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In this work, we investigate deterministic mechanisms that generate and perpetuate flutter and fibrillation in the right atrium of the human heart using mathematical models and high-performance computational simulations. Using a GPU, the solutions of systems of as much as 360 000 cells of 29 variables each were distributed among the available processors to simulate a cell-to-cell electric behavior of heart tissue. Moreover, in a smaller array of 462 cells, we showed that fibrillation, fluttering, and fibrillation-to-fluttering can be modeled even by using the simplest excitable cell models including only a few variables as well as with realistic models of heart cells, simply by implementing aperiodicity and fractality to the connections network. Micro-reentries which may be identified with fibrillation of the systems can be simulated in silico experiments where emerge several self-perpetuating, colliding waves associated with non-periodic and mathematically calculated pseudo-EG.

Cardiovascular diseases (CVDs) are major causes of mortality in developing countries. One of the challenges during CVDs studies is the creation of a damaged model of the heart. Many injured models of cardiac diseases are created by using chemical and biological materials. Many approaches were applied to simulate heart injury for investigating CVDs. In previous years, animal models could be used as a useful pattern in many investigations about the pathogenesis of the heart. Nowadays it has been proven that there are many differences between human and animal models in terms of responses or reactions to treatments. For such reasons, researchers prefer to use cellular models alongside the animal models for studying heart diseases. In this review, we collected information about some chemical and biological materials used to create damaged-heart models both in vitro and in vivo. After explaining the materials that induce cardiac damage, we explicate some methods for repairing the damage of heart. Finally, the role of extracellular vesicles as an important biological candidate for repairing heart damage is briefly discussed. This mini-review tried to explain some methods which can induce cardiac damage and repair of heart cells by use chemical and biological materials. We considered that various molecular pathways play a role in restoration and that most of these pathways are connected in a complex network and, to this end, different chemicals and drugs have been studied to date. Nonetheless, more studies are needed to ensure the performance and safety of the drugs and chemicals produced.

Phosphodiesterase II (PDE2) is mainly distributed in brain and heart cells, and it is a potential therapeutic target for the treatment of central nervous system (CNS) diseases such as Alzheimer’s disease. Based on the structure of the existing PDE2 inhibitor BAY60-7550, a series of novel phthalimides and phenylpyrazolo[1,5- a]pyrimidines have been designed and prepared. Furthermore, after evaluating their inhibitory activity toward PDE2, compound 7-oxo- N-phenethyl-5-phenyl-4,7-dihydropyrazolo[1,5- a]pyrimidine-3-carboxamide is found to have the optimum inhibitory potential (IC50: 1.82 ± 0.29 μM). Discovery Studio software used to simulate the structure–activity relationship between this compound and the PDE2 protein crystal 4HTX to illustrate the binding modes, which provides favorable guidance for the further development of effective PDE2 inhibitors.

Successful formation of electronic interfaces between living cells and electronic components requires both good cell viability and performance level. This paper presents a technology for the formation of nanostructured arrays of multi-walled carbon nanotubes (MWCNT) in biopolymer (albumin) layer for higher biocompatibility. The layer of liquid albumin dispersion was sprayed on synthesized MWCNT arrays by deposition system. These nanostructures were engineered using the nanosecond pulsed laser radiation mapping in the near-IR spectral range (λ = 1064 nm). It was determined that the energy density of 0.015 J/cm2 provided a sufficient structuring of MWCNT. The structuring effect occurred during the formation of C–C bonds simultaneously with the formation of a cellular structure of nanotubes in the albumin matrix. It led to a decrease in the nanotube defectiveness, which was observed during the Raman spectroscopy. In addition, laser structuring led to a more than twofold increase in the electrical conductivity of MWCNT arrays with albumin (215.8 ± 10 S/m). Successful electric stimulation of cells on the interfaces with the system based on a culture plate was performed, resulting in the enhanced cell proliferation. Overall, the MWCNT laser-structured arrays with biopolymers might be a promising material for extended biomedical applications.

