Predicting Lipid-Rich Plaque Progression in Coronary Arteries Using Multimodal Imaging and Wall Shear Stress Signatures.

BACKGROUND: Plaque composition and wall shear stress (WSS) magnitude act as well-established players in coronary plaque progression. However, WSS magnitude per se does not completely capture the mechanical stimulus to which the endothelium is subjected, since endothelial cells experience changes in the WSS spatiotemporal configuration on the luminal surface. This study explores WSS profile and lipid content signatures of plaque progression to identify novel biomarkers of coronary atherosclerosis. METHODS: Thirty-seven patients with acute coronary syndrome underwent coronary computed tomography angiography, near-infrared spectroscopy intravascular ultrasound, and optical coherence tomography of at least 1 nonculprit vessel at baseline and 1-year follow-up. Baseline coronary artery geometries were reconstructed from intravascular ultrasound and coronary computed tomography angiography and combined with flow information to perform computational fluid dynamics simulations to assess the time-averaged WSS magnitude (TAWSS) and the variability in the contraction/expansion action exerted by WSS on the endothelium, quantifiable in terms of topological shear variation index (TSVI). Plaque progression was measured as intravascular ultrasound-derived percentage plaque atheroma volume change at 1-year follow-up. Plaque composition information was extracted from near-infrared spectroscopy and optical coherence tomography. RESULTS: Exposure to high TSVI and low TAWSS was associated with higher plaque progression (4.00±0.69% and 3.60±0.62%, respectively). Plaque composition acted synergistically with TSVI or TAWSS, resulting in the highest plaque progression (≥5.90%) at locations where lipid-rich plaque is exposed to high TSVI or low TAWSS. CONCLUSIONS: Luminal exposure to high TSVI, solely or combined with a lipid-rich plaque phenotype, is associated with enhanced plaque progression at 1-year follow-up. Where plaque progression occurred, low TAWSS was also observed. These findings suggest TSVI, in addition to low TAWSS, as a potential biomechanical predictor for plaque progression, showing promise for clinical translation to improve patient prognosis.

Coronary Artery Stenting Affects Wall Shear Stress Topological Skeleton.

Despite the important advancements in the stent technology for the treatment of diseased coronary arteries, major complications still affect the postoperative long-term outcome. The stent-induced flow disturbances, and especially the altered wall shear stress (WSS) profile at the strut level, play an important role in the pathophysiological mechanisms leading to stent thrombosis (ST) and in-stent restenosis (ISR). In this context, the analysis of the WSS topological skeleton is gaining more and more interest by extending the current understanding of the association between local hemodynamics and vascular diseases. This study aims to analyze the impact that a deployed coronary stent has on the WSS topological skeleton. Computational fluid dynamics (CFD) simulations were performed in three stented human coronary artery geometries reconstructed from clinical images. The selected cases presented stents with different designs (i.e., two contemporary drug-eluting stents and one bioresorbable scaffold) and included regions with stent malapposition or overlapping. A recently proposed Eulerian-based approach was applied to analyze the WSS topological skeleton features. The results highlighted that the presence of single or multiple stents within a coronary artery markedly impacts the WSS topological skeleton. In particular, repetitive patterns of WSS divergence were observed at the luminal surface, highlighting a WSS contraction action exerted proximal to the stent struts and a WSS expansion action distal to the stent struts. This WSS action pattern was independent from the stent design. In conclusion, these findings could contribute to a deeper understanding of the hemodynamics-driven processes underlying ST and ISR.

Simultaneous kissing stents to treat unprotected left main stem coronary artery bifurcation disease; stent expansion, vessel injury, hemodynamics, tissue healing, restenosis, and repeat revascularization.

