What are the other Names for this Condition? (Also known as/Synonyms)

• Familial Pulmonary Arterial Hypertension (FPAH)
• Genetic Pulmonary Arterial Hypertension (GPAH)
• HPAH (Heritable Pulmonary Arterial Hypertension)

What is Heritable Pulmonary Arterial Hypertension? (Definition/Background Information)

• Pulmonary arterial hypertension (PAH) is a specific type of hypertension that is caused by increased blood pressure within the pulmonary (lung) arteries. When there is no identifiable cause for PAH, it is termed idiopathic pulmonary arterial hypertension (IPAH)
• When idiopathic pulmonary arterial hypertension affects multiple members of the same family, it is considered familial or Heritable Pulmonary Arterial Hypertension (HPAH). In other words, individuals who have one or more blood relatives with IPAH are said to have HPAH
• In general, pulmonary hypertension (PH) is a disorder characterized by very high blood pressure (above normal) in the lungs due to a variety of causes. It should not be confused with systemic hypertension, otherwise known as ‘high blood pressure’
• The World Health Organization (WHO) has clinically classified pulmonary hypertension according to certain groups. Heritable Pulmonary Arterial Hypertension forms part of WHO group 1 (sub group 1.2)
• The signs and symptoms of Heritable Pulmonary Arterial Hypertension may include shortness of breath, chest pain, fatigue, and dizziness. A diagnosis of the condition may involve procedures such as right-heart catheterization and acute vasodilator challenge
• Following a diagnosis of Heritable Pulmonary Arterial Hypertension, the treatment measures involves the use of medications, such as calcium channel blockers, and bringing about certain lifestyle modifications, among other measures
• The prognosis of Heritable Pulmonary Arterial Hypertension may be improved if it is diagnosed promptly and treated appropriately. However, the overall prognosis depends on several factors and may vary on a case-to-case basis

Who gets Heritable Pulmonary Arterial Hypertension? (Age and Sex Distribution)

• The age, gender, and racial distribution of Heritable Pulmonary Arterial Hypertension (HPAH) depends on genetic factors (specific gene mutations noted)
• In general, HPAH can occur at any age. It affects women almost 3 times more than men
• Individuals of all racial and ethnic groups are at risk

What are the Risk Factors for Heritable Pulmonary Arterial Hypertension? (Predisposing Factors)

The risk factors for Heritable Pulmonary Arterial Hypertension (HPAH) may include:

• A positive family history of Heritable Pulmonary Arterial Hypertension:
  • About 20% of individuals with a mutation in the gene encoding the BMPR2 protein are known to get HPAH. And, about 80% of those with diagnosed HPAH have a mutation in the BMPR2 gene
  • Individuals of families with the genetic condition, hereditary hemorrhagic telangiectasia (HHT), may also develop HPAH due to a mutation in the gene that encodes the ALK1 protein
  • Overall, approximately 6% of IPAH cases are familial, which means that there is a family history of the condition. The remainder of the cases (94% majority) are sporadic (sporadic IPAH), meaning that it occurs without a family history of the condition. In cases where there is no fam history, it is known as idiopathic PAH
• A mutation in any of the genes encoding the BMPR2, ALK1, ENG, SMAD9, 5HTT, CAV1, or KCNK3 proteins
• Female gender: Women are at a higher risk than men for the condition
• Those with increased endothelin blood levels, decreased nitrous oxide levels, or decreased prostacyclin blood levels are at an increased risk
• High estrogen blood levels has been associated with an increased risk

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Heritable Pulmonary Arterial Hypertension? (Etiology)

• Heritable Pulmonary Arterial Hypertension is often caused by an inherited change (mutation) in the genetic directions for making a protein called bone morphogenetic protein receptor 2 (BMPR2). Other implicated genes include the ALK1, ENG, SMAD9, 5HTT, CAV1, and KCNK3 genes
• The BMPR2 protein maintains the structure of the walls of the small arteries of the lungs by regulating growth of resident cells. Overgrowth or aberrant modulation of this pathway by mutations in BMPR2 can lead to stenosis (abnormal narrowing) and ultimately pulmonary arterial hypertension. Nevertheless, other factors are likely necessary to produce the disorder, as only 20% of individuals with mutations in BMPR2 are known to be affected
• There is some data that suggests that impairment of the voltage-gated potassium channels (KV) in the walls of pulmonary artery smooth muscle cells may also play a role in the pathogenesis of pulmonary arterial hypertension (PAH) by increasing pulmonary vascular tone

