Model Of Cardiac Tissue Research Articles

Dynamics of Pivoting Electrical Waves in a Cardiac Tissue Model.

Through a detailed mathematical analysis we seek to advance our understanding of how cardiac tissue conductances govern pivoting (spiral, scroll, rotor, functional reentry) wave dynamics. This is an important problem in cardiology since pivoting waves likely underlie most reentrant tachycardias. The problem is complex, and to advance our methods of analysis we introduce two new tools: a ray tracing method and a moving-interface model. When used in combination with an ionic model, they permit us to elucidate the role played by tissue conductances on pivoting wave dynamics. Specifically we simulate traveling electrical waves with an ionic model that can reproduce the characteristics of plane and pivoting waves in small patches of cardiac tissue. Then ray tracing is applied to the simulated pivoting waves in a manner to expose their real displacement. In this exercise we find loci with special characteristics, as well as zones where a part of a pivoting wave quickly transitions from a regenerative to a non-regenerative propagation mode. The loci themselves and the monitoring of the ionic model state variables in this zone permit to elucidate several aspects of pivoting wave dynamics. We then formulate the moving-interface model based on the information gathered with the above-mentioned analysis. Equipped with a velocity profile v(s), s: distance along of the pivoting wave contour and the steady- state action potential duration (APD) of a plane wave during entrainment, APDss(T), at period T, this simple model can predict: shape, orbit of revolution, rotation period, whether a pivoting wave will break up or not, and whether the tissue will admit pivoting waves or not. Because v(s) and APDss(T) are linked to the ionic model, dynamical analysis with the moving-interface model conveys information on the role played by tissue conductances on pivoting wave dynamics. The analysis conducted here enables us to better understand previous results on the termination of pivoting waves. We surmise the method put forth here could become a means to discover how to alter tissue conductances in a manner to terminate pivoting waves at the origin of reentrant tachycardias.

Effects of mechano-electrical feedback on the onset of alternans: A computational study.

Cardiac alternans is a heart rhythm instability that is associated with cardiac arrhythmias and may lead to sudden cardiac death. The onset of this instability, which is linked to period-doubling bifurcation and may be a route to chaos, is of particular interest. Mechano-electric feedback depicts the effects of tissue deformation on cardiac excitation. The main effect of mechano-electric feedback is delivered via the so-called stretch-activated ion channels and is caused by stretch-activated currents. Mechano-electric feedback, which is believed to have proarrhythmic and antiarrhythmic effects on cardiac electrophysiology, affects the action potential duration in a manner dependent on cycle length, but the mechanisms by which this occurs remain to be elucidated. In this study, a biophysically detailed electromechanical model of cardiac tissue is employed to show how a stretch-activated current can affect the action potential duration at cellular and tissue levels, illustrating its effects on the onset of alternans. Also, using a two-dimensional iterated map that incorporates stretch-activated current effects, we apply linear stability analysis to study the stability of the bifurcation. We show that alternans bifurcation can be prevented depending on the strength of the stretch-activated current.

In vitro aged, hiPSC-origin engineered heart tissue models with age-dependent functional deterioration to study myocardial infarction

Deaths attributed to ischemic heart disease increased by 41.7% from 1990 to 2013. This is primarily due to an increase in the aged population, however, research on cardiovascular disease (CVD) has been overlooking aging, a well-documented contributor to CVD. The use of young animals is heavily preferred due to lower costs and ready availability, despite the prominent differences between young and aged heart structure and function. Here we present the first human induced pluripotent stem cell (hiPSC)-derived cardiomyocyte (iCM)-based, in vitro aged myocardial tissue model as an alternative research platform. Within 4 months, iCMs go through accelerated senescence and show cellular characteristics of aging. Furthermore, the model tissues fabricated using aged iCMs, with stiffness resembling that of aged human heart, show functional and pharmacological deterioration specific to aged myocardium. Our novel tissue model with age-appropriate physiology and pathology presents a promising new platform for investigating CVD or other age-related diseases. Statement of SignificanceIn vitro and in vivo models of cardiovascular disease are aimed to provide crucial insight on the pathology and treatment of these diseases. However, the contribution of age-dependent cardiovascular changes is greatly underestimated through the use of young animals and premature cardiomyocytes. Here, we developed in vitro aged cardiac tissue models that mimic the aged heart tissue microenvironment and cellular phenotype and present the first evidence that age-appropriate in vitro disease models can be developed to gain more physiologically-relevant insight on development, progression, and amelioration of cardiovascular diseases.

