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A Novel Rat Model of Chronic Thromboembolic Pulmonary Hypertension
Author(s) -
Neves Evandro Neto,
Brown Mary Beth,
Zaretskaia Maria,
Goodwill Adam,
Kline Jeffrey
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb592
Subject(s) - medicine , pulmonary hypertension , pathophysiology , chronic thromboembolic pulmonary hypertension , right ventricular hypertrophy , saline , pathogenesis , cardiology , microsphere , muscle hypertrophy , lung , cardiac function curve , antagonist , cardiac output , rat model , receptor , endocrinology , blood pressure , heart failure , chemical engineering , engineering
Chronic thromboembolic pulmonary hypertension (CTEPH) pathophysiology is still unclear and deserves more attention. There is a lack of animal models which replicate major pathogenesis of human CTEPH. We hypothesized that the combination of two deleterious insults would be required to damage the pulmonary vasculature and produce sustained pulmonary hypertension and right ventricular (RV) dysfunction found in human CTEPH. CTEPH was induced in Sprague‐Dawley rats (400–450 g) with a combination of microspheres (221.000/100g, 85 μm, i.v.) and VEGF receptor antagonist (SU 5416, 20mg/kg, s.c.) in the PE+SU group. Additional groups received volume‐matched saline (SHAM), microspheres (PE) or SU5416 (SU) separately. CTEPH rats exhibited sustained pulmonary hypertension (RV systolic pressure, 62±12 and 53±9 mmHg at 3 and 6 weeks, respectively) compared to the Sham group (26±2 and 25±2 mmHg). Echocardiography showed robust RV dysfunction, hypertrophy and decreased cardiac output after CTEPH (P<0.05). Similarly, impaired RV contractile function (developed pressure and dP/dt max ) was observed by Langendorff's technique and was accompanied by increased RV mass in PE+SU group (>2 fold compared to Sham group, P<0.05). Approximately 25% decrement in aerobic capacity was observed in rats in PE and PE+SU groups after 3 days post‐injection. While more robust decreases were found after three (40%) and six (32%) weeks in PE+SU group, rats in PE group had their aerobic capacity recovered (P<0.05). Abundant lung vascularization can be observed in the PE group, whereas lung vascular rarefaction along with elevated endothelial injury makers were found in PE+SU group. We conclude that at least two injuries are required to replicate pulmonary obstruction and microvasculature injury to reproduce CTEPH in rats. Interestingly, progressive PH, RV dysfunction and marked hypertrophy were found associated with deficient lung vascularization in our rat model. Support or Funding Information AHA 14POST20170013 (E Neves PI). This study was made possible by the Lilly Endowment, Inc. Physician Scientist (J Kline PI).