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Heritable Pulmonary Arterial Hypertension

, MD, MSCI, , MD, and , MD, PhD.

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Initial Posting: ; Last Update: June 11, 2015.

Summary

Clinical characteristics.

Pulmonary arterial hypertension (PAH) is characterized by widespread obstruction and obliteration of the smallest pulmonary arteries. 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. When the right ventricle can no longer compensate for the increased resistance, progressive heart failure ensues. Initial symptoms include dyspnea (60%), fatigue (19%), syncope (8%), chest pain (7%), palpitations (5%), and leg edema (3%). All ages are affected, but the mean age at diagnosis is 36 years. Mean survival after diagnosis is 2.8 years; current therapy does improve clinical function but has modest effect on survival. The term 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 pathogenic variant has been identified. Most heritable PAH (75%) is caused by a pathogenic variant in BMPR2; pathogenic variants in other genes (i.e., ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B,) are considerably less common (1-3%). HPAH has identical symptoms, signs, and histology as PAH of unknown cause. The time from onset of symptoms to diagnosis may be shorter in individuals with familial PAH, possibly because of familial awareness of the disease. Three retrospective studies suggest that persons with PAH who have a BMPR2 pathogenic variant exhibit more severe disease.

Diagnosis/testing.

The diagnosis of PAH can be established clinically by confirming the presence of pulmonary arterial hypertension (i.e., mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg during exercise) and excluding other known causes of pulmonary hypertension (PH). The diagnosis of HPAH is confirmed by the presence of two or more family members with PAH or the identification of a pathogenic variant in a simplex case (i.e., a single occurrence in a family).

Management.

Treatment of manifestations: Referral centers specializing in PAH diagnosis and therapy are available in most regions of the US and consultation is encouraged for all patients suspected to have PAH. Continuous intravenous epoprostenol, the most effective therapy to date, is standard for individuals with life-threatening PAH; additional approved medications include other prostacyclin analogs, endothelin blockers, phophodiesterase inhibitors and guanylate cyclase stimulator. A small minority of individuals respond well long term to oral calcium channel blockers. Chronic anticoagulation therapy, diuretics, and supplemental oxygen are used routinely as needed. No medical therapy has been demonstrated to reverse the proliferative vascular disease which is the anatomic origin of PAH. Lung transplantation is effective, but long-term survival is limited by chronic rejection. 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.

Agents/circumstances to avoid: Appetite suppressants, such as fenfluramine/phentermine, dexfenfluramine, and amfepramone (diethylpropion); cocaine, amphetamines, and related compounds causing vasoconstriction; hypoxia (including that associated with high altitude); possibly estrogen compounds used as oral contraceptives or hormone replacement therapy. Illicit drug use, especially methamphetamine, is an important cause of PAH in some regions.

Evaluation of relatives at risk: Transthoracic echocardiographic screening of at-risk family members every few years is recommended by WHO guidelines to enable earlier detection and treatment. In families with a known pathogenic variant in one of the genes associated with HPAH, 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 pathogenic variant to safely forego clinical screening. However, the role of molecular genetic testing for early diagnosis of at-risk family members has yet to be established.

Other: Anecdotal reports of symptom onset of PAH during pregnancy raise concern about risks of pregnancy provoking onset of PAH. No consensus exists regarding the best method for birth control in women with PAH; however, recent advances in intrauterine devices suggest advantages to this method.

Genetic counseling.

HPAH is inherited in an autosomal dominant manner. The average penetrance of BMPR2 pathogenic variants is low, approximately 20% overall and is sex dependent. PAH develops across all ages, and the lifetime risk of developing PAH with a BMPR2 pathogenic variation in a male is 14%, whereas in a female it is 42%. (The penetrance of pathogenic variants in ACVRL1, KCNK3, CAV1, SMAD9, and BMPR1B is unknown.) If a parent of a proband has a pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%; however, because of the reduced penetrance of BMPR1B pathogenic variants, the risk to a sib of developing PAH is approximately 10% (50% x ~20%). Similarly, each child of an affected individual is at a 50% risk of inheriting the mutant allele; however, because of reduced penetrance the risk to offspring who inherit a BMPR2 pathogenic variant of developing PAH is approximately 10% (50% x ~20%). Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.