Decellularized extracellular matrix bioinks and the external stimuli to enhance cardiac tissue development in vitro

Engineered heart tissue (EHT) has ample potential as a model for in vitro tissue modeling or tissue regeneration. Using 3D cell printing technology, various hydrogels have been utilized as bioinks to fabricate EHT to date. However, its efficacy has remained limited due to poor functional properties of the cultured cardiomyocytes stemming from a lack of proper microenvironmental cues. Specifically, the surrounding matrix plays a key role in modulating cardiomyocyte differentiation and maturation. Recently, the use of heart tissue-derived extracellular matrix (hdECM) bioink has come to be seen as one of the most promising candidates due to its functional and structural similarities to native tissue. Here, we demonstrated a correlation between the synthesis of cardiomyocyte-specific proteins and the surrounding microenvironment irrespective of the similar material chemistry. Primary cardiomyocytes isolated from neonatal rats were encapsulated in different composition and concentration of bioinks (hdECM and collagen). The bioinks were sequentially printed using an extrusion-based 3D bioprinter and cultured either statically or dynamically. Qualitative and quantitative evaluation revealed enhanced maturation of cardiomyocytes in hdECM, unlike the collagen group under similar culture conditions. Specifically, 3D-printed EHT using a low concentration of hdECM promoted early differentiation of cardiomyocytes. Hence, the present study provides experimental insights regarding the establishment of a 3D-printed cardiac tissue model, highlighting that the matrix and the culture microenvironment can be decisive factors for cell-material interactions that affect cardiomyocyte maturation. Statement of SignificanceThe regulation of signal transduction and responses to extracellular matrices (ECMs) is of particular relevance in tissue maturation. In particular, there is a clear need to understand the structural and phenotypical modulation in cardiomyocytes with respect to the surrounding microenvironment. Exploration of the key regulators, such as the compositional and the biophysical properties of bioinks associated directly with cell-cell and cell-matrix interactions would assist with the fabrication of cardiac tissue constructs with enhanced functionality. Hence, we documented the synergistic effects of surrounding matrices and culture conditions on the maturation of cardiomyocytes. Additionally, we highlighted the potential of using 3D bioprinting techniques to fabricate uniformly aligned cardiac constructs for mid- to high-throughput drug testing platforms that have great reproducibility and versatility.

Implementation of scalable bidomain-based 3D cardiac simulations on a graphics processing unit cluster

Computational models of the human cardiac cells provide detailed properties of human ventricular cells. The execution time for a realistic 3D heart simulation based on these models is a major barrier for physicians to study and understand the heart diseases, and evaluate hypotheses rapidly toward developing treatments. Graphics processing unit (GPU)-based parallelization efforts to this date have been shown to be more effective than parallelization efforts on the CPU-based clusters in terms of addressing the 3D cardiac simulation time challenge. In this paper, we review all GPU-based studies and investigate both the cardiac cell models and cardiac tissue models in 3D space. We propose algorithmic optimizations based on red black successive over-relaxation method for reducing the number of simulation iterations and convergence method for dependence elimination between neighboring cells of the heart tissue. We investigate data transfer reduction and 2D mesh partitioning strategies, evaluate their impact on thread utilization, and propose a strongly scalable cardiac simulation. Our implementation results with reducing the execution time by a factor of five compared to the state-of-the-art baseline implementation. More importantly, our implementation is an important step toward achieving real-time cardiac simulations as it achieves the strongest scalability among all other cluster-based implementations.

A demonstration of modularity, reuse, reproducibility, portability and scalability for modeling and simulation of cardiac electrophysiology using Kepler Workflows.

