Heritable Pulmonary Arterial Hypertension

Heritable pulmonary arterial hypertension is a serious inherited condition that causes high blood pressure in the blood vessels of the lungs, potentially leading to heart failure.

Table of contents

• What is Heritable Pulmonary Arterial Hypertension?
• Medical Classification Codes
• Other Names for This Condition
• Who is Affected?
• Causes and Genetic Factors
• Signs and Symptoms
• How is HPAH Diagnosed?
• Living with HPAH

What is Heritable Pulmonary Arterial Hypertension?

Heritable pulmonary arterial hypertension, or HPAH, is a form of pulmonary arterial hypertension (PAH) caused by genetic changes inherited from a parent^[1]. This condition occurs whether or not there is a known family history of the disease. HPAH is characterized by elevated pressure in the pulmonary arteries—the blood vessels that carry blood from the heart to the lungs—which leads to strain on the right side of the heart and can ultimately result in right heart failure^[4].

HPAH includes both familial PAH, which occurs in two or more family members, and simplex PAH, which is a single occurrence in a family when a disease-causing genetic change has been identified^[2]. The condition is progressive and potentially fatal if left untreated.

Pulmonary hypertension is a general term for increased blood pressure in the lungs from any cause. It is classified into five groups by medical experts. PAH is classified as Group 1, and it is diagnosed by excluding other causes including heart disease, lung disease, blood clots in the lungs, and various other conditions^[2].

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Other Names for This Condition

Familial pulmonary arterial hypertension, HPAH, Hereditary pulmonary arterial hypertension, FPAH

Who is Affected?

HPAH represents less than 4% of all PAH cases. The prevalence is estimated at less than 1 in 1 million people^[4]. The condition can affect people of all ages, including the very young and the elderly, though the average age at diagnosis is in the mid-thirties^[4][2].

Women are affected more often than men. Females are twice as likely to be affected as males^[2][10]. This difference is even more pronounced in some populations.

Causes and Genetic Factors

HPAH has been linked to changes in several genes, with BMPR2 being the most common. Mutations in the BMPR2 gene account for the majority of cases^[4]. This gene plays a role in controlling the number of cells in certain tissues. When it doesn’t work properly, cells in the small arteries of the lungs may overgrow, causing these blood vessels to narrow.

Other genes that have been implicated in HPAH, though in fewer cases, include ACVRL1, KCNK3, CAV1, TBX4, and SMAD9^[4]. HPAH due to mutations in ACVRL1 or TBX4 genes occurs more commonly in children and tends to progress rapidly with a poor prognosis.

All PAH predisposing genes are transmitted in an autosomal dominant manner with incomplete penetrance^[4]. This means that only one copy of the altered gene is needed to increase the risk of developing the condition, but not everyone who inherits the genetic change will develop HPAH. In the case of BMPR2 mutations, the penetrance is estimated to be 42% in female mutation carriers and 14% in male mutation carriers^[4].

Patients displaying either a sporadic PAH or PAH occurring in a family context should be tested for mutations in the BMPR2 gene first. If no mutations in BMPR2 are identified in a patient with a family history of PAH, mutations in other PAH predisposing genes should be searched for successively^[4].

Signs and Symptoms

The early phases of HPAH may be asymptomatic, meaning people may not notice any symptoms at first. Symptoms usually develop slowly and get worse as the condition progresses^[2][4].

Initial symptoms of HPAH include shortness of breath (called dyspnea), which may first start during exercise and eventually happen at rest. Other common symptoms include^[2][4]:

• Fatigue or feeling extremely tired
• Chest pain or pressure
• Palpitations or a racing heartbeat
• Dizziness or fainting (called syncope)
• Swelling in the feet, ankles, legs, and eventually the belly and neck (called edema)
• Blue or gray skin color, particularly on the lips or fingers

Physical examination may reveal signs such as a loud second heart sound, a right ventricular heave (an abnormal movement of the chest wall), and heart murmurs. About 70% of patients present with heart failure classified as New York Heart Association functional class III or IV^[4].

Rarely, patients may experience clubbing of the fingers, Raynaud phenomenon (mostly in females), or coughing up blood (called hemoptysis)^[4]. Patients with HPAH tend to have severe disease with less response to certain medications, lower cardiac output, and higher resistance in the lung blood vessels.

How is HPAH Diagnosed?

The diagnosis of HPAH is established through clinical evaluation. A detailed medical history, thorough physical examination, and most importantly, a high index of suspicion are essential^[2]. Symptoms of HPAH can be similar to those of other heart and lung conditions, so diagnosis is often delayed. Studies have reported an average delay of 27 months from the onset of symptoms to diagnosis^[2].

To diagnose HPAH, doctors must confirm^[2]:

• The presence of PAH by measuring blood pressure in the pulmonary artery (mean pulmonary artery pressure greater than 20 mm Hg at rest during cardiac catheterization)
• Exclusion of other known causes of PAH
• Identification of a disease-causing genetic change in one of the genes known to be associated with HPAH, and/or confirmation of PAH in one or more family members

Multiple tests may be performed to evaluate the condition^[9][14]:

• Blood tests to help find the cause and complications of the disease
• Chest X-ray to check for other lung conditions
• Electrocardiogram (ECG or EKG) to record the heart’s electrical activity
• Echocardiogram, which uses sound waves to create pictures of the heart and measure pulmonary artery pressure
• Right heart catheterization, the definitive test to confirm the diagnosis, during which a thin tube is inserted into a blood vessel and guided to the heart to directly measure blood pressure in the pulmonary artery
• CT scan or ventilation-perfusion scan to check for blood clots or other lung problems

Genetic testing is an important part of diagnosing HPAH. If pulmonary arterial hypertension is confirmed and other causes are excluded, testing for mutations in PAH-associated genes should be considered^[7].

Living with HPAH

Living with HPAH requires ongoing medical care and lifestyle adjustments. While there is no cure, treatments are available to help manage symptoms, slow disease progression, and improve quality of life^[3].

Treatment options focus on medications that open up the blood vessels in the lungs, improve blood flow, and reduce heart strain^[16]. These include several classes of medications such as prostacyclins, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Supportive medications like diuretics (water pills) and blood thinners may also be prescribed.

Daily management strategies are crucial^[15]:

• Medication adherence: Taking prescribed medications consistently is essential. Using pill organizers and smartphone reminders can help
• Monitoring symptoms: Watch for changes in shortness of breath, fatigue, swelling, or other symptoms and report them to your healthcare provider
• Maintaining a healthy diet: Following dietary recommendations from your healthcare team
• Staying physically active: Engaging in appropriate exercise as recommended by your doctor
• Getting adequate rest: Ensuring sufficient sleep and rest periods
• Managing stress: Finding healthy ways to cope with the emotional impact of the disease

Regular monitoring and follow-up with healthcare providers are important to manage symptoms and adjust treatments as needed. Many patients benefit from care at specialized pulmonary hypertension centers where experts can provide comprehensive management^[16].

Emotional support is crucial for people living with HPAH. Support groups, counseling, and connecting with others who have the condition can provide valuable help. Family members and caregivers also play an important role in supporting the person with HPAH^[15][18].

Because HPAH is inherited, family members of affected individuals may benefit from genetic counseling and testing. This can help identify relatives who carry disease-causing genetic changes and may be at risk of developing the condition. Prenatal genetic testing and preimplantation diagnosis are options that may be considered for families with known mutations^[4].