Pulmonary Hypertension & Cor Pulmonale

The pulmonary circulation is built for low pressure. Normally "the pulmonary vasculature is characterized by low resistance, allowing efficient blood flow through the lungs," and normal pulmonary artery pressure is 11 to 20 mm Hg (NHLBI). About 1% of people worldwide have pulmonary hypertension.

The current number is above 20. "A mean pulmonary artery pressure (mPAP) greater than 20 mm Hg is above the upper normal limit." Recent definitions revised the abnormal cutoff "from at least 25 to greater than 20 mm Hg" and abnormal pulmonary vascular resistance from greater than 3 to greater than 2 Wood units (2022 ESC/ERS guidelines and the 6th World Symposium, as relayed by StatPearls). The measurement is made at right heart catheterization, at rest and supine — the only test that confirms the diagnosis.

The wedge pressure tells you where the pressure comes from. Pre-capillary PH has a pulmonary artery wedge pressure (PAWP) of 15 mm Hg or less with PVR above 2 Wood units — the problem is in the lung vessels. A wedge above 15 mm Hg means pressure is backing up from the left heart (post-capillary).

The common path is the right ventricle. "When this pressure gets too high, the pulmonary arteries become narrow or blocked. This makes the blood not flow as well, so the heart has to work harder to maintain blood flow into the lungs. Over time, this can cause damage to the heart and lungs." The thin-walled right ventricle is not built for high afterload — which is why right-sided heart failure is where most forms of PH end.

The WHO groups (NHLBI labels). Group 1: pulmonary arterial hypertension (PAH). Group 2: PH due to left-sided heart disease. Group 3: PH due to lung disease and/or hypoxia. Group 4: PH due to pulmonary artery obstructions, including chronic thromboembolic pulmonary hypertension (CTEPH). Group 5: unknown or multiple causes.

Group 2 is the most common in the United States — left heart failure, and in particular heart failure with preserved ejection fraction (at least half of those patients have post-capillary PH) and valve disease (60–70% of severe symptomatic mitral disease, 50% of symptomatic aortic stenosis). Lung disease, particularly COPD, comes next. For both, "The cornerstone of therapy in all these conditions is optimizing underlying cardiac disease," and for group 3 the goal is to optimize the lung disease.

Group 1 (PAH) is rare and specialist-treated — about 6 cases per million adults a year. More than half have no known cause; the rest include heritable disease (BMPR2 is the most common gene), connective-tissue disease (systemic sclerosis above all), HIV, portal hypertension, and drugs or toxins such as methamphetamines, fenfluramine and dasatinib. It is the group with the dedicated vasodilator drugs.

Group 4 (CTEPH) follows pulmonary embolism, among other risks, and is the one group with a surgical option — "CTEPH has an excellent long-term prognosis if the disease is operable." Group 5 includes chronic hemolytic anemias and myeloproliferative disorders; NHLBI lists sickle cell disease among the causes.

The term. Cor pulmonale was historically "used to refer to right ventricular hypertrophy and failure secondary to pulmonary disease"; modern teaching places it within pulmonary hypertension and right-ventricular dysfunction — essentially group 3.

Step 1 — hypoxia squeezes the vessels. "Pulmonary vasoconstriction in response to hypoxia plays a prominent role in the early phase of the disease process in both obstructive and restrictive lung disease." Prolonged hypoxemia reduces nitric oxide and prostaglandins and increases endothelin, raising pulmonary vascular resistance. Destroyed alveoli in COPD and fibrosis in IPF distort the vessels further.

Step 2 — the vessels remodel. In the late phase, smooth-muscle hyperplasia and intimal narrowing obliterate the lumen — the pressure becomes fixed, not just reactive.

Step 3 — the right ventricle hypertrophies, then fails. Because resistance rises slowly, the "RV adapts and hypertrophy to compensate for the high afterload," which causes diastolic dysfunction and eventually uncoupling from the pulmonary artery. "Under the persistently high afterload, RV eventually fails with reduced systolic function, and cor pulmonale ensues." Hyperinflation adds insult by reducing venous return to the right ventricle.

Why oxygen is a treatment, not just comfort. Reversing the first step reverses pressure: in COPD, long-term oxygen "has shown a decrease in the progression of PH when used for >15 hours and improvement in PAP when used for >18 hours." In COPD, PH is usually mild to moderate (mPAP 20–35 mm Hg) and is found in about 10–30% of mild-to-moderate disease — but it is "a strong predictor of survival."

Three pathways. PAH drugs target "antagonism of the endothelin system, agonism of the prostacyclin pathway, and agonism of the nitric oxide pathway." Endothelin receptor antagonists (ambrisentan, bosentan, macitentan) block a vasoconstrictor that also drives vessel growth; PDE-5 inhibitors (sildenafil, tadalafil) raise nitric oxide signalling; prostacyclins (epoprostenol, treprostinil) replace a dilator that is dysregulated in PAH. Under the 2022 ESC/ERS approach as StatPearls relays it, lower-risk patients start on an ERA plus a PDE-5 inhibitor, and high-risk patients add an IV or subcutaneous prostacyclin.

Calcium channel blockers only after the test. High-dose CCBs are first-line only in idiopathic, heritable or drug-induced PAH that tests positive on vasoreactivity testing during right heart catheterization — an mPAP fall of at least 10 mm Hg to 40 mm Hg or less with unchanged or increased output. They are not a general PH drug.

Epoprostenol and the rebound. Epoprostenol has a half-life of 3 to 5 minutes and runs as a continuous IV infusion. The FDA label warns: "Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of VELETRI may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia." A patient death in trials was judged attributable to an interruption. Pump malfunction and catheter obstruction cause dosing problems, and line infection and sepsis are serious risks — so sterile catheter care is part of the drug.

Group 3 is different. In lung-disease PH, the ERAs "have shown no benefit but may be harmful," a riociguat trial was stopped early for harm, and systemic vasodilators can worsen gas exchange by undoing hypoxic vasoconstriction. Inhaled treprostinil is FDA-approved for group 3 PH with interstitial lung disease.