Model Of Human Heart Research Articles

How viscous is the beating heart?: Insights from a computational study.

Understanding tissue rheology is critical to accurately model the human heart. While the elastic properties of cardiac tissue have been extensively studied, its viscous properties remain an issue of ongoing debate. Here we adopt a viscoelastic version of the classical Holzapfel Ogden model to study the viscous timescales of human cardiac tissue. We perform a series of simulations and explore stress-relaxation curves, pressure-volume loops, strain profiles, and ventricular wall strains for varying viscosity parameters. We show that the time window for model calibration strongly influences the parameter identification. Using a four-chamber human heart model, we observe that, during the physiologically relevant time scales of the cardiac cycle, viscous relaxation has a negligible effect on the overall behavior of the heart. While viscosity could have important consequences in pathological conditions with compromised contraction or relaxation properties, we conclude that, for simulations within the physiological range of a human heart beat, we can reasonably approximate the human heart as hyperelastic.

Left Ventricle Biomechanics of Low-Flow, Low-Gradient Aortic Stenosis: A Patient-Specific Computational Model.

This study aimed to create an imaging-derived patient-specific computational model of low-flow, low-gradient (LFLG) aortic stenosis (AS) to obtain biomechanics data about the left ventricle. LFLG AS is now a commonly recognized sub-type of aortic stenosis. There remains much controversy over its management, and investigation into ventricular biomechanics may elucidate pathophysiology and better identify patients for valve replacement. ECG-gated cardiac computed tomography images from a patient with LFLG AS were obtained to provide patient-specific geometry for the computational model. Surfaces of the left atrium, left ventricle (LV), and outflow track were segmented. A previously validated multi-scale, multi-physics computational human heart model was adapted to the patient-specific geometry, yielding a model consisting of 91,000 solid elements. This model was coupled to a virtual circulatory system and calibrated to clinically measured parameters from echocardiography and cardiac catheterization data. The simulation replicated key physiologic parameters within 10% of their clinically measured values. Global LV systolic myocardial stress was 7.1 ± 1.8 kPa. Mean stress of the basal, middle, and apical segments were 7.7 ± 1.8 kPa, 9.1 ± 3.8 kPa, and 6.4 ± 0.4 kPa, respectively. This is the first patient-specific computational model of LFLG AS based on clinical imaging. Low myocardial stress correlated with low ejection fraction and eccentric LV remodeling. Further studies are needed to understand how alterations in LV biomechanics correlates with clinical outcomes of AS.

Design and Development of Caged Ball Heart Valve Using Solid Works

Currently, over 2, 90,000 heart valve surgeries are performed worldwide annually and that number is estimated to triple by 2050. Even though patients with prosthetic valves lead a life relatively free from symptoms, problems like physiological complications and valve failure are significant. To date, all mechanical heart valves are plagued with complications associated with hemolysis and coagulation. These complications are believed to be associated with non-physiological blood flow patterns in the vicinity of the artificial heart valves. The geometry of the valve prosthesis with respect to the mitral valve annulus may significantly affect the flow dynamics in the human heart. It is thus essential to assess the hemodynamics of mitral prosthetic caged ball valve to improve the design of the device. This research work presents a 3D model of the left human heart with optimized mitral caged ball valve engineered by a computational tool (SolidWorks 2009). The performance of the valve like hemodynamics across the valve, stress analysis and physical properties like mass, surface area, etc. is assessed virtually. This limits the need to perform extensive, costly and timeconsuming in-vitro and animal tests. Thus optimization of the caged ball heart valve design facilitates reduction of flow-induced thrombogenicity and reduces the need for post-implant anticoagulants.

