Model Of Human Heart Research Articles

Investigating Cardiac Temperature During Heart Transplantation Using the Static Cold Storage Paradigm.

Static cold storage is a mainstay of the heart transplantation (HTx) process. However, the temperature distribution within the organ at each stage of HTx is unknown. In this study, we aimed to quantify how long it took for the heart to warm up and cool down and the nature of temperature distribution with the organ at each stage of HTx. We used high-fidelity computational time-varying biothermal modeling on an anatomical human heart model to model the HTx process in 5 interdependent stages, including cardioplegia, back-table preparation, static cold storage ice box storage and transport, back-table preparation at the recipient institution and warm-up within the recipient body before cross-clamp release. Results indicate that the heart experiences roller-coaster-like temperature changes in stage, including rapid cool down from body temperature to <10 °C within 15 min in stage 1 with a maximum cooling rate of 5 °C/min. This was followed by cooling and extended duration of temperatures <2 °C in the ice box and rapid warming up to body temperature within 10 min at rates of 2 °C/min and 4 °C/min for the left and right sides, respectively, during implantation. Temperature distribution throughout the heart was heterogeneous, with right-sided temperature change occurring nearly 2× faster than on the left side. We present, for the first time, detailed temperature distributions and evolution at each stage of HTx. Quantification of the rapid and heterogeneous temperature changes is crucial to optimize HTx and improve organ viability.

Fracture risk analysis of a stylet-driven lead for left bundle branch area pacing using a human beating heart model

Abstract Background Left bundle branch area pacing (LBBAP) has emerged as a promising approach to cardiac physiologic pacing. However, the mechanical stress and fracture risk has not been studied for stylet-driven leads implanted in the left bundle branch area (LBBA). Purpose The main purpose of this study was to evaluate the change in curvature during a cardiac cycle when a stylet-driven lead with a rigid distal end was implanted in LBBA and to identify any increased risk of conductor fracture for the LBBAP lead compared to those implanted at the His bundle (HB), traditional right atrium (RA) and right ventricle (RV) locations. Methods A high-resolution, four-dimensional human beating heart model was utilized for simulating the stress on the lead. The bending stiffness of lead body segments was measured with 3-pts bending test and the values were assigned to the finite element model. The curvature change of lead body during one cardiac cycle was measured. The safety factor of lead conductors was calculated using the curvature measurements, the conductor’s endurance limit, and the ultimate stress of the material (MP35N). A higher safety factor indicates better lead durability and lower risk of fracture. A parametric study was also performed to investigate how additional implant factors impact the safety factor of LBBAP leads: lead insertion angle, implant depth, degree of slack, and implant location (Figure 1). Results A total of 8 implant scenarios for LBBAP were defined and tested using the combination of the implant factors described above. Two RV implanted locations were tested: RV apex and RV apical septum. One HBP and one RA implant location were tested. The region with maximum change in curvature for LBBAP lead was at 0-10 mm proximal to the ring electrode (Figure 2A). The maximum change in curvature on the lead body for LBBAP, HBP, RV, and RA implants were: 0.022±0.005 (n=8), 0.033 (n=1), 0.036±0.002 (n=2), and 0.024 mm-1 (n=1), respectively (Figure 2B). The safety factor for the lead conductors for LBBAP, HBP, RV, and RA implants were 5.57±1.35 (n=8), 3.48 (n=1), 4.62±0.04 (n=2), and 4.65 (n=1), respectively (Figure 2C). The highest safety factor among all implant locations was 7.63, corresponding to a LBBAP implant scenario with mid-septum location, a 45 degree lead insertion angle towards apex, 7.5 mm lead depth in the septum, and low lead slack. HBP had the lowest safety factor among all implant locations. Conclusion The stylet-driven lead with a rigid distal end implanted at the left bundle branch area does not introduce any further risk of fracture compared to the HBP or traditional RA/RV implant locations in this computational modeling study.Fig 1: LBBAP implants testedFig 2: Lead curvature and safety factor

Differential effects of mechano-electric feedback mechanisms on whole-heart activation, repolarization, and tension.