Inheritance of the familial form of pulmonary arterial hypertension:

• Heritable Pulmonary Arterial Hypertension is inherited in an autosomal dominant manner; meaning, an affected BMPR2 protein inherited from the mother or the father is enough to cause the condition in the offspring
• To further elaborate, each parent contains two BMPR2 genes. If one is mutated, that parent has a 50% chance of passing that mutation onto their offspring and the offspring gains one BMPR2 gene from each parent
• By retrospective data analysis, it has been observed that if the offspring gains the mutated gene from one parent, the likelihood that they will develop FPAH is about 20%. If the offspring gain only the normal BMPR2 genes from each parent, their risk of developing IPAH is the same as the general population

Note: Some forms of HPAH are reportedly inherited in an autosomal recessive manner.

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Heritable Pulmonary Arterial Hypertension?

The signs and symptoms of Heritable Pulmonary Arterial Hypertension depend on a set of several factors that include the age and overall health status of the individual.

The common signs and symptoms exhibited by individuals with Heritable Pulmonary Arterial Hypertension are similar to most individuals with pulmonary hypertension. These include:

• Progressive shortness of breath, especially while exercising, is the most common symptom
• Fatigue (frequent tiredness)
• Chest pain
• Dizziness and fainting
• Swelling of the ankles/legs
• Palpitations
• Bluish lips and skin, observed during the later stages
• Irregular heartbeat (arrhythmias)
• Fluid in the abdomen (ascites)

How is Heritable Pulmonary Arterial Hypertension Diagnosed?

In order to diagnose Heritable Pulmonary Arterial Hypertension (HPAH), one or more blood relatives with idiopathic PAH should be documented/present. Sometimes, an incomplete family history, or due to the fact that the condition can skip generations, makes the diagnosis challenging.

To diagnose HPAH, a diagnosis of pulmonary hypertension (PH) must first be established. This involves certain preliminary diagnostic procedures. Depending on the results of these tests, confirmation will be made with a right-heart catheterization. After a diagnosis of PH is made, the healthcare provider should rule out all major causes of PH and make enquiries about other family members with existing PH.

The preliminary procedures may include:

• A complete physical examination of the patient 
• A thorough checking of the patient’s medical history and a detailed checking of the family history of the patient
• Blood tests: 
  • Blood tests help rule out other diseases, such as HIV infection, liver disease, rheumatoid or connective tissue disease, and thyroid disease
  • They also help in checking the blood oxygen levels
  • The measurement of brain natriuretic peptide (BNP) can be used to assess the strain on one’s heart
• Chest X-ray: Chest X-rays can reveal structural signs of pulmonary hypertension by identifying changes in the pulmonary arteries or enlargement of the right side of the heart
• Electrocardiogram (ECG): An electrocardiogram checks the electrical impulses of the heart. There are certain identifiable patterns on an ECG that may indicate pulmonary hypertension. However, ECG is not specific enough to diagnose the condition by itself, so a combination of tests may be recommended by the healthcare provider
• Echocardiogram: In this procedure, a sonogram of the heart is taken and used to measure overall functioning as well as measure the pressure within the chambers of the right heart. An echocardiogram is also often times used to monitor a patient’s condition after diagnosis and during treatment
• Pulmonary function tests: These tests help measure the quality of breathing and check the functioning of the lungs (such as how much air is breathed in and out, as well as the quality of oxygen exchange)
• Exercise tolerance test (six-minute walk test): This helps to measure the patient’s ability to exercise
• Nuclear scan (ventilation/perfusion scan or V/Q scan): This tool helps identify any new or chronic blood clots in the vessels of the lungs that could be causing pulmonary hypertension

The gold standard for pulmonary hypertension diagnosis and management is right-heart catheterization and acute vasodilator challenge.

