Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by fibrotic obstruction of the proximal pulmonary arteries, and it is believed to result from incomplete thrombus resolution after acute pulmonary embolism. While treatment for this condition with surgery and medical therapy has improved outcomes, our understanding of the molecular mechanisms underlying CTEPH is incomplete. Numerous risk factors have been associated with the development of CTEPH, including but not limited to acquired thrombophilias and chronic inflammatory states. A minority of patients with CTEPH have an abnormal fibrin structure that may delay thrombus resolution. Recently, examination of resected scar material in patients with CTEPH has suggested that deficient angiogenesis may play a role in thrombus nonresolution, and there is increasing interest in factors that drive intravascular scar formation. An additional challenge in CTEPH research is understanding the etiology and implications of the small-vessel disease present in many patients. Future work will likely be directed at understanding the pathways important to disease pathogenesis through further examinations of resected tissue material, continued work on animal models, and genomic approaches to identify alterations in gene expression or gene variants that may distinguish CTEPH from other forms of pulmonary hypertension.

Keywords: chronic intravascular inflammation; pulmonary embolism.

Figure 1

Pathogenesis of chronic thromboembolic pulmonary hypertension.^, PE: pulmonary embolism; CTEPH: chronic thromboembolic pulmonary hypertension; RV: right ventricular.

Figure 2

Vascular obstructive lesions in acute pulmonary embolism (A) and chronic thromboembolic pulmonary hypertension (CTEPH; B). The CTEPH patient underwent bilateral pulmonary endarterectomy; however, only the right-side specimen is shown. Images courtesy of Dr. Joyce Johnson (A) and Tarek Absi (B).

Figure 3

Pulmonary endarterectomy specimens stained with hematoxylin and eosin. A, Neointimal thickening, 18×; B, region of fibrotic chronic thromboembolic pulmonary hypertension clot containing extracellular matrix and spindle-shaped cells, 290×; C, fresh red clot within an area of organized clot, 100×; D, obstructing lesion with areas of recanalization, 170×.