Computational Investigation of Vessel Injury Due to Catheter Tracking During Transcatheter Aortic Valve Replacement.

Catheter reaction forces during transcatheter valve replacement (TAVR) may result in injury to the vessel or plaque rupture, triggering distal embolization or thrombosis. In vitro test methods represent the arterial wall using synthetic proxies to determine catheter reaction forces during tracking, but whether they can account for reaction forces within the compliant aortic wall tissue in vivo is unknown. Moreover, the role of plaque inclusions is not well understood. Computational approaches have predicted the impact of TAVR positioning, migration, and leaflet distortion, but have not yet been applied to investigate aortic wall reaction forces and stresses during catheter tracking. In this study, we investigate the role that catheter design and aorta and plaque mechanical properties have on the risk of plaque rupture during TAVR catheter delivery. We report that, for trackability testing, a rigid test model provides a reasonable estimation of the peak reaction forces experienced during catheter tracking within compliant vessels. We investigated the risk of rupture of both the aortic tissue and calcified plaques. We report that there was no risk of diseased aortic tissue rupture based on an accepted aortic tissue stress threshold (4.2 MPa). However, we report that both the aortic and plaque tissue exceed a rupture stress threshold (300 kPa) with and without the presence of stiff and soft plaque inclusions. We also highlight the potential risks associated with shorter catheter tips during catheter tracking and demonstrate that increasing the contact surface will reduce peak contact pressures experienced in the tissue.

Advancements in left ventricular assist devices to prevent pump thrombosis and blood coagulopathy.

Mechanical circulatory support (MCS) devices, such as left ventricular assist devices (LVADs) are very useful in improving outcomes in patients with advanced-stage heart failure. Despite recent advances in LVAD development, pump thrombosis is one of the most severe adverse events caused by LVADs. The contact of blood with artificial materials of LVAD pumps and cannulas triggers the coagulation cascade. Heat spots, for example, produced by mechanical bearings are often subjected to thrombus build-up when low-flow situations impair washout and thus the necessary cooling does not happen. The formation of thrombus in an LVAD may compromise its function, causing a drop in flow and pumping power leading to failure of the LVAD, if left unattended. If a clot becomes dislodged and circulates in the bloodstream, it may disturb the flow or occlude the blood vessels in vital organs and cause internal damage that could be fatal, for example, ischemic stroke. That is why patients with LVADs are on anti-coagulant medication. However, the anti-coagulants can cause a set of issues for the patient-an example of gastrointestinal (GI) bleeding is given in illustration. On account of this, these devices are only used as a last resort in clinical practice. It is, therefore, necessary to develop devices with better mechanics of blood flow, performance and hemocompatibility. This paper discusses the development of LVADs through landmark clinical trials in detail and describes the evolution of device design to reduce the risk of pump thrombosis and achieve better hemocompatibility. Whilst driveline infection, right heart failure and arrhythmias have been recognised as LVAD-related complications, this paper focuses on complications related to pump thrombosis, especially blood coagulopathy in detail and potential strategies to mitigate this complication. Furthermore, it also discusses the LVAD implantation techniques and their anatomical challenges.

A European update on transcatheter aortic valve implantation (TAVI) in the COVID era.

Minimally invasive approaches for aortic valve replacement are now at the forefront of pathological aortic valve treatment. New trials show comparability of these devices to existing therapies, not only in high-risk surgical cohorts but also in low-risk and intermediate-risk cohorts. This review provides vital clinical and anatomical background to aortic valvular disease treatment guidelines, while also providing an update on transcatheter aortic valve implantation (TAVI) devices in Europe, their interventional trials and associated complications.

In silico modelling of aortic valve implants - predicting in vitro performance using finite element analysis.

The competing structural and hemodynamic considerations in valve design generally require a large amount of in vitro hydrodynamic and durability testing during development, often resulting in inefficient "trial-and-error" prototyping. While in silico modelling through finite element analysis (FEA) has been widely used to inform valve design by optimising structural performance, few studies have exploited the potential insight FEA could provide into critical hemodynamic performance characteristics of the valve. The objective of this study is to demonstrate the potential of FEA to predict the hydrodynamic performance of tri-leaflet aortic valve implants obtained during development through in vitro testing. Several variations of tri-leaflet aortic valves were designed and manufactured using a synthetic polymer and hydrodynamic testing carried out using a pulsatile flow rig according to ISO 5840, with bulk hydrodynamic parameters measured. In silico models were developed in tandem and suitable surrogate measures were investigated as predictors of the hydrodynamic parameters. Through regression analysis, the in silico parameters of leaflet coaptation area, geometric orifice area and opening pressure were found to be suitable indicators of experimental in vitro hydrodynamic parameters: regurgitant fraction, effective orifice area and transvalvular pressure drop performance, respectively.

