Electrical Stimulation for Low-Energy Termination of Cardiac Arrhythmias: a Review.

Cardiac arrhythmias are a leading cause of morbidity and mortality in the developed world, estimated to be responsible for hundreds of thousands of deaths annually. Our understanding of the electrophysiological mechanisms of such arrhythmias has grown since they were formally characterized in the late nineteenth century, and this has led to the development of numerous devices and therapies that have markedly improved outcomes for patients affected by such conditions. Despite these advancements, the application of a single large shock remains the clinical standard for treating deadly tachyarrhythmias. Such defibrillating shocks are undoubtedly effective in terminating such arrhythmias; however, they are applied without forewarning, contributing to the patient's stress and anxiety; they can be intensely painful; and they can have adverse psychological and physiological effects on patients. In recent years, there has been interest in developing defibrillation protocols that can terminate arrhythmias without crossing the human pain threshold for energy delivery, generally estimated to be between 0.1 and 1 J. In this article, we review existing literature on the development of such low-energy defibrillation methods and their underlying mechanisms, in an attempt to broadly describe the current landscape of these technologies.

Insurance lesions: Does a second lesion make a difference?

INTRODUCTION: In radiofrequency ablation procedures for cardiac arrhythmia, the efficacy of creating repeated lesions at the same location ("insurance lesions") remains poorly studied. We assessed the effect of type of tissue, power, and time on the resulting lesion geometry during such multiple ablation procedures. METHODS: A custom ex vivo ablation model was used to assess lesion formation. An ablation catheter was oriented perpendicular to the tissue and used to create lesions that varied by type of tissue (atrial or ventricular free wall), power (30 or 50 W), and time (30, 40, or 50 s for standard ablations and 5, 10, or 15 s for high-power, short-duration [HPSD] ablations). Lesion dimensions were recorded and then analyzed. Radiofrequency ablations were performed on 57 atrial tissue samples (28 HPSD, 29 standard) and 28 ventricular tissue samples (all standard). RESULTS: With ablation parameters held constant, performing multiple ablations significantly increased lesion depth in ventricular tissue when ablations were performed at 30 W for 50 s. No other set of ablation parameters was shown to affect the width or depth of the resulting lesions in either tissue type. CONCLUSION: Multiple ablations created with the same power and time, delivered within 30 s of each other at the same exact location, offer no meaningful benefit in lesion depth or width over single ablations, with the exception of ventricular ablation at 30 W for 50 s. Given the risks associated with excessive ablation, our results suggest that this practice should be re-evaluated by clinical electrophysiologists.

An initial ex vivo evaluation of temperature profile and thermal injury formation on the epiesophageal surface during radiofrequency ablation.

INTRODUCTION: Few studies have examined heat transfer and thermal injury on the epiesophageal surface during radiofrequency application, or compared the risk of esophageal thermal injury between standard and high-power, short-duration (HPSD) ablation. We studied the thermodynamics of HPSD and standard ablation at different tissue interfaces between the left atrium and esophagus, focusing on epiesophageal temperature changes and thermal injury. METHODS AND RESULTS: Fresh porcine heart and esophageal sections were secured to a custom holder and submerged in a temperature-controlled, circulating water bath. During ablation, thermistors recorded temperatures at the catheter tip-atrial interface, epiesophageal-atrial interface, and esophageal lumen. Samples were ablated in triplicate with the following parameters: contact force (15/25g), power (10/20/30 W standard; 40/45/50 W HPSD), and duration (10/20/30 s standard; 5/10/15 s HPSD). Epiesophageal and endoluminal temperature rises were greater in HPSD than in standard ablation (epiesophageal: 5.9 ± 5.6 vs. 2.2 ± 2.0°C, p < .01; endoluminal: 0.7 ± 0.5 vs. 0.4 ± 0.2°C, p < .01). Six of 30 HPSD ablations and 1 of 26 standard ablations caused esophageal injury. The delay between the peak epiesophageal and endoluminal temperatures was greater in HPSD than in standard ablation (24.2 ± 22.1 vs. 13.0 ± 11.0 s, p = .023). Likewise, the peak epiesophageal surface temperature differed more from the concurrent endoluminal temperature in HPSD ablation (5.1 ± 5.3 vs. 1.7 ± 2.0°C, p < .01). CONCLUSION: Endoluminal temperature underestimates epiesophageal surface temperature substantially during HPSD ablation. Visible epiesophageal injury was associated with a 2.2 ± 2.1°C rise in endoluminal temperature, corresponding to a 10.2 ± 6.5°C rise in epiesophageal temperature.