Diagnosis

While the established diagnostic criteria for pulmonary arterial hypertension (PAH) have not changed [Hoeper et al 2013], 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 pathogenic variant in one of the known genes has been identified.

Note: Pulmonary hypertension (PH) is classified by WHO into five groups [Simonneau et al 2013]. PAH is classified as Group 1, and it is a clinical diagnosis which is established by excluding the others, including PH resulting from heart disease (Group 2), PH resulting from lung disease or hypoxia (Group 3), PH from chronic thromboembolic PH (Group 4), and a variety of miscellaneous causes, metabolic disorders, sarcoidosis, or splenectomy (Group 5).

Suggestive Findings

Diagnosis of heritable pulmonary arterial hypertension (HPAH) [Hoeper et al 2013] should be suspected in individuals with the following if other causative diseases are absent:

  • Symptoms: none, dyspnea, fatigue, chest pain, palpitation, syncope, or edema
  • Signs (abnormal findings on physical examination) including:
    • 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)

Clinical testing to confirm PAH and distinguish from other forms of PH:

  • Electrocardiography (ECG) may reveal changes suggestive of right atrial or right ventricular hypertrophy or strain. In individuals with PH associated with cardiac causes (Group 2 PH), ECG may reveal additional changes.
  • Pulmonary function testing may show mild restriction or be normal. In individuals with PH associated with parenchymal lung diseases (Group 3 PH), 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 (Group 3 PH), 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 (Group 4).
  • Chest CT shows normal lung parenchyma. In individuals with PH associated with parenchymal lung disease (Group 3 PH), 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) (Group 4 PH) 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 (Group 2 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 (Group 2 PH) may be a clinically cryptic cause of PH 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 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 not recommended for individuals in whom the other tests above are compatible with PAH, but on rare occasion lung histopathology does reveal other conditions [Palevsky et al 1989].

Establishing the Diagnosis

The diagnosis of HPAH is established clinically [Hoeper et al 2013] by the following in a proband:

  • 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 catheterization
  • Exclusion of other known causes of pulmonary hypertension (PH) (see Differential Diagnosis)
  • Identification of a heterozygous pathogenic variant in one of the genes known to be associated with HPAH (see Table 1a, Table 1b) and/or confirmation of PAH in one or more of the proband’s family members

Molecular testing approaches can include serial single-gene testing or the use of a multi-gene panel.

  • Serial single-gene testing can be considered if (1) mutation of a particular gene accounts for a large proportion of the disease OR (2) factors (including e.g., clinical findings, laboratory findings, ancestry) indicate that mutation of a particular gene is most likely. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. For HPAH, the recommended order for testing (related to the frequency which pathogenic variants commonly occur) is BMPR2, ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B.
  • A multi-gene panel that includes BMPR2, ACVRL1, KCNK3, CAV1, SMAD9, BMPR1B and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the sensitivity of multi-gene panels vary by laboratory and over time.

Table 1a.

Molecular Genetics of Heritable Pulmonary Arterial Hypertension (HPAH): Most Common Genetic Causes

Gene 1, 2% of HPAH Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detected by Test Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
BMPR275% 637%48%
ACVRL13% 7>95%None reported in HPAH 8

Pathogenic variants of any one of the genes included in this table account for >1% of HPAH.

1.

Genes are listed from most frequent to least frequent genetic cause of HPAH.

2.
3.

See Molecular Genetics for information on pathogenic allelic variants detected.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.

6.

BMPR2 pathogenic variants are detected in about 75% of individuals with familial PAH [Cogan et al 2006]. Of those mutations detected, 37% were single nucleotide variants 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 pathogenic variants are detectable by sequence analysis and 34% by deletion/duplication analysis. 15% of simplex cases (i.e., a single occurrence in a family) have an identifiable pathogenic variant in BMPR2 [Girerd et al 2010].

7.
8.