Diuretic therapy in congestive heart failure.

In heart failure, fluid overload is a major pathological mechanism leading to vascular congestion, pulmonary congestion and elevated jugular venous pressures. Diuretics play a significant role in the management of patients with congestive heart failure. It is used to relieve the congestive symptoms of heart failure. However, the appropriate use of diuretics remains challenging due to various complications like electrolyte abnormalities, worsening renal function and diuretic resistance. This has prompted towards the search of safer and effective alternatives. This review evaluates the use of diuretics in congestive heart failure and discusses the complications of different types of diuretics, which is essential for successful management of congestion in patients with heart failure and hence to optimise the outcome for the patients.

Acute Stent-Induced Endothelial Denudation: Biomechanical Predictors of Vascular Injury.

Recent concern for local drug delivery and withdrawal of the first Food and Drug Administration-approved bioresorbable scaffold emphasizes the need to optimize the relationships between stent design and drug release with imposed arterial injury and observed pharmacodynamics. In this study, we examine the hypothesis that vascular injury is predictable from stent design and that the expanding force of stent deployment results in increased circumferential stress in the arterial tissue, which may explain acute injury poststent deployment. Using both numerical simulations and ex vivo experiments on three different stent designs (slotted tube, corrugated ring, and delta wing), arterial injury due to device deployment was examined. Furthermore, using numerical simulations, the consequence of changing stent strut radial thickness on arterial wall shear stress and arterial circumferential stress distributions was examined. Regions with predicted arterial circumferential stress exceeding a threshold of 49.5 kPa compared favorably with observed ex vivo endothelial denudation for the three considered stent designs. In addition, increasing strut thickness was predicted to result in more areas of denudation and larger areas exposed to low wall shear stress. We conclude that the acute arterial injury, observed immediately following stent expansion, is caused by high circumferential hoop stresses in the interstrut region, and denuded area profiles are dependent on unit cell geometric features. Such findings when coupled with where drugs move might explain the drug-device interactions.

Device-Based Solutions to Improve Cardiac Physiology and Hemodynamics in Heart Failure With Preserved Ejection Fraction.

Characterized by a rapidly increasing prevalence, elevated mortality and rehospitalization rates, and inadequacy of pharmaceutical therapies, heart failure with preserved ejection fraction (HFpEF) has motivated the widespread development of device-based solutions. HFpEF is a multifactorial disease of various etiologies and phenotypes, distinguished by diminished ventricular compliance, diastolic dysfunction, and symptoms of heart failure despite a normal ejection performance; these symptoms include pulmonary hypertension, limited cardiac reserve, autonomic imbalance, and exercise intolerance. Several types of atrial shunts, left ventricular expanders, stimulation-based therapies, and mechanical circulatory support devices are currently under development aiming to target one or more of these symptoms by addressing the associated mechanical or hemodynamic hallmarks. Although the majority of these solutions have shown promising results in clinical or preclinical studies, no device-based therapy has yet been approved for the treatment of patients with HFpEF. The purpose of this review is to discuss the rationale behind each of these devices and the findings from the initial testing phases, as well as the limitations and challenges associated with their clinical translation.

Transdermal Delivery of Kidney-Targeting Nanoparticles Using Dissolvable Microneedles.

INTRODUCTION: Chronic kidney disease (CKD) affects approximately 13% of the world's population and will lead to dialysis or kidney transplantation. Unfortunately, clinically available drugs for CKD show limited efficacy and toxic extrarenal side effects. Hence, there is a need to develop targeted delivery systems with enhanced kidney specificity that can also be combined with a patient-compliant administration route for such patients that need extended treatment. Towards this goal, kidney-targeted nanoparticles administered through transdermal microneedles (KNP/MN) is explored in this study. METHODS: A KNP/MN patch was developed by incorporating folate-conjugated micelle nanoparticles into polyvinyl alcohol MN patches. Rhodamine B (RhB) was encapsulated into KNP as a model drug and evaluated for biocompatibility and binding with human renal epithelial cells. For MN, skin penetration efficiency was assessed using a Parafilm model, and penetration was imaged via scanning electron microscopy. In vivo, KNP/MN patches were applied on the backs of C57BL/6 wild type mice and biodistribution, organ morphology, and kidney function assessed. RESULTS: KNP showed high biocompatibility and folate-dependent binding in vitro, validating KNP's targeting to folate receptors in vitro. Upon transdermal administration in vivo, KNP/MN patches dissolved within 30 min. At varying time points up to 48 h post-KNP/MN administration, higher accumulation of KNP was found in kidneys compared with MN that consisted of the non-targeting, control-NP. Histological evaluation demonstrated no signs of tissue damage, and kidney function markers, serum blood urea nitrogen and urine creatinine, were found to be within normal ranges, indicating preservation of kidney health. CONCLUSIONS: Our studies show potential of KNP/MN patches as a non-invasive, self-administrable platform to direct therapies to the kidneys.