Reconstituting electrical conduction in soft tissue: the path to replace the ablationist.

Cardiac arrhythmias are a leading cause of morbidity and mortality in the developed world. A common mechanism underlying many of these arrhythmias is re-entry, which may occur when native conduction pathways are disrupted, often by myocardial infarction. Presently, re-entrant arrhythmias are most commonly treated with antiarrhythmic drugs and myocardial ablation, although both treatment methods are associated with adverse side effects and limited efficacy. In recent years, significant advancements in the field of biomaterials science have spurred increased interest in the development of novel therapies that enable restoration of native conduction in damaged or diseased myocardium. In this review, we assess the current landscape of materials-based approaches to eliminating re-entrant arrhythmias. These approaches potentially pave the way for the eventual replacement of myocardial ablation as a preferred therapy for such pathologies.

Confirming pericardial access by using impedance measurements from a micropuncture needle.

BACKGROUND: Pericardial access is complicated by two difficulties: confirming when the needle tip is in the pericardial space, and avoiding complications during access, such as inadvertently puncturing other organs. Conventional imaging tools are inadequate for addressing these difficulties, as they lack soft-tissue markers that could be used as guidance during access. A system that can both confirm access and avoid inadvertent organ injury is needed. METHODS: A 21G micropuncture needle was modified to include two small electrodes at the needle tip. With continuous bioimpedance monitoring from the electrodes, the needle was used to access the pericardium in porcine models (n  =  4). The needle was also visualized in vivo by using an electroanatomical map (n  =  2). Bioimpedance data from different tissues were analyzed retrospectively. RESULTS: Bioimpedance data collected from the subcutaneous space (992.8 ± 13.1 Ω), anterior mediastinum (972.2 ± 14.2 Ω), pericardial space (323.2 ± 17.1 Ω), mid-myocardium (349.7 ± 87.6 Ω), right ventricular cavity (235.0 ± 9.7 Ω), lung (1142.0 ± 172.0 Ω), liver (575.0 ± 52.6 Ω), and blood (177.5 ± 1.9 Ω) differed significantly by tissue type (P < .01). Phase data in the frequency domain correlated well with the needle being in the pericardial space. A simple threshold analysis effectively separated lung (threshold  =  1120.0 Ω) and blood (threshold  =  305.9 Ω) tissues from the other tissue types. CONCLUSIONS: Continuous bioimpedance monitoring from a modified micropuncture needle during pericardial access can be used to clearly differentiate tissues. Combined with traditional imaging modalities, this system allows for confirming access to the pericardial space while avoiding inadvertent puncture of other organs, creating a safer and more efficient needle-access procedure.

Age-related changes in aortic valve hemostatic protein regulation.

