The arteries of the lungs (also known as pulmonary arteries) normally carry blood from the right ventricle (RV; lower chamber on the right-side of the heart) to the lungs.

In normal humans without PH, the pulmonary arteries are relaxed, wide open, and are not stiff, so that blood flows very easily through the lungs. For this reason, blood pressure in the pulmonary arteries is normally very low.

In normal humans, the blood pressure in the pulmonary arteries (also known as pulmonary artery pressure = PAP) normally fluctuates continuously:

• PAP fluctuates between a high value (also known as systolic) of about 25 millimeters of mercury (= mm Hg) and a low value (also known as diastolic) of 10 mmHg. Thus, the PAP is said to be 25/10 mm Hg
• The average PAP (also known as mean PAP) is usually between 15-20 mmHg, but is always less than 25 mmHg in normal humans at rest
• PAP may rise slightly during exercise, but mean PAP is always less than 30 mm Hg in normal humans

PH is often due to disease in the smallest pulmonary arteries. These pulmonary arteries are narrowed, and some may even be closed, because of several abnormalities:

• The walls of the pulmonary arteries are thicker and stiffer
• There is scar tissue (also known as fibrosis) in the walls of the pulmonary arteries
• There are more cells in the walls of the pulmonary arteries. This is because cells have multiplied (also known as divided or proliferated) abnormally to create more cells. These cells include:
  • The inner lining cells (also known as endothelial cells) of the pulmonary arteries
  • The smooth muscle cells that contract to cause spasm of pulmonary arteries
  • The cells that make scar tissue (also known as fibroblasts)

In PH, because of the narrowed and closed pulmonary arteries, the lungs may grow new blood vessels. These new blood vessels are often very small, and twisted, and form little balls of blood vessels called “plexiform lesions”.

Because of the high blood pressure in the lungs in PH, the large pulmonary arteries can enlarge (also known as dilate). This can be seen on a chest x-ray or CT scan of the lungs.

PH is a disease of abnormally high blood pressure in the arteries of the lungs (also known as pulmonary arteries). In PH, the right ventricle (RV, lower chamber on the right side) of the heart has to work harder to pump blood through the lungs. This is because of several factors:

• The pulmonary arteries are narrowed, and some may be closed
• The walls of the pulmonary arteries are thicker and stiffer
• The blood pressure in the pulmonary arteries (also known as pulmonary artery pressure = PAP) is higher

As the RV works harder over time, this strain on the RV leads to the muscle of the RV getting thicker and stronger (also known as RV hypertrophy). In order for the thicker muscle (hypertrophy) of the RV to pump enough blood, it needs to be filled with more blood. This causes a back-up of blood into the right atrium (RA, upper chamber on the right side), and also behind the heart.

This back-up of blood behind the heart can be examined by your doctor:

• You may have a higher pressure in the jugular vein of the neck (also known as higher JVP = jugular venous pressure)
• You may have a swollen, enlarged, and tender liver, which can make you feel sick to your stomach (also known as nausea) or lose your appetite
• You may have swelling of the belly with fluid (also known as ascites)
• You may have swelling of the feet/ankles (also known as edema)

Because the RV has to work harder in PH, eventually, the RV gets weaker, and cannot pump enough blood for the body. This is known as RV failure, a type of heart failure. Patients with RV failure:

• Can feel extremely tired
• Can feel chest pain, especially on effort or exertion
• Can feel faint or lightheaded, especially on effort or exertion
• Can lose consciousness or pass out (also known as syncope)

If PH is not treated, many PH patients may eventually develop RV failure. In patients with RV failure, the risk of death can be very high, if therapy is not begun.

Yes, PH can be due to spasm of the pulmonary arteries (also known as vasospasm or vasoconstriction). Vasospasm narrows the pulmonary arteries, raising the blood pressure in the pulmonary arteries (higher pulmonary artery pressure = PAP).