ACVRL1 deletions were found in 6% of those with HHT [McDonald et al 2011]. Although none of those with ACVRL1 deletion were specifically reported to have PAH, it is known that those with HHT can develop PAH. See Differential Diagnosis.

Table 1b.

Molecular Genetics of Heritable Pulmonary Arterial Hypertension (HPAH): Less Common Genetic Causes

Gene 1, 2Comment
BMPR1BOne family reported [Chida et al 2012]
CAV1Two families reported [Austin et al 2012]
KCNK3Three families reported [Ma et al 2013]
SMAD9One family reported [Shintani et al 2009]

In about 15% of families with HPAH the pathogenic variant has not yet been discovered [Loyd, personal observation].

1.

Genes are listed in alphabetical order.

2.

Clinical Characteristics

Clinical Description

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.

The clinical characteristics and natural history of 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.

Because the symptoms of HPAH are nonspecific and develop slowly, affected individuals often mistakenly attribute their initial symptoms to aging, poor physical conditioning, or overweight. Some patients report no symptoms, and diagnosis is suspected on an incidental basis because of cardiac findings such as murmur, then supported by echocardiogram. Diagnosis is often delayed for months or even years, in part because HPAH 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.

Age of onset. HPAH affects all ages, including the very young and the elderly. A report describes identification of a BMPR2 pathogenic variant in an 83-year-old symptomatic man [Johri et al 2010].

Female preponderance. Females are twice as likely to be affected as males; however, survival is worse in males than females [Jacobs et al 2014]. Anecdotal reports suggest a possible association between development of PAH and pregnancy or exogenous estrogen therapy. Studies suggest that the female predisposition to PAH may be directly related to the effects of metabolites of estrogen [Austin et al 2009a]. Estrogen-driven suppression of BMPR-II signaling in female pulmonary artery smooth muscle contributes to a proliferative phenotype that may predispose females to PAH [Mair et al 2015]

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 further medical therapy against the incumbent risks of lung transplantation is more difficult now than in the past.

Pregnancy. The physiologic stress of pregnancy in a patient with HPAH 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 Correlations

BMPR2. About half of the known BMPR2 pathogenic variants are associated with nonsense-mediated decay (NMD) of the mutant transcript. Reports suggest that pathogenic variants which exhibit NMD and exhibit a haplo-insufficient mechanism may have milder phenotypes than pathogenic variants which exhibit other mechanisms [Austin et al 2009b].

No specific phenotypic differences have been recognized between HPAH caused by mutation of ACVRL1, KCNK3, CAV1, SMAD9, or BMPR1B and HPAH caused by mutation of BMPR2.

Penetrance

Penetrance (i.e., the presence of symptoms in an individual with a BMPR2 pathogenic variant) is 20% [Newman et al 2001].

Female sex is the factor best demonstrated to influence penetrance: the female to male ratio in both HPAH and PAH of unknown cause is 2.5 [Austin et al 2009a] and even higher in data included in other registries [Badesch et al 2010].

PAH develops across all ages, and the lifetime risk to develop PAH with a BMPR2 pathogenic variation in a male is 14%, whereas in a female it is 42%. [Larkin et al 2012].

Penetrance information for individuals with HPAH caused by mutation of ACVRL1, KCNK3, CAV1, SMAD9, or BMPR1B is not yet known.

Anticipation

Numerous reports from many countries during four decades suggested that HPAH was among those diseases which exhibit genetic anticipation. In a larger cohort studied for a longer time, it is now concluded that genetic anticipation is likely an artifact of incomplete time of observation [Larkin et al 2012].

Nomenclature

"Primary pulmonary hypertension" was the accepted terminology from 1950 until 2003, but was changed to Idiopathic pulmonary arterial hypertension in the absence of known causes of pulmonary hypertension.

At the World Congress on PAH held in Venice in 2003, the term "familial PAH" (FPAH) was adopted for PAH occurring in families and the term "idiopathic pulmonary arterial hypertension" (IPAH) for persons with PAH with a negative family history and no known genetic cause [Simonneau et al 2004].

