Non-physiologic Bioreactor Processing Conditions for Heart Valve Tissue Engineering Abstract Purpose Conventional methods of seeding decellularized heart valves for heart valve tissue engineering have led to inconsistent results in interstitial cellular repopulation, particularly of the distal valve leaflet, and notably distinct from documented re-endothelialization. The use of bioreactor conditioning mimicking physiologic parameters has been well explored but cellular infiltration remains challenging. Non-characteristic, non-physiologic conditioning parameters within a bioreactor, such as hypoxia and cyclic chamber pressure, may be used to increase the cellular infiltration leading to increased recellularization. Methods To investigate the effects of novel and perhaps non-intuitive bioreactor conditioning parameters, ovine aortic heart valves were seeded with mesenchymal stem cells and cultured in one of four environments: hypoxia and high cyclic pressures (120 mmHg), normoxia and high cyclic pressures, hypoxia and negative cyclic pressures (− 20 mmHg), and normoxia and negative cyclic pressures. Analysis included measurements of cellular density, cell phenotype, and biochemical concentrations. Results The results revealed that the bioreactor conditioning parameters influenced the degree of recellularization. Groups that implemented hypoxic conditioning exhibited increased cellular infiltration into the valve leaflet tissue compared to normoxic conditioning, while pressure conditioning did not have a significant effect of recellularization. Protein expression across all groups was similar, exhibiting a stem cell and valve interstitial cell phenotype. Biochemical analysis of the extracellular matrix was similar between all groups. Conclusion These results suggest the use of non-physiologic bioreactor conditioning parameters can increase in vitro recellularization of tissue engineered heart valve leaflets. Particularly, hypoxic culture was found to increase the cellular infiltration. Therefore, bioreactor conditioning of tissue engineered constructs need not always mimic physiologic conditions, and it is worth investigating novel or uncharacteristic culture conditions as they may benefit aspects of tissue culture.

Location-Specific Comparison Between a 3D In-Stent Restenosis Model and Micro-CT and Histology Data from Porcine In Vivo Experiments Abstract Background Coronary artery restenosis is an important side effect of percutaneous coronary intervention. Computational models can be used to better understand this process. We report on an approach for validation of an in silico 3D model of in-stent restenosis in porcine coronary arteries and illustrate this approach by comparing the modelling results to in vivo data for 14 and 28 days post-stenting. Methods This multiscale model includes single-scale models for stent deployment, blood flow and tissue growth in the stented vessel, including smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) production. The validation procedure uses data from porcine in vivo experiments, by simulating stent deployment using stent geometry obtained from micro computed tomography (micro-CT) of the stented vessel and directly comparing the simulation results of neointimal growth to histological sections taken at the same locations. Results Metrics for comparison are per-strut neointimal thickness and per-section neointimal area. The neointimal area predicted by the model demonstrates a good agreement with the detailed experimental data. For 14 days post-stenting the relative neointimal area, averaged over all vessel sections considered, was 20 ± 3% in vivo and 22 ± 4% in silico. For 28 days, the area was 42 ± 3% in vivo and 41 ± 3% in silico. Conclusions The approach presented here provides a very detailed, location-specific, validation methodology for in silico restenosis models. The model was able to closely match both histology datasets with a single set of parameters. Good agreement was obtained for both the overall amount of neointima produced and the local distribution. It should be noted that including vessel curvature and ECM production in the model was paramount to obtain a good agreement with the experimental data.

Cardiothoracic Morphology Measures in Heart Failure Patients to Inform Device Designs Abstract Purpose Approximately 5.7 million people in the US are affected by congestive heart failure. This study aimed to quantitatively evaluate cardiothoracic morphology and variability within a cohort of heart failure patients for the purpose of optimally engineering cardiac devices for a variety of heart failure patients. Methods Co-registered cardiac-gated and non-gated chest computed tomography (CT) scans were analyzed from 20 heart failure patients (12 males; 8 females) who were primarily older adults (79.5 ± 8.8 years). Twelve cardiothoracic measurements were collected and compared to study sex and left ventricular (LV) ejection fraction (EF) type differences in cardiothoracic morphology. Results Four measures were significantly greater in males compared to females: LV long-axis length, LV end diastolic diameter (LVEDD) at 50% length of the LV long-axis, the minimal distance between the sternum and heart, and the angle between the LV long-axis and coronal plane. Four measures were significantly greater in patients with reduced EF compared to preserved LV: LV long-axis length, LVEDD at 50% length of the LV long-axis, left ventricular volume normalized by body surface area, and the angle between the mitral valve plane and LV long-axis. Conclusions These cardiothoracic morphology measurements are important to consider in the design of cardiac devices for heart failure management (e.g. cardiac pacemakers, ventricular assist devices, and implantable defibrillators), since morphology differs by sex and ejection fraction.

