Electrochemical polishing, characterisation and in vitro evaluation of additively manufactured CoCr stents with personalised designs.

Additive manufacturing (AM) technology has paved the way for manufacturing personalised stents. However, there is a notable gap in comprehensive microstructure analyses and in vitro evaluations of the AM CoCr stents using advanced methodologies. To address this gap, this study focuses on investigating the microstructure and in vitro performance of personalised CoCr stents manufactured through micro-laser powder bed fusion (µ-LPBF). The evaluation process begins with the measurements of dimensions and surface roughness, followed by in-depth microstructural analyses. To improve surface roughness and reduce excessive strut size, the µ-LPBF stents undergo electrochemical polishing. Importantly, in vitro stent deployments are carried out in artificial arteries manufactured based on actual patients' data. Compared to the commercial MULTI-LINK VISION CoCr stent, the µ-LPBF personalised stents have rough surface finish (average roughness: 1.55 µm for µ-LPBF vs. 1.09 µm for commercial) and compromised grain microstructures (elongated for µ-LPBF vs. equiaxed for commercial). However, the personalised stents demonstrate better performances in in vitro tests. Notably, compared to the commercial stent in the two studied cases, they deliver larger lumen gains (up to 11.24 %) and reduced recoils (up to 4 times). This study validates the merit of the lesion-specific designs and the feasibility of using AM technology for stent fabrication.

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.

Computational modeling of in-stent restenosis: Pharmacokinetic and pharmacodynamic evaluation.

Persistence of the pathology of in-stent restenosis even with the advent of drug-eluting stents warrants the development of highly resolved in silico models. These computational models assist in gaining insights into the transient biochemical and cellular mechanisms involved and thereby optimize the stent implantation parameters. Within this work, an already established fully-coupled Lagrangian finite element framework for modeling the restenotic growth is enhanced with the incorporation of endothelium-mediated effects and pharmacological influences of rapamycin-based drugs embedded in the polymeric layers of the current generation drug-eluting stents. The continuum mechanical description of growth is further justified in the context of thermodynamic consistency. Qualitative inferences are drawn from the model developed herein regarding the efficacy of the level of drug embedment within the struts as well as the release profiles adopted. The framework is then intended to serve as a tool for clinicians to tune the interventional procedures patient-specifically.

Efficacy and Safety of Low-Dose Protamine in Reducing Bleeding Complications during TAVI: A Propensity-Matched Comparison.

OBJECTIVES: We aimed to evaluate the efficacy and safety of low-dose protamine in reducing access site-related complications during Transcatheter Aortic Valve Implantation (TAVI) as compared to full-dose protamine. BACKGROUND: Access site-related complications represent an independent predictor of poor outcomes of TAVI. Data regarding heparin reversal with protamine and the dosage needed to prevent bleeding complications are scarce among patients undergoing TAVI. METHODS: A total of 897 patients were retrospectively included in the study. Patients who underwent percutaneous coronary intervention within 4 weeks before or concomitantly with TAVI (n = 191) were given 0.5 mg protamine for each 100 units of unfractionated heparin. All other patients (n = 706) were considered as a control group and 1 mg protamine for each 100 units of heparin was administered. RESULTS: The combined intra-hospital endpoint of death, life-threatening major bleeding, and major vascular complications were significantly more frequent in patients receiving low-dose protamine [29 (15.2%) vs. 50 (7.1%), p < 0.001]. After propensity matching (n = 130 for each group) for relevant clinical characteristics including anti-platelet therapy [19 (14.6%) vs. 6 (4.6%), p = 0.006], low-dose protamine predicted the combined endpoint (OR 3.54, 95%-CI 1.36-9.17, p = 0.009), and even in multivariable analysis, low-dose protamine continued to be a predictor of the combined endpoint in the matched model (OR 3.07, 95%-CI 1.17-8.08, p = 0.023) alongside baseline hemoglobin. CONCLUSIONS: In this propensity-matched retrospective analysis, a low-dose protamine regime is associated with a higher rate of major adverse events compared to a full-dose protamine regime following transfemoral TAVI.

In-vivo assessment of vascular injury for the prediction of in-stent restenosis.

