A physics-informed deep learning framework for modeling of coronary in-stent restenosis.

Machine learning (ML) techniques have shown great potential in cardiovascular surgery, including real-time stenosis recognition, detection of stented coronary anomalies, and prediction of in-stent restenosis (ISR). However, estimating neointima evolution poses challenges for ML models due to limitations in manual measurements, variations in image quality, low data availability, and the difficulty of acquiring biological quantities. An effective in silico model is necessary to accurately capture the mechanisms leading to neointimal hyperplasia. Physics-informed neural networks (PINNs), a novel deep learning (DL) method, have emerged as a promising approach that integrates physical laws and measurements into modeling. PINNs have demonstrated success in solving partial differential equations (PDEs) and have been applied in various biological systems. This paper aims to develop a robust multiphysics surrogate model for ISR estimation using the physics-informed DL approach, incorporating biological constraints and drug elution effects. The model seeks to enhance prediction accuracy, provide insights into disease progression factors, and promote ISR diagnosis and treatment planning. A set of coupled advection-reaction-diffusion type PDEs is constructed to track the evolution of the influential factors associated with ISR, such as platelet-derived growth factor (PDGF), the transforming growth factor- ß (TGF- ß ), the extracellular matrix (ECM), the density of smooth muscle cells (SMC), and the drug concentration. The nature of PINNs allows for the integration of patient-specific data (procedure-related, clinical and genetic, etc.) into the model, improving prediction accuracy and assisting in the optimization of stent implantation parameters to mitigate risks. This research addresses the existing gap in predictive models for ISR using DL and holds the potential to enhance patient outcomes through predictive risk assessment.

In silico evaluation of additively manufactured 316L stainless steel stent in a patient-specific coronary artery.

Additive manufacturing (AM) is an emerging method for the fabrication of stents, which is cost-saving and capable of producing personalised stent designs. However, poor surface finish and dimension discrepancy in the manufactured stents can significantly affect not only their own mechanical behavior but also mechanical response of arteries. This study investigates the effects of surface irregularities and dimension discrepancy of a 316L stainless steel stent, manufactured using laser powder bed fusion (LPBF), on its biomechanical performance, in comparison with the original design and a commercial stent. In silico simulations of stent deployment in a patient-specific coronary artery, based on intravital optical coherency tomography imaging, are conducted to assess the stent deformation as well as arterial stress and damage. Severe plastic strain concentrations (with a maximum value of 1.93) occur in the LPBF stent after deployment due to surface irregularities, suggesting a high risk of stent fracture. The LPBF stent is harder to expand due to its thicker struts and closed-cell design (diameter of 4.14 mm at the peak inflating pressure during deployment, compared to 4.58 mm and 4.65 mm for the designed and MULTI-LINK RX ULTRA stents, respectively). Also, the LPBF stent induces a higher level of stress concentration (with a maximum value of 23.04 MPa) to the arterial layers, suggesting a higher risk of tissue damage and in-stent restenosis. This study demonstrates a clear need for further development of the AM process for manufacturing medical implants, especially the surface finish and dimension accuracy.

Intravenous iron supplementation in heart failure patients induces temporary endothelial dysfunction with release of endothelial microvesicles.

Background: Intravenous iron supplementation is an established therapy for patients with heart failure (HF) and concomitant iron deficiency reducing the risk of HF hospitalization. However, concerns persist regarding potential adverse vascular effects, since iron may induce oxidative stress, inflammation, and apoptosis of endothelial cells. To assess endothelial health following ferric carboxymaltose (FCM) administration, we analyzed the profile of circulating endothelial microvesicles (EMVs) and endothelial progenitor cells (EPCs) in a cohort of 23 HF patients using flow cytometry. Results: Compared to healthy subjects, baseline levels of CD31+/CD41- EMVs were higher and EMVs featured a more apoptotic phenotype in HF patients. Following FCM administration, EMV levels showed a rapid but transient increase and displayed an altered phenotype profile with dominant augmentation of EMVs expressing inducible markers CD62E and CD54, indicating endothelial inflammatory activation and injury. Levels of circulating vasoregenerative CD45lowCD34+KDR+ EPCs were lower in HF patients and FCM application resulted in an early decrease of EPCs followed by substantial mobilization into the circulation after one week. Levels of EMVs and EPCs returned to baseline values within two and four weeks, respectively. HF patients with additional chronic kidney disease showed an elevated EMV/EPC ratio and diminished EPC mobilization, suggesting impaired vascular repair capacity. Providing a mechanistic link, in vitro experiments with cultured endothelial cells revealed that FCM dose-dependently promotes endothelial apoptosis, increases expression of adhesion molecules and CXCL12, and triggers generation of EMVs. Conclusion: Intravenous iron supplementation with FCM in HF patients induces a biphasic response with initial increased release of CD62E+ and CD54+ enriched EMVs and subsequent mobilization of EPCs, indicating endothelial dysfunction upon FCM and suggesting consecutive engagement of a defense program aimed to reconstitute vascular health.