Three-Dimensional Contractile Mechanics of Artery Accounting for Curl of Axial Strip Sectioned from Vessel Wall Abstract Purpose It is well known that a sliced ring of arterial wall opens by a radial cut. An axial strip sectioned from arterial wall also curls into an arc. These phenomena imply that there exist residual strains in the circumferential and axial directions. How much do the axial residual strains affect the stress distributions of arterial wall? The aim of the present study is to know stress distributions of arterial wall with the residual strains under the passive and constricted conditions. Methods We analyzed the stress distributions under passive and constricted conditions with considering a Riemannian stress-free configuration. In the analysis, we used strain energy functions to describe the passive and active mechanical properties of artery. Results The present study provided distributions of stretch ratio with reference to the stress-free state (Riemannian stress-free configuration) and stress with and without the curl of axial strip of a homogenous cylindrical arterial model under the passive and constricted smooth muscle conditions. The circumferential and axial stresses with activated smooth muscle (noradrenaline 10−5 M) at the intraluminal pressure 16 kPa and the axial stretch ratio 1.5 with reference to the unloaded vessel decreased by 3.5 and 13.8% at the inner surface with considering the axial residual strain, respectively. Conclusions We have shown that the Riemannian stress-free configuration is appropriate tool to analyze stress distributions of arterial wall under passive and activated conditions with the residual stresses.

Automated Detection of Vulnerable Plaque for Intravascular Optical Coherence Tomography Images Abstract Purpose Vulnerable plaque detection is important to acute coronary syndrome (ACS) diagnosis. In recent years, intravascular optical coherence tomography (IVOCT) imaging has been used for vulnerable plaque detection. Current automated detection methods adopt the traditional image classification and object detection algorithms, such as the logistic regression model, SVM, and Haar-Adaboost, to detect vulnerable plaques. The detection quality of these methods is relatively low. The aim of this study is to improve the detection quality of vulnerable plaque. Methods We propose an automatic detection system of vulnerable plaque for IVOCT images based on deep convolutional neural network (DCNN). The system is mainly composed of four modules: pre-processing, deep convolutional neural networks (DCNNs), post-processing, and ensemble. The IVOCT images input to DCNNs are firstly pre-processed by using the methods of de-noising and data augmentation. Then multiple DCNNs are used to detect the vulnerable plaques in the IVOCT images; the vulnerable plaque regions and their corresponding labels and scores are output. Next, the output results of each network are processed by the post-processing module. We propose three algorithms, union of intersecting regions, duplicated region processing, and small gaps removal for post-processing. Finally, the output detection results of multiple networks are combined using a proposed combining method in ensemble module. Results We evaluated the proposed method in a dataset of 300 IVOCT images. Experimental results show that our system can achieve a precision rate of 88.84%, a recall rate of 95.02%, and an overlap rate of 85.09%; the detection quality score is 88.46%. Conclusions The proposed algorithms can detect vulnerable plaques with superior performance; our system can be used as an auxiliary diagnostic tool for vulnerable plaque detection in IVOCT images.

Vascular Parameters for Ambulatory Monitoring of Congestive Heart Failure Patients: Proof of Concept Abstract Purpose Prompt detection of congestion is an essential target in order to prevent heart failure (HF) related hospitalization, being ambulatory monitoring a promising strategy to do so. A successful non-invasive ambulatory monitoring system requires automatic devices for physiological data recording; these data must give information about HF deterioration early enough to predict HF-related adverse events. This work aims to evaluate seven vascular parameters for the ambulatory monitoring of congestive heart failure patients. Methods Seven vascular parameters are proposed as indicators of HF deterioration. These parameters are obtained using venous occlusion plethysmography; a technique that uses hardware able of being miniaturized and easily integrated into wearables for ambulatory monitoring. The ability of the proposed vascular parameters to detect congestion is evaluated in eight healthy volunteers and ten congestive heart failure patients with different congestion levels—mild, moderate and severe. Results Most parameters distinguish between healthy volunteers and heart failure patients, and some of them present significant differences between volunteers and low levels of congestion—mild or moderate. Conclusion Home monitoring of some of the proposed parameters could detect HF deterioration on its onset and alert to health personnel.

Haemodynamics Study of Tapered Stents Intervention to Tapered Arteries Abstract Purpose In-stent restenosis (ISR) is related to local haemodynamics in the arteries after stent intervention. However, the haemodynamics of stents implanted into tapered vessels is rarely studied and remains unclear. This study aimed to study the haemodynamic performance of a stent in a tapered artery to reveal the haemodynamic differences between tapered and cylindrical stents after stent implantation and guide the stent selection for the treatment of coronary artery stenosis. Methods Cylindrical and tapered stents were implanted into the tapered arteries. A model of a cylindrical stent implanted into a cylindrical artery was established as the contrast model. Using the finite element method, the flow velocity and wall shear stress distribution of the three models were compared. Results At t1, t2, t3 and t4, the flow rate of the tapered artery with tapered stents (TT) after the implantation increased by 8.59, 3.80, 12.81 and 3.66%, respectively. In addition, the wall shear stress in the tapered arteries of TT was 23.48, 36.67, 13.00 and 8.06% higher than that of the tapered arteries with cylindrical stents (TC). Conclusions The implantation of a tapered stent in the tapered artery can effectively improve intravascular haemodynamics. The tapered stent allows the tapered artery to obtain better haemodynamics and reduces the probability of ISR.