BACKGROUND: Despite optimizations of coronary stenting technology, a residual risk of in-stent restenosis (ISR) remains. Vessel wall injury has important impact on the development of ISR. While injury can be assessed in histology, there is no injury score available to be used in clinical practice. METHODS: Seven rats underwent abdominal aorta stent implantation. At 4 weeks after implantation, animals were euthanized, and strut indentation, defined as the impression of the strut into the vessel wall, as well as neointimal growth were assessed. Established histological injury scores were assessed to confirm associations between indentation and vessel wall injury. In addition, stent strut indentation was assessed by optical coherence tomography (OCT) in an exemplary clinical case. RESULTS: Stent strut indentation was associated with vessel wall injury in histology. Furthermore, indentation was positively correlated with neointimal thickness, both in the per-strut analysis (r = 0.5579) and in the per-section analysis (r = 0.8620; both p ≤ 0.001). In a clinical case, indentation quantification in OCT was feasible, enabling assessment of injury in vivo. CONCLUSION: Assessing stent strut indentation enables periprocedural assessment of stent-induced damage in vivo and therefore allows for optimization of stent implantation. The assessment of stent strut indentation might become a valuable tool in clinical practice.

Vitamin C Regulates the Profibrotic Activity of Fibroblasts in In Vitro Replica Settings of Myocardial Infarction.

Extracellular collagen remodeling is one of the central mechanisms responsible for the structural and compositional coherence of myocardium in patients undergoing myocardial infarction (MI). Activated primary cardiac fibroblasts following myocardial infarction are extensively investigated to establish anti-fibrotic therapies to improve left ventricular remodeling. To systematically assess vitamin C functions as a potential modulator involved in collagen fibrillogenesis in an in vitro model mimicking heart tissue healing after MI. Mouse primary cardiac fibroblasts were isolated from wild-type C57BL/6 mice and cultured under normal and profibrotic (hypoxic + transforming growth factor beta 1) conditions on freshly prepared coatings mimicking extracellular matrix (ECM) remodeling during healing after an MI. At 10 µg/mL, vitamin C reprogramed the respiratory mitochondrial metabolism, which is effectively associated with a more increased accumulation of intracellular reactive oxygen species (iROS) than the number of those generated by mitochondrial reactive oxygen species (mROS). The mRNA/protein expression of subtypes I, III collagen, and fibroblasts differentiations markers were upregulated over time, particularly in the presence of vitamin C. The collagen substrate potentiated the modulator role of vitamin C in reinforcing the structure of types I and III collagen synthesis by reducing collagen V expression in a timely manner, which is important in the initiation of fibrillogenesis. Altogether, our study evidenced the synergistic function of vitamin C at an optimum dose on maintaining the equilibrium functionality of radical scavenger and gene transcription, which are important in the initial phases after healing after an MI, while modulating the synthesis of de novo collagen fibrils, which is important in the final stage of tissue healing.

Transcatheter mitral valve repair is feasible and effective in oldest-old patients: results from real-world cohort.

OBJECTIVE: To evaluate the safety and efficacy of transcatheter mitral valve repair (TMVR) using MitraClip® devices in oldest-old patients compared to younger patients. METHODS: The study retrospectively included 340 consecutive patients who underwent TMVR. Patients were classified according to age into the oldest-old (age ≥ 85 years) patient group or the younger (age < 85 years) patient group. Immediate results of the procedure, intrahospital outcomes and one-year outcomes were compared. RESULTS: Oldest-old patients represented 15.9% (n = 54) of all patients. Procedure success was comparable for the oldest-old patient group and the younger patient group (92.6% vs. 95.8%, P = 0.30), and there was no difference in intrahospital mortality (9.2% vs. 4.2%, P = 0.12). At a one-year follow-up (interquartile range: 6-16 months), there was no significant difference in rehospitalization due to decompensated heart failure (25.5% vs. 34.3%, P = 0.24) or all-cause mortality (29.8% vs. 22.2%, P = 0.26) between the oldest-old patient group and the younger patient group. In patients with available echocardiographic follow-up, severity of residual mitral regurgitation was also comparable between the oldest-old patient group and the younger patient group. CONCLUSIONS: TMVR seems to be feasible and effective in oldest-old patients and should be considered for oldest-old patients presenting with symptomatic severe mitral regurgitation and high surgical risk.

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.

Outcome of transcatheter edge-to-edge mitral valve repair in patients with diabetes mellitus: Results from a real-world cohort.

