The Five WHO Groups of Pulmonary Hypertension Explained

After the first trimester, amlodipine and other calcium channel blockers are reasonably safe. For eclampsia or hypertension specifically during pregnancy, the preferred agent is a direct alpha agonist, such as prazosin.

Any mean pulmonary artery pressure greater than 20 mmHg combined with a pulmonary vascular resistance greater than 2 Wood units should be started on therapy — at minimum, a PDE5 inhibitor plus an endothelin receptor antagonist as double therapy. If the patient remains symptomatic, we add a prostacyclin analog to complete triple therapy. Escalating beyond triple therapy to sotatercept should only be considered after at least six months to a year of adequate triple therapy without sufficient response.

First, PDE5 inhibition, to promote vascular relaxation via the cGMP pathway. Second, soluble guanylate cyclase stimulation, to address back-pressure and encourage vasodilation. Third, endothelin receptor blockade, to retard smooth muscle cell hypertrophy and reduce pulmonary vascular resistance. Sotatercept adds a fourth, distinct pathway — anti-proliferative inhibition of activin signalling — which addresses the underlying vascular remodelling rather than just haemodynamics.

The right ventricle is a volume-handling ventricle, not designed for pressure overload — you can load it with considerable volume and it won't fail, because volume is its domain. But impose a pressure overload, as in pulmonary hypertension, and it hypertrophies to compensate before eventually failing. The left ventricle is a pressure-handling ventricle, built for exactly that load. That's why pulmonary hypertension causes right heart failure long before it affects the left.

Two mechanisms operate together. Viral proteins cause stiffness in the lung's interstitial tissue, which physically compresses the pulmonary blood vessels. At the same time, the immunocompromised state associated with HIV promotes smooth muscle hyperplasia within the vessel walls, narrowing the lumen from within. It's the combination of external compression and internal luminal narrowing that drives HIV-associated pulmonary hypertension.

Pulmonary hypertension is classified into five groups based on underlying cause, and the group a patient falls into determines both prognosis and treatment approach.

Group 1, covering idiopathic or hereditary pulmonary arterial hypertension, historically carried a near-certain prognosis of early death, though outcomes have changed substantially with newer therapies such as sotatercept.

Group 3 is caused by lung disease, including idiopathic pulmonary fibrosis, interstitial lung disease, COPD, obstructive sleep apnoea, and chronic hypoxia, all of which stiffen the lung and narrow pulmonary vessels through hypoxia.

Group 4 is chronic thromboembolic pulmonary hypertension, or CTEPH, formerly referred to as CTEF, and includes acute pulmonary emboli, organised clot, and vascular anomalies obstructing right ventricular forward flow.

For Groups 2, 3, and 5, treating the underlying root cause often resolves or significantly improves the pulmonary hypertension.