Pulmonary hypertension develops when blood pressure in the arteries connecting the heart to the lungs rises above normal levels, currently defined as a mean pulmonary artery pressure above 20 mmHg (lowered from the previous threshold of 25 mmHg in the 2022 European guidelines). The causes range widely, from heart failure and chronic lung disease to blood clots, genetic mutations, and even certain drugs. The World Health Organization classifies pulmonary hypertension into five groups based on the underlying mechanism, because identifying the root cause determines how the condition is treated.
How the Pulmonary Arteries Change
Regardless of the initial trigger, pulmonary hypertension ultimately comes down to structural changes in the walls of the small arteries inside the lungs. Under normal conditions, these arteries have thin, flexible walls made up of a single layer of endothelial cells lining the inside, a thin layer of smooth muscle in the middle, and an outer layer of connective tissue with fibroblasts. When something goes wrong, whether it’s low oxygen, inflammation, or abnormal blood flow, these layers thicken.
The smooth muscle cells in the middle layer multiply excessively, narrowing the opening of the artery. Fibroblasts in the outer layer proliferate and deposit extra collagen, stiffening the vessel wall. Immune cells, particularly macrophages, accumulate around the vessels and release growth signals that further accelerate smooth muscle growth and collagen production. Over time, muscle tissue extends into even the smallest arterioles that were previously non-muscular. The result is a pulmonary vascular system that resists blood flow, forcing the right side of the heart to pump harder and harder until it eventually weakens.
Left Heart Disease: The Most Common Cause
The single most frequent cause of pulmonary hypertension is left-sided heart disease, classified as Group 2. This includes heart failure (whether the heart pumps weakly or stiffens and can’t fill properly), as well as disease of the mitral or aortic valves.
The mechanism is relatively straightforward. When the left side of the heart can’t efficiently move blood forward, pressure backs up. The left ventricle’s filling pressure rises, which elevates pressure in the left atrium, which then transmits backward through the pulmonary veins into the pulmonary arteries. Initially this is a passive pressure increase. But over time, the sustained elevated pressure causes the pulmonary artery walls to thicken and remodel, and the hypertension becomes a fixed structural problem rather than just a consequence of backup pressure.
Lung Disease and Low Oxygen
Group 3 pulmonary hypertension is driven by chronic lung conditions or prolonged exposure to low oxygen levels. COPD, interstitial lung disease, and living at high altitude are classic triggers. Obstructive sleep apnea also plays a role.
The core mechanism is something called hypoxic pulmonary vasoconstriction. When oxygen levels drop in a region of the lung, the local arteries constrict to redirect blood toward better-ventilated areas. This is a useful short-term reflex. But when low oxygen is widespread or persistent, vasoconstriction becomes global, and pulmonary vascular resistance can increase by up to 300%. High carbon dioxide levels and acidosis in the blood amplify this effect further.
Chronic exposure to low oxygen doesn’t just cause ongoing constriction. It triggers permanent remodeling of the artery walls. Animal studies show that repetitive episodes of oxygen deprivation lasting just a few weeks are enough to cause thickening of the pulmonary arterioles and enlargement of the right ventricle. In people with sleep apnea, cyclical oxygen drops during sleep, sometimes lasting more than 40 seconds and occurring many times per hour, create a cumulative burden of intermittent hypoxia. This can lead to increased red blood cell production (the body’s attempt to carry more oxygen) and progressive pulmonary hypertension. The combination of vasoconstriction, abnormal chemical signaling, and vascular cell proliferation drives the structural changes that make the condition self-sustaining.
Pulmonary Arterial Hypertension
Group 1, called pulmonary arterial hypertension (PAH), involves disease that originates in the pulmonary arteries themselves rather than being caused by heart or lung problems. It’s less common than Groups 2 and 3 but often more severe. PAH can be idiopathic (no identifiable cause), heritable, or associated with other conditions.
Connective tissue diseases like scleroderma and lupus are among the most recognized triggers. HIV infection is another: PAH occurs at higher rates in people living with HIV than in the general population, alongside other cardiovascular complications like pericardial effusion and cardiomyopathy. Portal hypertension from liver disease, congenital heart defects, and schistosomiasis (a parasitic infection common in tropical regions) can also cause PAH.
Genetic Factors
A specific gene mutation plays a major role in heritable PAH. Mutations in the BMPR2 gene account for 70 to 80% of heritable PAH cases and are also found in 10 to 40% of people diagnosed with idiopathic PAH, where no other cause is apparent. Overall, BMPR2 mutations are present in 20 to 30% of all PAH patients. This gene normally helps regulate the growth of cells in blood vessel walls, so when it malfunctions, the unchecked cell proliferation that characterizes pulmonary hypertension becomes more likely.
Drugs and Toxins
Certain stimulants and appetite suppressants are definitively linked to PAH. The first drug implicated was aminorex fumarate, an amphetamine-derived weight loss pill used in parts of Europe in the 1960s that caused a spike in cases. Benfluorex, another weight loss drug, was eventually classified as a “definite” risk factor and pulled from European markets in 2009. Methamphetamine use is a well-established risk factor in current patients.
Chronic Blood Clots in the Lungs
Group 4, called chronic thromboembolic pulmonary hypertension (CTEPH), develops when blood clots in the pulmonary arteries don’t fully dissolve after a pulmonary embolism. The remaining scar tissue and organized clot material physically obstruct blood flow. Both the size of the original clot and whether someone experiences repeated episodes of pulmonary embolism contribute to the risk.
But simple obstruction doesn’t tell the whole story. The disease also involves a misguided vascular remodeling process in both the large and small pulmonary vessels. Factors that promote abnormal clotting, including “sticky” red blood cells, elevated platelet counts, and certain fibrin abnormalities, play a role. Inflammation, immune system dysfunction, infection, thyroid hormone replacement therapy, and cancer have all been identified as potential modifiers that influence whether someone develops CTEPH after a pulmonary embolism rather than recovering normally.
Rare and Overlapping Causes
Group 5 encompasses conditions where pulmonary hypertension arises through multiple mechanisms that don’t fit neatly into the other categories. Sarcoidosis is one of the more recognized examples: this inflammatory disease can affect the lung tissue, compress blood vessels with enlarged lymph nodes, and involve the heart simultaneously, making it hard to attribute the elevated pressure to a single pathway.
Several metabolic disorders also fall into this group. Thyroid disease, both overactive and underactive, is associated with pulmonary hypertension. Among the rarer metabolic causes, Gaucher disease (a genetic condition where fatty substances accumulate in cells and organs) has been linked to pulmonary hypertension in up to 30% of untreated patients based on echocardiography screening. Glycogen storage disease type 1, also known as von Gierke disease, is another rare metabolic trigger. Pulmonary Langerhans cell histiocytosis, a condition where abnormal immune cells accumulate in the lungs, rounds out the more notable Group 5 causes.
Because these conditions affect the pulmonary vasculature through several overlapping pathways at once, they can be especially challenging to diagnose and manage compared to the more clearly defined groups.