Pulmonary Hypertension

1 What is Pulmonary Hypertension?

Pulmonary hypertension is a rare lung disorder in which the arteries that carry blood from the heart to the lungs become narrowed, making it difficult for blood to flow through the vessels.

As a result, the blood pressure in these arteries - called pulmonary arteries - rises far above normal levels. This abnormally high pressure strains the right ventricle of the heart, causing it to expand in size.

Overworked and enlarged, the right ventricle gradually becomes weaker and loses its ability to pump enough blood to the lungs. This could lead to the development of right heart failure.

Pulmonary hypertension is much more common in young adults and is approximately twice as common in women as in men.

2 Symptoms

Signs and symptoms of pulmonary hypertension include:

  • Shortness of breath during routine activity, such as climbing two flights of stairs
  • Tiredness
  • Chest pain
  • A racing heartbeat
  • Pain on the upper right side of the abdomen
  • Decreased appetite

As PH worsens, you may find it hard to do any physical activities. At this point, other signs and symptoms may include:

  • Feeling light-headed, especially during physical activity
  • Fainting at times
  • Swelling in your legs and ankles
  • A bluish color on your lips and skin

3 Causes

Pulmonary hypertension is caused by changes to the pulmonary arteries, which are blood vessels that carry blood from your heart to your lungs.

The World Health Organization (WHO) has classified pulmonary hypertension into five different types, depending on the underlying cause. They are:

  • pulmonary arterial hypertension (PAH)
  • pulmonary hypertension associated with left heart disease
  • pulmonary hypertension associated with lung disease and hypoxia
  • pulmonary hypertension due to blood clots
  • pulmonary hypertension due to other causes

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is caused by problems with the smaller branches of the pulmonary arteries. In PAH, these changes are usually the main problem, rather than another condition.

As the pulmonary arteries are directly affected, they can be treated immediately, whereas in other types of pulmonary hypertension, the underlying cause must be treated first.

PAH can be further divided into specific subtypes, which are described below.

Idiopathic PAH

Idiopathic means that the cause is unknown. If tests cannot find an underlying reason for your condition, you may be diagnosed with idiopathic PAH. This is an extremely rare condition, only affecting around two people in every million each year.

Inherited PAH

Some cases of PAH run in families. A particular genetic mutation (a change in one of the genes you inherit from your parents) is sometimes thought to cause PAH. There may be a family history of the condition in up to 10% of idiopathic PAH cases.

PAH associated with other conditions

Other conditions or treatments associated with PAH include:

  • connective tissue diseases that affect the structure or composition of your body tissue – such as scleroderma (a disorder that causes hardening of the skin)
  • congenital heart problems – such as a hole in the heart
  • portal hypertension – blood pressure inside the liver is abnormally high, which causes veins to become swollen
  • HIV – about 1 in 200 people with HIV are thought to develop PAH
  • certain medications or drugs – such as fenfluramine and amphetamines
  • thyroid gland disorder
  • sickle cell disease and related conditions
  • glycogen storage disorders 

PAH can also be associated with rare conditions that affect your blood vessels, such as:

  • pulmonary veno-occlusive disease – a condition that causes high blood pressure in the lungs
  • pulmonary capillary hemangiomatosis – where tiny blood vessels (capillaries) grow within the lungs, causing blockages

Persistent pulmonary hypertension of the newborn

It is estimated that persistent pulmonary hypertension of the newborn affects around 2 in every 1,000 newborn babies.

Conditions that may also be associated with persistent pulmonary hypertension of the newborn include:

  • severe pulmonary hypoplasia – where your baby’s lungs are seriously underdeveloped
  • hypoglycaemia – an abnormally low level of glucose in the baby’s blood
  • sepsis – a life-threatening illness caused by very severe infection
  • meconium aspiration syndrome – where a newborn baby breathes in a mixture of amniotic fluid (the fluid that surrounds the baby in the womb) and meconium (their first faeces), which can block their airways

Left heart disease

Pulmonary hypertension is sometimes associated with diseases that affect the left side of the heart (the side that pumps blood around the whole body, apart from the lungs). The left side of the heart consists of:

  • the left atria
  • the left ventricle
  • the aortic and mitral valves – one-way valves that allow blood to flow through the heart in the correct direction

As blood flows through the pulmonary arteries to the lungs and then to the left side of the heart, any problem could have a backwards effect on this circuit and affect the pulmonary arteries. This in turn could cause pulmonary hypertension.