Developing 3D Automated Human Heart Model to Teach Abstract Concept of Biology

Models are direct replicas, images, or copies of real objects or figures. They are made in place of the original object and therefore used as such in place of the original. Inability to have access to mammalian internal organs is one of the challenges in teaching some concepts in Biology. Hence, the need to develop a 3-dimensional automated model of the human heart (3-DAMHH) to teach Biology concepts in Ilorin, Nigeria. The study was a developmental research design model. ADDIE model was adopted. The findings of this study revealed that a 3-dimensional (3D) automated model of the human heart was successfully developed with silicon gum, pop, oil paint, hosepipe, pumping devices, transformer, and diode. Findings also revealed that a 3-dimensional automated model of the human heart was cost-effective. This study recommends biology teachers use 3-DAMHH for teaching abstract concepts in biology.
 Abstrak
 Model adalah replika langsung, gambar atau salinan dari benda atau angka nyata yang dibuat sesuai dengan objek aslinya dan karenanya digunakan seperti objek aslinya. Ketidakmampuan untuk mengakses organ dalam mamalia merupakan salah satu tantangan dalam mengajarkan beberapa konsep dalam mata pelajaran Biologi. Oleh karena itu, perlu dikembangkan model jantung manusia otomatis 3 dimensi (3-DAMHH) untuk mengajarkan konsep Biologi. Dalam hal ini ini peneliti mengambil konteks di Ilorin, Nigeria. Penelitian ini merupakan penelitian pengembangan menggunakan model ADDIE. Temuan penelitian ini mengungkapkan bahwa: model jantung manusia otomasi 3 dimensi berhasil dikembangkan dengan permen karet silikon, pop, cat minyak, selang, perangkat pompa, transformator, dan dioda. Temuan lain juga mengungkapkan bahwa model otomatis 3 dimensi jantung manusia hemat biaya. Studi ini merekomendasikan agar para guru Biologi menggunakan 3-DAMHH untuk mengajar konsep abstrak dalam biologi dalam pembelajaran mereka.

Development of a human heart-on-a-chip model using induced pluripotent stem cells, fibroblasts and endothelial cells

Abstract Background The use of animal models in cardiovascular research is associated with two serious, intrinsic problems: inaccuracy in the extrapolation of data obtained from animals such as rodents due to different cardiac physiology and animal ethics. Purpose To develop an artificial human heart model for cardiovascular research using organ-on-a-chip technology and human cells Methods Organ chips made of silicone (polydimethylsiloxane) that have two microfluidic channels, a top channel and a bottom channel, separated by a 50-μm thick membrane with 7-μm pores hexagonally packed at 40-μm intervals (Figure 1), were used in this study. We seeded 10,000 human umbilical vein endothelial cells on the membrane surface in the bottom channel to mimic the vasculature. Next, we seeded a mixture of 100,000 human-induced pluripotent stem cells (hiPSCs) and 50,000 human gingival fibroblasts on the membrane surface in the top channel (Figure 1). Human gingival fibroblasts facilitate cardiac differentiation of hiPSCs [1]. We performed the cardiac differentiation of hiPSCs using a previously described protocol [1]. Culture medium was perfused at a constant rate of 60 μl/h to maintain the culture. Results We observed spontaneous contraction of hiPSC-derived cardiomyocytes 20–26 days after the start of the differentiation protocol. Simultaneously, we conducted live intracellular calcium imaging using a fluorogenic calcium-sensitive dye, Cal-520 AM (5 μM in the culture medium). hiPSC-derived cardiomyocytes exhibited a periodic, coordinated pattern of calcium influx synchronised with their contraction under fluorescence microscopy (Figure 2A). Moreover, we found that the β-adrenergic agonist noradrenaline elevated the heart rate of hiPSC-derived cardiomyocytes on the organ chips in a dose-dependent manner (Figures 2A, B). After observing the contraction and intracellular calcium influx of hiPSC-derived cardiomyocytes, we performed immunocytochemistry. Confocal microscopy indicated that the fluorescent signal obtained from anti-cardiac troponin T antibody staining in the top channel exhibited a typical striated pattern with 1.56±0.12-μm interval that reflected sarcomere structure (Figure 2C, yellow). Moreover, the fluorescent signal obtained from anti-CD31 antibody staining in the bottom channel exhibited a typical pattern at the boundary between cells, which is expected at the cell–cell junction of endothelial cells. Conclusion We developed a human heart-on-a-chip model that was confirmed by the functional response to noradrenaline and the histological evidence of sarcomere structure and vasculature, with a capability of live imaging. We expect that this model would be useful for examining the physiological function and for the pharmacological analysis of not only the normal heart but also the heart that reflects specific patient's pathophysiology using patient-derived hiPSCs. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science Figure 1Figure 2

Fluid dynamics in the human heart: Altered vortex formation and wash-out in mitral regurgitation simulations

Abstract Mitral regurgitation alters the flow conditions in the left ventricle. To account for quantitative changes and to investigate the behavior of different flow components, a realistic computational model of the whole human heart was employed in this study. While performing fluid dynamics simulations, a scalar transport equation was solved to analyze vortex formation and ventricular wash-out for different regurgitation severities. Additionally, a particle tracking algorithm was implemented to visualize single components of the blood flow. We confirmed a significantly lowered volume of the direct flow component as well as a higher vorticity in the diseased case.

Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart

Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences.

Application of 3D printing technology combined with PBL teaching model in teaching clinical nursing in congenital heart surgery: A case-control study.

