Pulmonary hypertension (PH) is defined by elevated blood pressure within the arteries of the lungs. The pulmonary circulation is a low-pressure system where blood travels from the right side of the heart to the lungs for oxygen exchange. In PH, this pressure rises, forcing the right side of the heart to work harder to push blood through narrowed or stiffened vessels. This continuous strain can eventually lead to right heart failure.
The precise hemodynamic measurement for diagnosing PH, established by the 6th World Symposium on Pulmonary Hypertension (WSPH), is a mean pulmonary artery pressure (mPAP) greater than 20 mmHg at rest. While PH is uncommon, it represents a significant health challenge due to its complexity and progressive nature.
The Purpose of the WHO Classification System
Pulmonary hypertension is not a single disease but a shared physiological state resulting from many different underlying conditions. The World Health Organization (WHO) system, based on consensus from the World Symposium on Pulmonary Hypertension (WSPH), divides PH into five distinct groups based on the underlying cause. This standardized classification is the global standard for diagnosis.
The classification is instrumental in guiding treatment decisions, as therapy must be specific to the cause rather than the symptom of high pressure alone. For instance, a medication effective for Group 1 PH may be ineffective or harmful for a patient with Group 2 PH. By categorizing PH based on etiology and pathophysiology, the system ensures patients receive the most appropriate, targeted interventions.
Group 1: Pulmonary Arterial Hypertension (PAH)
Group 1, Pulmonary Arterial Hypertension (PAH), is a rare subset characterized by disease affecting the small pulmonary arteries directly. Physical changes involve vasoconstriction and cell proliferation, causing artery walls to thicken and remodel. This progressive narrowing significantly increases the resistance to blood flow, known as pulmonary vascular resistance, a defining feature of PAH.
This group is classified as pre-capillary PH, meaning the pressure rise occurs before the lung capillaries. Hemodynamically, it is defined by an mPAP greater than 20 mmHg, a pulmonary arterial wedge pressure (PAWP) of 15 mmHg or less, and a pulmonary vascular resistance (PVR) of 3 Wood units or more.
PAH includes idiopathic PAH (cause unknown), heritable PAH (linked to genetic mutations like the BMPR2 gene), and PAH induced by certain drugs or toxins. It is also associated with conditions such as connective tissue diseases, HIV infection, or portal hypertension. Group 1 is the primary target for specific, advanced PH therapies that act as vasodilators to relax the pulmonary arteries.
Group 2: PH Due to Left Heart Disease
Group 2 Pulmonary Hypertension, caused by left heart disease, is the most common form of PH observed in clinical practice. In this group, pressure backs up from the left side of the heart, even though the pulmonary arteries are generally healthy. When the left ventricle fails or becomes stiff, it cannot efficiently pump blood, causing blood to pool and transmit “backward pressure” into the pulmonary circulation.
Conditions causing this high pressure include heart failure (with preserved or reduced ejection fraction) and significant valvular diseases. This type of PH is classified as post-capillary because the pressure rise originates after the capillaries in the pulmonary veins.
Treatment focuses entirely on optimizing the underlying left heart condition. Using PAH-specific drugs designed for Group 1 is not recommended and can potentially be harmful, making the distinction crucial for effective management.
Group 4: Chronic Thromboembolic PH (CTEPH)
Group 4 PH, or Chronic Thromboembolic Pulmonary Hypertension (CTEPH), develops when blood clots in the lung arteries fail to dissolve completely over time, typically following a pulmonary embolism. These residual clots become organized, scarring the vessel walls and leading to fixed mechanical blockages and a significant rise in pulmonary pressure.
The persistent obstruction causes a rise in pulmonary vascular resistance, forcing the right side of the heart to strain. The presence of these organized thrombi distinguishes CTEPH from the cellular remodeling seen in Group 1 PAH. Diagnosis often involves a ventilation-perfusion (VQ) scan to identify the blockages.
CTEPH is unique because potentially curative treatments are available to remove the mechanical obstruction. The gold standard is Pulmonary Endarterectomy (PEA), a surgical procedure that removes the scar tissue. For non-surgical candidates, alternative treatments include balloon pulmonary angioplasty (BPA) or targeted medical therapies.
Groups 3 and 5: PH Related to Lung Conditions or Multifactorial Causes
Group 3 Pulmonary Hypertension is directly linked to chronic lung diseases or conditions causing chronically low blood oxygen levels (hypoxia). Conditions such as Chronic Obstructive Pulmonary Disease (COPD), interstitial lung disease, and severe obstructive sleep apnea can trigger this form of PH. The mechanism involves the body’s response to low oxygen, where small blood vessels constrict to redirect blood flow.
Over time, this widespread vasoconstriction leads to structural changes and sustained high pressure. The therapeutic focus for Group 3 is on treating the underlying lung disorder, such as improving oxygenation, rather than relying on the specific vasodilators used for Group 1. This approach addresses the root cause of the pressure elevation.
Group 5 comprises PH with unclear, complex, or multifactorial mechanisms that do not fit neatly into the other four categories. This group encompasses conditions like hematologic disorders (e.g., chronic hemolytic anemia), systemic diseases like sarcoidosis, rare metabolic conditions, chronic kidney failure, and external compression of the pulmonary arteries by tumors. Due to the varied nature of the underlying diseases, Group 5 cases require highly individualized diagnostic workups and management strategies.