Inflammation and clot burden are insufficient to induce pulmonary hypertension after repetitive pulmonary embolism: a translational porcine study
S J Dragsbaek, A Overgaard, M E Kirk, C D Baltsen, C C E Pedersen, A Burade, M K Kalra, J E Christensen, B Hansen, J M Kalucka, M D Lyhne, A AndersenAbstract
Background
Chronic thromboembolic pulmonary disease (CTEPD) is a long-term complication after an acute pulmonary embolism (PE) and can present with or without pulmonary hypertension (PH). The transition from acute PE to CTEPD remains poorly understood. Inflammation is considered an important contributor to disease development.
Purpose
To investigate if experimental induction of local inflammation influences the long-term haemodynamic and immunological responses following repetitive PE in a porcine model.
Methods
We used a porcine model of repetitive autologous PE in a 30-day prospective study. Six pigs received repetitive PE with immune stimulation in which emboli contained cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) to induce local innate immune activation (RepPE+cGAMP). Findings were compared with six pigs receiving repetitive PE and tranexamic acid (RepPE+TXA). All animals underwent serial haemodynamic assessment, blood sampling, and computed tomography pulmonary angiography (CTPA), with final evaluation at day 30. Systemic inflammation was evaluated, and pulmonary inflammatory responses were assessed by quantifying cytokine levels in lung tissue (IP-10, TNF-α, IL-1β, IL-8) and by immunohistochemical analysis of organised thrombi.
Results
Repetitive PE resulted in increased mean pulmonary arterial pressure in both groups; however, pressures normalised by day 30, and none fulfilled criteria for pulmonary hypertension (18±3 mmHg in RepPE+cGAMP and 16±2 mmHg in RepPE+TXA, p=0.20) (Figure 1A). CTPA revealed persistent vascular obstruction at day 30 in both groups, with comparable obstruction percentage (85 [75-87] % in RepPE+cGAMP and 72 [50-80] % in RepPE+TXA), p=0.29) (Figure 1B). Systemic white blood cell, neutrophil, and lymphocyte counts were similar between groups at follow-up. Lung tissue analysis revealed higher IP-10 levels in the RepPE+cGAMP group compared with RepPE+TXA (9.1±5.0 vs. 3.8±1.9 ng/g, p=0.035), while IL-1β, TNF-α, and IL-8 did not differ (Figure 2A-D). Immunohistochemistry confirmed IP-10–positive inflammatory cell infiltration within the organised thrombi (Figure 2E-I).
Conclusion
Repetitive pulmonary embolisation with cGAMP induced sustained pulmonary immune activation and persistent vascular obstruction with organised thrombi at 30 days, as seen in CTEPD without pulmonary hypertension.