The human heart is subject to highly variable amounts of strain during day-to-day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro- and anti-arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano-electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole-heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin-bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch-activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin-bound calcium and stretch-activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano-electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate. KEY POINTS: The electrophysiological and mechanical function of the heart are tightly interrelated by excitation-contraction coupling (ECC) in the forward direction and mechano-electric feedback (MEF) in the reverse direction. While ECC is considered in many state-of-the-art computational models of cardiac electromechanics, less is known about the effect of different MEF mechanisms. Accounting for calcium bound to troponin increases stroke volume and delays repolarization. Geometry-mediated MEF leads to more heterogeneous activation and repolarization with steeper gradients. Both effects combine in an additive way. Non-selective stretch-activated channels as an additional MEF mechanism lead to heterogeneous diastolic transmembrane voltage, higher developed tension and delayed repolarization or afterdepolarizations in highly stretched parts of the atria. The differential and combined effects of these three MEF mechanisms during sinus rhythm activation in a human four-chamber heart model may have implications for arrhythmogenesis, both in terms of substrate (repolarization gradients) and triggers (ectopy).

Human Heart Stabilization using Mathematical Based Model with Proportional Integral and Derivative Controller

This paper presents human heart stabilization using mathematical based with Proportional Integral and Derivative (PID) controller. In order to improve the Hydro Electromechanical System (HEMS) of human heart models found in prior studies, the present paper introduced a PID model that integrates a low pass filter (F) to give a PIDF that provides control signal to adjust the heartbeat rate if it is disturbed and to command the cardiovascular system. The entire system was built and simulated in MATLAB/Simulink environment. The heartbeat model has been applied for steady state study of cardiovascular system when a disease attacks the heart. The result obtained proves the effectiveness of the developed control strategy. Simulation result revealed that the introduction of the PIDF controller ensured the stabilization of the heart to its right working state when compared to the heartbeat response of normal heartbeat.

In Silico Analysis of the MitraClip in a Realistic Human Left Heart Model

Mitral valve regurgitation is a common heart valve disorder associated with significant morbidity and mortality. Transcatheter mitral valve repair using the MitraClip device has emerged as a safe and effective alternative for patients unsuitable for conventional surgery. However, the structural and hemodynamic implications of MitraClip implantation in the left ventricle have not been extensively explored. This study aimed to assess the structural and hemodynamic performance of the MitraClip device using a high-fidelity model of the human heart, specifically focusing on a healthy mitral valve geometry. The implantation of the MitraClip device was simulated using the finite element method for structural analysis and the lattice Boltzmann method for computational flow analysis. MitraClip implantation induced geometrical changes in the mitral valve, resulting in local maxima of principal stress in the valve leaflet regions constrained by the device. Hemodynamic assessment revealed slow-moving nested helical flow near the left ventricular wall and high flow velocities in the apex regions. Vorticity analysis indicated abnormal hemodynamic conditions induced by the double-orifice area configuration of the mitral valve after MitraClip implantation. By predicting possible adverse events and complications in a patient-specific manner, computational modeling supports evidence-based decision making and enhances the overall effectiveness and safety of transcatheter mitral valve repairs.

Microfluidic organ-on-a-chip models of human lungs and heart: A review

A micro-physiological system is another term for an organ-on-a-chip. Due to the idea's widespread use in drug discovery, precision medicine, and drug screening, interest in it has increased recently. The primary message of this article is to illustrate how artificial drug proof can closely imitate the human body in every regard. Important work for a biomimetic system of physiological organs based on a microfluidic chip using cell biology, engineering, and biomaterials technology. In addition, the use and effectiveness of the gut-on-a-chip, liver-on-a-chip, lung-on-a-chip, and heart-on-a-chip are examined. We have discussed the current status of this project, OOC prospects for the future, and opportunities for microfluidic devices and organs on a chip in this section.

