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Understanding Pulmonary Hypertension Pathophysiology

Posted on December 13, 2021
Medically reviewed by
Steven C. Pugliese, M.D.
Article written by
Kristopher Bunting, M.D.

Pulmonary hypertension (PH) is a serious medical condition defined by high blood pressure in the lungs. PH can cause shortness of breath (dyspnea), fatigue, and other symptoms. Severe PH can damage the heart and lungs, sometimes even requiring a heart or lung transplantation.

Pathophysiology refers to the underlying processes that cause disease. In this article, we’ll discuss the pathophysiology of PH, or some of the reasons it develops.

PH is a complex disease with many different causes. At its most basic level, PH is a disease that is caused by problems in the heart, lungs, or blood vessels. These issues result in abnormally high blood pressure in the main blood vessels leading to the lungs. The root causes of PH are varied: Inherited genes; diseases of the heart, lungs, and blood vessels; and other diseases in the body that affect the heart, lungs, and blood vessels can all cause PH.

Understanding the pathophysiology of PH is no easy task. This article will give a simplified explanation — but with such a complicated disease, even the “simple” explanation can be overwhelming.

Understanding Normal Circulation

Having a basic understanding of the body’s circulation, or blood flow, can help you understand how PH occurs.

The circulatory system includes the heart, lungs, and blood vessels, which carry blood to the different parts of the body. The heart has four chambers: the right atrium, right ventricle, left atrium, and left ventricle. Together, each atrium and ventricle pair forms a pump. The right heart pumps blood toward the lungs, and the left heart pumps blood out into the body. The lungs take in oxygen from the air when we inhale and expel carbon dioxide when we exhale. The blood vessels in the body consist of arteries, veins, and capillaries.

The right side of the heart takes in oxygen-poor blood from the body and pumps it into the blood vessels around the lungs via the pulmonary artery. The pulmonary artery divides into smaller and smaller blood vessels, finally becoming capillaries. These tiny blood vessels allow oxygen from the lungs to pass into the blood and carbon dioxide to be passed out. Oxygen-rich blood then flows out from the lungs into the pulmonary vein and into the left side of the heart. The left side of the heart then pumps the oxygen-rich blood into the blood vessels for the rest of the body’s muscles and organs to use.

The blood vessels can widen (dilate) or narrow (constrict) to control blood pressure. When blood vessels widen, the blood pressure drops. When they narrow or constrict, the blood pressure rises. Changes to the normal anatomy or function of the heart, lungs, or blood vessels can cause PH.

Pathophysiology of Pulmonary Hypertension

PH is defined as increased blood pressure in the pulmonary artery — the blood vessel that transports oxygen-poor blood from the right heart to the lungs. In technical terms, PH is diagnosed when the blood pressure in the pulmonary artery is measured to be 25 mmHg or more during a heart procedure, like catheterization or an echocardiogram. There are three basic ways that PH can occur: when blood has difficulty entering the lungs, passing through the lungs, or exiting the lungs.

Some of the most common ways that blood flow in the lungs can be impaired include:

  • Obstruction
  • Left heart dysfunction
  • Heart valve disease
  • Chronically low oxygen levels (hypoxia and hypoxemia)
  • Chronic blood clots

One type of PH has no known underlying causes or risk factors; this is called idiopathic pulmonary arterial hypertension. Other processes and diseases can also cause PH, including liver disease, lupus, HIV, and scleroderma.

Obstruction

Obstruction in PH refers to blockages to normal blood flow in and out of the lungs. This can be due to genetic mutations, some lung diseases, and other disorders, including connective tissue diseases. Pulmonary arterial hypertension (PAH) is a type of PH where blood flow into the lungs is restricted. PAH occurs when there is narrowing of the small arteries in the lungs (Group 1 PH).

Pulmonary veno-occlusive disease (PVOD) limits blood flow out of the lungs. In this condition, the small veins that lead oxygen-rich blood back to the heart are narrowed. PVOD can cause PH, and it may also be present in many cases of idiopathic PAH (PAH of unknown cause).

Left Heart Dysfunction

The left side of the heart is the main pump that propels oxygen-rich blood into the body. Problems with the left heart can cause PH (Group 2 PH). Left heart disease happens when the pump begins to fail (like in heart failure), or when not enough blood can get into the pump because the heart muscle is too stiff (cardiac hypertrophy).

Both of these conditions lead to decreased cardiac output, or the amount of blood that the heart is able to pump into the body’s circulation. When the pump fails or blood is not able to properly pass through the left heart, it causes a backup of blood — and a rise in blood pressure — in the blood vessels around the heart and lungs.

