Exercise Facilitates Early Recognition of Cardiac and Vascular Remodeling in Chronic Thrombo-Embolic Pulmonary Hypertension in a Novel CTEPH Swine Model

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 4% of patients after pulmonary embolism and is accompanied by an impaired exercise tolerance, which is ascribed to the increased right ventricular (RV) afterload in combination with a ventilation/perfusion (V/Q) mismatch in the lungs. The present study aimed to investigate changes in arterial Po and hemodynamics in response to graded treadmill exercise during development and progression of CTEPH in a novel swine model. Swine were chronically instrumented and received multiple pulmonary embolisms by 1) microsphere infusion (Spheres) over 5 wk, 2) endothelial dysfunction by administration of the endothelial nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME) for 7 wk, 3) combined pulmonary embolisms and endothelial dysfunction (L-NAME + Spheres), or 4) served as sham-operated controls (sham). After a 9 wk followup, embolization combined with endothelial dysfunction resulted in CTEPH, as evidenced by mean pulmonary artery pressures of 39.5 ± 5.1 vs. 19.1 ± 1.5 mmHg (Spheres, P < 0.001), 22.7 ± 2.0 mmHg (L-NAME, P < 0.001), and 20.1 ± 1.5 mmHg (sham, P < 0.001), and a decrease in arterial Po that was exacerbated during exercise, indicating V/Q mismatch. RV dysfunction was present after 5 wk of embolization, both at rest (trend toward increased RV end-systolic lumen area, P = 0.085, and decreased stroke volume index, P = 0.042) and during exercise (decreased stroke volume index vs. control, P = 0.040). With sustained pulmonary hypertension, RV hypertrophy (Fulton index P = 0.022) improved RV function at rest and during exercise, but this improvement was insufficient in CTEPH swine to result in an exercise-induced increase in cardiac index. In conclusion, embolization in combination with endothelial dysfunction results in CTEPH in swine. Exercise increased RV afterload, exacerbated the V/Q mismatch, and unmasked RV dysfunction. NEW & NOTEWORTHY Here, we present the first double-hit chronic thromboembolic pulmonary hypertension swine model. We show that embolization as well as endothelial dysfunction is required to induce sustained pulmonary hypertension, which is accompanied by altered exercise hemodynamics and an exacerbated ventilation/perfusion mismatch during exercise.

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

“…Contrary to several other studies where microspheres alone did not sufficiently invoke a hemodynamic or histological response (15, 25), we showed its feasibility to induce RV failure in a large animal model of CTEPH as evidenced by a significantly reduced CI, EF, and TAPSE. The advantages of the microsphere models are the ease of delivery, comparatively less-invasive surgical procedures, and the ability to generate CTEPH in both lungs.…”

“…While we have shown the capability of this technique, one of the main disadvantages is the duration necessary to achieve these results. It required 6 months, on average (range 4–8 months), before sufficient levels of PH were observed, which is much longer than most studies have attempted (3, 18, 20, 21, 25).…”

“…Using a swine model of chronic PH (21, 22), Boulate et al did demonstrate acute RV failure when also inducing volume overload via saline infusion and iterative acute pulmonary embolization (24), but the chronic PH model relied on proximal obstruction of the right lower-lobe artery via tissue adhesive in conjunction with the PA ligation which exhibited no clinical evidence of RV failure at rest (19). Stam et al also created a swine model of CTEPH utilizing multiple microsphere injections in conjunction with an endothelial nitric synthase inhibitor to cause endothelial dysfunction (25). This model demonstrated decreased cardiac index (CI), RV remodeling, and exercise intolerance, but required open-chested procedures as well as a two-hit mechanism to induce hemodynamic changes.…”

Validation of 4D flow CMR against simultaneous invasive hemodynamic measurements: a swine study

“…Nine Yorkshire x Landrace swine (5–6 months old, 21 ± 1 kg at the time of surgery, 63 ± 4 kg at the time of the CMR scan) of either sex were included in the study. The swine included in this study were part of previously published studies [ 16 , 17 ].…”

Pulmonary microvascular remodeling in chronic thrombo-embolic pulmonary hypertension

“…We recently developed and hemodynamically characterized a swine model of CTEPH, using a combination of repeated microembolizations and eNOS inhibition to mimic endothelial dysfunction (54). In this study, microembolizations alone resulted in transient elevations in PAP but did not induce sustained PH.…”