DiagnosisWhile the established diagnostic criteria for pulmonary arterial hypertension (PAH) have not changed, the nomenclature has changed. Heritable PAH (HPAH) includes familial PAH (PAH that occurs in two or more family members) and simplex PAH (i.e., a single occurrence in a family) when a disease-causing mutation has been identified.See Badesch et al [2009] for the most current information on diagnosis.Clinical DiagnosisThe diagnosis of pulmonary arterial hypertension (PAH) may be suspected in individuals with the following if other causative diseases are absent: Symptoms: dyspnea, fatigue, chest pain, palpitation, syncope, or edema.Signs (abnormal findings on physical examination): Accentuation of the pulmonic component of the second heart sound Right ventricular heave or cardiac murmur such as tricuspid regurgitation resulting from right ventricular dilatation Signs of right ventricular failure such as increased venous pressure, edema, or hepatomegaly (later in the course) PAH can be established clinically by the following:Confirmation of the presence of pulmonary arterial hypertension (i.e., mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg during exercise) by right heart catheterizationExclusion of other known causes of pulmonary hypertension (PH) (see Differential Diagnosis) The presence of a BMPR2 mutation in an individual with PAH and/or the presence of PAH in another family member confirms the diagnosis of heritable PAH (HPAH). In individuals with PAH:Electrocardiography (ECG) may reveal changes suggestive of right atrial or right ventricular hypertrophy or strain. In individuals with PH associated with cardiac causes, ECG may reveal additional changes. Pulmonary function testing may show mild restriction or be normal. In individuals with PH associated with parenchymal lung diseases, pulmonary function testing may reveal evidence of obstructive and/or restrictive disorders. Chest radiography shows normal parenchyma and may show cardiomegaly. In those with PH associated with parenchymal lung disease, chest radiography may reveal changes of other lung diseases. Perfusion lung scanning demonstrates normal distribution or is mottled, or may reveal segmental or larger perfusion defects which indicate pulmonary embolism. Chest CT shows normal lung parenchyma. In individuals with PH associated with parenchymal lung disease, high-resolution imaging may show changes of interstitial lung diseases or emphysema. CT angiography has improved greatly and is noninvasive; thus it may be helpful in the evaluation of most individuals with PH. The angiographic features of chronic thromboembolic pulmonary hypertension (CTEPH) include pouching deformities and intravascular webs, which are distinctly different from the intraluminal filling defects of thrombus, as seen in acute pulmonary embolism.Echocardiography, a noninvasive procedure, sometimes may provide estimates of systolic pulmonary artery pressure and/or reveal changes in the right ventricle or right atrium. Echocardiography is also used to screen for valvular or left ventricular (LV) disease as an alternative cause of PH. Cardiac catheterization is used to confirm the diagnosis of PAH by directly measuring pulmonary artery pressures and excluding other cardiac abnormalities. Because increased wedge pressure resulting from LV diastolic dysfunction may be a clinically cryptic cause requiring different treatments, catheterization is recommended for all individuals with suspected PH. Challenge testing with vasodilators (i.e., inhaled nitric oxide) or fluid loading, or both, during catheterization is important to assess physiologic responses to guide appropriate therapy. Note: Challenge testing may not be available outside of referral centers.Lung biopsy or histopathology at the time of transplant reveals occlusion of small pulmonary arteries, and in some cases plexiform lesions, but is otherwise normal. Several pathophysiologic features may contribute to small pulmonary artery occlusion: proliferation of the intima and media of the vessel wall, vasospasm, and microthrombosis. Lung biopsy is rarely indicated for individuals in whom the other tests above are compatible with PAH, but on rare occasion lung biopsy does reveal other conditions [Palevsky et al 1989].Molecular Genetic TestingGene. Mutations in BMPR2 are responsible for 75% of familial PAH. Mutations are identified in 25% of individuals who represent simplex cases (i.e., a single occurrence in a family) [Thompson et al 2000]. Other loci. Mutations in other genes (i.e., ACVRL1, BMPR1B, CAV1, ENG, and SMAD9) are considerably less common (~1% each gene) [Harrison et al 2003, Shintani et al 2009, Girerd et al 2010, Austin et al 2012, Chida et al 2012]. In about 25% of families with FPAH the responsible mutation has not yet been discovered. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Heritable Pulmonary Arterial Hypertension (HPAH)View in own windowGene SymbolProportion of HPAH Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityBMPR275% ^{1, 2Sequence analysisSequence variants 3Clinical Deletion / duplication analysis 4Deletion1. BMPR2 mutations are detected in about 75% of individuals with familial PAH [Cogan et al 2006]. Of those mutations detected, 37% were point mutations in the coding region and 48% were intragenic deletion/duplications detected by MLPA or other comparable methods. Therefore, among all individuals with familial PAH, an estimated 30% of mutations are detectable by sequence analysis and 34% by deletion/duplication analysis. Twenty-five percent of simplex cases (i.e., a single occurrence in a family) have an identifiable mutation [Thompson et al 2000].2. Cogan et al [2006]3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. To confirm the diagnosis of HPAH in a proband, it is necessary either to confirm the diagnosis of PAH in two individuals in a family or to identify by molecular genetic testing a disease-causing mutation in an individual who represents a simplex case (i.e., a single occurrence in a family). Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersMutation of BMPR2 is also reported in the following:One family with pulmonary veno-occlusive disease [Runo et al 2003] Five individuals with appetite suppressant-related PH [Humbert et al 2002]A recent retrospective study that described a larger cohort of fenfluramine-associated pulmonary arterial hypertension (fen-PAH) in France. The records of all persons with a diagnosis of fen-PAH evaluated from 1986 to 2004 were studied. The median duration of fenfluramine exposure was six months, with a median of 4.5 years between exposure and onset of symptoms. Nine (22.5%) of the 40 persons evaluated had a BMPR 2 mutation [Souza et al 2008].Six individuals with congenital heart disease (complete type C atrioventricular canals, atrial septal defect, patent ductus arteriosus, partial anomalous pulmonary venous return, and aortopulmonary window with a ventricular septal defect) [Roberts et al 2004] One family with hereditary hemorrhagic telangiectasia (HHT) [Rigelsky et al 2008] (see also Differential Diagnosis)}

Natural HistoryThe clinical characteristics and natural history of pulmonary arterial hypertension (PAH) were reported in a multicenter study [Rich et al 1987] before the introduction of effective therapies. The study, involving 32 US centers, included 194 affected individuals in whom other causes of PH (e.g., pulmonary embolism) were excluded.Initial symptoms were dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), near syncope (5%), palpitations (5%), and leg edema (3%). Ten percent reported Raynaud phenomenon; 95% of these individuals were female. The mean age at diagnosis was 36 years, but individuals at any age can be affected.The clinical course varies considerably, but untreated individuals gradually deteriorate, with a mean survival of 2.8 years after diagnosis. The variability in survival across patients is broad, ranging from sudden death to decades (rare). Clinical functional capacity correlated closely with survival before the current therapies were introduced, such that individuals in New York Heart Association (NYHA) class IV had a mean survival of six months. In the current era of many medical therapies, prognosis at any point in time may be less clear, so weighing the potential benefits of current medical therapy against the incumbent risks of lung transplantation is more difficult now than in the past.Family history was positive for PAH in 6% of individuals in large series with PAH studied in the past. Similar prevalence was reported in a national registry in France [Humbert 2010]. Individuals with a family history of PAH had symptoms, signs, and clinical course identical to those in individuals with no family history of PAH. Because the symptoms of PAH are nonspecific and develop slowly, affected individuals often incorrectly attribute their initial symptoms to aging, poor conditioning, or overweight. Diagnosis is often delayed, in part because PAH is uncommon and thus rarely considered. The time to diagnosis from onset of symptoms may be shorter in familial PAH, perhaps because of heightened familial awareness.PAH affects all ages, including the very young and the elderly. A recent report describes identification of a BMPR2 mutation in an 83-year-old man [Johri et al 2010]. Females are twice as likely to be affected as males; however, disease severity and outcome appear similar in males and females. Anecdotal reports suggest a possible association between familial PAH or PAH of unknown cause and pregnancy or exogenous estrogen therapy. Recent studies suggest that the female predisposition to PAH may be directly related to the effects of metabolites of estrogen [Austin et al 2009a].The physiologic stress of pregnancy in a patient with PAH is significant and maternal mortality is believed to be substantial; however, it remains to be seen if new effective therapies may decrease this risk.Pathophysiology. PAH is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries [Runo & Loyd 2003, Hoeper & Rubin 2006]. When a sufficient number of vessels are occluded, the resistance to blood flow through the lungs increases and the right ventricle attempts to compensate by generating higher pressure to maintain pulmonary blood flow. Long-term outcome may depend on hypertrophy and compensation of the right ventricle, which also varies across individuals; however, when the heart can no longer compensate for the increased resistance, progressive heart failure ensues.