At the 2008 WHO PAH Congress, the term "heritable PAH" (HPAH) was selected to encompass both FPAH (with or without a known pathogenic variant) and "sporadic" PAH (also known as "idiopathic" IPAH) for persons who have a pathogenic variant but no family history of PAH [Simonneau et al 2009].

Prevalence

To date, more than 200 families with heritable PAH (including one family with 38 affected individuals) are known in the US [Newman et al 2001, Thomas et al 2001], including 120 families in whom the specific BMPR2 pathogenic variant is known [Machado et al 2009]. Several factors may lead to under-recognition of BMPR2-related PAH [Thomas et al 2001]:

  • Reduced penetrance (20%) with transmission via unaffected obligate heterozygotes [Newman et al 2001]
  • Inadequate family histories
  • Incorrect diagnosis of other affected family members
  • Inability of currently used test methods to detect some BMPR2 mutations, such as those occurring in its promoter region or introns

The number of new cases of PAH of unknown cause is estimated at one or two per million population per year. Of these, an estimated 6%-16% have a positive family history [Sztrymf et al 2008, Badesch et al 2010, Humbert 2010].

Insufficient information is available to determine whether specific populations have different frequencies of HPAH, but the distribution of reported families with PAH (including some with BMPR2 pathogenic variants) is worldwide excepting Africa.

Differential Diagnosis

Other 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 heart disease (WHO Group 2), lung disease or hypoxia (WHO Group 3), pulmonary embolism (WHO Group 4), connective tissue diseases, cirrhosis, and HIV infection [Badesch et al 2009].

  • Heart disease (Group 2). Most advanced cardiac conditions, including left ventricular dysfunction, congenital heart disease, valvular disease, and cardiomyopathy, can cause PH. Heart diseases are detected by physical examination, ECG, echocardiography, and cardiac catheterization.
  • Lung disease (Group 3). 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 (Group 4). 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 [Kim et al 2013].
  • Hereditary hemorrhagic telangiectasia (HHT). Hereditary hemorrhagic telangiectasia is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. 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. Large 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 severe vascular shunting, a rare HHT manifestation, has occurred mostly in individuals with pathogenic variants in ACVRL1, but has also been reported in individuals with pathogenic variants in ENG [Trembath et al 2001, Soubrier et al 2013].
  • Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatisis (PCH). Pulmonary veno-occlusive disease [Holcomb et al 2000, Eyries et al 2014] and pulmonary capillary hemangiomatosis [Best et al 2014] are disorders that also are limited to the vessels of the lungs, and were previously classified as pathologic subsets of PAH. Discoveries in 2014 that both PCH and PVOD are due to recessive pathogenic variants in the same gene, suggest that these disorders are variations on a spectrum, and are distinctly different from PAH. At the onset of symptoms, individuals with PVOD may have clinical findings identical to PAH and not be phenotypically distinguishable. During disease progression, those with PVOD typically develop signs of pulmonary capillary hypertension with time, including orthopnea, crackles, pleural effusion, interstitial edema or septal lines. Both disorders are, on rare occasion, familial. One team investigating PCH used a recessive model to identify EIF2AK4 pathogenic variants [Best et al 2014] and another team in France investigating PVOD identified 13 families [Eyries et al 2014] with pathogenic variants in the same gene.
  • Other causes of PH include connective tissue diseases, cirrhosis, HIV infection, and treatment with appetite suppressants.

Management

Evaluations Following Initial Diagnosis

Because pulmonary arterial hypertension (PAH) is a diagnosis of exclusion, the necessary evaluations are typically all completed as part of establishing the diagnosis.

A medical genetics consultation is recommended.

Treatment of Manifestations

See McLaughlin et al [2013], Taichman et al [2014] and Hill et al [2015] for evidenced-based treatment algorithms.

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.

Unprecedented approval of medications for PAH by the FDA in the last two decades has led to availability of a dozen therapies which all demonstrate some efficacy, but substantial limitations remain: none of them cures the disease, nor is effective in all patients, nor stops or reverses the underlying pathogenesis (obstruction of the pulmonary arteries).