Thermomechanical stress analyses of nanowarming-assisted recovery from cryopreservation by vitrification in human heart and rat heart models.

This study investigates thermomechanical stress in cryopreservation by vitrification of the heart, while exploring the effects of nanowarming-assisted recovery from cryogenic storage. This study expands upon a recently published study, combining experimental investigation and thermal analysis of cryopreservation on a rat heart model. Specifically, this study focuses on scenarios with variable concentrations of silica-coated iron-oxide nanoparticles (sIONPs), while accounting for loading limitations associated with the heart physiology, as well as the properties of cryoprotective agent (CPA) solution and the geometry of the container. Results of this study suggest that variable sIONP concentration based on the heart physiology will elevate mechanical stresses when compared with the mathematically simplified, uniform distribution case. The most dangerous part of rewarming is below glass transition and at the onset of nanowarming past the glass transition temperature on the way for organ recovery from cryogenic storage. Throughout rewarming, regions that rewarm faster, such as the chambers of the heart (higher sIONP concentration), undergo compressive stresses, while the slower rewarming regions, such as the heart myocardium (low sIONP concentration), undergo tension. Being a brittle material, the vitrified organ is expected to fail under tension in lower stresses than in compression. Unfortunately, the location and magnitude of the maximum stress in the investigated cases varied, while general rules were not identified. This investigation demonstrates the need to tailor the thermal protocol of heart cryopreservation on a case-by-case basis, since the location, orientation, magnitude, and instant at which the maximum mechanical stress is found cannot be predicted a priori. While thermomechanical stress poses a significant risk to organ integrity, careful design of the thermal protocol can be instrumental in reducing the likelihood of structural damage, while taking full advantage of the benefits of nanowarming.

Biotechnological advances and applications of human pluripotent stem cell-derived heart models.

In recent years, significant biotechnological advancements have been made in engineering human cardiac tissues and organ-like models. This field of research is crucial for both basic and translational research due to cardiovascular disease being the leading cause of death in the developed world. Additionally, drug-associated cardiotoxicity poses a major challenge for drug development in the pharmaceutical and biotechnological industries. Progress in three-dimensional cell culture and microfluidic devices has enabled the generation of human cardiac models that faithfully recapitulate key aspects of human physiology. In this review, we will discuss 3D pluripotent stem cell (PSC)-models of the human heart, such as engineered heart tissues and organoids, and their applications in disease modeling and drug screening.

Soft, bioresorbable, transparent microelectrode arrays for multimodal spatiotemporal mapping and modulation of cardiac physiology

Transparent microelectrode arrays (MEAs) that allow multimodal investigation of the spatiotemporal cardiac characteristics are important in studying and treating heart disease. Existing implantable devices, however, are designed to support chronic operational lifetimes and require surgical extraction when they malfunction or are no longer needed. Meanwhile, bioresorbable systems that can self-eliminate after performing temporary functions are increasingly attractive because they avoid the costs/risks of surgical extraction. We report the design, fabrication, characterization, and validation of a soft, fully bioresorbable, and transparent MEA platform for bidirectional cardiac interfacing over a clinically relevant period. The MEA provides multiparametric electrical/optical mapping of cardiac dynamics and on-demand site-specific pacing to investigate and treat cardiac dysfunctions in rat and human heart models. The bioresorption dynamics and biocompatibility are investigated. The device designs serve as the basis for bioresorbable cardiac technologies for potential postsurgical monitoring and treating temporary patient pathological conditions in certain clinical scenarios, such as myocardial infarction, ischemia, and transcatheter aortic valve replacement.

A role for ultra-high resolution three-dimensional printed human heart models.