Genotype-Phenotype CorrelationsAbout half of the known BMPR2 mutations are associated with nonsense-mediated decay (NMD) of the mutant transcript. Recent reports suggest that mutations which exhibit NMD and exhibit a haploinsufficient mechanism may have milder phenotypes than mutations which exhibit other mechanisms [Austin et al 2009b].

Differential DiagnosisOther cardiopulmonary causes of pulmonary hypertension (PH) are far more common than pulmonary arterial hypertension (PAH). Importantly, causes of PH associated with related conditions need to be excluded before the diagnosis of PAH can be established. Other causes of PH include lung disease, pulmonary embolism, heart disease, connective tissue diseases, cirrhosis, and HIV infection [Badesch et al 2009].Lung disease. The advanced stages of all lung diseases may cause PH. Most lung diseases that cause PH are identified by detection of abnormal lung sounds on physical examination, pulmonary function testing, and/or high-resolution computed tomographic lung imaging. Pulmonary embolism/disease of large pulmonary vessels. Pulmonary embolism or disease of large pulmonary vessels is detected by imaging procedures, traditionally screening by lung perfusion scanning with confirmation by pulmonary arteriography. Although CT angiography has improved greatly, nuclear medicine perfusion scanning still has a role in screening for chronic thromboembolic pulmonary hypertension (CTEPH), a disorder in which pulmonary emboli are not resorbed normally by fibrinolysis. It is important to correctly diagnose CTEPH because surgical pulmonary thromboendarterectomy is highly effective in the appropriate medical circumstances [Piazza & Goldhaber 2011].Heart disease. Most advanced cardiac conditions, including congenital heart disease, valvular disease, and cardiomyopathy, can cause PH. Heart diseases are detected by physical examination, ECG, echocardiography, and cardiac catheterization. Hereditary hemorrhagic telangiectasia (HHT). Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs). Small AVMs (or telangiectases) close to the surface of the skin and mucous membranes often bleed after slight trauma. The most common clinical manifestation is recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Approximately 25% of individuals with HHT have GI bleeding, which most commonly begins after age 50 years. AVMs often cause symptoms when they occur in the brain, liver, or lungs; complications from bleeding or shunting may be sudden and catastrophic. Pulmonary hypertension in the absence of shunt is a rare HHT manifestation, and usually occurs in individuals with mutations in ACVRL1 [Trembath et al 2001, Harrison et al 2003].
Rarely mutations in other genes in the TGF-β family are responsible; these include ENG (encoding endoglin) and SMAD9 (previously known as SMAD8) [Shintani et al 2009]. Other causes of PH include connective tissue diseases, cirrhosis, HIV infection, and treatment with appetite suppressants. Pulmonary veno-occlusive disease [Holcomb et al 2000] and pulmonary capillary hemangiomatosis, two other disorders that are limited to the vessels of the lungs, were previously classified as pathologic subsets of PH, but are now generally accepted as distinct conditions. Both disorders are, on very rare occasion, familial. Anecdotal reports suggest that an association may exist between PAH and pregnancy or exogenous estrogen therapy [Austin et al 2009a].

