Exercise Response in a New Porcine Model of Chronic Embolic Pulmonary Hypertension

Abstract

Chronic Thromboembolic Pulmonary hypertension (CTEPH) is a deadly disease initiated by thrombo‐embolisms persisting in the pulmonary vasculature, followed by remodelling of the pulmonary vascular bed, resulting in a sustained increase in afterload of the right ventricle (RV). Although the response of the pulmonary vasculature to the initiating thromboembolic events as well as the response of the RV to the increased afterload are known to be the most important determinants of patient outcome, the factors that underlie these processes are incompletely understood. In the present study, we developed a novel chronically instrumented swine model of CTEPH. CTEPH was induced by up to 5 weekly injections of polyethylene beads of 700 μm in combination with induction of endothelial dysfunction by eNOS‐inhibition. Swine were followed up to one month after the last embolization. Changes in mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were used as indices of RV afterload and pulmonary vascular remodeling. and assessed at rest and during treadmill exercise (EX) .
Repeated embolization resulted in increases in PAP and PVR. Control After first embolization Prior to sacrifice rest EX rest Ex Rest Ex PAP (mmHg) 16±1 33±3* 29±3† 61±7*† 47±15† 72±16*† PVR (mmHg.min.kg.L‐1) 86±13 98±16 160±42† 197±23† 510±237† 633±344† * P<0.05 vs Rest, † P< 0.05 vs Control The increase in PAP was exaggerated during exercise, and in two animals, limited the increase in cardiac output during exercise. The increase in PVR induced by repeated embolization correlated well with RV weight (r2=0.78), indicating that swine developed RV hypertrophy. Moreover, histology revealed increased muscularization of pulmonary arterioles.In conclusion, our new swine model of CTEPH mimics critical features of patients with CTEPH in that pulmonary vascular remodeling is present and exercise capacity is reduced.Supported by CVON‐ PHAEDRA2012‐08