Pulmonary Arterial Hypertension - PAH

Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary artery pressure (mPAP) >25 mm Hg in the setting of normal or reduced cardiac output and a normal pulmonary capillary wedge pressure. Most commonly, PAH is secondary and associated with other disorders such as left heart disease, lung disease, or chronic thromboembolic disease. PAH can also be a primary process, either inherited or idiopathic.

Diagnosis

Indications for Testing

  • Cough, wheezing, shortness of breath
  • Increased pulmonary artery pressures in the absence of underlying cause
  • Family history of PAH

Laboratory Testing

  • Molecular testing
    • Most appropriate when no obvious etiology for pulmonary hypertension is found or if family history of PAH exists
    • PAH panel – preferred first-line test (available as next generation sequencing)
      • Includes testing for ACVRL1, BMPR2, CAV1, EIF2AK4, ENG, KCNA5, KCNK3, and SMAD9 genes with variants responsible for some forms of PAH, hereditary hemorrhagic telangiectasia (HHT), pulmonary capillary hemangiomatosis (PCH), and pulmonary veno-occlusive disease (PVOD) (see table in Genetics section)
    • BMPR2 variant testing
      • Can be used as single test in the absence of HHT symptoms
      • BMPR2 variant testing captures most cases
    • Consider EIF2AK4 single gene testing when molecular testing for other genes associated with PAH has not identified a cause
  • Any testing necessary to exclude other common causes of symptoms (including secondary causes of PAH) – see Imaging Studies and Procedures and Differential Diagnosis 

Imaging Studies and Procedures

  • Electrocardiogram (ECG), chest radiography (CXR)
  • Right heart catheterization
    • Gold standard
    • Includes pulmonary arterial catheterization
    • Provides prognostic hemodynamics
  • Echocardiography
    • Complementary to right heart catheterization
    • Both are required per American College of Radiology (ACR) appropriateness criteria (Sirajuddin, 2016)
  • Computed tomography (CT) angiography
  • Exercise capacity – 6-minute walk
  • Pulmonary function testing
  • Overnight oximetry​

Prognosis

  • B-type natriuretic peptide (BNP) (McLaughlin, 2009) and N-terminal (NT)-proBNP (Rosenthal, 2014) testing can be used to assist with prognosis
    • Cutoffs have not been established (Rosenthal, 2014)
    • Low concentrations are associated with low risk, whereas high elevations correlate with worse outcomes (Rosenthal, 2014)

Differential Diagnosis

  • Heart disease
  • Pulmonary disease
    • Asthma
    • Chronic obstructive pulmonary disease (COPD)
    • Chronic thromboembolic disease
    • PVOD
    • PCH
    • Sleep-related breathing disorders
  • Pulmonary embolism
  • Infections
  • Connective tissue disease
    • Scleroderma
  • Cirrhosis

Background

Epidemiology

  • Incidence – ~1-3.3/million (Kiely, 2013)
  • Age – mean, 36-50 years
  • Gender – M<F; at least 1:1.7

Classifications

  • PAH (based on World Health Organization [WHO] 4th World Symposium on Pulmonary Hypertension, 2008)
    • Idiopathic – formerly known as primary pulmonary hypertension
    • Hereditary (familial) PAH
    • Associated PAH
      • Drugs and toxins (eg, fenfluramine, toxic rapeseed oil)
      • Connective tissue diseases
      • Infections (eg, HIVschistosomiasis)
      • Congenital heart disease
      • Portopulmonary hypertension
      • Chronic hemolytic diseases
    • Associated with significant venous or capillary involvement (pulmonary veno-occlusive disease [PVOD] or pulmonary capillary hemangioma [PCH])
    • Persistent pulmonary hypertension of the newborn
  • Other, non-PAH categories of pulmonary hypertension (PH)
    • PH with left heart disease
    • PH associated with lung disease and/or hypoxemia
    • PH due to chronic thrombotic and/or embolic disease
    • Miscellaneous

Genetics

Gene Symbol Condition Inheritance PAH Attributable to Gene Penetrance

ACVRL1ab

HHT2 AD ~1%

<1% for PAH

>95% for HHT

BMPR2ab

BMPR2-related PAH/PAH1; PVOD1

AD

~75% of familial cases

~25% of simplex cases

20%

CAV1ab

PAH3

AD

~1% Unknown

EIF2AK4ab

PVOD2

AR

>10% Unknown

ENGab

HHT1

AD

~1%

<1% for PAH

>95% for HHT

KCNA5b Familial atrial fibrillation 7 AD Unknown Unknown

KCNK3ab

PAH4

AD

Unknown

Unknown

SMAD9ab

PAH2

AD

Unknown  

AD, autosomal dominant; AR, autosomal recessive; HHT, hereditary hemorrhagic telangiectasia; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiomatosis; PVOD, pulmonary veno-occlusive disease

aGene included on Vascular Malformations Panel, Sequencing and Deletion/Duplication, 2007384

bGene included on Pulmonary Arterial Hypertension (PAH) Panel, Sequencing and Deletion/Duplication, 2009345

Pathophysiology

  • Widespread occlusion/destruction of smallest pulmonary arteries due to neointimal proliferation, smooth muscle hypertrophy, and adventitial expansion
  • Greater blood flow resistance increases right ventricle workload and leads to right ventricle failure once ventricle can no longer maintain sufficient pressure to generate blood flow

Clinical Presentation

  • Shortness of breath
  • Fatigue
  • Syncope
  • Chest pain
  • Palpitations
  • Edema

ARUP Laboratory Tests

Preferred test to confirm diagnosis of PAH, especially in those with a family history of PAH

Includes testing for ACVRL1, BMPR2, CAV1, EIF2AK4, ENG, KCNA5, KCNK3, and SMAD9 genes

Please see Test Fact Sheet for complete list of limitations

Preferred test to confirm diagnosis or assess carrier status for an EIF2AK4-related disorder such as PCH and PVOD

Large deletions/duplications, deep intronic mutations, and regulatory region mutations will not be detected

Diagnostic errors can occur due to rare sequence variations

Recommended test if there is a known familial variant identifiable by sequencing is known

A copy of the family member's lab report documenting the known familial variant is required

Consultation with a genetics counselor is advised

Related Tests

Preferred DNA test to confirm clinical diagnosis of a genetic-related vascular malformation disorder, ie, capillary malformation, arteriovenous malformation, cerebral cavernous malformation, glomuvenous malformation, hereditary hemorrhagic telangiectasia, multiple cutaneous and mucosal venous malformations, pulmonary arterial hypertension, or hereditary lymphedema syndrome, if no single specific diagnosis is strongly suspected

Refer to Test Fact Sheet for further information

Use to confirm the diagnosis of familial cerebral cavernous malformation in an individual with suggestive findings

Medical Experts

Contributor
Contributor

Best

Hunter Best, PhD, FACMG
Associate Professor of Clinical Pathology, University of Utah
Scientific Director, NGS and Biocomputing; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®