OBJECTIVES: To perform detailed analysis of stent expansion, vessel wall stress, hemodynamics, re-endothelialization, restenosis, and repeat PCI in the simultaneous kissing stents (SKS) technique of bifurcation left main stem (LMS) stenting. BACKGROUND: The SKS technique is useful to treat patients with true bifurcation disease of the LMS but remains controversial. METHODS AND RESULTS: Computational structural analysis of SKS expansion demonstrated undistorted and evenly expanded stents. Computational fluid dynamics modelling revealed largely undisturbed blood flow. 239 PCI procedures were performed on 217 patients with unprotected bifurcation LMS disease with SKS using DES (2004-2017). We electively studied 13 stable patients from baseline to 10 years post-SKS with repeat angiography and optical coherence tomography, and demonstrated tissue coverage of the stent struts at the carina, with no evidence of lacunae behind the stents. We studied all patients with symptomatic recurrence. Target lesion revascularization rate was 3.2% at 1 year and 4.6% at 2 years. Of all 20 patients with restenosis, the site was the LMS-Cx stent in 7, the LMS-LAD stent in 2 and both in 11. Two-year recurrence rate was 7/32 (5.3%) for first, and 4/108 (3.7%) for second generation DES. Treatment with repeat kissing techniques was undertaken in 19/20, with sustained clinical results with re-SKS. CONCLUSION: The SKS technique for treating unprotected LMS bifurcation disease does not distort the stents, is associated with favorable hemodynamics, tissue coverage of the exposed struts, and a low restenosis rate when performed with contemporary stents. Re-PCI with repeat SKS appears feasible, safe, and durable.

Differences in rotational positioning and subsequent distal main branch rewiring of the Tryton stent: An optical coherence tomography and computational study.

OBJECTIVES: To evaluate the occurrence of rewiring through one of the panels of the Tryton stent (instead of the assumed re-wiring in-between the panels) and the influence on stent geometry and mechanics. BACKGROUND: Tryton is a side branch stent used in combination with a main branch device. It is placed without the need of rotational orientation. However, it is unknown whether main branch re-wiring accidentally may occur through a panel, instead of in-between the panels. METHODS: We used three-dimensional optical coherence tomography to evaluate the location of distal main branch re-wiring through Tryton. Furthermore, we used computer simulations to evaluate the influence on stent geometry and mechanics. RESULTS: Rewiring through a panel (instead of in-between two panels) occurred in 45% of the cases. By using virtual stent deployment, we found minimal differences in ostial side branch stenoses (44.8% in-between the panels and 39.0% through a panel). There were no differences in minimum stent areas of the distal main branch (6.38 mm2 vs. 6.39 mm2 ). In both scenarios, the re-wired Tryton cell was large enough for main branch stenting (expressed as the diameter of the largest possible circle that fits within the cells): 3.40 mm (in-between the panels) vs. 3.02 mm (through a panel). CONCLUSIONS: In 45% of the Tryton implantations, distal main branch rewiring (and subsequent main branch stenting) was performed through one Tryton panel, instead of the assumed rewiring in-between the panels. However, this did not result in unfavorable stent geometries or mechanics, as evaluated with computer simulations.

Coronary fractional flow reserve measurements of a stenosed side branch: a computational study investigating the influence of the bifurcation angle.

BACKGROUND: Coronary hemodynamics and physiology specific for bifurcation lesions was not well understood. To investigate the influence of the bifurcation angle on the intracoronary hemodynamics of side branch (SB) lesions computational fluid dynamics simulations were performed. METHODS: A parametric model representing a left anterior descending-first diagonal coronary bifurcation lesion was created according to the literature. Diameters obeyed fractal branching laws. Proximal and distal main branch (DMB) stenoses were both set at 60 %. We varied the distal bifurcation angles (40°, 55°, and 70°), the flow splits to the DMB and SB (55 %:45 %, 65 %:35 %, and 75 %:25 %), and the SB stenoses (40, 60, and 80 %), resulting in 27 simulations. Fractional flow reserve, defined as the ratio between the mean distal stenosis and mean aortic pressure during maximal hyperemia, was calculated for the DMB and SB (FFRSB) for all simulations. RESULTS: The largest differences in FFRSB comparing the largest and smallest bifurcation angles were 0.02 (in cases with 40 % SB stenosis, irrespective of the assumed flow split) and 0.05 (in cases with 60 % SB stenosis, flow split 55 %:45 %). When the SB stenosis was 80 %, the difference in FFRSB between the largest and smallest bifurcation angle was 0.33 (flow split 55 %:45 %). By describing the ΔPSB-QSB relationship using a quadratic curve for cases with 80 % SB stenosis, we found that the curve was steeper (i.e. higher flow resistance) when bifurcation angle increases (ΔP = 0.451*Q + 0.010*Q (2) and ΔP = 0.687*Q + 0.017*Q (2) for 40° and 70° bifurcation angle, respectively). Our analyses revealed complex hemodynamics in all cases with evident counter-rotating helical flow structures. Larger bifurcation angles resulted in more pronounced helical flow structures (i.e. higher helicity intensity), when 60 or 80 % SB stenoses were present. A good correlation (R(2) = 0.80) between the SB pressure drop and helicity intensity was also found. CONCLUSIONS: Our analyses showed that, in bifurcation lesions with 60 % MB stenosis and 80 % SB stenosis, SB pressure drop is higher for larger bifurcation angles suggesting higher flow resistance (i.e. curves describing the ΔPSB-QSB relationship being steeper). When the SB stenosis is mild (40 %) or moderate (60 %), SB resistance is minimally influenced by the bifurcation angle, with differences not being clinically meaningful. Our findings also highlighted the complex interplay between anatomy, pressure drops, and blood flow helicity in bifurcations.

