Pulmonary hypertension (PH) describes a condition where the blood pressure in the arteries of the lungs is abnormally high, defined by a mean pulmonary artery pressure greater than 20 mmHg at rest. This elevated pressure forces the right side of the heart to work harder, which can eventually lead to right heart failure. Since PH can result from many different underlying causes, a standardized system is necessary to guide diagnosis and treatment. The World Health Organization (WHO) classification system organizes PH into five distinct groups based on the underlying disease mechanism, ensuring patients receive appropriate and targeted therapies.
Group 1: Pulmonary Arterial Hypertension
Group 1, known as Pulmonary Arterial Hypertension (PAH), is characterized by disease confined primarily to the small blood vessels, or arterioles, within the lungs. The inner lining and muscle layers of these small arteries undergo pathological remodeling, causing them to narrow and stiffen. This significantly increases resistance to blood flow, forcing the right ventricle of the heart to pump against greater pressure, a condition known as pre-capillary PH.
PAH is a diverse category that includes several specific subtypes. Idiopathic PAH (IPAH) is diagnosed when the cause is unknown. Heritable PAH involves genetic mutations, most commonly in the bone morphogenetic protein receptor type 2 ($BMPR2$) gene. PAH can also be associated with other systemic diseases, such as connective tissue disorders like scleroderma, HIV infection, or portal hypertension, which is high blood pressure in the liver’s circulation. Certain drugs and toxins, including methamphetamines and a class of diet pills used in the past, are known to induce this form of PH.
Group 2: PH Related to Left Heart Disease
Pulmonary hypertension due to left heart disease is the most common form of PH and is often referred to as post-capillary PH. This group arises when the left side of the heart, which receives oxygenated blood from the lungs, fails to function effectively. When the left ventricle struggles to pump blood out, or when the mitral or aortic valves are diseased, pressure builds up within the left atrium.
This increased pressure is transmitted backward through the pulmonary veins into the lungs, causing a passive rise in pulmonary artery pressure. Left-sided issues include both systolic dysfunction, where the heart cannot contract properly, and diastolic dysfunction, where the heart cannot relax and fill with blood. Over time, this chronic back-pressure can lead to secondary changes in the pulmonary blood vessels, creating a complex condition known as combined pre- and post-capillary PH.
Group 3: PH Associated with Lung Disease and Hypoxia
Group 3 PH results from chronic lung conditions or prolonged low oxygen levels in the blood, known as hypoxia. Chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILDs), such as pulmonary fibrosis, are the most common disorders in this category. These conditions either destroy the lung tissue and its vascular bed or cause chronic lack of oxygen in the air sacs.
Hypoxia triggers a protective mechanism called hypoxic pulmonary vasoconstriction, which constricts the pulmonary arteries to redirect blood flow away from poorly ventilated areas. When hypoxia is chronic, as seen in severe sleep apnea or prolonged exposure to high altitude, this sustained constriction leads to structural remodeling and thickening of the vessel walls. This combination of vascular destruction and chronic vasoconstriction results in elevated pulmonary pressures.
Group 4: Chronic Thromboembolic PH
Chronic Thromboembolic Pulmonary Hypertension (CTEPH), classified as Group 4, is a mechanically driven form of PH caused by persistent, organized blood clots in the pulmonary arteries. While most acute pulmonary embolisms resolve completely, in a small percentage of individuals, the clots fail to dissolve and instead scar and harden. These fibrotic obstructions permanently block or narrow the larger pulmonary arteries, creating a mechanical barrier to blood flow.
The resulting high resistance in the major vessels leads to a progressive increase in pulmonary artery pressure and strain on the right ventricle. Beyond the direct blockage, the areas of the lung still receiving blood flow can develop secondary changes in the smaller vessels, mimicking the remodeling seen in PAH. Diagnosing CTEPH involves confirming the presence of these chronic obstructions alongside the hemodynamic criteria for PH.
Group 5: PH with Unclear or Multifactorial Mechanisms
Group 5 is a heterogeneous category for PH that cannot be neatly classified into the first four groups because its cause is often unclear, multifactorial, or involves systemic processes. This group includes a wide variety of systemic, hematologic, and metabolic disorders. Specific examples are hematologic disorders like chronic hemolytic anemia, including sickle cell disease, and myeloproliferative disorders.
Systemic diseases such as sarcoidosis and chronic kidney failure also fall into this group. The mechanisms are diverse, ranging from extrinsic compression of the vessels to systemic inflammation and metabolic derangements that affect vascular function. The treatment approach for Group 5 PH must be tailored to address the specific primary condition alongside the pulmonary hypertension itself.