TY - JOUR
T1 - Cardiopulmonary remodeling following repetitive acute pulmonary emboli and inhibition of endogenous fibrinolysis in a porcine model
AU - Kirk, Mathilde Emilie
AU - Dragsbaek, Simone Juel
AU - Merit, Victor Tang
AU - Lyhne, Mads Dam
AU - Hansen, Jacob Valentin
AU - Kramer, Anders
AU - Schultz, Jacob Gammelgaard
AU - Pedersen, Christina Caroee Ejlskov
AU - Jujo-Sanada, Takayuki
AU - Karout, Lina
AU - Kalra, Mannudeep
AU - Nielsen-Kudsk, Jens Erik
AU - Andersen, Asger
N1 - Publisher Copyright:
© 2024
PY - 2025/9/15
Y1 - 2025/9/15
N2 - Background: The underlying pathophysiology of chronic thromboembolic pulmonary disease (CTEPD) with or without sustained pulmonary hypertension (pH) remains unclear, but repetitive pulmonary emboli (PE) and impaired fibrinolysis are known risk factors. We hypothesized that repetitive PE and inhibition of endogenous fibrinolysis would induce CTEPD with PH (CTEPH). Methods: Twenty-four Danish female slaughter pigs of ∼60 kg (4 groups of 6 pigs) were included in the study. Pigs received either autologous PE (PE group), PE plus tranexamic acid (PE + TXA), repetitive PE (day 0, 3, 7, and 10) plus tranexamic acid (REP PE + TXA), or saline infusion (SHAM). Pigs were evaluated at baseline and on day 30 using computed tomography pulmonary angiography (CTPA), invasive hemodynamics, and tissue samples. Results: CTPA showed increased pulmonary obstruction score on day 30 in REP PE + TXA group compared to remaining groups (0 ± 0 SHAM vs 31 ± 21 PE vs 42 ± 12 PE + TXA vs 69 ± 17 % REP PE + TXA, P = 0.004). Mean pulmonary arterial pressure was higher in REP PE + TXA group on day 30 than remaining groups (12 ± 2 SHAM vs 13 ± 1 PE vs 12 ± 2 PE + TXA vs 16 ± 2 mmHg REP PE + TXA, P = 0.002) yet none of the groups developed PH and right ventricular function was normalized after 30 days. In histological samples, we found chronic thromboembolic lesions with organized fibrotic thrombi, revascularization, and neointima formation, but no microvascular remodeling. Conclusions: Autologous repetitive PE and inhibited fibrinolysis caused chronic thrombi without PH in a porcine model. Our findings suggest that a repetitive PE and impaired endogenous fibrinolysis alone are insufficient to develop CTEPH. Translational aspect: This porcine model using autologous pulmonary emboli presents a realistic large animal model of chronic thromboembolic pulmonary disease particularly suitable to further investigate the vascular remodeling after acute PE. Future research should examine the role of inflammation, endothelial dysfunction and angiogenesis-driven clot resolution to improve understanding of the pathophysiological mechanisms.
AB - Background: The underlying pathophysiology of chronic thromboembolic pulmonary disease (CTEPD) with or without sustained pulmonary hypertension (pH) remains unclear, but repetitive pulmonary emboli (PE) and impaired fibrinolysis are known risk factors. We hypothesized that repetitive PE and inhibition of endogenous fibrinolysis would induce CTEPD with PH (CTEPH). Methods: Twenty-four Danish female slaughter pigs of ∼60 kg (4 groups of 6 pigs) were included in the study. Pigs received either autologous PE (PE group), PE plus tranexamic acid (PE + TXA), repetitive PE (day 0, 3, 7, and 10) plus tranexamic acid (REP PE + TXA), or saline infusion (SHAM). Pigs were evaluated at baseline and on day 30 using computed tomography pulmonary angiography (CTPA), invasive hemodynamics, and tissue samples. Results: CTPA showed increased pulmonary obstruction score on day 30 in REP PE + TXA group compared to remaining groups (0 ± 0 SHAM vs 31 ± 21 PE vs 42 ± 12 PE + TXA vs 69 ± 17 % REP PE + TXA, P = 0.004). Mean pulmonary arterial pressure was higher in REP PE + TXA group on day 30 than remaining groups (12 ± 2 SHAM vs 13 ± 1 PE vs 12 ± 2 PE + TXA vs 16 ± 2 mmHg REP PE + TXA, P = 0.002) yet none of the groups developed PH and right ventricular function was normalized after 30 days. In histological samples, we found chronic thromboembolic lesions with organized fibrotic thrombi, revascularization, and neointima formation, but no microvascular remodeling. Conclusions: Autologous repetitive PE and inhibited fibrinolysis caused chronic thrombi without PH in a porcine model. Our findings suggest that a repetitive PE and impaired endogenous fibrinolysis alone are insufficient to develop CTEPH. Translational aspect: This porcine model using autologous pulmonary emboli presents a realistic large animal model of chronic thromboembolic pulmonary disease particularly suitable to further investigate the vascular remodeling after acute PE. Future research should examine the role of inflammation, endothelial dysfunction and angiogenesis-driven clot resolution to improve understanding of the pathophysiological mechanisms.
KW - Chronic thromboembolic pulmonary disease
KW - Chronic thromboembolic pulmonary hypertension
KW - Pulmonary hypertension
KW - Pulmonary vascular disease
KW - Vascular remodeling
UR - http://www.scopus.com/inward/record.url?scp=105005590221&partnerID=8YFLogxK
U2 - 10.1016/j.ijcard.2025.133398
DO - 10.1016/j.ijcard.2025.133398
M3 - Journal article
C2 - 40389036
AN - SCOPUS:105005590221
SN - 0167-5273
VL - 435
JO - International Journal of Cardiology
JF - International Journal of Cardiology
M1 - 133398
ER -