The most effective among them, continuous IV prostanoids, are the most complicated to administer as they require patient management of a pump for continuous infusion, with a myriad of possible problems, including sepsis related to chronic central venous catheters. Patient preference often dictates the route of medication administration (continuous IV or subcutaneous (subQ), aerosol, oral) or side effects determine which agents are personally acceptable.

Continuous patient monitoring for progression of disease and medication adjustment requires a dedicated multidisciplinary team which communicates seamlessly with multiple specialty pharmacies and insurors.

Medications in use for PAH include the following:

  • Prostacyclin analogs
    Epoprostenol (continuous IV)
    Treprostinil (inhalation, oral, continuous subQ, or IV)
    Iloprost (inhalation)
  • Endothelin blockers (oral)
    Bosentan
    Ambrisenan
    Macitentan
  • Phosphodiesterase inhibitors (oral)
    Sildenafil
    Tadalafil
  • Guanylate cyclase stimulator (oral)
    Riociguat

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 debated how much 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 can delay the decision about timing of lung transplantation.

Prevention of Secondary Complications

Fluid balance. Fluid retention is a common complication and requires vigilant management and interaction with health care team.

Patients should weigh daily and chart their weights, and be instructed about what threshold to call for change in therapy.

Exercise regimen. A regular exercise regimen is desirable, and is tailored to the patient depending on their stage of disease. Exercise is valuable for restoration and maintenance of physical conditioning, but at the same time is a monitor for change in status of the PAH indicating need for a change in therapy.

Nutrition management. Many of the medications are associated with side effects of anorexia or nausea, so careful attention to nutritional status is needed to maintain overall health.

Infusion pump management. Maintaining and troubleshooting of continuous infusions of vasoactive medications requires extensive training and disaster preparation of both the patient and a care support person. Initial training requires 20 hours of in-person teaching per patient, and meticulous attention to detail is essential for therapy to be successful.

Central venous catheter. Maintaining and troubleshooting catheters requires meticulous attentive care to be done safely.

Surveillance

See McLaughlin et al [2013] for consensus document, including Reassessing Patients Over Time.

The clinical course of HPAH 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 Avoid

Individuals with or at risk for PAH should avoid all the following:

  • Appetite-suppressant medications (e.g., fenfluramine/phentermine, dexfenfluramine, and amfepramone [diethylpropion]), which have been associated with pulmonary hypertension (PH) [Abenhaim et al 1996, Abramowicz et al 2003]
  • Cocaine, amphetamines, and related compounds causing vasoconstriction, which have anecdotal association with PH and could be risk factors
  • Other medications that have anecdotal suggestion of increased risk of PH, including 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. Because avoidance of exogenous systemic estrogen is desirable, many experts prefer IUD [Austin et al 2009a, Sweeney & Voelkel 2009].
  • Hypoxia. The hypoxia that accompanies high altitude is associated with pulmonary vasoconstriction and PH in susceptible individuals.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • The WHO Symposia [Badesch et al 2009] recommends serial screening by echocardiography 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.
  • In families with a known pathogenic variant in one of the genes known to be associated with HPAH, the use of molecular genetic testing to clarify the genetic status of at-risk relatives can allow individuals who do not have the family-specific pathogenic variant to safely forego clinical screening. However, the role of molecular genetic testing for early diagnosis of at-risk family members has yet to be established [Newman et al 2001].

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 HPAH is significant and maternal mortality is believed to be substantial; newer effective therapies may decrease the risk.

Anecdotal reports of onset of PAH with pregnancy raise concern about risks of pregnancy as a basis for developing PAH, but no consensus exists regarding the best approach to birth control in women with HPAH [Austin et al 2009a, Sweeney & Voelkel 2009].