Multi-scale computational modeling is a major branch of computational biology as evidenced by the US federal interagency Multi-Scale Modeling Consortium and major international projects. It invariably involves specific and detailed sequences of data analysis and simulation, often with multiple tools and datasets, and the community recognizes improved modularity, reuse, reproducibility, portability and scalability as critical unmet needs in this area. Scientific workflows are a well-recognized strategy for addressing these needs in scientific computing. While there are good examples if the use of scientific workflows in bioinformatics, medical informatics, biomedical imaging and data analysis, there are fewer examples in multi-scale computational modeling in general and cardiac electrophysiology in particular. Cardiac electrophysiology simulation is a mature area of multi-scale computational biology that serves as an excellent use case for developing and testing new scientific workflows. In this article, we develop, describe and test a computational workflow that serves as a proof of concept of a platform for the robust integration and implementation of a reusable and reproducible multi-scale cardiac cell and tissue model that is expandable, modular and portable. The workflow described leverages Python and Kepler-Python actor for plotting and pre/post-processing. During all stages of the workflow design, we rely on freely available open-source tools, to make our workflow freely usable by scientists.

Hemodynamic Stimulation Using the Biomimetic Cardiac Tissue Model (BCTM) Enhances Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Human induced pluripotent stem cell (hiPSC)-derived cardio­myocytes (hiPSC-CMs) hold great promise for cardiovascular disease modeling and regenerative medicine. However, these cells are both structurally and functionally ­immature, primarily due to their differentiation into cardiomyocytes occurring under static culture which only reproduces biomolecular cues and ignores the dynamic hemo­dynamic cues that shape early and late heart development during cardiogenesis. To evaluate the effects of hemodynamic stimuli on hiPSC-CM maturation, we used the biomimetic cardiac tissue model to reproduce the hemodynamics and pressure/volume changes associated with heart development. Following 7 days of gradually increasing stimulation, we show that hemodynamic loading results in (a) enhanced alignment of the cells and extracellular matrix, (b) significant increases in genes associated with physiological hypertrophy, (c) noticeable changes in sarcomeric organization and potential changes to cellular metabolism, and (d) a significant increase in fractional shortening, suggestive of a positive force frequency response. These findings suggest that culture of hiPSC-CMs under conditions that accurately reproduce hemodynamic cues results in structural orga­nization and molecular signaling consistent with organ growth and functional maturation.

3094 Production of Engineered Cardiac Tissue for Disease Modeling

OBJECTIVES/SPECIFIC AIMS: Cardiovascular diseases (CVD) is the leading cause of death worldwide in both men and women due to lack of cardiac regeneration after disease or damaged is caused. There are many challenges to studying CVD since native cardiomyocytes cannot be cultured in vitro. With the advancements in biomaterial and pluripotent stem cells research, scientists are now able to produce engineered cardiac tissue models in vitro that mimic the native myocardium. This study shows our methods for producing engineered cardiac tissue with potential applications in cardiac regeneration, disease modeling, and scalable production. METHODS/STUDY POPULATION: In this study, human induced pluripotent stem cells (hiPSCs) were combined with two different photocrosslinkable hybrid biomaterials, poly (ethylene)- glycol fibrinogen (PF) and gelatin methacrylate (GelMa), in various tissue geometries to form 3D human engineered cardiac tissues (3D-hECTs). To study tissue growth and contraction, image and video analysis was performed at specific timepoints. To analyze differentiation efficiency and cell population, flow cytometry was performed using cardiac markers. To evaluate gene expression, qPCR was performed using pluripotency and cardiac specific primers. RESULTS/ANTICIPATED RESULTS: Direct cardiac differentiation of encapsulated hiPSCs resulted in synchronously contracting 3D-hECTs in both biomaterials and all tissue geometries. Spontaneous contractions started on Day 7 and increased in velocity, frequency, and synchronicity over time. 3D-hECTs had high cell viability with > 70% of cells positive for cardiac markers. Engineered tissues showed appropriate temporal changes in gene expression over time with pluripotency gene expression decreasing and cardiac gene expression increasing. DISCUSSION/SIGNIFICANCE OF IMPACT: This study shows the potential for direct differentiation of encapsulated hiPSCs to produce physiologically relevant engineered cardiac tissues. Resulting 3D-hECTS showed features of mature myocardium with appropriate cardiomyocyte populations, mechanical motion, and gene expression. Using this platform, we are able to produce engineered cardiac tissue in a variety of biomaterials and tissue geometries to study new therapeutics, mechanism of disease, and scalable tissue culture.