OBJECTIVE: Although valvular endothelial cells have unique responses compared with vascular endothelial cells, valvular regulation of hemostasis is not well-understood. Heart valves remodel throughout a person's lifetime, resulting in changes in extracellular matrix composition and tissue mechanical properties that may affect valvular endothelial cell hemostatic function. This work assessed valvular endothelial cell regulation of hemostasis in situ and in vitro as a function of specimen age. APPROACH AND RESULTS: Porcine aortic valves were assigned to 1 of 3 age groups: Young (YNG) (6 weeks); Adult (ADT) (6 months); or Elderly (OLD) (2 years). Histological examination of valves showed that secreted thrombotic/antithrombotic proteins localize at the valve endothelium and tissue interior. Gene expression and immunostains for von Willebrand factor (VWF), tissue factor pathway inhibitor, and tissue plasminogen activator in YNG porcine aortic valve endothelial cells were higher than they were for OLD, whereas plasminogen activator inhibitor 1 levels in OLD were higher than those for YNG and ADT. Histamine-stimulated YNG porcine aortic valve endothelial cells released higher concentrations of VWF proteins than OLD, and the fractions of VWF-140 fragments was not different between age groups. A calcific aortic valve disease in vitro model using valvular interstitial cells confirmed that VWF in culture significantly increased valvular interstitial cell nodule formation and calcification. CONCLUSIONS: Hemostatic protein regulation in aortic valve tissues and in valvular endothelial cells changes with age. The presence of VWF and other potential hemostatic proteins increase valvular interstitial cell calcification in vitro. Therefore, the increased capacity of elderly valves to sequester the hemostatic proteins, together with age-associated loss of extracellular matrix organization, warrants investigation into potential role of these proteins in the formation of calcific nodules.

Injectable hydrogel electrodes as conduction highways to restore native pacing.

There is an urgent clinical need for a treatment regimen that addresses the underlying pathophysiology of ventricular arrhythmias, the leading cause of sudden cardiac death. The current report describes the design of an injectable hydrogel electrode and successful deployment in a pig model with access far more refined than any current pacing modalities allow. In addition to successful cardiac capture and pacing, analysis of surface ECG tracings and three-dimensional electroanatomic mapping revealed a QRS morphology comparable to native sinus rhythm, strongly suggesting the hydrogel electrode captures the deep septal bundle branches and Purkinje fibers. In an ablation model, electroanatomic mapping data demonstrated that the activation wavefront from the hydrogel reaches the mid-myocardium and endocardium much earlier than current single-point pacing modalities. Such uniform activation of broad swaths of tissue enables an opportunity to minimize the delayed myocardial conduction of heterogeneous tissue that underpins re-entry. Collectively, these studies demonstrate the feasibility of a new pacing modality that most closely resembles native conduction with the potential to eliminate lethal re-entrant arrhythmias and provide painless defibrillation.

Enhancing boundary detection of radiofrequency ablation lesions through photoacoustic mapping.

Atrial fibrillation (A-fib) is the most common type of heart arrhythmia, typically treated with radiofrequency catheter ablation to isolate the heart from abnormal electrical signals. Monitoring the formation of ablation-induced lesions is crucial for preventing recurrences and complications arising from excessive or insufficient ablation. Existing imaging modalities lack real-time feedback, and their intraoperative usage is in its early stages. A critical need exists for an imaging-based lesion indexing (LSI) method that directly reflects tissue necrosis formation. Previous studies have indicated that spectroscopic photoacoustic (sPA) imaging can differentiate ablated tissues from their non-ablated counterparts based on PA spectrum variation. In this paper, we introduce a method for detecting ablation lesion boundaries using sPA imaging. This approach utilizes ablation LSI, which quantifies the ratio between the signal from ablated tissue and the total tissue signal. We enhance boundary detection accuracy by adapting a regression model-based compensation. Additionally, the method was cross-validated with clinically used intraoperative monitoring parameters. The proposed method was validated with ex vivo porcine cardiac tissues with necrotic lesions created by different ablation durations. The PA-measured lesion size was compared with gross pathology. Statistical analysis demonstrates a strong correlation (R > 0.90) between the PA-detected lesion size and gross pathology. The PA-detected lesion size also exhibits a moderate to strong correlation (R > 0.75) with local impedance changes recorded during procedures. These results suggest that the introduced PA imaging-based LSI has great potential to be incorporated into the clinical workflow, guiding ablation procedures intraoperatively.

Artificial Intelligence and Machine Learning in Cardiac Electrophysiology.