We aimed to explore the application of three-dimensional (3D) printing technology with problem-based learning (PBL) teaching model in clinical nursing education of congenital heart surgery, and to further improve the teaching quality of clinical nursing in congenital heart surgery. In this study, a total of 132 trainees of clinical nursing in congenital heart surgery from a grade-A tertiary hospital in 2019 were selected and randomly divided into 3D printing group or traditional group. The 3D printing group was taught with 3D printed heart models combined with PBL teaching technique, while the traditional group used conventional teaching aids combined with PBL technique for teaching. After the teaching process, the 2 groups of nursing students were assessed and surveyed separately to evaluate the results. Compared to the traditional group, the theoretical scores, clinical nursing thinking ability, self-evaluation for comprehensive ability, and teaching satisfaction from the questionnaires filled by the 3D printing group were all higher than the traditional group. The difference was found to be statistically significant (P < .05). Our study has shown the 3D printing technology combined with the PBL teaching technique in the clinical nursing teaching of congenital heart surgery achieved good results.

Three-Dimensional Bioprinting for Tissue Engineering and Regenerative Medicine in Down Under: 2020 Australian Workshop Summary.

Three-Dimensional Bioprinting for Tissue Engineering and Regenerative Medicine in Down Under: 2020 Australian Workshop Summary.

Brownian dynamics simulations of the interactions between lactate dehydrogenase (LDH) and G- or F-actin. Part II: mixed isoforms

Experimental studies have shown that many glycolytic enzymes bind cytoskeletal proteins reversibly including lactate dehydrogenase (LDH) and that the interaction may be electrostatic in nature. LDH is particularly interesting because different isoforms have different binding affinities. Herein, Brownian dynamics simulations examine the interactions of mixed LDH isoforms with F-actin based on models of human muscle (M) and heart (H) isoforms and rabbit muscle (M) and heart (H) isoforms built via homology modeling from a variety of mammalian forms of the enzyme. The LDH-mixed tetrameric isoforms, LDH-M3H, LDH-M2H2, LDH-MH3, give distinctive electrostatic potentials and charges; + 6.9 e for human LDH-M3H, −9.4 e for human LDH-MH3, the LDH-M2H2 gives three distinctively different pictures of the electrostatic potential and show different binding affinity depending on the nature of the quaternary structure of the tetramer. If the positive charge patch of LDH-M4 between subunits A/D and subunits B/C, which was identified as the binding site of LDH to F-actin for the muscle isoform (Part I of the companion paper), remains intact on one side of LDH-M2H2, the mixed isoform can still bind F-actin. If, however, the LDH-M2H2 isoform does not maintain this positively charged patch, the mixed isoform does not bind as strongly.

Modelling Diabetic Cardiomyopathy-Associated Dysfunction Using Human Induced Pluripotent Stem Cell-Derived Cardiovascular Cells

Diabetic cardiomyopathy represents a unique cardiac abnormality among type 2 diabetic patients, which predispose them to a higher risk of developing heart failure. Effective therapeutic options for diabetic cardiomyopathy are limited. The development of effective treatment for diabetic cardiomyopathy is impeded by the lack of robust preclinical human models. This project aims to establish a pre-clinical human diabetic heart model using human induced pluripotent stem cells (iPSCs).

Development of a model of human heart using organ-on-a-chip

Development of a model of human heart using organ-on-a-chip

FRESH 3D Bioprinting a Full-Size Model of the Human Heart.

Recent advances in embedded three-dimensional (3D) bioprinting have expanded the design space for fabricating geometrically complex tissue scaffolds using hydrogels with mechanical properties comparable to native tissues and organs in the human body. The advantage of approaches such as Freeform Reversible Embedding of Suspended Hydrogels (FRESH) printing is the ability to embed soft biomaterials in a thermoreversible support bath at sizes ranging from a few millimeters to centimeters. In this study, we were able to expand this printable size range by FRESH bioprinting a full-size model of an adult human heart from patient-derived magnetic resonance imaging (MRI) data sets. We used alginate as the printing biomaterial to mimic the elastic modulus of cardiac tissue. In addition to achieving high print fidelity on a low-cost printer platform, FRESH-printed alginate proved to create mechanically tunable and suturable models. This demonstrates that large-scale 3D bioprinting of soft hydrogels is possible using FRESH and that cardiac tissue constructs can be produced with potential future applications in surgical training and planning.

An Overview of Methods for Cardiac Rhythm Detection in Zebrafish.