Simulation of spiral wave superseding in the Luo–Rudy anisotropic model of cardiac tissue with circular-shaped fibres

Abnormal excitation of the heart can cause cardiac arrhythmias, which may result in cardiac arrest and sudden cardiac death. Currently, the most efficient way to stop lethal cardiac arrhythmias is high-voltage defibrillation. This method is extremely effective. However, it has serious disadvantages, as it is painful and can damage the heart. In this paper, we studied in-silico process of overdrive pacing of arrhythmia sources, which in some cases can also stop cardiac arrhythmias and does not require the application of high voltages. We investigated this process in the Luo–Rudy ionic model for cardiac cells and in case of circular anisotropy of cardiac tissue. We showed that we could efficiently remove the arrhythmia sources in the form of rotating spiral waves in such a system in a certain parameter range. However, anisotropy by itself can cause additional dynamics of the spiral waves: drift and break up. We studied manifestations of these effects and discussed their possible effects on the overdrive pacing. This paper is an extended version of the paper [1] which was submitted to the ICCS 2018 conference proceedings.

Rapid 3D bioprinting of in vitro cardiac tissue models using human embryonic stem cell-derived cardiomyocytes

There is a great need for physiologically relevant 3D human cardiac scaffolds for both short-term, the development of drug testing platforms to screen new drugs across different genetic backgrounds, and longer term, the replacement of damaged or non-functional cardiac tissue after injury or infarction. In this study, we have designed and printed a variety of scaffolds for in vitro diagnostics using light based Micro-Continuous Optical Printing (µCOP). Human embryonic stem cell-derived cardiomyocyte (hESC-CMs) were directly printed into gelatin hydrogel on glass to determine their viability and ability to align. The incorporation of Green Fluorescent Protein/Calmodulin/M13 Peptide (GCaMP3)-hESC-CMs allowed the ability to continuously monitor calcium transients over time. Normalized fluorescence of GCaMP3-hESC-CMs increased by 18 ± 6% and 40 ± 5% when treated with 500 nM and 1 µM of isoproterenol, respectively. Finally, GCaMP3-hESC-CMs were printed across a customizable 3D printed cantilever-based force system. Along with force tracking by visualizing the displacement of the cantilever, calcium transients could be observed in a non-destructive manner, allowing the samples to be examined over several days. Our µCOP-printed cardiac models presented here can be used as a powerful tool for drug screening and to analyze cardiac tissue maturation.

3D printed micro-scale force gauge arrays to improve human cardiac tissue maturation and enable high throughput drug testing

Human induced pluripotent stem cell – derived cardiomyocytes (iPSC-CMs) are regarded as a promising cell source for establishing in-vitro personalized cardiac tissue models and developing therapeutics. However, analyzing cardiac force and drug response using mature human iPSC-CMs in a high-throughput format still remains a great challenge. Here we describe a rapid light-based 3D printing system for fabricating micro-scale force gauge arrays suitable for 24-well and 96-well plates that enable scalable tissue formation and measurement of cardiac force generation in human iPSC-CMs. We demonstrate consistent tissue band formation around the force gauge pillars with aligned sarcomeres. Among the different maturation treatment protocols we explored, 3D aligned cultures on force gauge arrays with in-culture pacing produced the highest expression of mature cardiac marker genes. We further demonstrated the utility of these micro-tissues to develop significantly increased contractile forces in response to treatment with isoproterenol, levosimendan, and omecamtiv mecarbil. Overall, this new 3D printing system allows for high flexibility in force gauge design and can be optimized to achieve miniaturization and promote cardiac tissue maturation with great potential for high-throughput in-vitro drug screening applications. Statement of SignificanceThe application of iPSC-derived cardiac tissues in translatable drug screening is currently limited by the challenges in forming mature cardiac tissue and analyzing cardiac forces in a high-throughput format. We demonstrate the use of a rapid light-based 3D printing system to build a micro-scale force gauge array that enables scalable cardiac tissue formation from iPSC-CMs and measurement of contractile force development. With the capability to provide great flexibility over force gauge design as well as optimization to achieve miniaturization, our 3D printing system serves as a promising tool to build cardiac tissues for high-throughput in-vitro drug screening applications.

