A porcine in‐vivo model of acute pulmonary embolism

Abstract

Acute pulmonary embolism (PE) is the third most common cardiovascular cause of death after acute myocardial infarction and stroke. Patients are, however, often under-treated due to the risks associated with systemic thrombolysis and surgical embolectomy. Novel pharmacological and catheter-based treatment strategies show promise, but the data supporting their use in patients are sparse. We therefore aimed to develop an in vivo model of acute PE enabling controlled evaluations of efficacy and safety of novel therapies. Danish Landrace pigs (n = 8) were anaesthetized and mechanically ventilated. Two pre-formed autologous PEs (PE1, PE2, 20 × 1 cm) were administered consecutively via the right external jugular vein. The intact nature and central location were visualized in situ by magnetic resonance imaging (MRI). The hemodynamic and biochemical responses were evaluated at baseline (BL) and after each PE by invasive pressure measurements, MRI, plus arterial and venous blood analysis. Pulmonary arterial pressure increased after administration of the PEs (BL: 16.3 ± 1.2, PE1: 27.6 ± 2.9, PE2: 31.6 ± 3.1 mmHg, BL vs. PE1: P = 0.0027, PE1 vs. PE2: P = 0.22). Animals showed signs of right ventricular strain evident by increased end systolic volume (BL: 60.9 ± 5.1, PE1: 83.3 ± 5.0, PE2: 99.4 ± 6.5 mL, BL vs. PE1: P = 0.0005, PE1 vs. PE2: P = 0.0045) and increased plasma levels of Troponin T. Ejection fraction decreased (BL: 58.9 ± 2.4, PE1: 46.4 ± 2.9, PE2: 37.3 ± 3.5%, BL vs. PE1: p = 0.0008, PE1 vs. PE2: P = 0.009) with a compensatory increase in heart rate preserving cardiac output and systemic blood pressure. The hemodynamic and biochemical responses were comparable to that of patients suffering from intermediate-high-risk PE. This porcine model mirrors the anatomical and physiologic changes seen in human patients with intermediate-high-risk PE, and may enable testing of future therapies for this disease.

Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism

“…3,14,15,18,22 The present study shows that the pulmonary vasodilatory effects of NO-sGC-cGMP are preserved in a more clinically relevant setting using large central autologous pulmonary embolism. 24 While the design of this study does not allow us to evaluate statistically the correlation of dose-response, the graphical presentation in Figure 4 indicates that PVR decreased with increasing doses of all three treatments to a level close to baseline. For sildenafil and inhaled NO, the correlation appeared to be exponential with effects already at the lowest dose.…”

“…We used an in vivo porcine model of autologous intermediate-risk pulmonary embolism. 24 Two pre-formed autologous blood clots were administered to the pulmonary circulation. Animals were randomized to four increasing clinically equivalent doses of riociguat (n=6), sildenafil (n=6), inhaled NO (n=6) or vehicle (n=6).…”

“…The emboli were administered consecutively en bloc via the right jugular vein, and blood flow carried it from there to the pulmonary circulation. 24…”

“…Handling and instrumentation were performed as previously described in detail. 24 Briefly, female pigs (Cross of Land Race, Duroc and Yorkshire, ~ 60 kg) were anaesthetized (continuous intravenous infusion: fentanyl 5 mg/kg per h, propofol 2 mg/kg per h), intubated and mechanically ventilated (tidal volume 8 ml/kg, fraction of inspired oxygen 0.3, respiratory rate adjusted to Figure 1. Study design.…”

Imbalance of angiotensin-converting enzymes affects myocardial apoptosis during cardiac arrest induced by acute pulmonary embolism in a porcine model

“…Zagorski et al ( 22 ) reported that the mortality rate due to severe pulmonary embolism in rats was 37.8%, which is similar to the mortality rate of 47.4% in the model of the present study. Schultz et al ( 23 ) employed an in vivo APE model in pigs and mentioned that ‘a stable model of high-risk PE in pigs with an acceptable variance and mortality rate may therefore be difficult to develop.’ This suggests that the mortality rates in this model are expected to be high. This would justify the high percentage of mortality observed in the present study.…”