Fracture in drug-eluting stents increases focal intimal hyperplasia in the atherosclerosed rabbit iliac artery.

OBJECTIVES: Drug-eluting stent (DES) strut fracture (SF) is associated with higher incidence of In-stent restenosis (ISR)-return of blockage in a diseased artery post stenting-than seen with bare metal stents (BMS). We hypothesize that concomitance of drug and SF leads to greater neointimal response. BACKGROUND: Controlled release of therapeutic agents, such as sirolimus and its analogs, or paclitaxel from has reduced tissue based DES failure modes compared to BMS. ISR is dramatically reduced and yet the implications of mechanical device failure is magnified. METHODS: Bilateral Xience Everolimus-eluting stents (EES) were implanted in 20 New Zealand White rabbits on normal (n = 7) or high fat (HF)/high cholesterol (HC) (n = 13) diets. Implanted stents were intact or mechanically fractured. Everolimus concentration was as packaged or pre-eluted. After 21 days, stented vessels were explanted, resin embedded, MicroCT scanned, and analyzed histomorphometrically. RESULTS: Fractured EES were associated with significant (P < 0.05) increases in arterial stenosis and neointimal formation and lower lumen-to-artery area ratios compared to intact EES. Hyperlipidemic animals receiving pre-eluted EES revealed no significant difference between intact and fracture groups. CONCLUSIONS: SF increases intimal hyperplasia, post EES implant, and worse with more advanced disease. Pre-eluted groups, reflective of BMS, did not show significant differences, suggesting a synergistic effect of everolimus and mechanical injury, potentially explaining the lack of SF reports for BMS. Here, we report that ISR has a higher incidence with SF in EES, the clinical implication is that patients with SF after DES implantation merit careful follow-up.

In Silico analysis of stent deployment- effect of stent design.

Coronary artery disease (CAD) remains the leading cause of death in Europe and worldwide. One of the most common pathologic processes involved in CAD is atherosclerosis. Coronary stents are expandable scaffolds that are used to widen the occluded arteries and enable the blood flow restoration. To achieve an adequate delivery and placement of coronary stents different parameters play a significant role. Due to the strain that the stents are exposed to and the forces they should withstand, the stent design is dominant. This study focuses on investigating the effect of the stent design in two finite element models using two stents with difference in the strut thickness. The in silico deployment is performed in a reconstructed patient specific arterial segment. The results are analyzed in terms of stress in the stent and the arterial wall and demonstrate how stent expansion is extensively affected by the scaffold's design.

Coronary Stent Fracture: Clinical Evidence Vs. the Testing Paradigm.

PURPOSE: The United States' Food and Drug Administration (FDA) recommends that device manufacturers demonstrate 10 years of equivalent life duration for endovascular stents. Yet since the early 2000s clinical evidence of stent strut fracture defies the recommendations for these FDA approved devices. Stent strut fracture has been correlated with a higher incidence of adverse clinical events, such as in-stent thrombosis and in-stent restenosis. METHODS: This paper reviews the current clinical evidence, computational modelling relating to fatigue lifetimes, experimental testing of coronary stents, and the related regulatory guidance and standards. RESULTS: The scale of stent fracture is evident from the clinical data reviewed. In terms of model setups, either physical or computational the loadings, in particular, dictate the durability response. CONCLUSIONS: The full scale of stent fracture is most likely under-reported and its assessment is dependent on detection time and detection resolution. Within the event of SF it is not necessarily consequential; further research is warranted to distinguish when the event negatively impacts the patient.

Strain-induced accelerated asymmetric spatial degradation of polymeric vascular scaffolds.