Abstract 16773: Ablation of Cardiac Myosin Binding Protein-C in Human iPSC- Engineered Cardiac Tissue Model Causes Increased Calcium Sensitivity and Accelerated Contractile Kinetics

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease that can cause sudden cardiac arrest, diastolic dysfunction and heart failure. Mutations in cardiac myosin binding protein-C (cMyBP-C), a regulator of contractility, are among the most prevalent causes of HCM. cMyBP-C truncation mutations may affect as many as 1 in 1,600 Americans. Though murine models of cMyBP-C ablation have aided in understanding the role of cMyBP-C in health and disease, they are limited by differences in cardiac physiology between mice and humans. iPSC technology now allows researchers to study the effect of HCM mutations in iPSC-derived cardiomyocytes from HCM patients and controls, however differences in genetic background between patients and controls and clonal variation remain confounders. We hypothesized that cMyBP-C ablation in human cardiomyocytes would primarily alter cardiac contractility. CRISPR/Cas9 was used to introduce frame shift mutations in cMyBP-C in the well characterized DF19-9-11T human iPSC line. Human iPSCs were differentiated into cardiomyocytes and then cast into an integrated 3D engineered cardiac tissue (ECT) model for functional testing against non-targeted isogenic controls. Homozygous cMyBP-C ablation significantly accelerated contraction (CT 100 = 219±3 vs. 235±5ms; p = 0.02) and early relaxation (RT 50 = 144±2 vs. 167±4ms; p <0.001), while late relaxation was slowed (RT 50-90 = 127±2 vs. 112±2ms; p <0.001; n=6 for each group). These accelerated contractile kinetics were accompanied by a significantly blunted response to adrenergic stimulation and an increase in Ca 2+ sensitivity. Heterozygous cMyBP-C ablation resulted in acceleration in relaxation kinetics (RT 50 = 148±7 vs. 167±4ms; p = 0.04 and RT 50-90 = 96±4 vs. 112±2ms; p = 0.002), without significantly affecting the rate of contraction. The accelerated kinetics of contraction and early relaxation in cMyBP-C null ECT provides important human evidence that cMyBP-C acts as a brake on cardiac contractility. These data provide strong evidence that the human model system can be used to study the function of cMyBP-C and provide a platform to test therapies that may rectify the contractile defects caused by cMyBP-C haploinsufficiency.

Abstract 17349: The Biomimetic Cardiac Tissue Model (BCTM) Reproduces the Pathological Remodeling Seen in Hypertrophic and Dilated Cardiomyopathy

Introduction: Cardiovascular research and regenerative strategies have been significantly limited by the lack of relevant cell culture systems that can recreate complex hemodynamic stresses associated with pressure-volume changes in the heart. To address this issue, we designed a Biomimetic Cardiac Tissue Model (BCTM) where encapsulated cardiac cells can be cultured in 3D fibers and subjected to hemodynamic loading to mimic pressure-volume changes seen in the left ventricle. Hypothesis: We tested the hypothesis that stimulation under hemodynamic loads as seen in pressure and volume overload is capable of reproducing the pathological remodeling seen in vivo. Methods: The 3D fibers are suspended between two posts within a pumping chamber that is integrated within a flow loop. Various parameters associated with heart function like heart rate, peak-systolic pressure, end-diastolic pressure and volume, end-systolic pressure and volume, and duration ratio between systolic and diastolic can all be precisely manipulated allowing culture of various cardiac cell types under developmental, normal, and disease states. Using the BCTM we reproduced the pathophysiological mechanical stresses of pressure overload and volume overload. Results: Using H9c2 cells, a cardiomyogenic cell line, our results clearly show that culture within the BCTM under pathological hemodynamic loads accurately induces morphological and gene expression changes similar to those seen in both hypertrophic and dilated cardiomyopathies in vivo . Cells within the BCTM under pressure overload see increased hypertrophic remodeling and fibrosis whereas cells subject to prolonged volume overload experience significant changes to cellular aspect ratio through thinning and elongation of the engineered tissue. Conclusions: These results clearly demonstrate that the BCTM can accurately reproduce pathological remodeling and create highly relevant models for cardiovascular disease modeling.

Localized modulated wave solution of diffusive FitzHugh–Nagumo cardiac networks under magnetic flow effect

Motivated by often non-observance clinical effects attributed to some pathological heart diseases, we obtain in this paper the analytical solutions describing localized nonlinear excitations in an improved diffusive FitzHugh–Nagumo cardiac tissue model. The improved model includes the magnetic flux variable used to describe the effect of electromagnetic induction created by fluctuation in ionic concentration during the period when signals are initiated and propagated in the heart. To be consistent with physical units, memristor is used to achieve coupling between membrane potential and magnetic flux such that the induced current from electromagnetic induction is approached. Using the specific reductive perturbation approach in the semi-discrete approximation limit, we show that the whole system dynamics is governed by a modified complex Ginzburg–Landau equation, whose coefficients are dependent on memristive feedback gain. This suggests from biophysical point of view that cardiac electrical signals or waves initiated from the heart sinus node propagates in cardiac networks both in temporal and spatial dimensions in the form of a localized modulated solitonic wave thereby regulating heartbeat as powerful pacemaker. Our analytical solutions are then verified through numerical experiments.