Echocardiography is essential for diagnosing and assessing the severity of perioperative structural and functional heart disease. Yet, educational opportunities to better understand echocardiography-based cardiac anatomy remain limited by the two-dimensional display, lack of anatomic details, variability of heart models, and costs and global access of training. We performed micro computed tomography of human heart specimens not suitable for orthotopic transplantation. We created high-resolution computational 3D models of different human hearts, sliced them in the different recommended American Society of Echocardiography views, and 3D printed them using different materials. We scanned, 3D modeled, and 3D printed a variety of human hearts both healthy and diseased. We have made the models available in the cardiac operating rooms and routinely use them for teaching anesthesia residents and cardiothoracic anesthesia fellows about basic and advanced echocardiographic views, cardiopulmonary bypass cannulation strategies, and valvular pathology and planned interventions. We have generated a library of 3D printed hearts to display the recommended echocardiographic views as a unique educational tool designed to safely accelerate the understanding of absolute and relative human cardiac anatomy and pathology, especially related to gaining advanced appreciation of clinically employed perioperative echocardiography.

A multiphysical computational model of myocardial growth adopted to human pathological ventricular remodelling

We present a novel three-dimensional constitutive model that describes an electro-visco-elastic-growth response on the myocardium with a fully implicit staggered solution procedure for the strong electromechanical coupling. The novel formulations of the myocardium allows us to simulate and analyze the remodelling of actively contracting human ventricular heart models which consist of growing viscoelastic myocardium where the growth direction is determined based on its mechanical state at each time step. The total deformation gradient is multiplicatively decomposed into a mechanical-active part and a growth part, where the mechanical-active part is further split into elastic, viscous, and active components. Unconditional stability of time integration is ensured by a backward Euler integration scheme. With the developed model, the myocardium can experience stretch-driven longitudinal (fibre) growth and stress-driven transverse (cross-fibre) growth. To validate the developed approach, two simulations regarding pathological ventricular remodelling are implemented: two divergent types of remodelling of a left ventricular model driven by hemodynamic overloads and ventricular remodelling triggered by acute myocardial ischemia in a biventricular heart model.

Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational drug combinations for effective treatment of a virus that affects multiple organ systems.

Clinical significance of conduction velocity orientation vectors on cardiac mapping surfaces

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Lefoulon Delalande Foundation OBJECTIVE Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using 2D mapping tools. The basis of substrate-based functional assessment is to detect slow zones or slow CV of which isochronal late activation mapping (ILAM) is now commonly performed. We studied the accuracy of mapping surface 2D CV, compared to the 3D vectors, and the influence of mapping resolution in non-scarred animal and human heart models. Methods Two models were used: a healthy porcine Langendorff model with transmural needle electrodes and a computer stimulation model of the ventricles built from an MRI-segmented, excised human heart. Local activation times (LAT) within the 3D volume of the mesh were used to calculate true 3D CVs (direction and velocity) for different pixel resolutions ranging between 500 mm – 4 mm (3D CVs). CV was also calculated for endocardial surface-only LATs (2D CV). Results In the experimental model, surface (2D) CV was faster on the epicardium (0.509 m/s) compared to the endocardium (0.262 m/s, Figure 1). In stimulation models, 2D CV significantly exceeded 3D CVs across all mapping resolutions and increased as resolution decreased (Figure 2). 3D and 2D left ventricle CV at 500mm resolution increased from 429.2±189.3 mm/s to 527.7±253.8 mm/s (P&amp;lt;0.01), respectively with modest correlation (R=0.64). Decreasing the resolution to 4mm significantly increased 2D CV and weakened the correlation (R=0.46). The majority of CV vectors were not parallel (&amp;lt;30°) to the mapping surface providing a potential mechanistic explanation for erroneous LAT-based CV over-estimation. Conclusion Ventricular CV is overestimated when using 2D LAT-based CV calculation of the mapping surface and is significantly compounded by mapping resolution. These findings have implications for the current methodology of functional substrate assessment with ILAM and surface CV assessment.