• It used to be believed that many patients with PH (such as patients with IPAH) had PH because of vasospasm in their pulmonary arteries. It is because of this idea that many PH patients used to be treated with vasodilator medications (which relax pulmonary arteries) to reduce the blood pressure in the pulmonary arteries
• However, it is now clear that in most patients with PH, vasospasm is not an important cause of PH. As such, vasodilator medications are not useful in treating PH in most patients

Vasospasm of the pulmonary arteries happens when blood oxygen levels are low. Vasospasm is believed to cause some types of PH:

• WHO Group III PH: PH due to lung disease that causes low blood oxygen levels, such as emphysema of the lung or scarring (also known as fibrosis) of the lungs, or breathing problems during sleep (such as sleep apnea)
• Patients who are seriously ill in the intensive care unit (ICU) or after major surgery can also develop PH due to vasospasm

Yes, blood clots in the lungs (also known as pulmonary embolism) can cause or contribute to PH in many patients.

In some patients, PH is directly due to pulmonary embolism. These patients are said to have WHO Group IV PH, or chronic thromboembolic PH (CTEPH).

• The risk of PH after pulmonary embolism is quite small. In most patients with pulmonary embolism, the body is able to break up the clot, leaving no evidence of PH
• However, PH will develop within 2 years of pulmonary embolism in a small number of patients (up to 4%). The risk is highest in patients with multiple episodes of pulmonary embolism
• Patients with pulmonary embolism who also develop PH have a higher risk of dying

In many other patients with PH, blood clots in the lungs are not the cause of PH. However, even in these patients, PH itself causes damage to the innermost lining cells (also known as endothelial cells) of the pulmonary arteries. Damage to endothelial cells can lead to blood clots forming (also known as thrombosis) in the pulmonary arteries.

• This thrombosis in the pulmonary arteries narrows the pulmonary arteries
• This thrombosis in the pulmonary arteries can further increase the blood pressure in the pulmonary arteries (pulmonary artery pressure)
• This thrombosis in the pulmonary arteries can lead to the worsening of PH over time

No, doctors and scientists don’t think PH is a tumor or cancer.

However, there is scientific evidence that the innermost lining cells (also known as endothelial cells) of the pulmonary arteries may behave like tumor cells in patients with idiopathic PAH) IPAH. These endothelial cells have identical patterns of genes (also known as monoclonal), just like cancer cells. This idea of tumor-like endothelial cells in IPAH is an area of ongoing research.

Yes, in some patients, PH can be inherited from their parents. Patients with inherited PAH are said to have familial PAH (FPAH).

• FPAH should be suspected when more than one closely related person in a family (parent, child, sibling) has PAH
• In a family with known FPAH, the risk to individuals is still quite small. On average, only 1 in 10 will develop PAH
• In patients thought to have idiopathic PAH (IPAH), up to 1 in 5 may actually have FPAH. Sometimes, a very detailed or careful medical history of a family can suggest FPAH

Patients with FPAH have a mutation (error) in the DNA code of 1 gene or a number of genes out of the roughly 30,000 genes on the human genome. These mutant genes are transmitted to a patient from her/his parents.

• The first mutant gene that causes FPAH was discovered in 2000. This gene is called BMP-R2 (bone morphogenetic protein receptor 2). The normal function of the BMP-R2 gene is to allow cells to make a protein, called BMP-R2 protein. BMP-R2 protein helps the body control the behaviour of cells in the walls of pulmonary arteries, including endothelial cells and smooth muscle cells. In these cells, BMP-R2 controls:
  • How these cells grow and multiply (also known as reproduce or proliferate)
  • How these cells mature or change their function (also known as differentiate)
  • When these cells should normally die to make room for other cells
• Another mutant gene that causes FPAH is ALK-1

FPAH does not develop in all patients who inherit a gene that causes FPAH. Only about 20% (1 in 5) of persons who inherit a gene for FPAH actually develop FPAH.