Therapies Under Investigation

Several 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 strategies
  • Growth factor inhibitors
  • Endothelial progenitor cells/stem cells in lung repair
  • Developing therapies against right-ventricle remodeling

Trials of combination therapy, using selected combinations of the FDA-approved therapies mentioned in Treatment of Manifestations, are in progress [Gomberg-Maitland et al 2013]

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Heritable pulmonary arterial hypertension (HPAH) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals with an identified BMPR2 pathogenic variant inherited the pathogenic variant from a parent. However, penetrance is reduced and sex dependent. Only about 20% of those parents with the BMPR2 pathogenic variant are affected with PAH. (See Penetrance)
    • The penetrance of pathogenic variants in ACVRL1, KCNK3, CAV1, SMAD9, and BMPR1B is unknown.
  • De novo pathogenic variants in BMPR2 have been reported [Thomson et al 2000]. (The proportion of cases caused by de novo mutation of ACVRL1, KCNK3, CAV1, SMAD9, and BMPR1B is unknown.)
  • 15% of individuals who represent a simplex case (i.e., a single occurrence in a family) have a BMPR2 pathogenic variant [Girerd et al 2010]. These individuals may have a de novo pathogenic variant or a parent with the pathogenic variant who did not develop PAH (reduced penetrance).
  • It is appropriate to evaluate both parents for manifestations of PAH by performing a comprehensive clinical examination and echocardiogram. If a pathogenic variant in BMPR2, ACVRL1, KCNK3, CAV1, SMAD9, or BMPR1B has been identified in the proband, molecular genetic testing of both parents is also appropriate.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent has a BMPR2, ACVRL1, KCNK3, CAV1, SMAD9, or BMPR1B pathogenic variant (with or without findings of PAH), the risk to the sibs of inheriting the pathogenic variant is 50%.
  • A sib known to have inherited a BMPR2 pathogenic variant has a 20% chance of developing PAH. Penetrance is influenced by gender (see Penetrance).

Offspring of a proband

  • Each child of an individual with a BMPR2, ACVRL1, KCNK3, SMAD9, CAV1, or BMPR1B pathogenic variant (with or without PAH) is at a 50% risk of inheriting the pathogenic variant.
    • For a BMPR2 variant, the risk to offspring of developing PAH is approximately 10% (50% x ~20%) because of reduced penetrance [Newman et al 2001].
    • The penetrance of pathogenic variants in ACVRL1, KCNK3, CAV1, SMAD9, and BMPR1B is unknown.
  • An offspring known to have inherited the BMPR2 pathogenic variant has a 20% chance of developing PAH. Penetrance is influenced by gender (see Penetrance).

Other family members

  • The risk to other family members depends on the genetic status of the proband's parents.
  • If a parent is heterozygous for a BMPR2, ACVRL1, KCNK3, SMAD9, CAV1, or BMPR1B pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic counseling for family members at risk of having a BMPR2 pathogenic variant and HPAH is complicated because of decreased penetrance and variable age of onset. (The penetrance of pathogenic variants in ACVRL1, KCNK3, CAV1, SMAD9, and BMPR1B is unknown.)

Because most individuals in families with FPAH already recognize the likely genetic basis for the disease, they generally welcome information that provides new understanding of its underlying cause in their family. This is in contrast to individuals who represent simplex cases in whom identification of a pathogenic variant provides the first information that the disease has a genetic basis; thus, the molecular genetic test result may be received with alarm, anger, and/or disappointment because of the implications for progeny and sibs.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adult relatives of individuals with HPAH is possible using molecular genetic testing (if the specific pathogenic variant in the family has been identified) and /or echocardiography. (Testing for cardiac changes in the absence of definite symptoms of the disease may detect relatives who have mild disease or who are presymptomatic.) Molecular genetic testing of asymptomatic adults should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Molecular genetic testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If a BMPR2, ACVRL1, KCNK3, CAV1, SMAD9, or BMPR1B pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like HPAH) do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which a BMPR2, ACVRL1, KCNK3, SMAD9, CAV1, or BMPR1B pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Heart Association
  • National Library of Medicine Genetics Home Reference
  • Pulmonary Hypertension Association (PHA)
    801 Roeder Road
    Suite 1000
    Silver Spring MD 20910
    Phone: 800-748-7274 (Toll-free Helpline); 301-565-3004
    Fax: 301-565-3994
    Email: PHinfo@PHAssociation.org
  • American Lung Association
    1301 Pennsylvania Avenue Northwest
    Washington DC 20004
    Phone: 800-548-8252 (Toll-free HelpLine); 800-586-4872 (toll-free); 202-785-3355
    Fax: 202-452-1805
    Email: info@lungusa.org