A microscale biomimetic platform for generation and electro-mechanical stimulation of 3D cardiac microtissues.

Organs-on-chip technology has recently emerged as a promising tool to generate advanced cardiac tissue in vitro models, by recapitulating key physiological cues of the native myocardium. Biochemical, mechanical, and electrical stimuli have been investigated and demonstrated to enhance the maturation of cardiac constructs. However, the combined application of such stimulations on 3D organized constructs within a microfluidic platform was not yet achieved. For this purpose, we developed an innovative microbioreactor designed to provide a uniform electric field and cyclic uniaxial strains to 3D cardiac microtissues, recapitulating the complex electro-mechanical environment of the heart. The platform encompasses a compartment to confine and culture cell-laden hydrogels, a pressure-actuated chamber to apply a cyclic uniaxial stretch to microtissues, and stainless-steel electrodes to accurately regulate the electric field. The platform was exploited to investigate the effect of two different electrical stimulation patterns on cardiac microtissues from neonatal rat cardiomyocytes: a controlled electric field [5 V/cm, or low voltage (LV)] and a controlled current density [74.4 mA/cm2, or high voltage (HV)]. Our results demonstrated that LV stimulation enhanced the beating properties of the microtissues. By fully exploiting the platform, we combined the LV electrical stimulation with a physiologic mechanical stretch (10% strain) to recapitulate the key cues of the native cardiac microenvironment. The proposed microbioreactor represents an innovative tool to culture improved miniaturized cardiac tissue models for basic research studies on heart physiopathology and for drug screening.

Analysis of heterogeneous cardiac pacemaker tissue models and traveling wave dynamics

The sinoatrial-node (SAN) is a complex heterogeneous tissue that generates a stable rhythm in healthy hearts, yet a general mechanistic explanation for when and how this tissue remains stable is lacking. Although computational and theoretical analyses could elucidate these phenomena, such methods have rarely been used in realistic (large-dimensional) gap-junction coupled heterogeneous pacemaker tissue models. In this study, we adapt a recent model of pacemaker cells (Severi et al., 2012), incorporating biophysical representations of ion channel and intracellular calcium dynamics, to capture physiological features of a heterogeneous population of pacemaker cells, in particular “center” and “peripheral” cells with distinct intrinsic frequencies and action potential morphology. Large-scale simulations of the SAN tissue, represented by a heterogeneous tissue structure of pacemaker cells, exhibit a rich repertoire of behaviors, including complete synchrony, traveling waves of activity originating from periphery to center, and transient traveling waves originating from the center. We use phase reduction methods that do not require fully simulating the large-scale model to capture these observations. Moreover, the phase reduced models accurately predict key properties of the tissue electrical dynamics, including wave frequencies when synchronization occurs, and wave propagation direction in a variety of tissue models. With the reduced phase models, we analyze the relationship between cell distributions and coupling strengths and the resulting transient dynamics. Further, the reduced phase model predicts parameter regimes of irregular electrical dynamics. Thus, we demonstrate that phase reduced oscillator models applied to realistic pacemaker tissue is a useful tool for investigating the spatial-temporal dynamics of cardiac pacemaker activity.

Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload

The integration of in vitro cardiac tissue models, human induced pluripotent stem cells (hiPSCs) and genome-editing tools allows for the enhanced interrogation of physiological phenotypes and the recapitulation of disease pathologies. Here, in a cardiac tissue model consisting of filamentous 3D matrices populated with cardiomyocytes (CMs) derived from healthy wild-type hiPSCs (WT hiPSC-CMs) or from isogenic hiPSCs deficient in the sarcomere protein cardiac myosin binding protein C (MYBPC3−/− hiPSC-CMs), we show that the WT microtissues adapted to the mechanical environment with increased contraction force commensurate to matrix stiffness, whereas the MYBPC3−/− microtissues exhibited impaired force-development kinetics regardless of matrix stiffness and deficient contraction force only when grown on matrices with high fiber stiffness. Under mechanical overload, the MYBPC3−/− microtissues had a higher degree of calcium transient abnormalities, and exhibited an accelerated decay of calcium dynamics as well as calcium desensitization, which accelerated when contracting against stiffer fibers. Our findings suggest that MYBPC3 deficiency and the presence of environmental stresses synergistically lead to contractile deficits in the cardiac tissues.

