Pulmonary hypertension pathophysiology


 * Assistant Editor(s)-in-Chief: Ralph Matar

Overview

 * Whatever the cause is, an initiating factor leads to increased resistance in the pulmonary vasculature causing narrowing of the vessels and impaired blood flow, much as it is harder to make water flow through a narrow pipe as opposed to a wide one.


 * As a consequence, the right ventricle adapts by increasing right ventricular systolic pressures to preserve the cardiac output from the right heart.


 * Over time, increasing right ventricular systolic pressures will subsequently result in chronic changes in the pulmonary circulation and progressively the affected blood vessels become both stiffer and thicker, further increasing the blood pressure within the lungs and impairing blood flow.


 * In addition, the increased workload of the heart causes thickening and enlargement of the right ventricle, making the heart less able to pump blood through the lungs, causing right heart failure.


 * As the blood flowing through the lungs decreases, the left side of the heart receives less blood. This blood may also carry less oxygen than normal. Therefore it becomes harder and harder for the left side of the heart to pump to supply sufficient oxygen to the rest of the body, especially during physical activity.

A role for endothelial injury
All classes of pulmonary hypertension are associated with narrowing and obliteration of the pulmonary arterioles due to thickening of the intima by fibromuscular dysplasia.This constant finding has created increased our interest in the role of endothelial injury and the release of vasoactive mediators in the pathogenesis of pulmonary hypertension.These mediators include both vasoconstrictors and vasodilators.The main vasoconstrictor is Endothelin, whereas Nitric Oxide (NO), PGI2 and endothelium derived hyperpolarizing factor (EDHF) are vasodilators of which NO is the most potent in reversing the effects of Endothelin.

Factors determining the ability of the RV to adapt to increased PVR

 * 1) Age of the patient at onset.
 * 2) Rapidity of onset of pulmonary hypertension.
 * 3) Coexisting hypoxemia.

Histopathology:

 * Pulmonary arterial hypertension is a panvasculopathy predominantly affecting small pulmonary arterioles which regulate resistance to blood flow in the lungs.


 * Pulmonary hypertension is characterized by a variety of abnormalities that can be diffuse or local:
 * 1) Intimal hyperplasia.
 * 2) Medial hypertrophy.
 * 3) Adventitial proliferation.
 * 4) In-situ thrombosis.
 * 5) Inflammation
 * 6) Plexiform arteriopathy.

Medial hypertrophy is considered an early and reversible lesion in contrast to intimal fibrosis or plexogenic arteriopathy.

Pathobiologic/Molecular abnormalities:

 * Pulmonary arterial hypertension is characterized by endothelial dysfunction such that there is an imbalance between apoptosis and pulmonary artery smooth muscle proliferation favoring the proliferation. There is also thickened and disordered adventitia due to excessive amounts of adventitial metalloproteases.


 * Mutations of two genes in the TGF-beta receptor pathway have been identified in familial pulmonary arterial hypertension:
 * 1) BMPR2: Modulates vascular cell growth. A loss of function mutation would cause unregulated smooth muscle growth.
 * 2) Activin-like kinase 1: detected in patients with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. Mutation would cause growth-promoting alterations.

Both genes are involved SMAD-dependant signaling pathways.