The heart is the most important muscular organ of the cardiovascular system, which pumps blood and circulates, supplying oxygen and nutrients to peripheral tissues. Zebrafish have been widely explored in cardiotoxicity research. For example, the zebrafish embryo has been used as a human heart model due to its body transparency, surviving several days without circulation, and facilitating mutant identification to recapitulate human diseases. On the other hand, adult zebrafish can exhibit the amazing regenerative heart muscle capacity, while adult mammalian hearts lack this potential. This review paper offers a brief description of the major methodologies used to detect zebrafish cardiac rhythm at both embryonic and adult stages. The dynamic pixel change method was mostly performed for the embryonic stage. Other techniques, such as kymography, laser confocal microscopy, artificial intelligence, and electrocardiography (ECG) have also been applied to study heartbeat in zebrafish embryos. Nevertheless, ECG is widely used for heartbeat detection in adult zebrafish since ECG waveforms’ similarity between zebrafish and humans is prominent. High-frequency ultrasound imaging (echocardiography) and modern electronic sensor tag also have been proposed. Despite the fact that each method has its benefits and limitations, it is proved that zebrafish have become a promising animal model for human cardiovascular disease, drug pharmaceutical, and toxicological research. Using those tools, we conclude that zebrafish behaviors as an excellent small animal model to perform real-time monitoring for the developmental heart process with transparent body appearance, to conduct the in vivo cardiovascular performance and gene function assays, as well as to perform high-throughput/high content drug screening.

Gaussian Process-Based Spatiotemporal Modeling of Electrical Wave Propagation in Human Atrium.

Rhythm regularity of the heart depends on how electrical impulses spread through the cardiac conduction system. Any abnormal activities in the electrical impulses can lead to serious cardiac disorders or sudden death. It is important to understand the electrical activities of the human heart in both healthy and diseased conditions to determine the cause of cardiac disorders and explore the best therapeutic designs. Mathematical models calibrated with clinical and/or in-vitro data are popularly used to study cardiac function and investigate treatment effects. Most of the current human heart models are highly integrated and couple over a hundred equations across different organizational scales of ion channel, cell, and muscle. The model complex poses a significant computational challenge on cardiac simulation. This study developed a metamodel to replace the time-consuming simulation model. Specifically, Gaussian Process (GP) is used to reconstruct the spatiotemporal variations of the cell membrane potential in left atrium. Four different covariance functions were used to infer the potential distributions. The GP model provides an accurate estimation of the spatiotemporal propagation of electrical waves with a small set of data and shows great advantage in computations as compared to traditional models.

Longitudinal metabolic profiling of cardiomyocytes derived from human-induced pluripotent stem cells.

Human-induced pluripotent stem cells (h-iPSCs) are a unique in vitro model for cardiovascular research. To realize the potential applications of h-iPSCs-derived cardiomyocytes (CMs) for drug testing or regenerative medicine and disease modeling, characterization of the metabolic features is critical. Here, we show the transcriptional profile during stages of cardiomyogenesis of h-iPSCs-derived CMs. CM differentiation was not only characterized by the expression of mature structural components (MLC2v, MYH7) but also accompanied by a significant increase in mature metabolic gene expression and activity. Our data revealed a distinct substrate switch from glucose to fatty acids utilization for ATP production. Basal respiration and respiratory capacity in 9daysh-iPSCs-derived CMs were glycolysis-dependent with a shift towards a more oxidative metabolic phenotype at 14 and 28day old CMs. Furthermore, mitochondrial analysis characterized the early and mature forms of mitochondria during cardiomyogenesis. These results suggest that changes in cellular metabolic phenotype are accompanied by increased O2 consumption and ATP synthesis to fulfill the metabolic needs of mature CMs activity. To further determine functionality, the physiological response of h-iPSCs-derived CMs to β-adrenergic stimulation was tested. These data provide a unique in vitro human heart model for the understanding of CM physiology and metabolic function which may provide useful insight into metabolic diseases as well as novel therapeutic options.

Cardiolipin deficiency elevates susceptibility to a lipotoxic hypertrophic cardiomyopathy