BACKGROUND: There are only limited data on patients with diabetes undergoing transcatheter edge-to-edge repair (TEER) in real-world settings. Previous data indicated patients with diabetes to have a worse prognosis. This study sought to evaluate safety and efficacy of TEER in patients with diabetes in a real-world cohort. METHODS: In this monocentric study 340 consecutive patients with severe primary and secondary mitral regurgitation (MR) undergoing TEER were included. Immediate results of the procedure, intrahospital and one-year outcome were compared between patients with and without diabetes. RESULTS: Diabetes was present in 109 patients (32%). Patients with diabetes were younger (77 y (71, 81) vs. 79 y (74, 83); p = 0.003), had more often ischemic cardiomyopathy (68% vs. 48%; p<0.001), previous coronary-artery bypass graft (35% vs. 20%; p = 0.002) and arterial hypertension (89% vs. 75%; p<0.001) compared to those without diabetes. Baseline NYHA class, type of MR (primary vs. secondary), left ventricular dimensions and function (ejection fraction: 37% (28, 50) vs. 40% (29, 55); p = 0.10) as well as severity of MR were not different between both groups. Success of the procedure (95% vs. 95%; p = 0.84), intrahospital mortality (5.5% vs. 4.8%; p = 0.98) and one-year follow-up regarding all-cause mortality (24.2% vs. 23.0%; p = 0.72), hospitalization for heart failure (37.4% vs. 31.0%, p = 0.23), NYHA class (p = 0.14) or MR severity (p = 0.59) did not differ between both groups. CONCLUSION: Our real-world data suggest that TEER seems to be similarly safe and effective in patients with severe MR and diabetes compared to those without diabetes.

A multiphysics modeling approach for in-stent restenosis: Theoretical aspects and finite element implementation.

Development of in silico models that capture progression of diseases in soft biological tissues are intrinsic in the validation of the hypothesized cellular and molecular mechanisms involved in the respective pathologies. In addition, they also aid in patient-specific adaptation of interventional procedures. In this regard, a fully-coupled high-fidelity Lagrangian finite element framework is proposed within this work which replicates the pathology of in-stent restenosis observed post stent implantation in a coronary artery. Advection-reaction-diffusion equations are set up to track the concentrations of the platelet-derived growth factor, the transforming growth factor-ß, the extracellular matrix, and the density of the smooth muscle cells. A continuum mechanical description of volumetric growth involved in the restenotic process, coupled to the evolution of the previously defined vessel wall constituents, is presented. Further, the finite element implementation of the model is discussed, and the behavior of the computational model is investigated via suitable numerical examples. Qualitative validation of the computational model is presented by emulating a stented artery. Patient-specific data are intended to be integrated into the model to predict the risk of in-stent restenosis, and thereby assist in the tuning of stent implantation parameters to mitigate the risk.

Dose-dependent impact of statin therapy intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention for the treatment of acute versus chronic coronary syndrome.

BACKGROUND: By low-density lipoprotein (LDL) reduction, statins play an important role in cardiovascular risk modification. Incompletely understood pleiotropic statin effects include vasoprotection that might originate from mobilisation and differentiation of vascular progenitor cells. Data on the potentially differential impact of statin treatment intensity on circulating progenitor cells in patients undergoing percutaneous coronary intervention (PCI) are scarce. This study examines the potential association of different permanent statin treatment regimens on circulating progenitor cells in patients with coronary syndrome. METHODS AND RESULTS: In a monocentric prospective all-comers study, 105 consecutive cases scheduled for coronary angiography due to either (A) non-invasive proof of ischemia and chronic coronary syndrome (CCS) or (B) troponin-positive acute coronary syndrome (ACS) were included. According to the 2018 American College of Cardiology Guidelines on Blood Cholesterol, patients were clustered depending on their respective permanent statin treatment regimen in either a high- to moderate-intensity statin treatment (HIST) or a low-intensity statin treatment (LIST) group. Baseline characteristics including LDL levels were comparable. From blood drawn at the time of PCI, peripheral blood mononuclear cells were isolated, cultivated and counted and, by density gradient centrifugation, levels of circulating progenitor cells were determined using fluorescence-activated cell sorting (FACS) analysis. In ACS patients both absolute and relative numbers of circulating early-outgrowth endothelial progenitor cells (EPCs) concurrently were significantly lower in the HIST group as compared to the LIST group. This effect was more pronounced in ACS patients than in CCS patients. Both in ACS and CCS patients, HIST caused a significant reduction of the number of circulating SMPCs. CONCLUSIONS: In patients undergoing PCI, a dose intensity-dependent and LDL level-independent pro-differentiating vasoprotective pleiotropic capacity of statins for EPC and SMPC is demonstrated.