Cardiac electrophysiology requires the processing of several patient-specific data points in real time to provide an accurate diagnosis and determine an optimal therapy. Expanding beyond the traditional tools that have been used to extract information from patient-specific data, machine learning offers a new set of advanced tools capable of revealing previously unknown data patterns and features. This new tool set can substantially improve the speed and level of confidence with which electrophysiologists can determine patient-specific diagnoses and therapies. The ability to process substantial amounts of data in real time also paves the way to novel techniques for data collection and visualization. Extended realities such as virtual and augmented reality can now enable the real-time visualization of 3-dimensional images in space. This enables improved preprocedural planning and intraprocedural interventions. Machine learning supplemented with novel visualization technologies could substantially improve patient care and outcomes by helping physicians to make more informed patient-specific decisions. This article presents current applications of machine learning and their use in cardiac electrophysiology.

Manifold Approximating Graph Interpolation of Cardiac Local Activation Time.

OBJECTIVE: Local activation time (LAT) mapping of cardiac chambers is vital for targeted treatment of cardiac arrhythmias in catheter ablation procedures. Current methods require too many LAT observations for an accurate interpolation of the necessarily sparse LAT signal extracted from intracardiac electrograms (EGMs). Additionally, conventional performance metrics for LAT interpolation algorithms do not accurately measure the quality of interpolated maps. We propose, first, a novel method for spatial interpolation of the LAT signal which requires relatively few observations; second, a realistic sub-sampling protocol for LAT interpolation testing; and third, a new color-based metric for evaluation of interpolation quality that quantifies perceived differences in LAT maps. METHODS: We utilize a graph signal processing framework to reformulate the irregular spatial interpolation problem into a semi-supervised learning problem on the manifold with a closed-form solution. The metric proposed uses a color difference equation and color theory to quantify visual differences in generated LAT maps. RESULTS: We evaluate our approach on a dataset consisting of seven LAT maps from four patients obtained by the CARTO electroanatomic mapping system during premature ventricular complex (PVC) ablation procedures. Random sub-sampling and re-interpolation of the LAT observations show excellent accuracy for relatively few observations, achieving on average 6% lower error than state-of-the-art techniques for only 100 observations. CONCLUSION: Our study suggests that graph signal processing methods can improve LAT mapping for cardiac ablation procedures. SIGNIFICANCE: The proposed method can reduce patient time in surgery by decreasing the number of LAT observations needed for an accurate LAT map.

RT-RCG: Neural Network and Accelerator Search Towards Effective and Real-time ECG Reconstruction from Intracardiac Electrograms.

There exists a gap in terms of the signals provided by pacemakers (i.e., intracardiac electrogram (EGM)) and the signals doctors use (i.e., 12-lead electrocardiogram (ECG)) to diagnose abnormal rhythms. Therefore, the former, even if remotely transmitted, are not sufficient for doctors to provide a precise diagnosis, let alone make a timely intervention. To close this gap and make a heuristic step towards real-time critical intervention in instant response to irregular and infrequent ventricular rhythms, we propose a new framework dubbed RT-RCG to automatically search for (1) efficient Deep Neural Network (DNN) structures and then (2) corresponding accelerators, to enable Real-Time and high-quality Reconstruction of ECG signals from EGM signals. Specifically, RT-RCG proposes a new DNN search space tailored for ECG reconstruction from EGM signals, and incorporates a differentiable acceleration search (DAS) engine to efficiently navigate over the large and discrete accelerator design space to generate optimized accelerators. Extensive experiments and ablation studies under various settings consistently validate the effectiveness of our RT-RCG. To the best of our knowledge, RT-RCG is the first to leverage neural architecture search (NAS) to simultaneously tackle both reconstruction efficacy and efficiency.

A novel convolutional neural network for reconstructing surface electrocardiograms from intracardiac electrograms and vice versa.