A comprehensive and biophysically detailed computational model of the whole human heart electromechanics

While ventricular electromechanics is extensively studied in both physiological and pathological conditions, four-chamber heart models have only been addressed recently; most of these works however neglect atrial contraction. Indeed, as atria are characterized by a complex anatomy and a physiology that is strongly influenced by the ventricular function, developing computational models able to capture the physiological atrial function and atrioventricular interaction is very challenging. In this paper, we propose a biophysically detailed electromechanical model of the whole human heart that considers both atrial and ventricular contraction. Our model includes: (i) an anatomically accurate whole-heart geometry; (ii) a comprehensive myocardial fiber architecture; (iii) a biophysically detailed microscale model for the active force generation; (iv) a 0D closed-loop model of the circulatory system, fully-coupled with the mechanical model of the heart; (v) the fundamental interactions among the different core models, such as the mechano-electric feedback or the fibers-stretch and fibers-stretch-rate feedbacks; (vi) specific constitutive laws and model parameters for each cardiac region. Concerning the numerical discretization, we propose an efficient segregated-intergrid-staggered scheme that includes a computationally efficient strategy to handle the non-conductive regions. We also propose extending recent stabilization techniques – regarding the circulation and the fibers-stretch-rate feedback – to the whole heart, demonstrating their cruciality for obtaining a stable formulation in a four-chamber scenario. We are able to reproduce the healthy cardiac function for all the heart chambers, in terms of pressure–volume loops, time evolution of pressures, volumes and fluxes, and three-dimensional cardiac deformation, with volumetric indexes within reference ranges for cardiovascular magnetic resonance. We also show the importance of considering atrial contraction, fibers-stretch-rate feedback and the proposed stabilization techniques, by comparing the results obtained with and without these features in the model. In particular, we show that the fibers-stretch-rate feedback, often neglected due to the numerical challenges that it entails, plays a fundamental role in the regulation of the blood flux ejected by ventricles. The proposed model represents the state-of-the-art electromechanical model of the iHEART ERC project – an Integrated Heart Model for the Simulation of the Cardiac Function – and is a fundamental step toward the building of physics-based digital twins of the human heart.

Performance of an Irrigated Bipolar Radiofrequency Ablation Clamp on Explanted Human Hearts

BackgroundBipolar radiofrequency (RF) clamps are commonly used during surgical ablation for atrial fibrillation (AF). This study examined the efficacy of an irrigated bipolar RF clamp to create transmural lesions in an ex vivo human heart model. MethodsTen donor hearts, turned down for transplantation, were explanted and arrested with cold cardioplegia. The ablations of the Cox Maze IV procedure were performed using the Cardioblate LP (Medtronic, Inc) irrigated bipolar RF clamp. In the first 5 hearts, each lesion was created with a single application of RF, whereas in the remaining 5 hearts, each lesion was created with a double application of RF without unclamping. Each lesion was cross-sectioned and stained with 2,3,5-triphenyl-tetrazolium chloride to assess ablation depth and transmurality. ResultsA total of 100 lesions were analyzed. In the single-ablation group, 222 of 260 sections (85%) and 37 of 50 lesions (74%) were transmural. The efficacy improved significantly in the double-ablation group, in which 348 of 359 sections (97%, P < .001) and 46 of 50 lesions (92%, P = .017) were transmural. Overall, in nontransmural lesions, the epicardial fat thickness was significantly greater (1.69 ± 0.70 mm vs 0.45 ±0.10 mm, P < .001) than the transmural lesions. ConclusionsA single ablation on human atrial tissue with an irrigated bipolar RF clamp was insufficient to reliably create transmural lesions, but a double ablation significantly increased the lesion and section transmurality. Nontransmural lesions were associated with significantly thicker layers of epicardial fat, which likely decreased tissue energy delivery due to the higher resistance of fat to current flow.

A mathematical model that integrates cardiac electrophysiology, mechanics, and fluid dynamics: Application to the human left heart.