It is important to realize that in most patients with PH (all types other than FPAH), there is no evidence that PH is inherited.

Yes, in some patients, PH is due to an infection. Specific types of infection can cause PH:

• The parasitic infection of the bowels and liver, schistosomiasis, is a very common cause of PH around the world, but is very rare in Canada
• Infection with HIV, the virus which causes AIDS. HIV infection can lead to PAH
• Infection with hepatitis viruses B and C, which can lead to chronic liver disease, including chronic hepatitis and cirrhosis. Cirrhosis can lead to PAH

In patients with idiopathic PAH IPAH, a research study found evidence of infection with human herpes virus type 8 (HHV-8) in the lungs.

• HHV-8 is the virus that causes Kaposi’s sarcoma, a type of blood vessel cancer, in patients with HIV infection
• However, whether HHV-8 causes IPAH is controversial, as another study did not find evidence of HHV-8 in IPAH patients

It is important to realize that in most PH patients, PH is not due to an infection.

PH is not contagious, and is not transmitted from 1 person to another. Thus, PH cannot be “caught” from anther person or patient with PH.

However, infections can cause certain types of PH. These infections themselves can spread between people (also known as contagious). In a patient who is exposed to one of these infections and falls ill, there is a risk of also developing PH. These infections include:

• Infection with HIV, the virus which causes AIDS. HIV infection can lead to PAH
• Infection with hepatitis viruses B and C, which can lead to chronic liver disease, including chronic hepatitis and cirrhosis. Cirrhosis can lead to PAH

Endothelial cells (EC) are the innermost lining cells of all blood vessels. EC represent the barrier between blood flowing in the blood vessel, and the wall of the blood vessel.

EC normally function to keep blood vessels healthy. For example, EC in the pulmonary arteries:

• Produce chemical substances (also known as mediators) that relax the pulmonary arteries, keeping the blood pressure very low in the pulmonary arteries in normal humans. These important vasodilator chemicals include nitric oxide (NO) and prostacyclin
• Produce chemical substances that act on other cells in the wall of the blood vessels (such as smooth muscle cells and fibroblasts), and prevent these cells from growing or multiplying. These chemicals include nitric oxide (NO) and prostacyclin
• Produce chemical substances that prevent blood clots (also known as thrombosis) from forming. These anti-thrombotic chemicals include thrombomodulin and TPA (tissue plasminogen activator)

There is much scientific evidence that endothelial cells (EC) are abnormal in the pulmonary arteries of patients with PH. EC could be abnormal for several reasons:

• EC can be affected by the presence of defective genes (also known as mutant genes), such as the genes that cause FPAH
• EC can be damaged by the high blood pressure in the pulmonary arteries in PH (also known as high PAP)
• EC can be damaged by high blood flow through the pulmonary arteries in birth defects of the heart (also known as congenital heart disease = CHD), such as ASD (atrial septal defect) and VSD (ventricular septal defect)
• EC can be damaged by blood clots forming in the pulmonary arteries in PH
• EC can be damaged by some infections, such as infection with the HIV virus

Abnormal EC in the pulmonary arteries lead to more damage to the pulmonary arteries and worsening of PH. Abnormal EC lead to:

• Higher pulmonary artery pressure (PAP) due to production of less vasodilator chemicals such as NO and prostacyclin, and production of more vasoconstrictor chemicals such as endothelin-1 (ET-1), and serotonin
• Increased growth of EC in the pulmonary arteries
• Increased multiplication (also known as proliferation) of EC in the pulmonary arteries
• Narrowing and closing of pulmonary arteries due to increased growth and numbers of other cells in the walls of pulmonary arteries, such as smooth muscle cells and fibroblasts
• Narrowing and closing of pulmonary arteries due to scarring of the blood vessel walls
• Increased formation of blood clots in the pulmonary arteries (also known as thrombosis)