Fluid-structure interaction simulation of mechanical aortic valves: a narrative review exploring its role in total product life cycle.

Over the last years computer modelling and simulation has emerged as an effective tool to support the total product life cycle of cardiovascular devices, particularly in the device preclinical evaluation and post-market assessment. Computational modelling is particularly relevant for heart valve prostheses, which require an extensive assessment of their hydrodynamic performance and of risks of hemolysis and thromboembolic complications associated with mechanically-induced blood damage. These biomechanical aspects are typically evaluated through a fluid-structure interaction (FSI) approach, which enables valve fluid dynamics evaluation accounting for leaflets movement. In this context, the present narrative review focuses on the computational modelling of bileaflet mechanical aortic valves through FSI approach, aiming to foster and guide the use of simulations in device total product life cycle. The state of the art of FSI simulation of heart valve prostheses is reviewed to highlight the variety of modelling strategies adopted in the literature. Furthermore, the integration of FSI simulations in the total product life cycle of bileaflet aortic valves is discussed, with particular emphasis on the role of simulations in complementing and potentially replacing the experimental tests suggested by international standards. Simulations credibility assessment is also discussed in the light of recently published guidelines, thus paving the way for a broader inclusion of in silico evidence in regulatory submissions. The present narrative review highlights that FSI simulations can be successfully framed within the total product life cycle of bileaflet mechanical aortic valves, emphasizing that credible in silico models evaluating the performance of implantable devices can (at least) partially replace preclinical in vitro experimentation and support post-market biomechanical evaluation, leading to a reduction in both time and cost required for device development.

Determining the Mechanical Properties of Super-Elastic Nitinol Bone Staples Through an Integrated Experimental and Computational Calibration Approach.

Super-elastic bone staples have emerged as a safe and effective alternative for internal fixation. Nevertheless, several biomechanical aspects of super-elastic staples are still unclear and require further exploration. Within this context, this study presents a combined experimental and computational approach to investigate the mechanical characteristics of super-elastic staples. Two commercially available staples with distinct geometry, characterized by two and four legs, respectively, were examined. Experimental four-point bending tests were conducted to evaluate staple performance in terms of generated forces. Subsequently, a finite element-based calibration procedure was developed to capture the unique super-elastic behavior of the staple materials. Finally, a virtual bench testing framework was implemented to separate the effect of geometry from that of the material characteristics on the mechanical properties of the devices, including generated force, strain distribution, and fatigue behavior. The experimental tests indicated differences in the force vs. displacement curves between staples. The material calibration procedure revealed marked differences in the super-elastic properties of the materials employed in staple 1 and staple 2. The results obtained from the virtual bench testing framework have showed that both geometric features and material characteristics had a substantial impact on the mechanical properties of the device, especially on the generated force, whereas their effect on strain distribution and fatigue behavior was comparatively less pronounced. To conclude, this study advances the biomechanical understanding of Nitinol super-elastic staples by separately investigating the impact of geometry and material characteristics on the mechanical properties of two commercially available devices.

Smartphone-based particle tracking velocimetry for the in vitro assessment of coronary flows.

