Molecular Pathophysiology of Chronic Thromboembolic Pulmonary Hypertension: A Clinical Update from a Basic Research Perspective

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but severe condition characterized by persistent obstruction and vascular remodeling in the pulmonary arteries following an acute pulmonary embolism (APE). Although APE is a significant risk factor, up to 25% of CTEPH cases occur without a history of APE or deep vein thrombosis, complicating the understanding of its pathogenesis. Herein, we carried out a narrative review discussing the mechanisms involved in CTEPH development, including fibrotic thrombus formation, pulmonary vascular remodeling, and abnormal angiogenesis, leading to elevated pulmonary vascular resistance and right heart failure. We also outlined how the disease's pathophysiology reveals both proximal and distal pulmonary artery obstruction, contributing to the development of pulmonary hypertension. We depicted the risk factors predicting CTEPH, including thrombotic history, hemostatic disorders, and certain medical conditions. We finally looked at the molecular mechanisms behind the role of endothelial dysfunction, gene expression alterations, and inflammatory processes in CTEPH progression and detection. Despite these insights, there is still a need for improved diagnostic tools, biomarkers, and therapeutic strategies to enhance early detection and management of CTEPH, ultimately aiming to reduce diagnostic delay and improve patient outcomes.

Keywords: acute pulmonary embolism; chronic thromboembolic pulmonary hypertension; fibrotic thrombus formation; gene expression; pulmonary hypertension; pulmonary vascular remodeling.

Figure 1

Primary risk factors for the development of chronic thromboembolic pulmonary hypertension. Previous episodes of pulmonary embolism, coagulation disorders, splenectomy, chronic infections, hypothyroidism treatment, cancer, and prolonged inflammatory states contribute to CTEPH development. These factors lead to persistent vascular obstruction and remodeling and increased pulmonary resistance, which are crucial features for CTEPH progression and aggravation. PE: pulmonary embolism; CTEPH: chronic thromboembolic pulmonary hypertension.

Figure 2

Cross-section representation showing heart–lung interactions in chronic thromboembolic pulmonary hypertension. In CTEPH, pulmonary vascular obstruction due to an unresolved clot increases pulmonary vascular resistance, resulting in right ventricular pressure overload. This overload causes RV hypertrophy and dilation, reduced cardiac output, and impaired ventriculoarterial coupling. The bidirectional interaction between the heart and lungs exacerbates right heart failure and contributes to the progressive deterioration of patients that conduces to less coronary perfusion pressure, increased oxygen demand, and finally, death. RV: right ventricular; LV: left ventricular; CTEPH: chronic thromboembolic pulmonary hypertension; O2: oxygen; ↑, increase; ↓, decrease.

Figure 3

Pathophysiology of chronic thromboembolic pulmonary hypertension. Following acute pulmonary embolism, unresolved thrombus leads to persistent vascular obstruction. This phenomenon triggers a cascade of events, including increased hypercoagulability, abnormal clot lysis, impaired angiogenesis, and inflammatory thrombosis. Chronic inflammation and impaired fibrinolysis result in fibroblast and smooth muscle cell proliferation, inflammatory cell infiltration, and deposition of collagen and elastin, contributing to the formation of fibrotic, non-resolving thromboembolic material, also referred to as organized thrombi. These events also increase pulmonary artery pressure and vascular resistance, contributing to microvascular remodeling. The interplay of these factors results in right ventricular strain, a central feature of CTEPH pathogenesis. PASMCs: pulmonary artery smooth muscle cells; PAECs: pulmonary artery endothelial cells; PAP: pulmonary artery pressure; RVP: pulmonary vascular resistance; RAP: right atrial pressure; RVH: right ventricle hypertrophy; RHD: right ventricle dysfunction; CTEPH: chronic thromboembolic pulmonary hypertension.

Figure 4

Summary of the main molecular mechanisms involved in developing chronic thromboembolic pulmonary hypertension. Central molecular mechanisms participate in CTEPH development, including the signaling pathways mediated by Rho, ROK, JNK, Ras, and MAPK. These molecular cascades lead to PASMC proliferation and migration into the intimal media, causing increased contraction and vasoconstriction in the pulmonary artery. ET-1, NO, and PIG2 activate PAEC proliferation and migration, contributing to concentric intimal thickening. Together with impaired fibrinolysis and angiogenesis, inflammatory thrombosis, and pulmonary endothelial dysfunction, increased vasoconstriction exacerbates vascular remodeling, generating proximal organized thrombus and remodeling of distal pulmonary artery segments not occluded by a clot. Finally, these changes lead to persistent pulmonary artery obstruction and increased pulmonary vascular resistance, two pivotal features of CTEPH. CTEPH: chronic thromboembolic pulmonary hypertension; PASMCs: pulmonary artery smooth muscle cells; Rho: GTP-binding GTPase RhoA; ROK: Rho-associated protein kinase; JNK: c-Jun N-terminal kinase; Ras: Ras GTPase superfamily; MAPK: mitogen-activated protein kinase; DAG: diacylglycerol; IP3: inositol phosphate; PAEC: pulmonary artery endothelial cells; ET-1: endothelin-1; NO: nitric oxide; PGI2: prostaglandin E2.