Polymer-based bioresorbable scaffolds (BRS) seek to eliminate long-term complications of metal stents. However, current BRS designs bear substantially higher incidence of clinical failures, especially thrombosis, compared with metal stents. Research strategies inherited from metal stents fail to consider polymer microstructures and dynamics--issues critical to BRS. Using Raman spectroscopy, we demonstrate microstructural heterogeneities within polymeric scaffolds arising from integrated strain during fabrication and implantation. Stress generated from crimping and inflation causes loss of structural integrity even before chemical degradation, and the induced differences in crystallinity and polymer alignment across scaffolds lead to faster degradation in scaffold cores than on the surface, which further enlarge localized deformation. We postulate that these structural irregularities and asymmetric material degradation present a response to strain and thereby clinical performance different from metal stents. Unlike metal stents which stay patent and intact until catastrophic fracture, BRS exhibit loss of structural integrity almost immediately upon crimping and expansion. Irregularities in microstructure amplify these effects and can have profound clinical implications. Therefore, polymer microstructure should be considered in earliest design stages of resorbable devices, and fabrication processes must be well-designed with microscopic perspective.

Stents: Biomechanics, Biomaterials, and Insights from Computational Modeling.

Coronary stents have revolutionized the treatment of coronary artery disease. Improvement in clinical outcomes requires detailed evaluation of the performance of stent biomechanics and the effectiveness as well as safety of biomaterials aiming at optimization of endovascular devices. Stents need to harmonize the hemodynamic environment and promote beneficial vessel healing processes with decreased thrombogenicity. Stent design variables and expansion properties are critical for vessel scaffolding. Drug-elution from stents, can help inhibit in-stent restenosis, but adds further complexity as drug release kinetics and coating formulations can dominate tissue responses. Biodegradable and bioabsorbable stents go one step further providing complete absorption over time governed by corrosion and erosion mechanisms. The advances in computing power and computational methods have enabled the application of numerical simulations and the in silico evaluation of the performance of stent devices made up of complex alloys and bioerodible materials in a range of dimensions and designs and with the capacity to retain and elute bioactive agents. This review presents the current knowledge on stent biomechanics, stent fatigue as well as drug release and mechanisms governing biodegradability focusing on the insights from computational modeling approaches.

In silico assessment of the effects of material on stent deployment.

Coronary stents are expandable scaffolds that are used to widen occluded diseased arteries and restore blood flow. Because of the strain they are exposed to and forces they must resist as well as the importance of surface interactions, material properties are dominant. Indeed, a common differentiating factors amongst commercially available stents is their material. Several performance requirements relate to stent materials including radial strength for adequate arterial support post-deployment. This study investigated the effect of the stent material in three finite element models using different stents made of: (i) Cobalt-Chromium (CoCr), (ii) Stainless Steel (SS316L), and (iii) Platinum Chromium (PtCr). Deployment was investigated in a patient specific arterial geometry, created based on a fusion of angiographic data and intravascular ultrasound images. In silico results show that: (i) the maximum von Mises stress occurs for the CoCr, however the curved areas of the stent links present higher stresses compared to the straight stent segments for all stents, (ii) more areas of high inner arterial stress exist in the case of the CoCr stent deployment, (iii) there is no significant difference in the percentage of arterial stress volume distribution among all models.

Vascular Response to Experimental Stent Malapposition and Under-Expansion.

Up to 80% of all endovascular stents have malapposed struts, and while some impose catastrophic events others are inconsequential. Thirteen stents were implanted in coronary arteries of seven healthy Yorkshire pigs, using specially-designed cuffed balloons inducing controlled stent malapposition and under-expansion. Optical coherence tomography (OCT) imaging confirmed that 25% of struts were malapposed (strut-wall distance

Structural Mechanics Predictions Relating to Clinical Coronary Stent Fracture in a 5 Year Period in FDA MAUDE Database.

Endovascular stents are the mainstay of interventional cardiovascular medicine. Technological advances have reduced biological and clinical complications but not mechanical failure. Stent strut fracture is increasingly recognized as of paramount clinical importance. Though consensus reigns that fractures can result from material fatigue, how fracture is induced and the mechanisms underlying its clinical sequelae remain ill-defined. In this study, strut fractures were identified in the prospectively maintained Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience Database (MAUDE), covering years 2006-2011, and differentiated based on specific coronary artery implantation site and device configuration. These data, and knowledge of the extent of dynamic arterial deformations obtained from patient CT images and published data, were used to define boundary conditions for 3D finite element models incorporating multimodal, multi-cycle deformation. The structural response for a range of stent designs and configurations was predicted by computational models and included estimation of maximum principal, minimum principal and equivalent plastic strains. Fatigue assessment was performed with Goodman diagrams and safe/unsafe regions defined for different stent designs. Von Mises stress and maximum principal strain increased with multimodal, fully reversed deformation. Spatial maps of unsafe locations corresponded to the identified locations of fracture in different coronary arteries in the clinical database. These findings, for the first time, provide insight into a potential link between patient adverse events and computational modeling of stent deformation. Understanding of the mechanical forces imposed under different implantation conditions may assist in rational design and optimal placement of these devices.