We propose a novel convolutional neural network framework for mapping a multivariate input to a multivariate output. In particular, we implement our algorithm within the scope of 12-lead surface electrocardiogram (ECG) reconstruction from intracardiac electrograms (EGM) and vice versa. The goal of performing this task is to allow for improved point-of-care monitoring of patients with an implanted device to treat cardiac pathologies. We will achieve this goal with 12-lead ECG reconstruction and by providing a new diagnostic tool for classifying five different ECG types. The algorithm is evaluated on a dataset retroactively collected from 14 patients. Correlation coefficients calculated between the reconstructed and the actual ECG show that the proposed convolutional neural network model represents an efficient, accurate, and superior way to synthesize a 12-lead ECG when compared to previous methods. We can also achieve the same reconstruction accuracy with only one EGM lead as input. We also tested the model in a non-patient specific way and saw a reasonable correlation coefficient. The model was also executed in the reverse direction to produce EGM signals from a 12-lead ECG and found that the correlation was comparable to the forward direction. Lastly, we analyzed the features learned in the model and determined that the model learns an overcomplete basis of our 12-lead ECG space. We then use this basis of features to create a new diagnostic tool for classifying different ECG arrhythmia's on the MIT-BIH arrhythmia database with an average accuracy of 0.98.

Functional characterization of fibronectin-separated valve interstitial cell subpopulations in three-dimensional culture.

BACKGROUND AND AIM OF THE STUDY: Myxomatous mitral valves (MVs) contain elevated proportions of myofibroblasts, a valve interstitial cell (VIC) subpopulation that may be important in disease pathogenesis. A novel technique was recently developed for the isolation of VIC myofibroblasts using time-dependent adhesion to fibronectin (FN). Cells that adhere rapidly to FN ('FAST') demonstrate myofibroblast cell phenotype markers, in contrast to cells that fail to adhere after a longer time ('SLOW'). The study aim was to characterize the functionality of these subpopulations using three-dimensional (3D) collagen constructs. METHODS: The VICs were harvested from porcine mitral valve posterior leaflets. FAST and SLOW subpopulations, as well as unseparated VIC populations grown on FN and tissue culture plastic (TCP) (UNSEP FN, UNSEP TCP), were seeded within 3D collagen gels and cultured for three weeks. Collagen gel contraction was assessed throughout the culture duration; the mechanical properties of the resultant collagen constructs were assessed using uniaxial tensile testing. RESULTS: FAST cells demonstrated a greater contraction of collagen gels compared to SLOW cells, particularly after 10 days (p < 0.05). Interestingly, the collagen gel contraction by both FN-separated VIC subpopulations (FAST and SLOW) was greater than for gels seeded with UNSEP TCP VICs (p < 0.05). Further, the contraction of UNSEP FN gels was greater than UNSEP TCP throughout the culture duration (p < OR = 0.002), suggesting that the subculture of VICs on FN potentiated these phenotypic changes. Finally, the collagen constructs seeded with FAST cells were stiffer than those seeded with SLOW, followed by UNSEP TCP (p < 0.001). The same pattern was found for failure stress (p = 0.006). CONCLUSION: Time-dependent adhesion to FN produced a VIC subpopulation (FAST), the function of which in 3D culture was consistent with that of myofibroblasts; FN exposure alone also caused VICs to function similarly to myofibroblasts. This novel isolation method may prove valuable in future studies of myofibroblasts in valve disease.

Alcohol Ablation of Cardiac Tissues Quantified and Evaluated Using CIELAB Euclidean Distances.