Up to 60% of people with a condition that causes severe left ventricle dysfunction have pulmonary hypertension. Almost all people with a severe mitral valve condition, and nearly two-thirds of those with a severe aortic valve condition, have pulmonary hypertension.

Lung disease and hypoxia

Pulmonary hypertension is also sometimes associated with lung diseases or hypoxia (a shortage of oxygen in the body). This includes:

  • chronic obstructive pulmonary disease (COPD) – a term that describes a number of lung diseases that affect breathing; up to half of people with advanced COPD may also have pulmonary hypertension, although it's usually mild
  • interstitial lung disease – a group of lung disorders that cause scarring of the lung tissue, which makes it difficult to get enough oxygen into your body; about a third of people with interstitial lung disease may have pulmonary hypertension
  • sleep-disordered breathing – conditions that affect breathing while you are in deep sleep, such as obstructive sleep apnoea (OSA)

These types of conditions can restrict the amount of oxygen able to get into your lungs and enter your blood. A low level of oxygen in the blood causes the pulmonary arteries to constrict (get narrower). As these vessels are narrower, the blood is squeezed into a smaller space, which increases the blood pressure and results in pulmonary hypertension.

Blood clots

Pulmonary hypertension is sometimes the result of a blood clot that causes narrowing or a blockage in the pulmonary arteries or veins.

A blood clot that blocks one of the blood vessels that supply your lungs is known as a pulmonary embolism.

Other, less common, causes of pulmonary hypertension include: 

  • sarcoidosis – a condition that causes inflammation of different organs, including the lungs and lymph nodes
  • histiocytosis X – a rare condition that causes scarring (granulomas) and air-filled cysts, predominantly in the lungs
  • Compression of the blood vessels in the lungs – for example, due to a tumour.

4 Making a Diagnosis

The diagnosis of pulmonary hypertension can be summarized in 4 general stages:

1. Clinical suspicion of PAH:

PAH should be considered in the differential diagnosis of patients presenting with exertional dyspnea, syncope, angina, and or progressive limitation of exercise capacity, particularly in patients without apparent risk factors, symptoms or signs of common cardiovascular and respiratory disorders.

2. Exclusion of left heart disease and lung disease:

Clinical history, signs and symptoms, electrocardiogram, chest radiograph, echocardiogram, pulmonary function tests, high resolution computed tomography help to exclude disorders of lung and left heart.

  • ECG may provide suggestive or supportive evidence of PH by demonstrating right ventricular (RV) hypertrophy and strain, and right atrial dilatation
  • Doppler echocardiography provides several variables that correlate with right heart haemodynamics — Doppler echocardiography should always be performed in the case of suspected PH
  • Chest radiography may show evidence of cardiomegaly and enlarged pulmonary arteries and allows the reasonable exclusion of associated moderate to severe lung diseases or pulmonary venous hypertension due to left heart disease
  • Pulmonary function tests and arterial blood gas samples will identify the contribution of underlying airway or parenchymal lung disease
  • HRCT provides detailed views of the lung parenchyma and facilitates the diagnosis of interstitial lung disease and emphysema

3. Exclusion of chronic thromboembolism:

  • A ventilation/perfusion lung scan is used to exclude chronic thromboembolic pulmonary hypertension (CTEPH); where there is evidence of multiple segmental perfusion defects, a diagnosis of CTEPH should be suspected
  • The final diagnosis of CTEPH requires CT pulmonary angiography, right heart catheterisation, and selective pulmonary angiography

