Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition

Abstract

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.

Isolated heart model demonstrates evidence of contractile and diastolic dysfunction in right ventricles from rats with sugen/hypoxia-induced pulmonary hypertension

“…We recently employed the isolated heart preparation in a novel rat model of CTEPH, where we noted extensive RV contractile dysfunction (also characterized by echocardiography and pressure volume relationship in vivo), similar to what we observed in our current model (Neto‐Neves et al. ). However, no diastolic dysfunction was observed in CTEPH RVs.…”

“…We have recently employed this preparation for characterization of a novel rat model of chronic thromboembolic PH (CTEPH) (Neto‐Neves et al. ). However, to the best of our knowledge, the Langendorff preparation has not yet been employed for the study of RVs from SuHx rats.…”

“…In addition, these studies did not evaluate RV diastolic function, a clinically highly relevant parameter (Rain et al 2013). We have recently employed this preparation for characterization of a novel rat model of chronic thromboembolic PH (CTEPH) (Neto-Neves et al 2017). However, to the best of our knowledge, the Langendorff preparation has not yet been employed for the study of RVs from SuHx rats.…”

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement

“…Mechanisms of development of CTEPH after acute PE are incompletely understood and need further study. Recently developed rat and piglet models (113)(114)(115) will facilitate such studies.…”

miRNA-PDGFRB/HIF1A-lncRNA CTEPHA1 Network Plays Important Roles in the Mechanism of Chronic Thromboembolic Pulmonary Hypertension

“…As it is difficult to obtain the tissue of the human pulmonary artery, most of the studies on CTEPH are at the animal level. [19][20][21] In our previous studies, we performed the gene chip analysis of miRNA, lncRNA, and mRNA using the tissue of pulmonary arteries obtained from the CTEPH patients who underwent pulmonary endarterectomy, and the lung cancer patients who underwent pulmonary lobectomy. [14][15][16] However, the relationships between miRNA, lncRNA, and genes were not analyzed.…”