A variety of diseases can cause left heart dysfunction, including a heart attack, high blood pressure, and viral infection of the heart (viral cardiomyopathy).

Heart Valve Disease

Valves in the heart make sure that blood only flows one way: from the right side of the heart to the left. If the heart valves are damaged or malfunctioning, then blood can “leak” backward, disrupting normal blood flow and blood pressure. There are valves that prevent blood from flowing back into the heart from the blood vessels, as well as valves that separate the chambers of the heart.

Blood leaking backward through valves (regurgitation) can cause blood pressure to build in parts of the heart that are not designed to handle it. Stiffening and scarring of the valves can also impair blood from flowing in the normal direction, leading to a backup. For example, mitral valve disease can cause blood pressure to build in the pulmonary vein, lungs, and pulmonary artery.

Chronically Low Oxygen Levels

Diseases that reduce people’s oxygen intake over the long term can cause PH (Group 3 PH). One chronic lung disease, interstitial lung disease, causes scarring in the lungs, resulting in stiffness that restricts blood flow through the lungs. As a result, less oxygen can be transferred to the blood.

Chronic obstructive pulmonary disease (emphysema and chronic bronchitis) is another type of lung disease that restricts air flow in the lungs. This condition leads to difficulty properly oxygenating the blood.

Other factors, such as living at high altitudes where the oxygen concentration in the air is lower, can also cause PH.

Chronic Blood Clots

Chronic blood clots in the lung’s blood vessels are blood clots that the body cannot break down. They can block blood flow through small arteries, and they eventually cause scarring and narrowing of blood vessels. Both of these factors increase the lung’s blood pressure. This condition is called chronic thromboembolic pulmonary hypertension (CTEPH) (Group 4 PH).

Blood clots in the lungs can cause what is called a ventilation/perfusion mismatch. Blood flow to the lungs (perfusion) does not go to all of the areas of the lungs that are filled with air (ventilation). This means that the lungs are not as efficient at passing oxygen to the blood vessels.

Causes of CTEPH include diseases that increase blood clotting or prevent normal blood clot breakdown. CTEPH is one of the few types of PH that may be treated with surgery — in this case, surgery to remove the blood clots in the lungs.

The Body’s Response To Pulmonary Hypertension

Having long-term high blood pressure in the pulmonary artery can damage the heart. This creates a vicious cycle, since heart damage can make PH worse.

Right ventricular failure can occur as a result of increased pulmonary artery pressure. The right ventricle of the heart is built to work at lower pressures than the left ventricle; it does not need to push blood through the entire body, only through the lungs. As pressure backs up into the right ventricle, the right heart can become strained. Over time, this added strain can lead to right heart failure, which further reduces blood flow to the lungs — and makes symptoms like shortness of breath even worse.

Vascular Remodeling

Vascular remodeling refers to scarring of the blood vessels in PH. Diseases that cause blood vessel scarring can cause or contribute to PH.

Vascular remodeling can involve a process called endothelial dysfunction. This causes thickening of the blood vessels and narrowing of the inside of those vessels from too much cell growth. These blood vessel changes can occur in response to increased blood pressure or due to other factors like genetics. Vascular remodeling also leads to increased lung blood pressure.

Disease-modifying therapies for PH are currently being researched. These drugs help to prevent or reverse damage to blood vessels. They block processes on a cellular level that occur in response to high blood pressure, helping to prevent the disease from getting worse.

Current targeted therapies for PH include:

  • Endothelin receptor antagonists — Open blood vessels by blocking the endothelin system, which causes narrowing of the blood vessels (vasoconstriction)
  • Phosphodiesterase-5 inhibitors — Target phosphodiesterase enzyme activity to help widen blood vessels
  • Soluble guanylate cyclase stimulators — Mimic the action of nitric oxide, a chemical produced in the body that opens up blood vessels
  • Prostacyclins — Enhance or replace normal prostaglandin function in the body to help lower blood pressure

Pulmonary Hypertension Risk Factors

The risk factors for PH depend on what the underlying cause is. Heart and lung defects present at birth (congenital defects) and genetic factors are two risk factors for PH. Congenital defects can cause PH in children. Hereditary or genetic factors also contribute to PH. One type of Group 1 PH, heritable pulmonary arterial hypertension (HPAP), has genetic risk factors that are unique to PH and related diseases.

Congenital Defects

Congenital heart disease and other anatomic abnormalities can cause PH in both adults and children.

Two common heart defects are atrial septal defects and ventricular septal defects. These conditions cause blood to flow backward from the left to the right side of the heart, decreasing pressure on the left side and increasing pressure on the right. These alterations in blood flow can cause or contribute to increases in pulmonary arterial blood pressure.