Cardiovascular diseases are the leading cause of lethal issues worldwide. The most effective way to combat these diseases is the real-time monitoring of the electrocardiogram (ECG) that reflects the electrical signals generated by the heart cells. So far, the ECG is recorded by using the cutaneous conventional medical electrodes (Ag/AgCl). These electrodes are not adapted for long-term use as they are not fully integrated into underwear and generally can provoke skin irritation, because of the ionic gel that serves to reduce the impedance of the electrode/ skin interface. The first part of this paper concerns the design and realization by embroidery of three different patterns of conductive tracks that could be adopted as connection lines between an electronic module and ECG electrodes. In order to make these conductive tracks washable, two encapsulation methods have been investigated. The reliability of the developed conductive tracks and encapsulation methods has been analyzed. The second part of this study is focused on the development of washable embroidered ECG bands operating without any ionic gel as alternatives to medical electrodes (Ag/AgCl). The acquisition of ECG signals has been carried out on 3 female and 6 male healthy subjects aged between 25 and 55 years. In the last stage of this paper, we explore the ECG signal in static condition, the spectral power density of the ECG signal, the signal-to-noise ratio (SNR) of ECG electrodes before and after 50 washing cycles.

Testudinid herpesviruses (TeHVs) and ranaviruses are important pathogens of tortoises, but no treatments are available. Lysine may inhibit herpesvirus (HV) replication, although its effectivity has been questioned. Lactoferrin has antiviral activity against a range of viruses by inhibiting adsorption to cells. Media were supplemented with 6.25–10 mg/ml lysine and 0.625–1 mg/ml lactoferrin, individually or combined, and the effects measured against the replication of TeHV-1, TeHV-3, or a ranavirus in Terrapene heart cells (TH-1). Cytotoxicity testing was also carried out with the same concentrations. Lysine alone inhibited cell growth after 24 and 48 h, whereas lactoferrin only reduced cell growth after 24 h. TeHV-1 titers were only reduced by the addition of a combination of 10 mg/ml lysine and 1 mg/ml lactoferrin after 48 h (43.8% reduction) and by 10 mg/ml lysine (82.2% reduction). The same concentration of the combined substances led to an average reduction in TeHV-3 titers of 43.8% after 24 h and 68.4% after 48 h, respectively, while 10 mg/ml lysine led to an average reduction of 92.5% after 48 h. Lactoferrin alone did not reduce HV titers. Both concentrations of the combined substances led to titer reductions of the ranavirus (86.7–96.8%), and testing of the individual substances led to a reduction of 97.6% after 48 h with 10 mg/ml lysine and of 82.2% after 24 h with 1 mg/ml lactoferrin.

Cyclic calcium release and uptake in heart cells has an important role in heart rhythm and contraction, and it is known that the malregulation of calcium release is a predictor for cardiac arrhythmia. A model of this calcium release process was proposed, which consists of a large number of discrete calcium release sites, each involving stiff, stochastic, and nonlinear systems. In this paper we have developed a simulation of this calcium release model, which is parallel across the problem. The simulation is developed in a CUDA framework to be solved using GPUs. Computational efficiency is enhanced by using a DIIRK solver and taking advantage of the sparsity of the Jacobian. The output is shown to display behaviour similar to empirical observations, in particular displaying behaviour known as calcium waves.

Science museums play an important role in science education, both engaging the public with science concepts and building support for scientific research. Designing museum exhibits to meet increasing public interests in the life sciences is particularly important, yet remains challenging. In this report we describe Give Heart Cells a Beat, a permanent interactive science exhibit that allows museum visitors to synchronize the beating of live stem cell-derived cardiomyocytes to their own heart rate in real-time. Evaluation with museum visitors reveals that the exhibit engaged the public with the specimen and prompted curiosity in heart biology and, to a lesser degree, stem cells and electrophysiology. Give Heart Cells a Beat is the product of a close collaboration between a museum and a research laboratory, and, to our knowledge, the first example of the use of live human heart cells in an interactive exhibit. We hope this exhibit will serve as an example for the implementation of stem cell technology in the field of informal science education and encourage others to pursue close working relationships between academia and public science venues such as museums.

Genetic factors undoubtedly affect the development of congenital heart disease (CHD) but still remain ill defined. We sought to identify genetic risk factors associated with CHD and to accomplish a functional analysis of SNP-carrying genes. We performed a genome-wide association study (GWAS) of 4034 White patients with CHD and 8486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified 4 highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence the expression of WNT3, and the variant rs870142 related to septal defects is proposed to influence the expression of MSX1. We analyzed the expression of all 4 genes during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNA-Seq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3, and MSX1 play an essential functional role in heart development at the embryonic and newborn stages.