The present study adopts a smartphone-based approach for the experimental characterization of coronary flows. Technically, Particle Tracking Velocimetry (PTV) measurements were performed using a smartphone camera and a low-power continuous wave laser in realistic healthy and stenosed phantoms of left anterior descending artery with inflow Reynolds numbers approximately ranging from 20 to 200. A Lagrangian-Eulerian mapping was performed to convert Lagrangian PTV velocity data to a Eulerian grid. Eulerian velocity and vorticity data obtained from smartphone-based PTV measurements were compared with Particle Image Velocimetry (PIV) measurements performed with a smartphone-based setup and with a conventional setup based on a high-power double-pulsed laser and a CMOS camera. Smartphone-based PTV and PIV velocity flow fields substantially agreed with conventional PIV measurements, with the former characterized by lower average percentage differences than the latter. Discrepancies emerged at high flow regimes, especially at the stenosis throat, due to particle image blur generated by smartphone camera shutter speed and image acquisition frequency. In conclusion, the present findings demonstrate the feasibility of PTV measurements using a smartphone camera and a low-power light source for the in vitro characterization of cardiovascular flows for research, industrial and educational purposes, with advantages in terms of costs, safety and usability.

Impact of Tissue Damage and Hemodynamics on Restenosis Following Percutaneous Transluminal Angioplasty: A Patient-Specific Multiscale Model.

Multiscale agent-based modeling frameworks have recently emerged as promising mechanobiological models to capture the interplay between biomechanical forces, cellular behavior, and molecular pathways underlying restenosis following percutaneous transluminal angioplasty (PTA). However, their applications are mainly limited to idealized scenarios. Herein, a multiscale agent-based modeling framework for investigating restenosis following PTA in a patient-specific superficial femoral artery (SFA) is proposed. The framework replicates the 2-month arterial wall remodeling in response to the PTA-induced injury and altered hemodynamics, by combining three modules: (i) the PTA module, consisting in a finite element structural mechanics simulation of PTA, featuring anisotropic hyperelastic material models coupled with a damage formulation for fibrous soft tissue and the element deletion strategy, providing the arterial wall damage and post-intervention configuration, (ii) the hemodynamics module, quantifying the post-intervention hemodynamics through computational fluid dynamics simulations, and (iii) the tissue remodeling module, based on an agent-based model of cellular dynamics. Two scenarios were explored, considering balloon expansion diameters of 5.2 and 6.2 mm. The framework captured PTA-induced arterial tissue lacerations and the post-PTA arterial wall remodeling. This remodeling process involved rapid cellular migration to the PTA-damaged regions, exacerbated cell proliferation and extracellular matrix production, resulting in lumen area reduction up to 1-month follow-up. After this initial reduction, the growth stabilized, due to the resolution of the inflammatory state and changes in hemodynamics. The similarity of the obtained results to clinical observations in treated SFAs suggests the potential of the framework for capturing patient-specific mechanobiological events occurring after PTA intervention.

Modelling lower-limb peripheral arterial disease using clinically available datasets: impact of inflow boundary conditions on hemodynamic indices for restenosis prediction.

BACKGROUND AND OBJECTIVES: The integration of hemodynamic markers as risk factors in restenosis prediction models for lower-limb peripheral arteries is hindered by fragmented clinical datasets. Computed tomography (CT) scans enable vessel geometry reconstruction and can be obtained at different times than the Doppler ultrasound (DUS) images, which provide information on blood flow velocity. Computational fluid dynamics (CFD) simulations allow the computation of near-wall hemodynamic indices, whose accuracy depends on the prescribed inlet boundary condition (BC), derived from the DUS images. This study aims to: (i) investigate the impact of different DUS-derived velocity waveforms on CFD results; (ii) test whether the same vessel areas, subjected to altered hemodynamics, can be detected independently of the applied inlet BC; (iii) suggest suitable DUS images to obtain reliable CFD results. METHODS: CFD simulations were conducted on three patients treated with bypass surgery, using patient-specific DUS-derived inlet BCs recorded at either the same or different time points than the CT scan. The impact of the chosen inflow condition on bypass hemodynamics was assessed in terms of wall shear stress (WSS)-derived quantities. Patient-specific critical thresholds for the hemodynamic indices were applied to identify critical luminal areas and compare the results with a reference obtained with a DUS image acquired in close temporal proximity to the CT scan. RESULTS: The main findings indicate that: (i) DUS-derived inlet velocity waveforms acquired at different time points than the CT scan led to statistically significantly different CFD results (p<0.001); (ii) the same luminal surface areas, exposed to low time-averaged WSS, could be identified independently of the applied inlet BCs; (iii) similar outcomes were observed for the other hemodynamic indices if the prescribed inlet velocity waveform had the same shape and comparable systolic acceleration time to the one recorded in close temporal proximity to the CT scan. CONCLUSIONS: Despite a lack of standardised data collection for diseased lower-limb peripheral arteries, an accurate estimation of luminal areas subjected to altered near-wall hemodynamics is possible independently of the applied inlet BC. This holds if the applied inlet waveform shares some characteristics - derivable from the DUS report - as one matching the acquisition time of the CT scan.