Ethanol solubilizes cell membranes, making it useful for various ablation applications. We examined the effect of time and alcohol type on the extent of ablation, quantified as Euclidean distances between color coordinates. We obtained biopsy punch samples (diameter, 6 mm) of left atrial appendage, atrial, ventricular, and septal tissue from porcine hearts and placed them in transwell plates filled with ethanol or methanol for 10, 20, 30, 40, 50, or 60 min. Control samples were taken for each time point. At each time point, samples were collected, cut transversely, and photographed. With use of a custom MATLAB program, all images were analyzed in the CIELAB color space, which is more perceptually uniform than the red-green-blue color space. Euclidean distances were calculated from CIELAB coordinates. The mean and standard error of these distances were analyzed. Two-way analysis of variance was used to test for differences among time points, and 2-tailed t tests, for differences between the alcohol datasets at each time point. Generally, Euclidean distances differed significantly between all time points, except for those immediately adjacent, and methanol produced larger Euclidean distances than ethanol did. Some tissue showed a plateauing effect, potentially indicating transmurality. Mean Euclidean distances effectively indexed alcohol ablation in cardiac tissue. Furthermore, we found that methanol ablated tissue more effectively than ethanol did. With ethanol, the extent of ablation for atrial tissue was largest at 60 min. We conclude that to achieve full transmurality in clinical applications, ethanol must remain in contact with atrial tissue for at least one hour.

Bipolar ablation's unique paradigm: Duration and power as respectively distinct primary determinants of transmurality and steam pop formation.

BACKGROUND: Bipolar radiofrequency (RF) ablation strategies are increasingly used, mainly to target deep myocardial reentrant circuits responsible for ventricular tachycardia that cannot be extinguished with traditional unipolar RF ablation. Because this strategy is novel, factors that affect lesion geometry and steam pop formation require further investigation. OBJECTIVE: To assess the effect of contact force, power, and time on the resulting lesion geometry and the risk of steam pop formation during bipolar RF ablation of thick myocardial tissue. METHODS: A custom ex vivo bipolar ablation model was used to assess lesion formation. A combination of parallel and perpendicular configurations of ablation catheters was used to create lesions by varying force (20g, 30g, or 40g), power (30 or 40 W), and time (20, 30, 45, or 60 seconds). Lesion dimensions and the incidence of steam pops were recorded and then analyzed with binary logistic regression and multiple linear regression. RESULTS: In bipolar ablation, lesion transmurality was most affected by the amount of time RF energy was applied. Durations longer than 20 seconds resulted in lesions deeper than half the tissue thickness. Steam pop formation was more frequent in thinner tissue, at longer ablation times, and at higher powers. CONCLUSION: The parameters assessed in this ex vivo model could be used as guidelines for future in vivo work and clinical evaluation of interventricular septal bipolar ablation.

Synchronized Biventricular Heart Pacing in a Closed-chest Porcine Model based on Wirelessly Powered Leadless Pacemakers.

About 30% of patients with impaired cardiac function have ventricular dyssynchrony and seek cardiac resynchronization therapy (CRT). In this study, we demonstrate synchronized biventricular (BiV) pacing in a leadless fashion by implementing miniaturized and wirelessly powered pacemakers. With their flexible form factors, two pacemakers were implanted epicardially on the right and left ventricles of a porcine model and were inductively powered at 13.56 MHz and 40.68 MHz industrial, scientific, and medical (ISM) bands, respectively. The power consumption of these pacemakers is reduced to µW-level by a novel integrated circuit design, which considerably extends the maximum operating distance. Leadless BiV pacing is demonstrated for the first time in both open-chest and closed-chest porcine settings. The clinical outcomes associated with different interventricular delays are verified through electrophysiologic and hemodynamic responses. The closed-chest pacing only requires the external source power of 0.3 W and 0.8 W at 13.56 MHz and 40.68 MHz, respectively, which leads to specific absorption rates (SARs) 2-3 orders of magnitude lower than the safety regulation limit. This work serves as a basis for future wirelessly powered leadless pacemakers that address various cardiac resynchronization challenges.

Author Correction: Synchronized Biventricular Heart Pacing in a Closed-chest Porcine Model based on Wirelessly Powered Leadless Pacemakers.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Poly(ethylene glycol)-Based Coatings for Bioprosthetic Valve Tissues: Toward Restoration of Physiological Behavior.