Variants of arterial supply to the inferior (diaphragmatic) surface of the ventricles of the heart and the influence on age at death.

Coronary artery systems of the inferior wall of the ventricles vary considerably. Schlesinger's concept distinguishes dominance of the right or left coronary artery (LCA) or balanced type. LCA dominance has been reported to be associated with increased mortality. Early angiography studies have shown that the anterior interventricular artery (AIVA), a branch of the LCA, often continues on the inferior surface of the heart and may replace the inferior interventricular artery. Others considered an AIVA on the inferior surface of the heart a rare variant. A long AIVA is a strong predictor of death in acute anterior wall myocardial infarction. We determined coronary artery variance at the inferior surface of the ventricles in 134 dissected human hearts and analyzed a possible association between coronary artery variance and age at death. The AIVA extended to the inferior side in 64.9% of the hearts, but rarely reached the basal half of the inferior interventricular groove. Most frequently (53%), it extended into the apical two-fifths of the length of the inferior ventricular walls. An AIVA extending to the apical 40% of the length of the inferior ventricular walls may therefore be considered a common variant. In 20.1% of the hearts, a right inferior diagonal artery was also found. Statistical analysis neither revealed an association between mean AIVA length at the inferior ventricular surface and type of coronary artery dominance nor an association between AIVA length at the inferior ventricular surface or coronary artery dominance type and age at death.

Prediction of procedural success of transcatheter mitral valve repair with normal and extended clip arms.

TMVR using different clip sizes is a treatment option for selected patients with mitral regurgitation (MR). This study sought to identify predictors of successful transcatheter mitral valve repair (TMVR) by 3-dimensional (3D) echocardiography and to compare different effects of the larger XTR and the smaller NT/NTR devices. 3D transesophageal echocardiography was performed on 54 patients with secondary MR undergoing TMVR with one clip (55.6% NT/NTR, 44.4% XTR). All NT/NTR and 96% of XTR patients had MR reduction ≤ 2+. Despite more severe baseline MR (3D vena contracta area (VCA): 0.67 ± 0.34 cm2 vs. 0.43 ± 0.19 cm2, p = 0.004) and greater mitral valve area (MVA) (6.8 ± 2.1 cm2 vs. 5.1 ± 1.6 cm2, p = 0.001) in the XTR group, MR severity after TMVR was not different between XTR and NT/NTR patients (3D VCA: 0.19 ± 0.14 vs. 0.17 ± 0.10, p = 0.51). Baseline 3D VCA > 0.45 cm2 in NT/NTR (AUC = 0.802, 95% CI 0.602 to 1.000) and 3D VCA > 0.54 cm2 in XTR devices (AUC = 0.868, 95% CI 0.719 to 1.000) were associated with ineffective MR reduction defined as residual VCA ≤ 0.2 cm2. Baseline MVA ≤ 4.2 cm2 in NT/NTR (AUC = 0.920, 95% CI 0.809 to 1.000) and MVA ≤ 6.0 cm2 in XTR devices (AUC = 0.865, 95% CI 0.664 to 1.000) were associated with postprocedural transmitral pressure gradient (TMPG) ≥ 5 mmHg. TMVR using the XTR device resulted in an equally effective reduction of MR despite of a greater baseline MR. Distinct cut-off values of baseline 3D VCA and MVA for prediction of successful MR reduction and postprocedural increase of TMPG were identified for the different devices.

Engagement of the CXCL12-CXCR4 Axis in the Interaction of Endothelial Progenitor Cell and Smooth Muscle Cell to Promote Phenotype Control and Guard Vascular Homeostasis.