Blood Flow Energy Identifies Coronary Lesions Culprit of Future Myocardial Infarction.

The present study establishes a link between blood flow energy transformations in coronary atherosclerotic lesions and clinical outcomes. The predictive capacity for future myocardial infarction (MI) was compared with that of established quantitative coronary angiography (QCA)-derived predictors. Angiography-based computational fluid dynamics (CFD) simulations were performed on 80 human coronary lesions culprit of MI within 5 years and 108 non-culprit lesions for future MI. Blood flow energy transformations were assessed in the converging flow segment of the lesion as ratios of kinetic and rotational energy values (KER and RER, respectively) at the QCA-identified minimum lumen area and proximal lesion sections. The anatomical and functional lesion severity were evaluated with QCA to derive percentage area stenosis (%AS), vessel fractional flow reserve (vFFR), and translesional vFFR (ΔvFFR). Wall shear stress profiles were investigated in terms of topological shear variation index (TSVI). KER and RER predicted MI at 5 years (AUC = 0.73, 95% CI 0.65-0.80, and AUC = 0.76, 95% CI 0.70-0.83, respectively; p < 0.0001 for both). The predictive capacity for future MI of KER and RER was significantly stronger than vFFR (p = 0.0391 and p = 0.0045, respectively). RER predictive capacity was significantly stronger than %AS and ΔvFFR (p = 0.0041 and p = 0.0059, respectively). The predictive capacity for future MI of KER and RER did not differ significantly from TSVI. Blood flow kinetic and rotational energy transformations were significant predictors for MI at 5 years (p < 0.0001). The findings of this study support the hypothesis of a biomechanical contribution to the process of plaque destabilization/rupture leading to MI.

Association Between Automated 3D Measurement of Coronary Luminal Narrowing and Risk of Future Myocardial Infarction.

This study focuses on identifying anatomical markers with predictive capacity for long-term myocardial infarction (MI) in focal coronary artery disease (CAD). Eighty future culprit lesions (FCL) and 108 non-culprit lesions (NCL) from 80 patients underwent 3D quantitative coronary angiography. The minimum lumen area (MLA), minimum lumen ratio (MLR), and vessel fractional flow reserve (vFFR) were evaluated. MLR was defined as the ratio between MLA and the cross-sectional area at the proximal lesion edge, with lower values indicating more abrupt luminal narrowing. Significant differences were observed between FCL and NCL in MLR (0.41 vs. 0.53, p < 0.001). MLR correlated inversely with translesional vFFR (r = - 0.26, p = 0.0004) and was the strongest predictor of MI at 5 years (AUC = 0.75). Lesions with MLR < 0.40 had a fourfold increased MI incidence at 5 years. MLR is a robust predictor of future adverse coronary events.

Impact of endothelial shear stress on coronary atherosclerotic plaque progression and composition: A meta-analysis and systematic review.

BACKGROUND AND AIMS: Intracoronary pressure gradients and translesional flow patterns have been correlated with coronary plaque progression and lesion destabilization. In this study, we aimed to determine the relationship between endothelial shear stress and plaque progression and to evaluate the effect of shear forces on coronary plaque features. METHODS: A systematic review was conducted in medical on-line databases. Selected were studies including human participants who underwent coronary anatomy assessment with computational fluid dynamics (CFD)-based wall shear stress (WSS) calculation at baseline with anatomical evaluation at follow-up. A total of six studies were included for data extraction and analysis. RESULTS: The meta-analysis encompassed 31'385 arterial segments from 136 patients. Lower translesional WSS values were significantly associated with a reduction in lumen area (mean difference -0.88, 95% CI -1.13 to -0.62), an increase in plaque burden (mean difference 4.32, 95% CI 1.65 to 6.99), and an increase in necrotic core area (mean difference 0.02, 95% CI 0.02 to 0.03) at follow-up imaging. Elevated WSS values were associated with an increase in lumen area (mean difference 0.78, 95% CI 0.34 to 1.21) and a reduction in both fibrofatty (mean difference -0.02, 95% CI -0.03 to -0.01) and fibrous plaque areas (mean difference -0.03, 95% CI -0.03 to -0.03). CONCLUSION: This meta-analysis shows that WSS parameters were related to vulnerable plaque features at follow-up. These results emphasize the impact of endothelial shear forces on coronary plaque growth and composition. Future studies are warranted to evaluate the role of WSS in guiding clinical decision-making.