Cilostazol Promotes Angiogenesis and Increases Cell Proliferation After Myocardial Ischemia–Reperfusion Injury Through a cAMP-Dependent Mechanism Abstract Purpose Previous study indicated the protective role of cilostazol in ischemia–reperfusion (I/R) injury. Here, we aimed to explore the function of cilostazol in myocardial I/R injury and the underlying mechanism. Methods The myocardial I/R injury rat model was constructed, and the expression levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor receptor b (PDGF-B) and the number of new blood vessels were measured by qRT-PCR and immunohistochemistry. VSMC and HUVEC cells were treated with hypoxia to induce in vivo I/R injury model. The protein expression of AKT, endothelial nitric oxide synthase (eNOS) and apoptosis-related protein levels were detected by western blotting. Besides, the positive staining rate and cell viability were tested by 5-bromo-2-deoxyuridine (Brdu)/4′,6-diamidino-2-phenylindole (DAPI) or DAPI/TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and MTT assay. Results Cilostazol promoted angiogenesis by increasing the number of new blood vessels and up-regulating the expression of VEGF, HGF, bFGF and PDGF-B in myocardial I/R-injury rat model. The in vitro experiments showed that cilostazol increased the level of eNOS and AKT, and also enhanced cell proliferation in hypoxia-treated VSMC and HUVEC cells. Furthermore, after 8-Br-cAMP treatment, VEGF, HGF, bFGF, PDGF-B, p-AKT and p-eNOS expression were up-regulated, while cleaved-caspase 3 and cleaved-PARP expression were down-regulated. In addition, the effects of cilostazol on cell viability and apoptosis were aggravated by 8-Br-cAMP and attenuated after KT-5720 treatment. Conclusion Cilostazol could promote angiogenesis, increase cell viability and inhibit cell apoptosis, consequently protecting myocardial tissues against I/R-injury through activating cAMP.

Optimization Framework for Patient-Specific Cardiac Modeling Abstract Purpose Patient-specific models of the heart can be used to improve the diagnosis of cardiac diseases, but practical application of these models can be impeded by the computational costs and numerical uncertainties of fitting mechanistic models to clinical measurements from individual patients. Reliable and efficient tuning of these models within clinically appropriate error bounds is a requirement for practical deployment in the time-constrained environment of the clinic. Methods We developed an optimization framework to tune parameters of patient-specific mechanistic models using routinely-acquired non-invasive patient data more efficiently than manual methods. We employ a hybrid particle swarm and pattern search optimization algorithm, but the framework can be readily adapted to use other optimization algorithms. Results We apply the proposed framework to tune full-cycle lumped parameter circulatory models using clinical data. We show that our framework can be easily adapted to optimize cross-species models by tuning the parameters of the same circulation model to four canine subjects. Conclusions This work will facilitate the use of biomechanics and circulatory cardiac models in both clinical and research environments by ameliorating the tedious process of manually fitting the parameters.

Embolus Transport Simulations with Fully Resolved Particle Surfaces Abstract Purpose There has been interest in recent work in using computational fluid dynamics with Lagrangian analysis to calculate the trajectory of emboli-like particles in the vasculature. While previous studies have provided an understanding of the hemodynamic factors determining the fates of such particles and their relationship to risk of stroke, most analyses have relied on a particle equation of motion that assumes the particle is “small” e.g., much less than the diameter of the vessel. This work quantifies the limit when a particle can no longer be considered “small”. Methods The motion of embolus-like particles are simulated using an overset mesh technique. This allows the fluid stresses on the particle surface to be fully resolved. Consequently, the particles can be of arbitrary size or shape. The trajectory of resolved particles and “small” particles are simulated through a patient-specific carotid artery bifurcation model with particles 500, 1000, and 2000 μm in diameter. The proportions of particles entering the internal carotid artery are treated as the outcome of the particle fate, and statistical comparisons are made to ascertain the importance of non-small particle effects. Results For the 2000 μm embolus, the proportion of particles traveling to the internal carotid artery is 74.7 ± 1.3% (mean ± 95% confidence margin) for the “small” particle model and is 85.7 ± 5.4% for a resolved particle model. The difference is statistically significant, \(p< 0.05\), based on the binomial test for the particle outcomes. No statistically discernible differences are found for the smaller diameter particles. Conclusions Quantitative differences are observable for the 2000 μm trajectories between the “small” and resolved particle models which is a particle diameter 27% relative to the common carotid artery diameter. A fully resolved particle model ought to be considered for emboli trajectory simulations when the particle size ratio is ≳ 20%.