4. PAH evaluation and classification:

  • If a ventilation/perfusion scan is normal, or shows only subsegmental patchy perfusion defects, a tentative diagnosis of PAH is made.
  • A CT pulmonary angiography may also show signs suggestive of pulmonary veno-occlusive disease (PVOD)
  • Additional specific diagnostic tests including haematology, biochemistry, immunology, serology, and ultrasonography will allow the final diagnosis to be refined:
      • Cardiac magnetic resonance (CMR) imaging provides a direct evaluation of RV size, morphology, and function, and allows non-invasive assessment of blood flow including stroke volume, cardiac output (CO), distensibility of pulmonary artery, and RV mass; CMR is also used to distinguish PAH associated with congenital heart disease
      • Blood, immunology, and serological tests are important to detect underlying connective tissue disease, human immunodeficiency virus (HIV) infection, and hepatitis; liver function tests and hepatitis serology should be examined if clinical abnormalities are noted
      • An abdominal ultrasound scan can reliably exclude liver cirrhosis and/or portal hypertension
      • Right heart catheterization (RHC) represents the diagnostic gold standard for the confirmation of a diagnosis of PAH, and usually includes vasoreactivity testing
      • The degree of limitation to the patient caused by PAH is assessed by determining functional class and by exercise tests such as the six-minute walk test. This gives both a baseline measure against which to assess progression or response to treatment, and provides prognostic information.

5 Treatment

Treatments for pulmonary hypertension are several-fold and range from symptomatic relief to improvement in the physical limitations imposed by their disease, such as:

  • improving functional class,
  • delaying disease progression.

General measures

General measures aim to limit any potentially deleterious effects of the patient's external circumstances on their PAH disease. These recommendations are largely based on expert opinion, and include measures such as avoiding pregnancy, prevention and prompt treatment of chest infections, and awareness of the potential effects of altitude.

Conventional or supportive therapy

A range of treatment approaches have been shown to provide some degree of symptomatic benefit to PAH patients. However, there is no evidence that they have an effect on the disease process or prognosis. Such measures include:

  • Oxygen: For patients with dyspnoea associated with PAH, supplemental oxygen provides symptomatic relief and improves patient comfort, although there is no consistent evidence supporting any long-term benefit. It is generally considered important to maintain oxygen saturation above 90% at all times, and oxygen may be indicated in some patients.
  • Anticoagulants: clinical data supportive of the use of anticoagulant therapy in PAH are limited; however, improved survival has been reported with oral anticoagulation in patients with idiopathic PAH and because of high risk of in situ thrombosis within the small pulmonary arteries, there is a rationale for the use of oral anticoagulants in PAH patients.
  • Diuretics:Clinical experience shows clear symptomatic benefit in fluid-overloaded patients with decompensated right heart failure associated with PAH
  • Calcium channel blockers (CCBs): CCBs may be of benefit in a small proportion of patients with PAH. Suitable patients are detected by acute vasoreactivity testing during right heart catheterization. A positive vasoreactive response indicating potential suitability for CCB therapy is shown by around 10% of patients, and approximately 7% of these patients have a sustained response. Patients who respond to vasoreactivity testing and are subsequently treated with CCBs need regular assessment and repeat testing, as the vasoreactivity status may change.

Advanced therapy (also termed PAH-specific therapy)

PAH-specific therapies have been developed specifically to target one of three major pathways known to be involved in the development of PAH and have, to varying degrees, been shown to affect the disease process:

  • Endothelin receptor antagonists (ERAs): endothelin is implicated in the pathogenesis of PAH through its actions on the pulmonary vasculature. Endothelin is elevated in patients with PAH and levels are directly related to disease severity and prognosis. Endothelin receptor antagonists are oral treatments that act by blocking the binding of endothelin to either one (single antagonist) or both (dual antagonist) of its receptors.
  • Prostacyclin therapy: synthetic prostacyclins and prostacyclin analogues act by helping to correct the deficiency of endogenous prostacyclin seen in patients with PAH. The clinical use of prostacyclins in patients with PAH has been extended by the synthesis of more stable anologs for intravenous infusion, as well as those that can be given by subcutaneous infusion, or by inhalation.
  • Phosphodiesterase-5 (PDE-5) inhibitors: these oral agents act on the nitric oxide (NO) pathway to induce vasodilation and also have antiproliferative effects on vascular smooth muscle cells. Clinical trials have shown that treatment with PDE-5 inhibitors has a beneficial effect on exercise capacity, hemodynamic parameters, and symptoms in patients with PAH.

