Thus, the penetrance of BMPR2-associated PAH is reduced, which suggests that as yet unknown factors modify disease risk by influencing normal homeostatic mechanisms in the pulmonary vasculature (18).

Adopted from Toshner M et al. Br Med Bull 2010;94:21-32 (http://bmb.oxfordjournals.org/content/94/1/21.full.pdf+html) with permission from Oxford University Press.

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Below is a selection of relevant publications in the field of PAH with particular focus on the genetic features of the disease, although there is a vast and excellent body of literature beyond this selection.

Title	Journal/Year
Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene.	Am J Hum Genet. 2000
Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension.	Nat Genet. 2000
BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension.	Am J Hum Genet. 2001
Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred.	N Engl J Med. 2001
Genetics and genomics of pulmonary arterial hypertension.	J Am Coll Cardiol. 2009
Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension.	Am J Respir Crit Care Med. 2010
Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension.	Circ Cardiovasc Genet. 2012
Molecular pathogenesis of pulmonary arterial hypertension.	J Clin Invest. 2012
Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension.	Nat Genet. 2013

References:

1. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009;54:S3-9.

2. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. Accf/aha 2009 expert consensus document on pulmonary hypertension a report of the american college of cardiology foundation task force on expert consensus documents and the american heart association developed in collaboration with the american college of chest physicians; american thoracic society, inc.; and the pulmonary hypertension association. J Am Coll Cardiol 2009;53:1573-1619.

3. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54.

4. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon M. Pulmonary arterial hypertension: Baseline characteristics from the reveal registry. Chest 2009.

5. Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol 2008;51:1527-1538.

6. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G. Pulmonary arterial hypertension in france: Results from a national registry. Am J Respir Crit Care Med 2006;173:1023-1030.

7. Yang X, Mardekian J, Sanders KN, Mychaskiw MA, Thomas J, 3rd. Prevalence of pulmonary arterial hypertension in patients with connective tissue diseases: A systematic review of the literature. Clinical rheumatology 2013.

8. Humbert M, Sitbon O, Yaici A, Montani D, O'Callaghan DS, Jais X, Parent F, Savale L, Natali D, Gunther S, Chaouat A, Chabot F, Cordier JF, Habib G, Gressin V, Jing ZC, Souza R, Simonneau G. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J;36:549-555.

9. Macchia A, Marchioli R, Tognoni G, Scarano M, Marfisi R, Tavazzi L, Rich S. Systematic review of trials using vasodilators in pulmonary arterial hypertension: Why a new approach is needed. Am Heart J 2010;159:245-257.

10. Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez MA, Martensson G, Galie N, Manes A, Corris P, Simonneau G, Humbert M, Morrell NW, Trembath RC. Bmpr2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006;27:212-213.

11. Fujiwara M, Yagi H, Matsuoka R, Akimoto K, Furutani M, Imamura S, Uehara R, Nakayama T, Takao A, Nakazawa M, Saji T. Implications of mutations of activin receptor-like kinase 1 gene (alk1) in addition to bone morphogenetic protein receptor ii gene (bmpr2) in children with pulmonary arterial hypertension. Circulation journal : official journal of the Japanese Circulation Society 2008;72:127-133.

12. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, 3rd, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in bmpr2, encoding a tgf-beta receptor, cause familial primary pulmonary hypertension. The international pph consortium. Nat Genet 2000;26:81-84.

13. Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, Eickelberg O, Olschewski H, Elliott CG, Glissmeyer E, Carlquist J, Kim M, Torbicki A, Fijalkowska A, Szewczyk G, Parma J, Abramowicz MJ, Galie N, Morisaki H, Kyotani S, Nakanishi N, Morisaki T, Humbert M, Simonneau G, Sitbon O, Soubrier F, Coulet F, Morrell NW, Trembath RC. Mutations of the tgf-beta type ii receptor bmpr2 in pulmonary arterial hypertension. Hum Mutat 2006;27:121-132.

14. Thomson J, Machado R, Pauciulo M, Morgan N, Yacoub M, Corris P, McNeil K, Loyd J, Nichols W, Trembath R. Familial and sporadic primary pulmonary hypertension is caused by bmpr2 gene mutations resulting in haploinsufficiency of the bone morphogenetic protein tuype ii receptor. J Heart Lung Transplant 2001;20:149.

15. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JSR, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC. 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;37:741-745.

16. Austin ED, Phillips JA, 3rd, Cogan JD, Hamid R, Yu C, Stanton KC, Phillips CA, Wheeler LA, Robbins IM, Newman JH, Loyd JE. Truncating and missense bmpr2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. Respir Res 2009;10:87.

17. Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, West JD, Phillips JA, 3rd, Hamid R, Loyd JE. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:892-896.

18.Newman JH, Phillips JA, 3rd, Loyd JE. Narrative review: The enigma of pulmonary arterial hypertension: New insights from genetic studies. Ann Intern Med 2008;148:278-283.