Pathophysiology and new advances in pulmonary hypertension

Figures

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  Figure 1. Overview of major inflammatory pathways involved in the pathogenesis of pulmonary arterial hypertension. Initial vascular injuries lead to increase in cytokines in vascular cells. After secretion into the bloodstream, cytokines promote accumulation of circulating neutrophils and monocytes, and T and B lymphocytes, resulting in increased vascular proliferation and damage. TNF-α=tumour necrosis factor α; IL=interleukin, MCP=monocyte chemoattractant protein, SMC=smooth muscle cell, CCL=C-C motif chemokine ligand

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  Figure 2. Current theory of change in endothelial cell phenotype in pulmonary artery hypertension and progression to irreversible disease. During the early stages of pulmonary artery hypertension, initial endothelial cell injury (shear stress, hypoxia, inflammation) leads to endothelial cell apoptosis (1), causing a reduction in pulmonary vessels. The remaining endothelial cells become hyperproliferative and resistant to apoptosis (2), leading to formation of plexiform lesions. In the terminal stages of pulmonary artery hypertension, endothelial cells become senescent (3), making the disease irreversible.

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  Figure 3. Overview of major glycolytic and mitochondrial changes in pulmonary arterial hypertension. Glycolysis is upregulated in pulmonary arterial hypertension, and characterised by an increase in expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and lactate dehydrogenase-B (LDHB) in lung cells. Upregulation of LDHB is associated with inhibition of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK), leading to accumulation of lactate in cytoplasm and reduced mitochondrial biogenesis. Reduction in generation of ATP by tricarboxylic cycle (TCA) occurs in pulmonary vascular cells, associated with reduction in quantity of mitochondrial DNA (mtDNA) and increase in production of reactive oxygen species (ROS). Changes in fatty acid oxidation have not been fully elucidated. These abnormalities have been found in pulmonary artery endothelial cells, pulmonary artery smooth muscle cells, and in the right ventricle. G6P=glucose 6-phosphate; F6P=fructose 6-phosphate; F2,6P2=fructose 2,6-bisphosphate; F1,6P2=fructose 1,6-bisphosphate

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  Figure 4. Changes in the right ventricle in pulmonary hypertension. In early pulmonary hypertension, the right ventricle undergoes compensatory changes, including angiogenesis, hypertrophy of cardiac myocytes, and increased wall thickness, and right ventricle and pulmonary artery afterload remain coupled. In late pulmonary hypertension, the right ventricle undergoes maladaptive changes, including metabolic reprogramming, capillary rarefaction, fibrosis, apoptosis, inflammation and immune cell recruitment, oxidative stress, and neurohormonal and dysregulation of the renin-angiotensin-aldosterone system (RAAS); the right ventricle dilates and the septum bows into the left ventricle, and right ventricle and pulmonary artery load become uncoupled. Original figure created with BioRender.com. ROS=reactive oxygen species