Influence of intracoronary hemodynamic forces on atherosclerotic plaque phenotypes.

BACKGROUND AND AIMS: Coronary hemodynamics impact coronary plaque progression and destabilization. The aim of the present study was to establish the association between focal vs. diffuse intracoronary pressure gradients and wall shear stress (WSS) patterns with atherosclerotic plaque composition. METHODS: Prospective, international, single-arm study of patients with chronic coronary syndromes and hemodynamic significant lesions (fractional flow reserve [FFR] ≤ 0.80). Motorized FFR pullback pressure gradient (PPG), optical coherence tomography (OCT), and time-average WSS (TAWSS) and topological shear variation index (TSVI) derived from three-dimensional angiography were obtained. RESULTS: One hundred five vessels (median FFR 0.70 [Interquartile range (IQR) 0.56-0.77]) had combined PPG and WSS analyses. TSVI was correlated with PPG (r = 0.47, [95% Confidence Interval (95% CI) 0.30-0.65], p < 0.001). Vessels with a focal CAD (PPG above the median value of 0.67) had significantly higher TAWSS (14.8 [IQR 8.6-24.3] vs. 7.03 [4.8-11.7] Pa, p < 0.001) and TSVI (163.9 [117.6-249.2] vs. 76.8 [23.1-140.9] m-1, p < 0.001). In the 51 vessels with baseline OCT, TSVI was associated with plaque rupture (OR 1.01 [1.00-1.02], p = 0.024), PPG with the extension of lipids (OR 7.78 [6.19-9.77], p = 0.003), with the presence of thin-cap fibroatheroma (OR 2.85 [1.11-7.83], p = 0.024) and plaque rupture (OR 4.94 [1.82 to 13.47], p = 0.002). CONCLUSIONS: Focal and diffuse coronary artery disease, defined using coronary physiology, are associated with differential WSS profiles. Pullback pressure gradients and WSS profiles are associated with atherosclerotic plaque phenotypes. Focal disease (as identified by high PPG) and high TSVI are associated with high-risk plaque features. CLINICAL TRIAL REGISTRATION: https://clinicaltrials,gov/ct2/show/NCT03782688.

Predicting 1-year in-stent restenosis in superficial femoral arteries through multiscale computational modelling.

In-stent restenosis in superficial femoral arteries (SFAs) is a complex, multi-factorial and multiscale vascular adaptation process whose thorough understanding is still lacking. Multiscale computational agent-based modelling has recently emerged as a promising approach to decipher mechanobiological mechanisms driving the arterial response to the endovascular intervention. However, the long-term arterial response has never been investigated with this approach, although being of fundamental relevance. In this context, this study investigates the 1-year post-operative arterial wall remodelling in three patient-specific stented SFA lesions through a fully coupled multiscale agent-based modelling framework. The framework integrates the effects of local haemodynamics and monocyte gene expression data on cellular dynamics through a bi-directional coupling of computational fluid dynamics simulations with an agent-based model of cellular activities. The framework was calibrated on the follow-up data at 1 month and 6 months of one stented SFA lesion and then applied to the other two lesions. The calibrated framework successfully captured (i) the high lumen area reduction occurring within the first post-operative month and (ii) the stabilization of the median lumen area from 1-month to 1-year follow-ups in all the stented lesions, demonstrating the potentialities of the proposed approach for investigating patient-specific short- and long-term responses to endovascular interventions.

Investigating the effect of drug release on in-stent restenosis: A hybrid continuum - agent-based modelling approach.