Other congenital defects can also cause PH by affecting pulmonary blood flow. Diaphragmatic hernia is a congenital condition where abdominal organs push up into the chest cavity through a hole in the diaphragm, preventing proper lung development before birth. Diaphragmatic hernia can cause PH, but, like some other congenital defects, it can be repaired with surgery.

Genetics

HPAP is passed down through families, and it has been linked to mutations in specific genes. The most commonly affected gene in HPAP is BMPR2 (bone morphogenetic protein receptor type 2). As many as 80 percent of families with pulmonary arterial hypertension (PAH) have BMPR2 mutations. Also, up to 20 percent of cases of idiopathic PAH are due to BMPR2 mutations. How malfunctioning BMPR2 protein causes PAH is not understood, but it may cause narrowing of small arteries in the lungs, increasing resistance and blood pressure.

BMPR2 mutations are also linked to some cases of pulmonary veno-occlusive disease (PVOD). PVOD can also cause PH by causing narrowing of pulmonary veins that carry blood from the lungs to the heart. EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4) gene mutations are also linked to both PAH and PVOD. Mutations in EIF2AK4 are the most common genetic cause of PVOD.

Mutations in other genes have been linked to PAH; some of these include ACVRL1 (activin A receptor like type 1), CAV1 (caveolin-1), and ENG (endoglin). These genes play various roles in controlling cell multiplication, cell death, and blood vessel growth. TBX4 (T-box 4) gene mutations are a common cause of genetic PAH in children. Many other gene mutations have also been identified that can cause PAH.

PH Has a Complicated Pathophysiology

There are many causes of PH and many underlying mechanisms that can cause or worsen PH. New research and scientific discoveries are constantly expanding our understanding of how PH develops and progresses. This knowledge can lead to better treatment and prevention of PH.

Talk With Others Who Understand

On myPHteam, the social network for people with pulmonary hypertension and their loved ones, more than 39,000 members come together to ask questions, give advice, and share their stories with others who understand life with pulmonary hypertension.

Are you living with pulmonary hypertension? Share your experience in the comments below, or start a conversation by posting on your Activities page.

References
  1. Pulmonary Hypertension: Symptoms and Causes — Mayo Clinic
  2. About Pulmonary Hypertension — Pulmonary Hypertension Association
  3. Chronic Obstructive Pulmonary Disease (COPD) — MedlinePlus
  4. Pulmonary Veno-Occlusive Disease — MedlinePlus
  5. Left Ventricular Heart Failure and Pulmonary Hypertension — European Heart Journal
  6. Understanding Cardiac Output — Critical Care
  7. Heart Valve Disease: Symptoms and Causes — Mayo Clinic
  8. Pulmonary Hypertension in Aortic and Mitral Valve Disease — Frontiers in Cardiovascular Medicine
  9. Interstitial Lung Disease (ILD) — American Lung Association
  10. Pathophysiology of the Right Ventricle and of the Pulmonary Circulation in Pulmonary Hypertension: An Update — European Respiratory Journal
  11. Pulmonary Vascular Remodeling in Pulmonary Hypertension — Cell and Tissue Research
  12. Endothelial Dysfunction in Pulmonary Hypertension — Circulation
  13. The Search for Disease-Modifying Therapies in Pulmonary Hypertension — Journal of Cardiovascular Pharmacology and Therapeutics
  14. Congenital Heart Defects — MedlinePlus
  15. Facts About Diaphragmatic Hernia — Centers for Disease Control and Prevention
  16. Genetics and Genomics of Pulmonary Arterial Hypertension — European Respiratory Journal
  17. Pulmonary Veno-Occlusive Disease Caused by an Inherited Mutation in Bone Morphogenetic Protein Receptor II — American Journal of Respiratory and Critical Care Medicine
  18. BMPR2 Gene — MedlinePlus
  19. EIF2AK4 Gene — MedlinePlus
  20. ACVRL1 Gene — MedlinePlus
  21. CAV1 Gene — MedlinePlus
  22. ENG Gene — MedlinePlus
All updates must be accompanied by text or a picture.
Steven C. Pugliese, M.D. is affiliated with the Hospital of the University of Pennsylvania in Philadelphia, serving as the director of the pulmonary embolism response team, co-director of the comprehensive pulmonary embolism program, and an assistant professor of clinical medicine. Review provided by VeriMed Healthcare Network. Learn more about him here.
Kristopher Bunting, M.D. studied chemistry and life sciences at the U.S. Military Academy, West Point, and received his doctor of medicine degree from Tulane University. Learn more about him here.

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