ManagementEvaluations Following Initial DiagnosisBecause pulmonary arterial hypertension (PAH) is a diagnosis of exclusion, the necessary evaluations are all completed as part of establishing the diagnosis. Treatment of ManifestationsSee McLaughlin et al [2009] for evidenced-based treatment algorithm.Referral centers specializing in diagnosis and therapy of PAH are available across the US (see Pulmonary Hypertension Association Web site). Consultation is encouraged for all persons suspected of having PAH because of the complexity and continuing evolution of diagnosis and treatment.Epoprostenol (Flolan®). A randomized controlled trial of continuous intravenous infusion of epoprostenol, an analog of prostacyclin, in individuals with PAH demonstrated substantial benefit in symptoms, functional status, and survival at three months. Because continuous intravenous epoprostenol appears to be the most effective therapy tested so far, it has become standard for individuals with serious or life-threatening PAH. Epoprostenol is effective for most individuals with PAH, but it is expensive and its administration is difficult because it requires continuous infusion via portable infusion pump and chronic central venous catheter. Dosing of epoprostenol is complicated by tachyphylaxis and a serious discontinuation response; if the infusion is stopped, sudden worsening or even death may occur. Treprostinil (Remodulin®) subcutaneous. A randomized controlled trial of continuous subcutaneous infusion of treprostinil, an analog of prostacyclin, demonstrated efficacy and is now FDA approved. Pain at the subcutaneous infusion site limits dose escalation in many individuals [Simonneau et al 2002, McLaughlin et al 2003]. Treprostinil (Remodulin®) intravenous. Continuous intravenous use of treprostinil is also effective and has been FDA approved. Treprostinil (Tyvaso®) inhalation. Inhalation of treprostinil is also effective and has been FDA approved. Bosentan (Tracleer®). A randomized control trial of oral bosentan, a nonselective (A and B receptors) endothelin blocker, demonstrated efficacy and is now FDA approved [Rubin et al 2002]. Ambrisenan (Letairis®) is a selective endothelin blocker which demonstrated efficacy and is now FDA approved [McLaughlin et al 2009].Sildenafil (Revatio®). A randomized trial of oral sildenafil, a phosphodiesterase inhibitor, demonstrated efficacy and is now FDA approved. Tadalafil (Adcirca®). A randomized trial of oral tadalafil, a phosphodiesterase inhibitor, demonstrated efficacy and is now FDA approved. Inhalation iloprost (Ventavis®). Inhalation of this prostacyclin analog circumvents the need for parenteral administration and is FDA approved. Calcium channel blockers. A minority of individuals with PAH have a favorable long-term clinical response to oral calcium channel blockers. Such responders may be identified by a positive acute pulmonary vasodilator response (inhaled nitric oxide) assessed during cardiac catheterization. Three retrospective studies suggest that individuals with HPAH are less likely to demonstrate an acute pulmonary vasodilator response or have more severe disease than those with PAH of unknown cause [Elliott et al 2006, Rosenzweig et al 2008, Sztrymf et al 2008]. Adjunctive agents. Fluid retention may be ameliorated by diuretic therapy, hypoxemia may be helped by supplemental oxygen, and anticoagulation therapy may prevent superimposed thrombosis, especially common for indwelling catheters needed to deliver continuous infusion of a prostanoid. Lung transplantation is an effective treatment for selected patients with PAH, but has many limitations, among them insufficient availability of donor lungs and limited long-term survival after lung transplantation for most recipients because of chronic graft rejection. Mean survival after lung transplantation is about five years.Lung transplantation is appropriate only for patients whose lives are threatened by lung disease. Although the many effective PAH medications can improve symptoms, they do not reverse the underlying pulmonary vascular disease and it is unknown if they prolong overall survival [Humbert 2010, Macchia et al 2010]. The time span of months usually needed to assess the benefit of the many different medications or combinations of medications available can delay the decision about timing of lung transplantation. SurveillanceSee McLaughlin et al [2009] for consensus document including Reassessing Patients over Time.The clinical course of PAH is highly variable, ranging from rapid progression to long periods of stable clinical status. The appropriate surveillance measures and timing are determined by the relative stability of the patient's clinical condition. Patients who are declining should be in frequent contact with their health care providers so that therapies may be changed or added.Agents/Circumstances to AvoidAppetite-suppressant medications, such as fenfluramine/phentermine, dexfenfluramine, and amfepramone (diethylpropion) have been associated with pulmonary hypertension (PH) [Abenhaim et al 1996, Abramowicz et al 2003].Cocaine, amphetamines, and