Heart organoids have the potential to generate primary heart-like anatomical structures and hold great promise as in vitro models for cardiac disease. However, their properties have not yet been carefully studied, which hinders a wider spread application. Here we report the development of differentiation systems for ventricular and atrial heart organoids, enabling the study of heart disease with chamber defects. We show that our systems generate organoids comprising of major cardiac cell types, and we used single cell RNA sequencing together with sample multiplexing to characterize the cells we generate. To that end, we also developed a machine learning label transfer approach lever-aging cell type, chamber, and laterality annotations available for primary human fetal heart cells. We then used this model to analyze organoid cells from an isogeneic line carrying an Ebstein’s anomaly associated genetic variant, and we successfully recapitulated the disease’s atrialized ventricular defects. In summary, we have established a workflow integrating heart organoids and computational analysis to model heart development in normal and disease states.

Sir Jagadis Chandra Bose, India’s first modern biologist departed boldly from mainstream botany by claiming that plants possess “nerves” and “pulsating cells” that function respectively much like the nerve and heart cells of animals. These ideas were based on highly sensitive measurements he made of various plant functions by means of assorted ingenious instruments of his own design. Despite being the most internationally celebrated plant biologist of the early 20th century, by the end of his life, Bose had become a scientific pariah whose work was expunged from Western histories of plant biology for nearly a century. In the 21st century, Bose’s contributions to biology have begun to be appreciated anew, particularly within the plant neurobiology community. The present contribution examines the motivating factors behind the anti-Bose camp in the United States in the 1920s. It is concluded that the opposition to Bose’s ideas during this period had less to do with scientific dialectics than with jealousy over Bose’s international acclaim and the prevailing racism of the era.

Human iPS cell (iPSC)-derived cardiomyocytes (CMs) hold promise for drug discovery for heart diseases and cardiac toxicity tests. To utilize human iPSC-derived CMs, the establishment of three-dimensional (3D) heart tissues from iPSC-derived CMs and other heart cells, and a sensitive bioassay system to depict physiological heart function are anticipated. We have developed a heart-on-a-chip microdevice (HMD) as a novel system consisting of dynamic culture-based 3D cardiac microtissues derived from human iPSCs and microelectromechanical system (MEMS)-based microfluidic chips. The HMDs could visualize the kinetics of cardiac microtissue pulsations by monitoring particle displacement, which enabled us to quantify the physiological parameters, including fluidic output, pressure, and force. The HMDs demonstrated a strong correlation between particle displacement and the frequency of external electrical stimulation. The transition patterns were validated by a previously reported versatile video-based system to evaluate contractile function. The patterns are also consistent with oscillations of intracellular calcium ion concentration of CMs, which is a fundamental biological component of CM contraction. The HMDs showed a pharmacological response to isoproterenol, a β-adrenoceptor agonist, that resulted in a strong correlation between beating rate and particle displacement. Thus, we have validated the basic performance of HMDs as a resource for human iPSC-based pharmacological investigations.