We propose a mathematical and numerical model for the simulation of the heart function that couples cardiac electrophysiology, active and passive mechanics and hemodynamics, and includes reduced models for cardiac valves and the circulatory system. Our model accounts for the major feedback effects among the different processes that characterize the heart function, including electro-mechanical and mechano-electrical feedback as well as force-strain and force-velocity relationships. Moreover, it provides a three-dimensional representation of both the cardiac muscle and the hemodynamics, coupled in a fluid-structure interaction (FSI) model. By leveraging the multiphysics nature of the problem, we discretize it in time with a segregated electrophysiology-force generation-FSI approach, allowing for efficiency and flexibility in the numerical solution. We employ a monolithic approach for the numerical discretization of the FSI problem. We use finite elements for the spatial discretization of partial differential equations. We carry out a numerical simulation on a realistic human left heart model, obtaining results that are qualitatively and quantitatively in agreement with physiological ranges and medical images.

Orientation of conduction velocity vectors on cardiac mapping surfaces.

Electroanatomical maps using automated conduction velocity (CV) algorithms are now being calculated using two-dimensional (2D) mapping tools. We studied the accuracy of mapping surface 2D CV, compared to the three-dimensional (3D) vectors, and the influence of mapping resolution in non-scarred animal and human heart models. Two models were used: a healthy porcine Langendorff model with transmural needle electrodes and a computer stimulation model of the ventricles built from an MRI-segmented, excised human heart. Local activation times (LATs) within the 3D volume of the mesh were used to calculate true 3D CVs (direction and velocity) for different pixel resolutions ranging between 500 μm and 4 mm (3D CVs). CV was also calculated for endocardial surface-only LATs (2D CV). In the experimental model, surface (2D) CV was faster on the epicardium (0.509 m/s) compared to the endocardium (0.262 m/s). In stimulation models, 2D CV significantly exceeded 3D CVs across all mapping resolutions and increased as resolution decreased. Three-dimensional and 2D left ventricle CV at 500 μm resolution increased from 429.2 ± 189.3 to 527.7 ± 253.8 mm/s (P < 0.01), respectively, with modest correlation (R = 0.64). Decreasing the resolution to 4 mm significantly increased 2D CV and weakened the correlation (R = 0.46). The majority of CV vectors were not parallel (<30°) to the mapping surface providing a potential mechanistic explanation for erroneous LAT-based CV over-estimation. Ventricular CV is overestimated when using 2D LAT-based CV calculation of the mapping surface and significantly compounded by mapping resolution. Three-dimensional electric field-based approaches are needed in mapping true CV on mapping surfaces.

ETV2 Upregulation Marks the Specification of Early Cardiomyocytes and Endothelial Cells During Co-differentiation.

The ability to differentiate human-induced pluripotent stem cells (hiPSCs) efficiently into defined cardiac lineages, such as cardiomyocytes and cardiac endothelial cells, is crucial to study human heart development and model cardiovascular diseases in vitro. The mechanisms underlying the specification of these cell types during human development are not well understood which limits fine-tuning and broader application of cardiac model systems. Here, we used the expression of ETV2, a master regulator of hematoendothelial specification in mice, to identify functionally distinct subpopulations during the co-differentiation of endothelial cells and cardiomyocytes from hiPSCs. Targeted analysis of single-cell RNA-sequencing data revealed differential ETV2 dynamics in the 2 lineages. A newly created fluorescent reporter line allowed us to identify early lineage-predisposed states and show that a transient ETV2-high-state initiates the specification of endothelial cells. We further demonstrated, unexpectedly, that functional cardiomyocytes can originate from progenitors expressing ETV2 at a low level. Our study thus sheds light on the in vitro differentiation dynamics of 2 important cardiac lineages.