Endothelial progenitor cells (EPCs) are involved in vascular repair and modulate properties of smooth muscle cells (SMCs) relevant for their contribution to neointima formation following injury. Considering the relevant role of the CXCL12-CXCR4 axis in vascular homeostasis and the potential of EPCs and SMCs to release CXCL12 and express CXCR4, we analyzed the engagement of the CXCL12-CXCR4 axis in various modes of EPC-SMC interaction relevant for injury- and lipid-induced atherosclerosis. We now demonstrate that the expression and release of CXCL12 is synergistically increased in a CXCR4-dependent mechanism following EPC-SMC interaction during co-cultivation or in response to recombinant CXCL12, thus establishing an amplifying feedback loop Additionally, mechanical injury of SMCs induces increased release of CXCL12, resulting in enhanced CXCR4-dependent recruitment of EPCs to SMCs. The CXCL12-CXCR4 axis is crucially engaged in the EPC-triggered augmentation of SMC migration and the attenuation of SMC apoptosis but not in the EPC-mediated increase in SMC proliferation. Compared to EPCs alone, the alliance of EPC-SMC is superior in promoting the CXCR4-dependent proliferation and migration of endothelial cells. When direct cell-cell contact is established, EPCs protect the contractile phenotype of SMCs via CXCL12-CXCR4 and reverse cholesterol-induced transdifferentiation toward a synthetic, macrophage-like phenotype. In conclusion we show that the interaction of EPCs and SMCs unleashes a CXCL12-CXCR4-based autoregulatory feedback loop promoting regenerative processes and mediating SMC phenotype control to potentially guard vascular homeostasis.

Endothelial Progenitor Cells Modulate the Phenotype of Smooth Muscle Cells and Increase Their Neointimal Accumulation Following Vascular Injury.

BACKGROUND: Smooth muscle cells (SMCs) are the main driver of neointima formation and restenosis following vascular injury. In animal models, endothelial progenitor cells (EPCs) accelerate endothelial regeneration and reduce neointima formation after arterial injury; however, EPC-capture stents do not reduce target vessel failure compared with conventional stents. Here we examined the influence of EPCs on features of SMCs pivotal for their impact on injury-induced neointima formation including proliferation, migration, and phenotype switch. METHODS AND RESULTS: EPCs, their conditioned medium, and EPC-derived microparticles induced proliferation of SMCs while limiting their apoptosis. In transwell membrane experiments and scratch assays, EPCs stimulated migration of SMCs and accelerated their recovery from scratch-induced injury. Treatment of SMCs with an EPC-derived conditioned medium or microparticles triggered transformation of SMCs toward a synthetic phenotype. However, co-cultivation of EPCs and SMCs enabling direct cell-cell contacts preserved their original phenotype and protected from the transformative effect of SMC cholesterol loading. Adhesion of EPCs to SMCs was stimulated by SMC injury and reduced by blocking CXCR2 and CCR5. Interaction of EPCs with SMCs modulated their secretory products and synergistically increased the release of selected chemokines. Following carotid wire injury in athymic mice, injection of EPCs resulted not only in reduced neointima formation but also in altered cellular composition of the neointima with augmented accumulation of SMCs. CONCLUSION: EPCs stimulate proliferation and migration of SMCs and increase their neointimal accumulation following vascular injury. Furthermore, EPCs context-dependently modify the SMC phenotype with protection from the transformative effect of cholesterol when a direct cell-cell contact is established.

General Anesthesia Leads to Underestimation of Regurgitation Severity in Patients With Secondary Mitral Regurgitation Undergoing Transcatheter Mitral Valve Repair.

OBJECTIVES: To evaluate the effect of general anesthesia (GA) on severity of mitral regurgitation (MR) in patients undergoing transcatheter mitral valve repair (TMVR). DESIGN: Retrospective cohort study. SETTING: Tertiary care university hospital. PARTICIPANTS: Fifty consecutive patients with symptomatic severe MR and extremely high surgical risk. INTERVENTION: TMVR under GA. MEASUREMENTS AND RESULTS: Transesophageal echocardiography was performed during the preprocedural workup under conscious sedation and during TMVR under GA. After the parameters of MR were assessed, color-flow jet area (CJA), vena contracta (VC), effective regurgitant orifice area (EROA), regurgitant volume (RVOL), three-dimensional (3D) vena contracta area (VCA), and severity of MR were compared between the two examinations. In patients with primary MR (n = 11), there were no significant differences in CJA, VC, EROA, RVOL, or 3D-VCA between pre- and intraprocedural transesophageal echocardiography. In patients with secondary MR (n = 39), GA led to significant decreases of CJA (10 ± 7 v 7 ± 3 cm², p < 0.001), VC (5.5 ± 1.6 v 4.7 ± 1.5 mm, p = 0.002), EROA (30 ± 11 v 24 ± 10 mm², p < 0.001), and RVOL (47 ± 17 v 34 ± 13 mL/beat, p < 0.001). Consequently, GA led to a downgrade of regurgitation severity classification in 44% of patients when assessed by two-dimensional analysis. When evaluated by 3D analysis, GA also led to a significant but less extensive decrease of MR (3D-VCA: 66 ± 27 v 60 ± 29 mm², p = 0.002), and subsequent downgrade of MR classification in 20% of patients. CONCLUSIONS: GA underestimates regurgitation severity in patients with secondary, but not primary MR, undergoing TMVR. This effect must be considered when evaluating the immediate result of the procedure.