An unusual case of aortic metastasis from lung cancer.

In patients with cardiovascular events, such as myocardial infarction or aortic dissection without known risk factors for cardiovascular disease, neoplastic disease should be considered as a differential diagnosis. In this report, we present a case of a 51-year old man with previously undiagnosed non-small lung cancer leading to fatal cardiovascular complications due to hemovascular spread, diagnosed post-mortem. This case illustrates the value of autopsy in unexpected deaths.

In vivo Molecular Imaging of Glutamate Carboxypeptidase II Expression in Re-endothelialisation after Percutaneous Balloon Denudation in a Rat Model.

The short- and long-term success of intravascular stents depends on a proper re-endothelialisation after the intervention-induced endothelial denudation. The aim of this study was to evaluate the potential of in vivo molecular imaging of glutamate carboxypeptidase II (GCPII; identical with prostate-specific membrane antigen PSMA) expression as a marker of re-endothelialisation. Fifteen Sprague Dawley rats underwent unilateral balloon angioplasty of the common carotid artery (CCA). Positron emission tomography (PET) using the GCPII-targeting tracer [18F]DCFPyL was performed after 5-21 days (scan 60-120 min post injection). In two animals, the GCPII inhibitor PMPA (23 mg/kg BW) was added to the tracer solution. After PET, both CCAs were removed, dissected, and immunostained with the GCPII specific antibody YPSMA-1. Difference of GCPII expression between both CCAs was established by PCR analysis. [18F]DCFPyL uptake was significantly higher in the ipsilateral compared to the contralateral CCA with an ipsi-/contralateral ratio of 1.67 ± 0.39. PMPA blocked tracer binding. The selective expression of GCPII in endothelial cells of the treated CCA was confirmed by immunohistological staining. PCR analysis verified the site-specific GCPII expression. By using a molecular imaging marker of GCPII expression, we provide the first non-invasive in vivo delineation of re-endothelialisation after angioplasty.

Follow-up results after interventional treatment of infarct-related saphenous vein graft occlusion.

BACKGROUND: Acute occlusion of saphenous vein grafts resulting in acute coronary syndromes may be treated with interventional revascularization. Few data are available on intermediate and long-term results after revascularization of acute saphenous vein graft occlusion. METHODS: Fifty patients (67+/-10 years, 47 male) with troponin-positive acute coronary syndrome because of acute total or subtotal occlusion [thrombolysis in myocardial infarction (TIMI) flow 0=39, TIMI 1=8, TIMI 2=3] of one saphenous vein graft (12.0+/-5.3 years after surgery, 3.6+/-0.9 grafts) were treated with percutaneous coronary intervention (39 patients using bare-metal stents, 11 patients using drug-eluting stents). Clinical follow-up was obtained in all patients. Angiographic 6-month follow-up was performed in 35 patients (70%). RESULTS: Acute revascularization of the infarct-related saphenous vein graft (lesion length 17.6+/-10.3 mm, reference diameter 3.1+/-0.8 mm) was possible in 94% of patients. After a mean follow-up of 32.5+/-17.4 months, 13 patients (26%) died, 13 patients (26%) had recurrent myocardial infarction, and 20 patients (40%) had recurrent coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting). Angiographic follow-up showed reocclusion of the vein graft in three cases (9%). Twenty-one percent of lesions were found to be restenotic. CONCLUSION: Acute revascularization of an infarct-related saphenous vein graft is possible in the majority of cases. Angiographic follow-up data show a high patency rate at 6-month follow-up. Still, the clinical prognosis of patients with revascularized infarct-related saphenous vein graft is quite poor.

Stress/rest myocardial perfusion scintigraphy in patients without significant coronary artery disease.