BACKGROUND AND OBJECTIVE: In-stent restenosis (ISR) following percutaneous coronary intervention with drug-eluting stent (DES) implantation remains an unresolved issue, with ISR rates up to 10%. The use of antiproliferative drugs on DESs has significantly reduced ISR. However, a complete knowledge of the mechanobiological processes underlying ISR is still lacking. Multiscale agent-based modelling frameworks, integrating continuum- and agent-based approaches, have recently emerged as promising tools to decipher the mechanobiological events driving ISR at different spatiotemporal scales. However, the integration of sophisticated drug models with an agent-based model (ABM) of ISR has been under-investigated. The aim of the present study was to develop a novel multiscale agent-based modelling framework of ISR following DES implantation. METHODS: The framework consisted of two bi-directionally coupled modules, namely (i) a drug transport module, simulating drug transport through a continuum-based approach, and (ii) a tissue remodelling module, simulating cellular dynamics through an ABM. Receptor saturation (RS), defined as the fraction of target receptors saturated with drug, is used to mediate cellular activities in the ABM, since RS is widely regarded as a measure of drug efficacy. Three studies were performed to investigate different scenarios in terms of drug mass (DM), drug release profiles (RP), coupling schemes and idealized vs. patient-specific artery geometries. RESULTS: The studies demonstrated the versatility of the framework and enabled exploration of the sensitivity to different settings, coupling modalities and geometries. As expected, changes in the DM, RP and coupling schemes illustrated a variation in RS over time, in turn affecting the ABM response. For example, combined small DM - fast RP led to similar ISR degrees as high DM - moderate RP (lumen area reduction of ∼13/17% vs. ∼30% without drug). The use of a patient-specific geometry with non-equally distributed struts resulted in a heterogeneous RS map, but did not remarkably impact the ABM response. CONCLUSION: The application to a patient-specific geometry highlights the potential of the framework to address complex realistic scenarios and lays the foundations for future research, including calibration and validation on patient datasets and the investigation of the effects of different plaque composition on the arterial response to DES.

Impact of nickel-titanium super-elastic material properties on the mechanical performance of self-expandable transcatheter aortic valves.

Self-expandable transcatheter aortic valves (TAVs) elastically resume their initial shape when implanted without the need for balloon inflation by virtue of the nickel-titanium (NiTi) frame super-elastic properties. Experimental findings suggest that NiTi mechanical properties can vary markedly because of a strong dependence on the chemical composition and processing operations. In this context, this study presents a computational framework to investigate the impact of the NiTi super-elastic material properties on the TAV mechanical performance. Finite element (FE) analyses of TAV implantation were performed considering two different TAV frames and three idealized aortic root anatomies, evaluating the device mechanical response in terms of pullout force magnitude exerted by the TAV frame and peak maximum principal stress within the aortic root. The widely adopted NiTi constitute model by Auricchio and Taylor (1997) was used. A multi-parametric sensitivity analysis and a multi-objective optimization of the TAV mechanical performance were conducted in relation to the parameters of the NiTi constitutive model. The results highlighted that: five NiTi material model parameters (EA, σtLS, σtUS, σtUE and σcLS) are significantly correlated with the FE outputs; the TAV frame geometry and aortic root anatomy have a marginal effect on the level of influence of each NiTi material parameter; NiTi alloy candidates with pareto-optimal characteristics in terms of TAV mechanical performance can be successfully identified. In conclusion, the proposed computational framework supports the TAV design phase, providing information on the relationship between the super-elastic behavior of the supplied NiTi alloys and the device mechanical response.

Multi-objective design optimization of bioresorbable braided stents.

BACKGROUND AND OBJECTIVES: Bioresorbable braided stents, typically made of bioresorbable polymers such as poly-l-lactide (PLLA), have great potential in the treatment of critical limb ischemia, particularly in cases of long-segment occlusions and lesions with high angulation. However, the successful adoption of these devices is limited by their low radial stiffness and reduced elastic modulus of bioresorbable polymers. This study proposes a computational optimization procedure to enhance the mechanical performance of bioresorbable braided stents and consequently improve the treatment of critical limb ischemia. METHODS: Finite element analyses were performed to replicate the radial crimping test and investigate the implantation procedure of PLLA braided stents. The stent geometry was characterized by four design parameters: number of wires, wire diameter, initial stent diameter, and braiding angle. Manufacturing constraints were considered to establish the design space. The mechanical performance of the stent was evaluated by defining the radial force, foreshortening, and peak maximum principal stress of the stent as objectives and constraint functions in the optimization problem. An approximate relationship between the objectives, constraint, and the design parameters was defined using design of experiment coupled with surrogate modelling. Surrogate models were then interrogated within the design space, and a multi-objective design optimization was conducted. RESULTS: The simulation of radial crimping was successfully validated against experimental data. The radial force was found to be primarily influenced by the number of wires, wire diameter, and braiding angle, with the wire diameter having the most significant impact. Foreshortening was predominantly affected by the braiding angle. The peak maximum principal stress exhibited contrasting behaviour compared to the radial force for all parameters, with the exception of the number of wires. Among the Pareto-optimal design candidates, feasible peak maximum principal stress values were observed, with the braiding angle identified as the differentiating factor among these candidates. CONCLUSIONS: The exploration of the design space enabled both the understanding of the impact of design parameters on the mechanical performance of bioresorbable braided stents and the successful identification of optimal design candidates. The optimization framework contributes to the advancement of innovative bioresorbable braided stents for the effective treatment of critical limb ischemia.