Bioprosthetic valves (BPVs) have a limited lifespan in the body necessitating repeated surgeries to replace the failed implant. Early failure of these implants has been linked to various surface properties of the valve. Surface properties of BPVs are significantly different from physiological valves because of the fixation process used when processing the xenograft tissue. To improve the longevity of BPVs, efforts need to be taken to improve the surface properties and shield the implant from the bodily interactions that degrade it. Toward this goal, we evaluated the use of hydrogel coatings to attach to the BPV tissue and impart surface properties that are close to physiological. Hydrogels are well characterized for their biocompatibility and highly tunable surface characteristics. Using a previously published coating method, we deposited hydrogel coatings of poly(ethylene glycol)diacrylate (PEGDA) and poly(ethylene glycol)diacrylamide (PEGDAA) atop BPV samples. Coated samples were evaluated against the physiological tissue and uncoated glutaraldehyde-fixed tissue for deposition of hydrogel, surface adherence, mechanical properties, and fixation properties. Results showed both PEGDA- and PEGDAA-deposited coatings were nearly continuous across the valve leaflet surface. Further, the PEGDA- and PEGDAA-coated samples showed restoration of physiological levels of protein adhesion and mechanical stiffness. Interestingly, the coating process rather than the coating itself altered the material behavior yet did not alter the cross-linking from fixation. These results show that the PEG-based coatings for BPVs can successfully alter surface properties of BPVs and help promote physiological characteristics without interfering with the necessary fixation.

A Review of Integrin-Mediated Endothelial Cell Phenotype in the Design of Cardiovascular Devices.

Sustained biomaterial thromboresistance has long been a goal and challenge in blood-contacting device design. Endothelialization is one of the most successful strategies to achieve long-term thromboresistance of blood-contacting devices, with the endothelial cell layer providing dynamic hemostatic regulation. It is well established that endothelial cell behavior is influenced by interactions with the underlying extracellular matrix (ECM). Numerous researchers have sought to exploit these interactions to generate improved blood-contacting devices by investigating the expression of hemostatic regulators in endothelial cells on various ECM coatings. The ability to select substrates that promote endothelial cell-mediated thromboresistance is crucial to advancing material design strategies to improve cardiovascular device outcomes. This review provides an overview of endothelial cell regulation of hemostasis, the major components found within the cardiovascular basal lamina, and the interactions of endothelial cells with prominent ECM components of the basement membrane. A summary of ECM-mimetic strategies used in cardiovascular devices is provided with a focus on the effects of key adhesion modalities on endothelial cell regulators of hemostasis.

Elucidating the role of graft compliance mismatch on intimal hyperplasia using an ex vivo organ culture model.

There is a growing clinical need to address high failure rates of small diameter (<6 mm) synthetic vascular grafts. Although there is a strong empirical correlation between low patency rates and low compliance of synthetic grafts, the mechanism by which compliance mismatch leads to intimal hyperplasia is poorly understood. To elucidate this relationship, synthetic vascular grafts were fabricated that varied compliance independent of other graft variables. A computational model was then used to estimate changes in fluid flow and wall shear stress as a function of graft compliance. The effect of compliance on arterial remodeling in an ex vivo organ culture model was then examined to identify early markers of intimal hyperplasia. The computational model prediction of low wall shear stress of low compliance grafts and clinical control correlated well with alterations in arterial smooth muscle cell marker, extracellular matrix, and inflammatory marker staining patterns at the distal anastomoses. Conversely, high compliance grafts displayed minimal changes in fluid flow and arterial remodeling, similar to the sham control. Overall, this work supports the intrinsic link between compliance mismatch and intimal hyperplasia and highlights the utility of this ex vivo organ culture model for rapid screening of small diameter vascular grafts. STATEMENT OF SIGNIFICANCE: We present an ex vivo organ culture model as a means to screen vascular grafts for early markers of intimal hyperplasia, a leading cause of small diameter vascular graft failure. Furthermore, a computational model was used to predict the effect of graft compliance on wall shear stress and then correlate these values to changes in arterial remodeling in the organ culture model. Combined, the ex vivo bioreactor system and computational model provide insight into the mechanistic relationship between graft-arterial compliance mismatch and the onset of intimal hyperplasia.