• Right-heart catheterization:
  • If pulmonary hypertension is suspected based off preliminary tests and procedures, a right-heart catheterization test is ordered to help confirm the diagnosis
  • This test can accurately quantify right-heart pressures (measure the pressure within the chambers of the right heart), especially the pressure inside the pulmonary arteries
  • During this procedure, a very small catheter is inserted into a large vein (either within the patient’s groin or neck) and passed into the patient’s heart and vasculature to measure the internal blood pressures 
• Vasodilator study (acute vasodilator challenge):
  • While this test is not used to necessarily “diagnose” pulmonary hypertension, it is used to evaluate the patient for possible therapeutic management
  • Like right-heart catheterization, a catheter is placed within the pulmonary artery to test for vasodilation (or relaxation) in response to a class of medications called calcium channel blockers (CCBs)
  • The response and dosing of CCBs can be evaluated with this procedure

In addition to the above-mentioned diagnostic procedures, genetic testing utilizing patient DNA can be used to identify mutations in the BMPR2 or other culprit genes in the patient and immediate family members. Identifying a specific mutation in a culprit gene of an individual is of significant value because that specific mutation can be studied within members of a family, rather than a full panel screen that may take a lot of time and resources. For example, over 100 mutations in the BMPR2 gene have been identified to date.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Hereditary Pulmonary Hypertension?

Following are the possible complications that may arise due to Heritable Pulmonary Arterial Hypertension:

• Right-sided heart failure with hepatic congestion (due to deposition of stones in the liver)
• Pedal edema: Swelling of the leg or ankle
• Pleural effusions: Building-up of excess fluid around the lungs
• Worsening dyspnea (shortness of breath) upon exertion

How is Heritable Pulmonary Arterial Hypertension Treated?

The treatment of Heritable Pulmonary Arterial Hypertension (HPAH) depends on a set of several factors that includes the severity of the signs and symptoms, age of the individual, and overall health of the individual.

HPAH is a rare condition and is best treated at a medical center with appropriate expertise. Several medical treatments are highlighted below:

• Conventional medical therapies:
  • Calcium channel blockers (CCBs): These are a group of medications that help vasodilate (or relax) the arteries. However, CCBs are only appropriate for patients demonstrating a favorable response to the vasodilator study
  • Inotropic agents: These are medications that assist in the pumping of the heart 
  • Diuretics, salt limitation, and weight monitoring may be recommended, to limit excess strain on the heart
  • Supplemental oxygen may help an individual meet the ‘oxygen needs’ for normal daily activities
  • Blood thinners: These medications help prevent blood clots, especially in the lung blood vessels
• Oral, inhaled, subcutaneous, or intravenous treatment options:
  • Endothelin receptor antagonists (ERAs) help in preventing pulmonary blood vessels from narrowing which helps keep the pressures towards normal levels
  • Phosphodiesterase inhibitors (PDE 5 Inhibitors), prostacyclin analogues, and soluble guanylate cyclase (sGC) stimulators, all aid in allowing vessels of the lungs to vasodilate (or relax)
• Additional treatment options may include:
  • Lifestyle modifications, such as nutrition, exercise, avoiding tobacco, and limiting alcohol consumption, are beneficial
  • Judicious exercising may be effective in limiting deconditioning (by building stamina), improving the quality of life, and exercising capacities. Isometric exercises, such as heavy weightlifting, should be avoided
  • Lung transplantation may be required with advanced forms of the disorder

How can Heritable Pulmonary Arterial Hypertension be Prevented?

Sporadic idiopathic pulmonary arterial hypertension and Heritable/Familial Pulmonary Arterial Hypertension are a result of genetic factors. There are no current methods available to prevent the condition. However, an early and effective treatment is critical and imperative.

• If there is a family history of pulmonary hypertension, then genetic counseling will help assess risks, before planning for a child
• Avoidance of recreational drugs, various toxic agents, and inappropriate weight loss drugs is important
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Heritable Pulmonary Arterial Hypertension? (Outcomes/Resolutions)

The prognosis of Heritable Pulmonary Arterial Hypertension differs from one individual to another, depending on the severity of the condition/pulmonary hypertension. The disorder has no cure, but earlier and focused treatment can help improve outcomes. The prognosis also depends the overall health status of the individual and whether he/she responds to treatment measures.

• Pulmonary hypertension is a negative prognostic sign in many medical conditions, meaning that the presence of pulmonary hypertension makes the overall health outcomes worse (such as COPD or heart failure)
• Individuals with advanced heart disease, a suboptimal 6-minute walk test (exercise tolerance test to measure one’s ability to exercise without significant signs and symptoms), and with conditions, such as advanced liver disease and connective tissue disease, have poor prognosis

Additional and Relevant Useful Information for Idiopathic Pulmonary Arterial Hypertension:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/pulmonary-hypertension-ph/