Surgical intervention

For patients with severe PAH, who do not respond satisfactorily to treatment with advanced therapies, surgery may be the only option.

  • Balloon atrial septostomy: atrial septostomy creates a small hole between the right and left atria, allowing blood to pass from the right atrium directly to the left, bypassing the restricted pulmonary circulation. This aims to increase the left ventricular preload and the systemic blood flow (cardiac output), resulting in an improved systemic oxygen transport, and to reduce the pressure and therefore the stress on the right heart, but at the cost of lower oxygen levels in the blood (hypoxaemia).
  • Transplantation: lung transplantation or heart and lung transplantation are considered for patients who have failed medical therapy.

6 Prevention

The best preventive measure to avoid forms of pulmonary hypertension is making healthy lifestyle changes, such as:

  • quitting smoking,
  • cutting down on salt,
  • eating healthy foods,
  • regular exercise.

Maintaining general good health with proper diet and exercise may lower your chances of developing pulmonary hypertension.

7 Lifestyle and Coping

Lifestyle modifications are necessary in order to cope with pulmonary hypertension.

Dietary changes

  • Eat foods that are high in nutrients like potassium (e.g., dried fruits, bananas, oranges) and magnesium (e.g., peanuts, tofu, and broccoli) and vitamins.
  • Limit your total daily calories, if necessary, to achieve your ideal body weight.
  • Limit foods that contain refined sugar, saturated fats, and cholesterol.
  • Eat foods that are high in fiber, including whole grains, brans, fruits, and vegetables.
  • Reduce your sodium intake:
    • Buy foods that are low in sodium. Choose foods with labels that read "low salt" and "low sodium."
    • Avoid table salt and seasoning salt.Avoid smoked, cured, salted, and canned meat products.
    • Avoid fast food and limit prepared foods; they usually have high sodium content.
    • Monitor your fluid intake. Cut down intake of fluids if you have become more short of breath or if you notice swelling.

Lifestyle changes

  • Monitor your weight: weigh yourself at the same time each day and record your weight in a diary or on a calendar. If you notice a rapid weight gain of 2 pounds in one day or 5 pounds over one week, inform your doctor.
  • Lose weight if you are overweight (follow your doctor’s recommendations).
  • Have annual health check-ups with your primary care physician.
  • Activity guidelines:
      • Restrict lifting, pushing, or shoving to less than 20 pounds, since these activities increase the pressure in your arteries and lungs.
      • Walking is important to keep your muscles strong and improve circulation. However, more strenuous forms of aerobic exercise should not be done regularly since your lungs may not be able to keep up with the oxygen demands placed on your body during these activities. Any activities that cause shortness of breath, dizziness, or chest pain should be stopped immediately. Contact your doctor if any of these symptoms occur.
      • Do not smoke or chew tobacco.
      • Avoid or reduce alcohol intake.
      • Avoid pregnancy; use contraceptives to prevent pregnancy.
      • Maintain close contact with your health care providers.

8 Risks and Complications

There are several complications associated with pulmonary hypertension, which include:

  • Right heart enlargement
  • Convulsions
  • Heart failure
  • Cor Pulmonale
  • Tricuspid valve incompetence
  • Right ventricular hypertrophy
  • Pulmonary valve incompetence
  • Respiratory failure
  • Hemoptysis
  • Right bundle branch block
  • T wave inversion

9 Related Clinical Trials