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.

Pioneering personalised design of femoropopliteal nitinol stents.

BACKGROUND/MOTIVATION: Percutaneous femoropopliteal artery intervention moves towards personalised therapy, which requires design of unique lesion-specific stents. However, to date, not much progress has been made in the development of personalised stents. OBJECTIVE: This paper aims to design personalised nitinol stents for femoropopliteal arteries based on medical imaging of patients and advanced computational mechanics, which is the first attempt to the authors' best knowledge. METHODS: The design process is based on three objectives: (i) achieving the healthy lumen area; (ii) reducing the stress in the media layer; (iii) improving the lumen shape after stenting. The design parameters include the strut width and thickness, the crown length, the nominal radius and the number of strut units per crown. Using representative unit-cell models, the effects of the five geometric parameters on the stent performance are investigated thoroughly with numerical simulations. Then, design protocols, especially for the circumferentially varying strut size and the oval stent shape, are developed and fully evaluated for an asymmetric stenosis. RESULTS: Using the design protocols, full personalised stents are designed for arteries with diffuse and focal plaques, based on medical imaging of patients. The personalised stent designs provide a double lumen gain, a reduced stress in the media layer and an improved lumen shape compared to a commercial stent. CONCLUSIONS: The suggested protocols prove their high effectiveness in design of personalised stents, and the suggested approach can be applied to development of personalised therapies involving the use of stent technology including percutaneous coronary artery intervention, transcatheter aortic valve implantation, endovascular aneurysm repair and ureteric stenting.

Apolipoprotein E4 Is Associated with Right Ventricular Dysfunction in Dilated Cardiomyopathy-An Animal and In-Human Comparative Study.

ApoE abnormality represents a well-known risk factor for cardiovascular diseases. Beyond its role in lipid metabolism, novel studies demonstrate a complex involvement of apoE in membrane homeostasis and signaling as well as in nuclear transcription. Due to the large spread of apoE isoforms in the human population, there is a need to understand the apoE's role in pathological processes. Our study aims to dissect the involvement of apoE in heart failure. We showed that apoE-deficient rats present multiple organ damages (kidney, liver, lung and spleen) besides the known predisposition for obesity and affected lipid metabolism (two-fold increase in tissular damages in liver and one-fold increase in kidney, lung and spleen). Heart tissue also showed significant morphological changes in apoE-/- rats, mostly after a high-fat diet. Interestingly, the right ventricle of apoE-/- rats fed a high-fat diet showed more damage and affected collagen content (~60% less total collagen content and double increase in collagen1/collagen3 ratio) compared with the left ventricle (no significant differences in total collagen content or collagen1/collagen3 ratio). In patients, we were able to find a correlation between the presence of ε4 allele and cardiomyopathy (χ2 = 10.244; p = 0.001), but also with right ventricle dysfunction with decreased TAPSE (15.3 ± 2.63 mm in ε4-allele-presenting patients vs. 19.8 ± 3.58 mm if the ε4 allele is absent, p < 0.0001*) and increased in systolic pulmonary artery pressure (50.44 ± 16.47 mmHg in ε4-allele-presenting patients vs. 40.68 ± 15.94 mmHg if the ε4 allele is absent, p = 0.0019). Our results confirm that the presence of the ε4 allele is a lipid-metabolism-independent risk factor for heart failure. Moreover, we show for the first time that the presence of the ε4 allele is associated with right ventricle dysfunction, implying different regulatory mechanisms of fibroblasts and the extracellular matrix in both ventricles. This is essential to be considered and thoroughly investigated before the design of therapeutical strategies for patients with heart failure.