Cardiolipin (CL) is a unique tetra-acyl phospholipid localized to the inner mitochondrial membrane and essential for normal respiratory function. It has been previously reported that the failing human heart and several rodent models of cardiac pathology have a selective loss of CL. A rare genetic disease, Barth syndrome (BTHS), is similarly characterized by a cardiomyopathy due to reduced levels of cardiolipin. A mouse model of cardiolipin deficiency was recently developed by knocking-down the cardiolipin biosynthetic enzyme tafazzin (TAZ KD). These mice develop an age-dependent cardiomyopathy due to mitochondrial dysfunction. Since reduced mitochondrial capacity in the heart may promote the accumulation of lipids, we examined whether cardiolipin deficiency in the TAZ KD mice promotes the development of a lipotoxic cardiomyopathy. In addition, we investigated whether treatment with resveratrol, a small cardioprotective nutraceutical, attenuated the aberrant lipid accumulation and associated cardiomyopathy. Mice deficient in tafazzin and the wildtype littermate controls were fed a low-fat diet, or a high-fat diet with or without resveratrol for 16 weeks. In the absence of obesity, TAZ KD mice developed a hypertrophic cardiomyopathy characterized by reduced left-ventricle (LV) volume (~36%) and 30–50% increases in isovolumetric contraction (IVCT) and relaxation times (IVRT). The progression of cardiac hypertrophy with tafazzin-deficiency was associated with several underlying pathological processes including altered mitochondrial complex I mediated respiration, elevated oxidative damage (~50% increase in reactive oxygen species, ROS), the accumulation of triglyceride (~250%) as well as lipids associated with lipotoxicity (diacylglyceride ~70%, free-cholesterol ~44%, ceramide N:16–35%) compared to the low-fat fed controls. Treatment of TAZ KD mice with resveratrol maintained normal LV volumes and preserved systolic function of the heart. The beneficial effect of resveratrol on cardiac function was accompanied by a significant improvement in mitochondrial respiration, ROS production and oxidative damage to the myocardium. Resveratrol treatment also attenuated the development of cardiac steatosis in tafazzin-deficient mice through reduced de novo fatty acid synthesis. These results indicate for the first time that cardiolipin deficiency promotes the development of a hypertrophic lipotoxic cardiomyopathy. Furthermore, we determined that dietary resveratrol attenuates the cardiomyopathy by reducing ROS, cardiac steatosis and maintaining mitochondrial function.

Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure.

MicroRNAs are small, noncoding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant microRNA expression contributes to the heart failure (HF) phenotype; however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action of microRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF. We found that microRNA-152 (miR-152) expression was upregulated in the failing human heart and experimental animal models of HF. Transgenic mice with cardiomyocyte-specific miR-152 overexpression developed systolic dysfunction (mean difference, -38.74% [95% CI, -45.73% to -31.74%]; P<0.001) and dilated cardiomyopathy. At the cellular level, miR-152 overexpression perturbed mitochondrial ultrastructure and dysregulated key genes involved in cardiomyocyte metabolism and inflammation. Mechanistically, we identified Glrx5 (glutaredoxin 5), a critical regulator of mitochondrial iron homeostasis and iron-sulfur cluster synthesis, as a direct miR-152 target. Finally, a proof-of-concept of the therapeutic efficacy of targeting miR-152 in vivo was obtained by utilizing a locked nucleic acid-based inhibitor of miR-152 (LNA 152) in a murine model of HF subjected to transverse aortic constriction. We demonstrated that animals treated with LNA-152 (n=10) showed preservation of systolic function when compared with locked nucleic acid-control treated animals (n=9; mean difference, 18.25% [95% CI, 25.10% to 11.39%]; P<0.001). The upregulation of miR-152 expression in the failing myocardium contributes to HF pathophysiology. Preclinical evidence suggests that miR-152 inhibition preserves cardiac function in a model of pressure overload-induced HF. These findings offer new insights into the pathophysiology of HF and point to miR-152-Glrx5 axis as a potential novel therapeutic target.

Virtual reality is more efficient in learning human heart anatomy especially for subjects with low baseline knowledge

New technologies make their way into education and one of the most prominent of them is the immersive Virtual Reality (IVR). But the scientific data about its efficiency in the educational process is controversial. In the present study three randomized groups of students, who did not have biological and medical classes amongst their courses, studied human heart anatomy using three different learning methods – a paper (text and images); a 3D interactive human heart model presented on a computer display; an IVR human heart model. Prior and after learning session students performed the test of human heart anatomy with 28 open questions. The IVR group showed the increase of correct answers within the group and compared with other groups. Also, the subjects with lesser baseline knowledge in IVR group showed the greater increase of correct answers following IVR session. The structure and the way how the learning material should be presented in IVR and how it affects the learning outcomes are discussed.

Targeted Remuscularization can Reduce Ventricular Tachycardia (VT) Burden in a Computational Human Heart Model of Post-Myocardial Infarction (MI)

Remuscularization with pluripotent stem cell-derived cardiomyocyte (PSC-CM) patches has been shown to address post-MI muscle deficiency that contributes to heart failure. In preclinical studies, however, arrhythmias have been observed but remain under explored. Specifically, how remuscularization can be optimized remains unknown. We evaluate the effects of transplantation site and PSC-CM alignment in patches in silico using a MRI-based, biophysically-detailed, patient-specific ventricular model of post-MI.