Peter K. Henke

Background: Venous stent preclinical testing typically uses large animal models. We created two models of infrarenal inferior vena cava (IVC) stenting to study patency, flow rate, wall shear stress, and endothelial coverage over the stents in a microsurgery rodent model. Methods: In Group 1, Sprague-Dawley rats underwent IVC stenting. Patency was measured by ultrasonography immediately postoperatively (POD-0) and at postoperative day 1 (POD-1). Stents underwent histological analysis up to 21 days postimplantation. Group 2 stented rats received periprocedural anticoagulation (enoxaparin 6 mg/kg SC) and were harvested to evaluate stent coverage using scanning electron microscopy (SEM). En face immunofluorescence (IF) staining was performed in Group 3. Human samples from stent occlusions were collected in the endovascular suite and compared with the animal histological findings. Results: In Group 1, 65% of the stented animals (13/20) were patent POD-0, increasing to 85% (17/20) by POD-1. Histologically, in-stent restenosis (ISR) was 6.2 ± 3.8%, and residual thrombosis (RT) was 32.01 ± 23.12% of the IVC total luminal stent area (LSA). These animals’ pathological processes are similar to those in humans. The mean IVC vein wall thickness (VWT) was 80.18 ± 13.14 μm. In Group 2, all animals were patent (21/21) postimplantation and remained patent in POD-1. IF demonstrated stent coverage with CD31 ⁺ endothelial cells. Total stent endothelialization by SEM reached 69.53 ± 14.84% at 7 days and increased to 91.51 ± 11.23% at 21 days. Conclusion: Quantifying rat venous stent patency and endothelialization via histology and microscopy revealed complete patency with anticoagulation and pathological occlusions (RT, ISR) when withholding anticoagulation. This rodent model will facilitate the preclinical testing of future venous stents.

Background: Saddle pulmonary embolism (SPE) is defined as large emboli located at the bifurcation of the main pulmonary artery. The prevalence and optimal intervention for SPE remain unclear. Herein, we focus on contemporary epidemiology and reperfusion strategies for SPE with acute cor pulmonale (SPE-ACP). Methods: The National Inpatient Sample of the USA (2016–2022) was analyzed. Diagnoses and procedures were identified by International Classification of Diseases, Tenth Revision (ICD-10) codes. Therapies were classified as conventional therapy (CT), systemic fibrinolysis (SF), catheter-directed thrombolysis (CDTL), and catheter-directed mechanical thrombectomy (CDMT). Outcomes evaluated were bleeding, transfusion, discharge to home, and in-hospital mortality. Statistical analyses included chi-squared tests, Wilcoxon rank-sum tests, propensity score matching, and logistic regression. Results: SPE-ACP constituted 1.7% of all PEs (frequency-trend, 2016–2022, p _trend < 0.001); 49.2% of patients received CT. Among advanced reperfusion therapies (ARTs), SF was associated with higher risks of major bleeding and mortality (vs CDTL/CDMT, p < 0.05). CDTL was associated with lower transfusion risk (vs SF/CDMT, p < 0.01) and higher rates of discharge to home (vs SF, p = 0.009). Notably, CDMT showed increasing trends in utilization and discharge to home, and decreasing trends in transfusion and mortality (2016–2022, all p _trend < 0.05). Except for transfusion ( p = 0.013), the outcomes became comparable between CDTL and CDMT (2020–2022, all p > 0.10). SPE-ACP with acute popliteal/femoral deep vein thrombosis (DVT) was associated with lower mortality risk (vs no femoropopliteal DVT, all p < 0.05). Conclusion: SPE-ACP, an uncommon condition, showed a substantially increased prevalence over time. Among ARTs, favorable outcomes were observed with CDTL during 2016–2022; CDMT may be evolving into an alternative strategy given its relatively comparable outcomes during 2020 to 2022. SPE-ACP with concomitant acute femoral/popliteal DVT may be associated with lower mortality risk.

Venous thromboembolism (VTE) is a massive clinical challenge, annually affecting millions of patients globally. VTE is a particularly consequential pathology, as incidence is correlated with extremely common risk factors, and a large cohort of patients experience recurrent VTE after initial intervention. Altered hemodynamics, hypercoagulability, and damaged vascular tissue cause deep-vein thrombosis and pulmonary embolism, the two permutations of VTE. Venous valves have been identified as likely locations for initial blood clot formation, but the exact pathway by which thrombosis occurs in this environment is not entirely clear. Several risk factors are known to increase the likelihood of VTE, particularly those that increase inflammation and coagulability, increase venous resistance, and damage the endothelial lining. While these risk factors are useful as predictive tools, VTE diagnosis prior to presentation of outward symptoms is difficult, chiefly due to challenges in successfully imaging deep-vein thrombi. Clinically, VTE can be managed by anticoagulants or mechanical intervention. Recently, direct oral anticoagulants and catheter-directed thrombolysis have emerged as leading tools in resolution of venous thrombosis. While a satisfactory VTE model has yet to be developed, recent strides have been made in advancing in silico models of venous hemodynamics, hemorheology, fluid–structure interaction, and clot growth. These models are often guided by imaging-informed boundary conditions or inspired by benchtop animal models. These gaps in knowledge are critical targets to address necessary improvements in prediction and diagnosis, clinical management, and VTE experimental and computational models.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal. Here, we report a design concept towards polyP inhibition, termed macromolecular polyanion inhibitors (MPI), with high binding affinity and specificity. Lead antithrombotic candidates are identified through a library screening of molecules which possess low charge density at physiological pH but which increase their charge upon binding to polyP, providing a smart way to enhance their activity and selectivity. The lead MPI candidates demonstrates antithrombotic activity in mouse models of thrombosis, does not give rise to bleeding, and is well tolerated in mice even at very high doses. The developed inhibitor is anticipated to open avenues in thrombosis prevention without bleeding risk, a challenge not addressed by current therapies.