related compounds causing vasoconstriction have anecdotal association with PH and could be risk factors. Other medications that have anecdotal suggestion of increased risk of PH include estrogen compounds used as oral contraceptives or hormone replacement therapy. Anecdotal reports associating pregnancy with onset of PH raise some concern about the risks involved with pregnancy; however, there is no published consensus regarding the best approach to birth control in women with PAH [Austin et al 2009a, Sweeney & Voelkel 2009].The hypoxia that accompanies high altitude is associated with pulmonary vasoconstriction and PH in susceptible individuals. Individuals with PAH should avoid hypoxia. Evaluation of Relatives at RiskThe WHO Symposia [Badesch et al 2009] recommend echocardiographic screening of at-risk family members every three to five years to enable earlier detection and treatment. However, many health insurers do not provide coverage for screening tests for asymptomatic individuals. No studies describe the frequency of compliance with the WHO recommendation.The possible role of molecular genetic testing for early diagnosis of at-risk family members is yet to be established [Newman et al 2001]. However, in families with a known BMPR2 mutation the use of molecular genetic testing to clarify the genetic status of at-risk relatives can permit individuals who do not have the family-specific mutation to safely forego clinical screening. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management The physiologic stress of pregnancy in a woman with PAH is significant and maternal mortality is believed to be substantial; newer effective therapies may decrease this risk.Anecdotal reports of onset of PAH with pregnancy raise concern about risks of pregnancy, but no consensus exists regarding the best approach to birth control in women with PAH [Austin et al 2009a, Sweeney & Voelkel 2009].Therapies Under InvestigationSeveral investigations are actively seeking new treatment directions or compounds, and many have shown promising results in experimental models or pilot studies in affected individuals, including the following [Ghofrani et al 2009]: Antiangiogenesis strategiesGrowth factor inhibitorsEndothelial progenitor cells/stem cells in lung repair Developing therapies against right-ventricle remodelingTrials of combination therapy, using selected combinations of the FDA-approved therapies mentioned in Treatment of Manifestations, are in progress [Barst et al 2009]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Heritable Pulmonary Arterial Hypertension: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDBMPR22q33​.1-q33.2Bone morphogenetic protein receptor type-2BMPR2 homepage - Mendelian genesBMPR2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Heritable Pulmonary Arterial Hypertension (View All in OMIM) View in own window 178600PULMONARY HYPERTENSION, PRIMARY, 1; PPH1 600799BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE II; BMPR2Normal allelic variants. BMPR2 comprises 13 exons [Machado et al 2001]. Pathologic allelic variants. More than 300 unique mutations have been reported. [Machado et al 2009]. Approximately 30% of mutations localize to exon 12. Normal gene product. Bone morphogenetic protein receptor type-2 (BMPR-2) is a member of the transforming growth factor β (TGF-β) superfamily of cell-signaling molecules. BMPR-2, with different reported protein isoforms, forms a heterodimer with BMPR1 to transduce BMP signaling via SMAD proteins. Foletta et al [2003] analyzed interactions with BMPR-2 and discovered the ability of LIMK1 to phosphorylate cofilin, which could then be alleviated by addition of BMP4. A BMPR-2 mutant containing the smallest COOH-terminal truncation described in an individual with BMPR2-related PAH failed to bind or inhibit LIMK1. This study identified the first function of the BMPR-2 tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of BMPR2-related PAH. Tctex-1, a light chain of the motor complex dynein, interacts with the cytoplasmic domain of BMPR-2 and is phosphorylated by BMPR-2 [Machado et al 2003]. BMPR-2 and Tctex-1 colocalize to endothelium and smooth muscle within the media of pulmonary arterioles, key sites of vascular remodeling in PAH. Progressively more knowledge is being obtained about BMPR2 function, but the specific pathways by which mutation leads to the proliferative vascular disease in PAH remain incompletely understood at this time. Bmpr2 mutation mouse models develop pulmonary hypertension and recapitulate the human condition, and are valuable for preclinical trials [West et al 2008, Johnson et al 2010].Abnormal gene product. Haploinsufficiency of BMPR-2 is reported to be a molecular mechanism of HPAH [Machado et al 2001]. Fifty-eight percent of reported BMPR2 mutations lead to truncated BMPR-2 protein product. Machado et al [2003] determined that phosphorylation of Tctex-1 is disrupted by disease-causing mutations within exon 12. Nishihara et al [2002] determined that missense mutations within the extracellular and kinase domains of BMPR-2 abrogated its signal-transducing abilities.