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Dr. F.A. (Erik) Klok ,
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening cardiovascular disease characterized by obstruction of pulmonary artery branches by unresolved thrombofibrotic material and is classified as group 4 of pulmonary hypertension (PAH). Currently, there is no therapy to ‚prevent‘ development of CTEPH after venous thromboembolism, and treatment consists mostly of surgical extraction of the thrombofibrotic material. Mutation of genes encoding TGFβ signaling molecules have been implicated in the pathophysiology of other forms of pulmonary arterial hypertension. Furthermore, endothelin receptor antagonists are one of the main therapeutic components in the management of patients with PAH and it has been shown that endothelin-1 play a role in pulmonary artery vasoconstriction, pulmonary arterial smooth muscle cell proliferation and pulmonary hypertension.
In the manuscript entitled: "Activated endothelial TGFβ1 signaling promotes venous thrombus non-resolution in mice via endothelin-1: potential role for Chronic Thromboembolic Pulmonary Hypertension" by Bochenek ML et al, using two transgenic mouse lines (platelets-specific deletion of TGFβ1 and endothelial-specific deletion of TGFβRII), pulmonary endarterectomy specimens of patients with CTEPH and human and mouse pulmonary endothelial cells, the authors showed that increased TGFβ1 signaling in endothelial cells via ALK5/TGFβRI receptors delays the resolution of venous thrombi in mice and results in chronic pulmonary thromboembolism. Furthermore, they identified activated TGFβ signaling and plasma levels of endothelin-1 (ET-1) as a potential pathomechanism underlying venous thrombus non-resolution and thromboembolism. Finally, upon inhibition of ET-1 with bosentan (ET-1 receptor antagonist) the authors reversed the conversion of endothelial cells to myofibroblasts (endothelial-to-mesenchymal transition) and improved venous thrombus resolution but also inhibited thrombotic pulmonary obstruction.
Comments by the Author (Dr. M.L. Bochenek):
The authors believe that shown mechanism provide a pathophysiological basis of current clinical practice and may have clinically relevant implications for patients with, or at risk of developing CTEPH.
Circ Res. 2020 Jan 17;126(2):162-181
Sharma S, Lang IM. Current understanding of the pathophysiology of chronic thromboembolic pulmonary hypertension. Thromb Res. 2018;164:136– 144.
Naito A, Sakao S, Lang IM, Voelkel NF, Jujo T, Ishida K, Sugiura T, Matsumiya, G, Yoshino I, Tanabe N, et al. Endothelial cells from pulmonary endarterectomy specimens possess a high angiogenic potential and express high levels of hepatocyte growth factor. BMC Pulm Med. 2018;18:197
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