Finite element analysis of stent implantation in a three-dimensional reconstructed arterial segment.

Endovascular stent deployment is a mechanical procedure used to rehabilitate a diseased arterial segment by restoring blood flow in occluded regions. The success or failure of the stent implantation depends on the stent device and the deployment technique. The optimal stent deployment can be predicted by investigating the factors that influence this minimally invasive procedure. In this study, we propose a methodology which evaluates the alterations in the arterial environment caused by stent deployment. A finite element model of a reconstructed right coronary artery with a stenosis was created based on anatomical information provided by intravascular ultrasound and angiography. The model was used to consider placement and performance after intervention with a commercially available Leader Plus stent. The performance of the stent, within this patient-specific arterial segment is presented, as well as the induced arterial deformation and straightening. The arterial stress distribution is analyzed with respect to possible regions of arterial injury. Our approach can be used to optimize stent deployment and to provide cardiologists with a valuable tool to visually select the position and deploy stents in patient-specific reconstructed arterial segments, thereby enabling new methods for optimal cardiovascular stent positioning.

Sexual dimorphism of male face shape, partnership status and the temporal context of relationship sought modulate women's preferences for direct gaze.

Most previous studies of face preferences have investigated the physical cues that influence face preferences. Far fewer studies have investigated the effects of cues to the direction of others' social interest (i.e. gaze direction) on face preferences. Here we found that unpartnered women demonstrated stronger preferences for direct gaze (indicating social interest) from feminine male faces than from masculine male faces when judging men's attractiveness for long-term relationships, but not when judging men's attractiveness for short-term relationships. Moreover, unpartnered women's preferences for direct gaze from feminine men were stronger for long-term than short-term relationships, but there was no comparable effect for judgements of masculine men. No such effects were evident among women with romantic partners, potentially reflecting different motivations underlying partnered and unpartnered women's judgements of men's attractiveness. Collectively these findings (1) complement previous findings whereby women demonstrated stronger preferences for feminine men as long-term than short-term partners, (2) demonstrate context-sensitivity in the integration of physical and social cues in face preferences, and (3) suggest that gaze preferences may function, at least in part, to facilitate efficient allocation of mating effort.

View-contingent aftereffects suggest joint coding of face shape and view.

While it is well established that different neural populations code different face views, behavioural evidence that these neurons also code other aspects of face shape is equivocal. For example, previous studies have interpreted the partial transfer of face aftereffects across different viewpoints as evidence for either view-specific coding of face shape or that the locus of adaptation is in face-coding mechanisms that are relatively robust to changes in face view. Here we show that it is possible to simultaneously induce aftereffects in opposite directions for 3/4 and front views of upright faces with manipulated mouth position (experiment 1). For example, simultaneous adaptation to 3/4 views with raised mouth position and front views with lowered mouth position caused raised mouth position to appear more normal for 3/4 views of novel faces, but less normal for front views. View-contingent adaptation did not occur for inverted faces, however (experiment 2). Dissociable aftereffects for different views of upright faces, but not for different views of inverted faces, suggest that neurons that code face view can also code other aspects of face shape.

Integrating physical and social cues when forming face preferences: differences among low and high-anxiety individuals.

This study investigated individual differences in the integration of social (i.e., direction of social interest) and physical (i.e., apparent health) cues in a face preference test. While low-anxiety individuals demonstrated preferences for social engagement from healthy-looking faces, but not from unhealthy-looking faces, high-anxiety individuals preferred social engagement from both healthy and unhealthy individuals. Importantly, anxious individuals were not simply less discriminating in their face preferences generally: anxiety levels were positively related to the strength of overall preferences for positive social interest. Collectively, our findings show that perceptions of gaze and expression can be modulated by aspects of facial appearance and that systematic variation among individuals exists in the extent to which this modulation occurs. Furthermore, since previous studies have demonstrated hypersensitive amygdala responses among anxious individuals when viewing faces, our findings suggest that the amygdala may play an important role in determining how different facial cues are integrated in person perception.