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)

178600PULMONARY HYPERTENSION, PRIMARY, 1; PPH1
600799BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE II; BMPR2
601047CAVEOLIN 1; CAV1
601284ACTIVIN A RECEPTOR, TYPE II-LIKE 1; ACVRL1
603220POTASSIUM CHANNEL, SUBFAMILY K, MEMBER 3; KCNK3
603248BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE IB; BMPR1B
603295MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 9; SMAD9
615342PULMONARY HYPERTENSION, PRIMARY, 2; PPH2
615343PULMONARY HYPERTENSION, PRIMARY, 3; PPH3
615344PULMONARY HYPERTENSION, PRIMARY, 4; PPH4

BMPR2

Gene structure. BMPR2 comprises 13 exons [Machado et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 300 unique pathogenic variants have been reported [Machado et al 2009]. Approximately 30% of pathogenic variants 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. Understanding of BMPR2 function is progressing; however, the specific pathways by which mutation leads to the proliferative vascular disease in PAH remain incompletely understood at this time. Expression of BMPR2 is decreased in many models and causes of PH in addition to those caused by pathogenic variants, so it may be a mechanism across many causes.

Bmpr2 pathogenic variant mouse models develop pulmonary hypertension and recapitulate the human condition, and are thus 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]. 58% of reported BMPR2 pathogenic variants lead to truncated BMPR-2 protein product. Machado et al [2003] determined that phosphorylation of Tctex-1 is disrupted by pathogenic variants within exon 12. Nishihara et al [2002] determined that missense variants within the extracellular and kinase domains of BMPR-2 abrogated its signal-transducing abilities.

ACVRL1

Gene structure. ACVRL1 (NG_009549.1) spans approximately 14 kb; the longer transcript variant NM_000020.2 has ten exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. ACVRL1 pathogenic variants reported in PAH include 23 missense, three nonsense , three frameshifts from small deletions/insertions, and one in-frame deletion [Girerd et al 2010].

Normal gene product. ACVRL1 encodes a 503-amino acid type I cell-surface receptor for the TGF-beta superfamily of ligands. It shares with other type I receptors a high degree of similarity in serine-threonine kinase subdomains, a glycine- and serine-rich region (called the GS domain) preceding the kinase domain, and a short C-terminal tail. The encoded protein, sometimes termed ALK1, shares similar domain structures with other closely related ALK or activin receptor-like kinase proteins that form a subfamily of receptor serine/threonine kinases

Abnormal gene product. Current data suggest that most pathogenic variants in ACVRL1 result in protein non-expression.

BMPR1B, CAV1, KCNK3, and SMAD9. See Table 1b.

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Suggested Reading

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Chapter Notes

Author Notes

Pulmonary Hypertension Clinical & Research Team

Research Registry of PAH Families
Ms Lisa Wheeler, Coordinator
Vanderbilt University
Phone: 800-288-0378

Revision History

  • 11 June 2015 (me) Comprehensive update posted to live Web site
  • 20 December 2012 (cd) Revision: pathogenic varaints in ACVRL1, BMPR1B, CAV1, ENG, and SMAD9 found in rare cases to cause FPAH
  • 29 March 2011 (me) Comprehensive update posted live
  • 15 November 2007 (cd) Revision: prenatal diagnosis available
  • 18 July 2007 (me) Comprehensive update posted to live Web site
  • 24 March 2006 (jl) Revision: duplication/deletion testing using Southern blot clinically available
  • 29 June 2005 (jl) Revision: sequence analysis clinically available
  • 2 November 2004 (me) Comprehensive update posted to live Web site
  • 8 December 2003 (jl) Revision: Summary
  • 18 July 2002 (me) Review posted to live Web site
  • 14 January 2002 (jl) Original submission
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