A Large Animal Model of Right Ventricular Failure due to Chronic Thromboembolic Pulmonary Hypertension: A Focus on Function

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease that progresses to right ventricular (RV) failure and death if left untreated. Little is known regarding the progression of RV failure in this disease, greatly limiting effective prognoses, and therapeutic interventions. Large animal models enable the use of clinical techniques and technologies to assess progression and diagnose failure, but the existing large animal models of CTEPH have not been shown to replicate the functional consequences of the RV, i.e., RV failure. Here, we created a canine embolization model of CTEPH utilizing only microsphere injections, and we used a combination of right heart catheterization (RHC), echocardiography (echo), and magnetic resonance imaging (MRI) to quantify RV function. Over the course of several months, CTEPH led to a 6-fold increase in pulmonary vascular resistance (PVR) in four adult, male beagles. As evidenced by decreased cardiac index (0.12 ± 0.01 v. 0.07 ± 0.01 [L/(min*kg)]; p < 0.05), ejection fraction (0.48 ± 0.02 v. 0.31 ± 0.02; p < 0.05), and ventricular-vascular coupling ratio (0.95 ± 0.09 v. 0.45 ± 0.05; p < 0.05), as well as decreased tricuspid annular plane systolic excursion (TAPSE) (1.37 ± 0.06 v. 0.86 ± 0.05 [cm]; p < 0.05) and increased end-diastolic volume index (2.73 ± 0.06 v. 2.98 ± 0.02 [mL/kg]; p < 0.05), the model caused RV failure. The ability of this large animal CTEPH model to replicate the hemodynamic consequences of the human disease suggests that it could be utilized for future studies to gain insight into the pathophysiology of CTEPH development, following further optimization.

Model of Chronic Thromboembolic Pulmonary Hypertension in Rats Caused by Repeated Intravenous Administration of Partially Biodegradable Sodium Alginate Microspheres

“…The leading mechanism for the formation of pulmonary hypertension in most previously developed models of CTEPH using artificial microspheres involves reducing the vascular bed of the pulmonary circulation (PC) [ 19 , 20 ]. However, the current understanding of CTEPH pathogenesis goes far beyond chronic obstruction caused by unfragmented thrombotic masses.…”

Chronic Thromboembolic Pulmonary Hypertension – What Have We Learned From Large Animal Models

“…Other studies in dogs also show that repeated embolization (Sephadex beads of 100-300 µm in diameter) does result in sustained CTEPH (38,57), but this requires a large number of embolizations over a period of several months. A total of ∼50,000 beads was injected over a period of several months (57), which is similar to the number of beads required to induced sustained CTEPH in our swine model. However, it should be noted that these smaller beads penetrate deeper into the pulmonary vasculature, and that the number of pulmonary small arteries increases with decreasing size.…”

“…Conversely, when a similar protocol was used in dogs, CTEPH was successfully induced in the absence of eNOS inhibition (54). Other studies in dogs also show that repeated embolization (Sephadex beads of 100-300 µm in diameter) does result in sustained CTEPH (38,57), but this requires a large number of embolizations over a period of several months. A total of ∼50,000 beads was injected over a period of several months (57), which is similar to the number of beads required to induced sustained CTEPH in our swine model.…”

Pharmacokinetics of single dose sildenafil orally administered in canine models of chronic embolic pulmonary hypertension

“…The dogs were cathethetised with propofol (6 mg/kg, IV) and intubated, which was maintained using a continuous-rate infusion of propofol (0.1-0. CEPH was induced according to a modified version of a previously described method [18,24]. Briefly, 300-µm microspheres (GE Healthcare, Chicago, IL, USA) were 8 injected into the pulmonary artery through the 4-Fr catheter monitoring PAP.…”