Pulmonary hypertension pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Ralph Matar; Rim Halaby

Overview

Pulmonary hypertension (PH) is a pathological condition of the pulmonary vasculature present in several disease states and leading to hemodynamical derangement. PH is defined as an elevated mean pulmonary artery pressure (PAP) as measured by right heart catheterization at rest. The factors that are in involved in the pathophysiology of the increase in the mean pulmonary arterial pressure are: increase in pulmonary vascular resistance, increase in the right sided cardiac output and increase in the mean pulmonary venous pressure. To note that “Pulmonary arterial hypertension” (PAH) refers to group 1 PAH in the updated WHO classification. “Pulmonary hypertension” (PH) refers to any of group 2 PH through group 5 PH. PH is also used when referring to all five groups collectively.

Pathophysiology

The pathophysiology of pulmonary hypertension[1][2][3][4][5][6]

PH is defined as an elevated mean pulmonary artery pressure (PAP) ≥ 25 mmHg as measured by right heart catheterization at rest. The elevation in PAP results from an elevation in the pulmonary vascular resistance caused by a multifactorial pathogenesis involving genetic and environmental factors.

Pulmonary hypertension has several pathophysiologic mechanisms depending on the underlying etiology. Nevertheless, the following sequence of events is almost always present:

  • An initiating factor leads to increased resistance in the pulmonary vasculature causing narrowing of the vessels and impaired blood flow.
  • Over time, increasing right ventricular systolic pressures will subsequently result in chronic changes in the pulmonary circulation and the affected blood vessels progressively become 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. Factors that might affect the ability of the right ventricle to adapt to an increased pulmonary vascular resistance are:
    • Age of the patient at onset
    • Rapidity of onset of pulmonary hypertension
    • Coexisting hypoxemia

Pulmonary Arterial Hypertension

Molecular and Cellular Changes

  • Pulmonary arterial hypertension is characterized by endothelial dysfunction resulting from an imbalance between apoptosis and proliferation of pulmonary artery smooth muscle cells favoring the proliferation.
  • There is also thickened and disordered adventitia due to excessive amounts of adventitial metalloproteinases.
  • Several pathways are implicated in development of vascular remodeling, which is the hallmark of pathologic changes in pulmonary hypertension:

1. Thrombosis-mediated remodeling

2. Vasoconstriction-mediated remodeling

3. Proliferation-mediated remodeling

4. Inflammation-mediated remodeling

Shown below is an image depicting remodeling in pulmonary arterial hypertension.

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Genetic Mutations

TGF-β Receptor Pathway

  • Bone morphogenetic protein receptor II (BMPR2) gene encodes a serine/threonine kinase that functions as a receptor for bone morphogenetic proteins which forms a heterodimer cytoplasmic complex of two type II and two type I receptors. The downstream signaling involves activation of SMAD transcription factor which mediates anti-proliferation in smooth muscle cells.
  • Activin-like kinase 1 gene mutations are detected in patients with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension. Mutation would cause growth-promoting alterations.

Serotoninergic Pathway

  • 5- Hydroxytryptamine (serotonin) transporter mutations have also been associated with the proliferation of smooth muscle cells of pulmonary arteries.[7]

Histopathology

PH is a pathological condition present in different disease states that share similar clinical manifestation and some common histopathological features. Shown below is a table that summarizes the classification of PH based on histopathology findings.[8]

Class Histopathological findings[8] Images
Pulmonary arteriopathy Constrictive lesions in pulmonary arteries
  • Medial hypertrophy
  • Intimal thickening
  • Adventitial thickening

Complex lesions in pulmonary arteries

  • Plexiform lesions
  • Dilatation lesions
  • Arteritis
Pulmonary arteriopathy with venous-venular changes Changes similar to pulmonary arteriopathy
PLUS
Changes in venules and veins
Pulmonary occlusive venopathy
(with or without arteriopathy)
Changes in venules and veins
  • Diffuse fibrotic occlusion
  • Intimal thickening
  • Medial thickening
  • Adventitial thickening

Changes in the capillaries

  • Dilatation
  • Congestion

Changes in the interstitium

Pulmonary microvasculopathy
(with or without arteriopathy and/on venopathy)
Changes in the capillaries
  • Localized capillary proliferation

Changes in the interstitium

Unclassified Non specific changes

Gallery

The images below are courtesy of Dr. Yale Rosen (Source:Wikimedia Commons).

References

  1. Marcos E, Fadel E, Sanchez O, Humbert M, Dartevelle P, Simonneau G, Hamon M, Adnot S, Eddahibi S (May 2004). "Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension". Circ. Res. 94 (9): 1263–70. doi:10.1161/01.RES.0000126847.27660.69. PMID 15059929.
  2. Eddahibi S, Fabre V, Boni C, Martres MP, Raffestin B, Hamon M, Adnot S (February 1999). "Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin". Circ. Res. 84 (3): 329–36. PMID 10024307.
  3. Huber LC, Bye H, Brock M (2015). "The pathogenesis of pulmonary hypertension--an update". Swiss Med Wkly. 145: w14202. doi:10.4414/smw.2015.14202. PMID 26479975.
  4. Peacock A (March 2013). "Pulmonary hypertension". Eur Respir Rev. 22 (127): 20–5. doi:10.1183/09059180.00006912. PMID 23457160.
  5. Tuder RM, Stacher E, Robinson J, Kumar R, Graham BB (December 2013). "Pathology of pulmonary hypertension". Clin. Chest Med. 34 (4): 639–50. doi:10.1016/j.ccm.2013.08.009. PMID 24267295.
  6. Michelakis ED (June 2014). "Pulmonary arterial hypertension: yesterday, today, tomorrow". Circ. Res. 115 (1): 109–14. doi:10.1161/CIRCRESAHA.115.301132. PMID 24951761.
  7. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F; et al. (2001). "Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension". J Clin Invest. 108 (8): 1141–50. doi:10.1172/JCI12805. PMC 209526. PMID 11602621.
  8. 8.0 8.1 Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM; et al. (2004). "Pathologic assessment of vasculopathies in pulmonary hypertension". J Am Coll Cardiol. 43 (12 Suppl S): 25S–32S. doi:10.1016/j.jacc.2004.02.033. PMID 15194175.

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