Assessment of extracranial carotid artery disease using digital twins - A pilot study.

To improve risk stratification in extracranial internal carotid artery disease (CAD), patients who would benefit maximally from revascularization must be identified. In cardiology, the fractional flow reserve (FFR) has become a reference standard for evaluating the functional severity of coronary artery stenosis, and noninvasive surrogates thereof relying on computational fluid dynamics (CFD) have been developed. Here, we present a CFD-based workflow using digital twins of patients' carotid bifurcations derived from computed tomography angiography for the noninvasive functional assessment of CAD. We reconstructed patient-specific digital twins of 37 carotid bifurcations. We implemented a CFD model using common carotid artery peak systolic velocity (PSV) acquired with Doppler ultrasound (DUS) as inlet boundary condition and a two-element Windkessel model as oulet boundary condition. The agreement between CFD and DUS on the PSV in the internal carotid artery (ICA) was then compared. The relative error for the agreement between DUS and CFD was 9% ± 20% and the intraclass correlation coefficient was 0.88. Furthermore, hyperemic simulations in a physiological range were feasible and unmasked markedly different pressure drops along two ICA stenoses with similar degree of narrowing under comparable ICA blood flow. Hereby, we lay the foundation for prospective studies on noninvasive CFD-based derivation of metrics similar to the FFR for the assessment of CAD.

[Pulmonary Endarterectomy and Treatment for Chronic Thromboembolic Pulmonary Hypertension]. / Pulmonale Endarteriektomie und Behandlung der chronisch thromboembolischen pulmonalen Hypertonie.

Pulmonary Endarterectomy and Treatment for Chronic Thromboembolic Pulmonary Hypertension Abstract. Chronic thromboembolic pulmonary hypertension is a relatively rare disease which mostly evolves as a complication of acute pulmonary embolism resulting from the fibrotic organization of residual thrombotic material despite adequate anticoagulation leading to precapillary pulmonary hypertension and persistence of its symptoms. The elevated pulmonary vascular resistance leads to right ventricular heart failure, its symptoms and reduced prognosis. The therapy of choice is the pulmonary endarterectomy, which leads to a reduction of symptoms, optimization of the hemodynamics and improved prognosis. Misdiagnosis and delayed referral often lead to disease progression along with poor surgical outcome. In case of more distal, surgically non-accessible disease, treatment consists of balloon pulmonary angioplasty and pulmonary vasodilator drugs.

CD26 as a target against fibrous formation in chronic airway rejection lesions.

AIMS: Chronic lung allograft dysfunction (CLAD) after lung transplantation (Tx) is the clinical result of chronic airway rejection lesions (CARL), histomorphologically described as either obliterative remodeling of small airways or alveolar fibroelastosis, or as a combination of both. We here investigated the CD26-inhibitory effect on CD26-expressing CARL. MAIN METHODS: CARL were induced by BALB/c â†’ C57BL/6 mouse Tx under mild immunosuppression. CARL-related pro-fibrotic mediators were determined by RT-qPCR and western blotting (WB), EMT and ERK markers by WB. CD26 co-expression by immunofluorescence. CD26 was inhibited by Vildagliptin, gene depleted by CD26-/- mice. Primary lung fibroblasts were employed for ex vivo analyses. Samples from lung transplant patients with CLAD were analyzed by immunohistochemistry. KEY FINDINGS: CARL revealed a significantly higher expression of profibrotic proteins vs. normal lungs (p < 0.05). CD26 and EMT co-expressed in CARL with significantly higher Vimentin, Slug, Hif-1α, α-SMA expression vs. normal lungs (p < 0.05). Vildagliptin decreased the expression of α-SMA and N-cadherin in wild type (WT) lung fibroblasts (p < 0.05). Primary lung fibroblasts from WT and CD26-/- mice treated with TGF-ß1, IFN-γ, and FGF showed a reduction of EMT protein expression, proliferation, and reduced activation of ERK in CD26-/- mice vs. WT mice. CD26-positive cells were found in patient samples with CLAD in areas of loose fibrosis, but not in areas of dense fibrosis. SIGNIFICANCE: CD26 is expressed in CARL-developing lung transplants and CD26-inhibition downregulates fibrosis-forming mediators and fibroblast proliferation. CD26 thus qualifies as a target to attenuate the development of CARL mainly via modulation of ERK and the EMT pathway.

Chronic Airway Fibrosis in Orthotopic Mouse Lung Transplantation Models-An Experimental Reappraisal.

BACKGROUND: Several mouse lung transplantation (Tx) models have been proposed for the study of chronic airway fibrosis (CAF), the most prevalent complication seen in human lung transplant recipients, termed chronic lung allograft dysfunction. Alternatively, it has been called for to establish an experimental animal model for restrictive allograft syndrome, another phenotype of chronic lung allograft dysfunction. However, these mouse transplant models exhibit significant heterogeneity in consistency and reproducibility. We therefore aimed at reevaluating current available models. METHODS: Four different Tx combinations were used that manifest CAF: 2 minor antigen-mismatched Tx combinations (MINOR, donor: C57BL/10, recipient: C57BL/6J); or MINOR-N using recipient C57BL/6N, major histocompatibility antigen-mismatched immunosuppressed Tx (MAJOR, donor: BALB/c, recipient: C57BL/6J), and syngeneic Tx (donor and recipient: C57BL/6J) as control. The recipients were harvested and analyzed at week 8. Oxygenation, histology, reverse transcription polymerase chain reaction, and magnetic resonance imaging were performed to analyze outcome of those models. RESULTS: The most prominent manifestation of CAF, thickest subepithelial fibrotic changes, worst oxygenation, and the most severe acute rejection were detected in the MAJOR group compared with all other (P < 0.05). Gene expressions of TNF-α and TGF-ß1 were higher, and IL-10 was lower in the MAJOR group. Immunohistochemistry found pleuroparenchymal fibrotic change in both the MAJOR and MINOR-J groups. CONCLUSIONS: We propose the major mismatch model under mild immunosuppression as the most suitable model for studying posttransplant CAF, and both the major and minor mismatch models for the restrictive phenotype.