Abstract 10305: A Bioresorbable Pacemaker With Transient Closed-Loop System

Introduction: Conventional temporary pacemakers with percutaneous pacing leads limit patient mobility, create risks for infections, require removal procedures following completion of therapy and demand an additional collection of wired devices to monitor the status of the patient and to provide closed-loop operation. Recently reported wireless, bioresorbable pacemakers avoid the first set of disadvantages, but they must still be paired with conventional wired-based systems for cardiac monitoring, power delivery and control. Methods: We present a bioresorbable pacemaker that combines with a wirelessly networked collection of temporary, body-integrated devices to (1) power, control, and monitor processes of cardiac stimulation, (2) track cardiopulmonary status via comprehensive, multi-modal measurements, (3) provide patient-specific multi-haptic feedback on device and physiological status, and (4) support transient operation through bioresorption and gentle removal from the skin. Results: Data captured from various locations of the body yield detailed information of patient status, across various aspects of cardiopulmonary health and physical activity. The results define autonomous rate-adaptive pacing parameters to match metabolic demand via wireless powering of the bioresorbable module. Operation is possible over extended periods to match clinical needs, enabled by advanced mechanical designs and drug eluting configurations of the battery-free, bioresorbable pacemaker platform. Replacement of the cardiac module can occur in a manner that does not disrupt continuous pacing. The skin-interfaced devices can be easily peeled away for removal after patient recovery, due to their soft, flexible construction. Conclusions: We demonstrate for the first time that a bioresorbable pacemaker with transient closed-loop system is feasible in a clinically relevant, large animal and human whole heart model. Further improvements in this technology could open doors for out of hospital temporary pacing for varying periods of time, without the need for permanent hardware.

Human in vitro neurocardiac coculture (ivNCC) assay development for evaluating cardiac contractility modulation.

Two of the most prominent organ systems, the nervous and the cardiovascular systems, are intricately connected to maintain homeostasis in mammals. Recent years have shown tremendous efforts toward therapeutic modulation of cardiac contractility and electrophysiology by electrical stimulation. Neuronal innervation and cardiac ganglia regulation are often overlooked when developing in vitro models for cardiac devices, but it is likely that peripheral nervous system plays a role in the clinical effects. We developed an in vitro neurocardiac coculture (ivNCC) model system to study cardiac and neuronal interplay using human induced pluripotent stem cell (hiPSC) technology. We demonstrated significant expression and colocalization of cardiac markers including troponin, α-actinin, and neuronal marker peripherin in neurocardiac coculture. To assess functional coupling between the cardiomyocytes and neurons, we evaluated nicotine-induced β-adrenergic norepinephrine effect and found beat rate was significantly increased in ivNCC as compared to monoculture alone. The developed platform was used as a nonclinical model for the assessment of cardiac medical devices that deliver nonexcitatory electrical pulses to the heart during the absolute refractory period of the cardiac cycle, that is, cardiac contractility modulation (CCM) therapy. Robust coculture response was observed at 14 V/cm (5V, 64 mA), monophasic, 2ms pulse duration for pacing and 20 V/cm (7V, 90 mA) phase amplitude, biphasic, 5.14 ms pulse duration for CCM. We observed that the CCM effect and kinetics were more pronounced in coculture as compared to cardiac monoculture, supporting a hypothesis that some part of CCM mechanism of action can be attributed to peripheral nervous system stimulation. This study provides novel characterization of CCM effects on hiPSC-derived neurocardiac cocultures. This innervated human heart model can be further extended to investigate arrhythmic mechanisms, neurocardiac safety, and toxicity post-chronic exposure to materials, drugs, and medical devices. We present data on acute CCM electrical stimulation effects on a functional and optimized coculture using commercially available hiPSC-derived cardiomyocytes and neurons. Moreover, this study provides an in vitro human heart model to evaluate neuronal innervation and cardiac ganglia regulation of contractility by applying CCM pulse parameters that closely resemble clinical setting. This ivNCC platform provides a potential tool for investigating aspects of cardiac and neurological device safety and performance.