A multi-cellular 3D bioprinting approach for vascularized heart tissue engineering based on HUVECs and iPSC-derived cardiomyocytes

The myocardium behaves like a sophisticated orchestra that expresses its true potential only if each member performs the correct task harmonically. Recapitulating its complexity within engineered 3D functional constructs with tailored biological and mechanical properties, is one of the current scientific priorities in the field of regenerative medicine and tissue engineering. In this study, driven by the necessity of fabricating advanced model of cardiac tissue, we present an innovative approach consisting of heterogeneous, multi-cellular constructs composed of Human Umbilical Vein Endothelial Cells (HUVECs) and induced pluripotent cell-derived cardiomyocytes (iPSC-CMs). Cells were encapsulated within hydrogel strands containing alginate and PEG-Fibrinogen (PF) and extruded through a custom microfluidic printing head (MPH) that allows to precisely tailor their 3D spatial deposition, guaranteeing a high printing fidelity and resolution. We obtained a 3D cardiac tissue compose of iPSC-derived CMs with a high orientation index imposed by the different defined geometries and blood vessel-like shapes generated by HUVECs which, as demonstrated by in vivo grafting, better support the integration of the engineered cardiac tissue with host’s vasculature.

Propagation of Parametric Uncertainty in Aliev-Panfilov Model of Cardiac Excitation.

Models of cardiac electrophysiology are useful for studying heart functions and cardiac disease mechanisms. However, cardiac models often have a great level of complexity, and it is often computationally prohibitive to simulate tissue and organ activities in a real-time fashion. To address the challenge, simplified models such as Aliev-Panfilov model are developed to reduce model complexity, while providing necessary details of cardiac functions. Simplified models may induce uncertainty, which can deteriorate the accuracy and reliability of cardiac models. In addition, model parameters are calibrated with noisy data and cannot be known with certainty. It is important to assess the effect of parametric uncertainty on model predictions. For the probabilistic, time-invariant parametric uncertainty, a generalized polynomial chaos (gPC) expansion-based method is presented in this work to quantify and propagate uncertainty onto model predictions. Using gPC, a measure of confidence in model predictions can be quickly estimated. As compared with sampling-based uncertainty propagation techniques, e.g., Monte Carlo (MC) simulations, the gPC-based method in this work shows its advantages in terms of computational efficiency and accuracy, which has the potentials for dealing with complicated cardiac models, e.g., 2D tissue and 3D organ models.

Mechanical perturbation control of cardiac alternans.

Cardiac alternans is a disturbance in heart rhythm that is linked to the onset of lethal cardiac arrhythmias. Mechanical perturbation control has been recently used to suppress alternans in cardiac tissue of relevant size. In this control strategy, cardiac tissue mechanics are perturbed via active tension generated by the heart's electrical activity, which alters the tissue's electric wave profile through mechanoelectric coupling. We analyze the effects of mechanical perturbation on the dynamics of a map model that couples the membrane voltage and active tension systems at the cellular level. Therefore, a two-dimensional iterative map of the heart beat-to-beat dynamics is introduced, and a stability analysis of the system of coupled maps is performed in the presence of a mechanical perturbation algorithm. To this end, a bidirectional coupling between the membrane voltage and active tension systems in a single cardiac cell is provided, and a discrete form of the proposed control algorithm, that can be incorporated in the coupled maps, is derived. In addition, a realistic electromechanical model of cardiac tissue is employed to explore the feasibility of suppressing alternans at cellular and tissue levels. Electrical activity is represented in two detailed ionic models, the Luo-Rudy 1 and the Fox models, while two active contractile tension models, namely a smooth variant of the Nash-Panfilov model and the Niederer-Hunter-Smith model, are used to represent mechanical activity in the heart. The Mooney-Rivlin passive elasticity model is employed to describe passive mechanical behavior of the myocardium.