An agent-based model of cardiac allograft vasculopathy: toward a better understanding of chronic rejection dynamics.

Cardiac allograft vasculopathy (CAV) is a coronary artery disease affecting 50% of heart transplant (HTx) recipients, and it is the major cause of graft loss. CAV is driven by the interplay of immunological and non-immunological factors, setting off a cascade of events promoting endothelial damage and vascular dysfunction. The etiology and evolution of tissue pathology are largely unknown, making disease management challenging. So far, in vivo models, mostly mouse-based, have been widely used to study CAV, but they are resource-consuming, pose many ethical issues, and allow limited investigation of time points and important biomechanical measurements. Recently, agent-based models (ABMs) proved to be valid computational tools for deciphering mechanobiological mechanisms driving vascular adaptation processes at the cell/tissue level, augmenting cost-effective in vivo lab-based experiments, at the same time guaranteeing richness in observation time points and low consumption of resources. We hypothesize that integrating ABMs with lab-based experiments can aid in vivo research by overcoming those limitations. Accordingly, this work proposes a bidimensional ABM of CAV in a mouse coronary artery cross-section, simulating the arterial wall response to two distinct stimuli: inflammation and hemodynamic disturbances, the latter considered in terms of low wall shear stress (WSS). These stimuli trigger i) inflammatory cell activation and ii) exacerbated vascular cell activities. Moreover, an extensive analysis was performed to investigate the ABM sensitivity to the driving parameters and inputs and gain insights into the ABM working mechanisms. The ABM was able to effectively replicate a 4-week CAV initiation and progression, characterized by lumen area decrease due to progressive intimal thickening in regions exposed to high inflammation and low WSS. Moreover, the parameter and input sensitivity analysis highlighted that the inflammatory-related events rather than the WSS predominantly drive CAV, corroborating the inflammatory nature of the vasculopathy. The proof-of-concept model proposed herein demonstrated its potential in deepening the pathology knowledge and supporting the in vivo analysis of CAV.

Aortic Remodeling Kinetics in Response to Coarctation-Induced Mechanical Perturbations.

Background: Coarctation of the aorta (CoA; constriction of the proximal descending thoracic aorta) is among the most common congenital cardiovascular defects. Coarctation-induced mechanical perturbations trigger a cycle of mechano-transduction events leading to irreversible precursors of hypertension including arterial thickening, stiffening, and vasoactive dysfunction in proximal conduit arteries. This study sought to identify kinetics of the stress-mediated compensatory response leading to these alterations using a preclinical rabbit model of CoA. Methods: A prior growth and remodeling (G&R) framework was reformulated and fit to empirical measurements from CoA rabbits classified into one control and nine CoA groups of various severities and durations (n = 63, 5-11/group). Empirical measurements included Doppler ultrasound imaging, uniaxial extension testing, catheter-based blood pressure, and wire myography, yielding the time evolution of arterial thickening, stiffening, and vasoactive dysfunction required to fit G&R constitutive parameters. Results: Excellent agreement was observed between model predictions and observed patterns of arterial thickening, stiffening, and dysfunction among all CoA groups. For example, predicted vascular impairment was not significantly different from empirical observations via wire myography (p-value > 0.13). Specifically, 48% and 45% impairment was observed in smooth muscle contraction and endothelial-dependent relaxation, respectively, which were accurately predicted using the G&R model. Conclusions: The resulting G&R model, for the first time, allows for prediction of hypertension precursors at neonatal ages that is currently challenging to examine in preclinical models. These findings provide a validated computational tool for prediction of persistent arterial dysfunction and identification of revised severity-duration thresholds that may ultimately avoid hypertension from CoA.