AIM: To define the prognostic impact of stress myocardial perfusion scintigraphy (MPS) in patients with angiographic exclusion of significant coronary artery disease. METHODS: Angiographic and MPS databases were matched to define patients without significant coronary artery disease by quantitative angiography (diameter stenosis <50%) who underwent stress MPS and coronary angiography within a time period of 3 months. A total of 118 patients were identified and followed for a mean of 6.3 +/- 1.2 years for death, a composite of death, myocardial infarction, bypass surgery, or percutaneous coronary intervention [MAE]) as well as occurrence of symptoms (angina or dyspnoe class CCS II to IV). Stress and rest MPS (using (99m)Tc-MIBI or tetrofosmin) were analyzed by quantitative perfusion SPECT (QPS) for summed stress and rest scores (SSS/SRS). RESULTS: There were 16 deaths, 29 MAE, and 76 patients with MAE or significant symptoms during follow-up. Significant differences in SSS were found between patients who died (9.5 +/- 6.9 vs. 5.4 +/- 5.6, P = 0.012), had MAE (8.7 +/- 7.2 vs. 5.2 +/- 5.0, P = 0.010), or had MAE or significant clinical symptoms (7.2 +/- 7.1 vs. 4.6 +/- 6.2, P = 0.042) compared to those without the respective event. Logistic regression analysis demonstrated SSS to be a predictor of death (OR = 1.074 [95% CI: 1.004-1.149], P = 0.026) and MAE (OR = 1.087 [95% CI: 1.004-1.181], P = 0.027). CONCLUSIONS: In patients without significant angiographic coronary artery disease, the result of stress MPS is a predictor of long-term prognosis. Quantitative analysis of MPS allows definition of patients with a higher likelihood to develop clinical events or symptoms.

Blockade of angio-associated migratory cell protein inhibits smooth muscle cell migration and neointima formation in accelerated atherosclerosis.

OBJECTIVES: The aim of this study was to elucidate the role of angio-associated migratory cell protein (AAMP) for the migration of vascular smooth muscle cells (SMCs) and for the development of neointimal hyperplasia after vascular injury. BACKGROUND: Although AAMP has been shown to participate in angiogenesis and cancerogenesis and is predominantly expressed in cells with a migratory phenotype, involvement of AAMP during neointima (NI) formation after arterial injury has not been analyzed previously. METHODS: The AAMP content in SMCs was examined using 2-photon laser-scanning microscopy and subcellular fractioning. Migratory potential of SMCs transiently transfected with AAMP expression vectors, transfected with small interfering ribonucleic acid (siRNA), or treated with antirecombinant angio-associated migratory cell protein-antibody (anti-rAAMP-ab) was examined using transwell migration chamber assays. Expression of AAMP was determined in the atherogenic apolipoprotein E knockout (apoE(-/-)) mouse model and in the porcine coronary restenosis model by immunohistochemistry and by Western blot. ApoE(-/-) mice were treated intraperitoneally with anti-rAAMP-ab, and wire-injured carotid arteries were examined. RESULTS: Angio-associated migratory cell protein is localized in the membrane of SMCs, and its expression is enhanced in NI-derived SMCs. The AAMP overexpression increases, while both treatment with anti-rAAMP-ab and transfection with siRNA decreases SMC migration. Knockdown of AAMP decreases RhoA activity in the membrane fraction of SMCs. The AAMP expression by SMCs is enhanced in both animal models. Anti-rAAMP-ab reduces neointimal SMC density at 1 week and NI formation at 4 weeks in apoE(-/-) mice without affecting proliferation of SMCs. CONCLUSIONS: These data reveal an important functional role of AAMP in the migration of SMCs, identifying AAMP as a potential target to limit lesion formation after injury.

Downregulation of N-cadherin in the neointima stimulates migration of smooth muscle cells by RhoA deactivation.

OBJECTIVE: The aim of the study was to analyze whether cadherin- and Rho-family GTPases-mediated dynamic rearrangement of cell-cell adhesion play an important role during human arterial smooth muscle cell (haSMC) migration. METHODS: Expression patterns of N-cadherin and beta-catenin were analyzed in a domestic pig restenosis model after 14, 28, and 90 days as well as in quiescent and migratory haSMCs in vitro. N-cadherin expression was upregulated by transient sense; downregulation was induced by antisense transfection. For functional inhibition, antibody GC-4 was used. Cell migration was quantified using Boyden chamber assays. Regulation of RhoA GTPase was tested by assessment of RhoA activity. RESULTS: In vivo analysis of N-cadherin expression in a porcine restenosis model revealed downregulation in the neointima after 14 days. After 28 days, N-cadherin expression was slightly restored, while after 90 days, no difference between medial and neointimal expression was detectable. beta-Catenin levels remained unchanged during the whole period. According to the in vivo situation, N-cadherin was significantly downregulated in migratory haSMCs compared to quiescent cells in vitro. After N-cadherin overexpression, haSMC migration was reduced by 87% (P<0.001). By contrast, inhibition of N-cadherin in quiescent haSMCs by GC-4 increased the migratory potential by 87% (P<0.01). In haSMCs overexpressing N-cadherin, a significant upregulation of RhoA activity was demonstrated, while RhoA activity was blocked by GC-4. CONCLUSIONS: These results indicate that the regulation of haSMC attachment by N-cadherins is essential for haSMC migration. Modification of N-cadherin expression and activity induces RhoA signaling with relevance for the reorganization of the actin cytoskeleton.