Cardiac pumping depends on the morphological structure of the heart, but also on its subcellular (ultrastructural) architecture, which enables cardiac contraction. In cases of congenital heart defects, localized ultrastructural disruptions that increase the risk of heart failure are only starting to be discovered. This is in part due to a lack of technologies that can image the three-dimensional (3D) heart structure, to assess malformations; and its ultrastructure, to assess organelle disruptions. We present here a multiscale, correlative imaging procedure that achieves high-resolution images of the whole heart, using 3D micro-computed tomography (micro-CT); and its ultrastructure, using 3D scanning electron microscopy (SEM). In a small animal model (chicken embryo), we achieved uniform fixation and staining of the whole heart, without losing ultrastructural preservation on the same sample, enabling correlative multiscale imaging. Our approach enables multiscale studies in models of congenital heart disease and beyond., eLife digest The heart is our hardest-working organ and beats around 100,000 times a day, pumping blood through a vast system of vessels to all areas of the body. Specialized heart cells make the heart contract rhythmically, enabling it to work efficiently. Contractile molecules inside these cells, called myofibrils, align within the heart cells, and heart cells align to each other, so that the heart tissue contracts effectively. However, when the heart has defects or is diseased this organization can be lost, and the heart may no longer pump blood efficiently, leading to sometimes life-threatening complications. For example, around one in a hundred newborn babies suffer from congenital heart defects, and despite medical advances, these conditions remain the main cause of non-infectious mortality in children. Many cases of congenital heart disease are diagnosed before a baby is born during an ultrasound scan. However, these scans, as well as subsequent diagnostic tools, lack the precision to detect problems within the heart cells. Now, Rykiel et al. used two complementary imaging techniques known as micro-computed tomography and scanning electron microscopy to acquire pictures of the whole heart as well as of the organization inside the heart cells. This made it possible to capture the structure of the heart tissue at both micrometer (the whole heart) and nanometer resolution (the inside of the cells), and to study what happens within the heart and its cells when the heart has a defect. Rykiel et al. tested the imaging technology on the hearts of chicken embryos, at stages equivalent to a five to six-month-old human fetus, and compared a healthy heart with a heart with a defect called tetralogy of Fallot. They found that the tissues in the heart with a defect had a sponge-like appearance, with increased space in between cells. Moreover, the myofibrils of the heart with a defect were aligned differently compared to those in the normal heart. More research is needed to fully understand what happens when the heart has a defect. However, the imaging technology used in this study offers the possibility of examining the heart at an unprecedented level of detail. This will deepen our understanding of how structural heart defects arise and how they affect the pumping of the heart, and will give us clues to design better treatments for patients with heart defects and other heart anomalies.

Functional heart cells and tissues sourced from human pluripotent stem cells (hPSCs) have great potential for substantially advancing treatments of cardiovascular maladies. Realization of this potential will require the development of cost-effective and tunable bioprocesses for manufacturing hPSC-based cell therapeutics. Here, we report the development of a xeno-free platform for guiding the cardiogenic commitment of hPSCs. The system is based on a fully defined, open-source formulation without complex supplements, which have varied and often undetermined effects on stem cell physiology. The formulation was used to systematically investigate factors inducing the efficient commitment to cardiac mesoderm of three hPSC lines. Contractile clusters of cells appeared within a week of differentiation in planar cultures and by day 13 over 80% of the cells expressed cardiac progeny markers such as TNNT2. In conjunction with expansion, this differentiation strategy was employed in stirred-suspension cultures of hPSCs. Scalable differentiation resulted in 0.4-2 million CMs/ml or ∼5-20 TNNT2-positive cells per seeded hPSC without further enrichment. Our findings will contribute to the engineering of bioprocesses advancing the manufacturing of stem cell-based therapeutics for heart diseases.

Although coronavirus disease 2019 (COVID-19) causes cardiac dysfunction in up to 25% of patients, its pathogenesis remains unclear. Exposure of human induced pluripotent stem cell (iPSC)-derived heart cells to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed productive infection and robust transcriptomic and morphological signatures of damage, particularly in cardiomyocytes. Transcriptomic disruption of structural genes corroborates adverse morphologic features, which included a distinct pattern of myofibrillar fragmentation and nuclear disruption. Human autopsy specimens from patients with COVID-19 reflected similar alterations, particularly sarcomeric fragmentation. These striking cytopathic features in cardiomyocytes provide insights into SARS-CoV-2-induced cardiac damage, offer a platform for discovery of potential therapeutics, and raise concerns about the long-term consequences of COVID-19 in asymptomatic as well as severe cases., Infection of human iPSC-derived cardiomyocytes by SARS-CoV-2 leads to specific cytopathic features reflected in patient autopsy samples.

Background: According to American heart association, over 70 % diabetic patients die from heart and stroke related diseases. The term “diabetic heart diseases” includes coronary heart disease, heart failure and diabetic cardiomyopathy in diabetic patients. Epigenetic and epitranscriptomic modifications play critical roles in progress of diabetic heart disease. Recent evidences indicated that m 6 A methylation involved in ischemic cardiomyopathy. But, the role of m 6 A mRNA methylation in cardiovascular diseases along with diabetic co-morbidity factors has not been studied in details. Thus, here we hypothesize that alterations in m 6 A mRNA methylation under hypoxic and hyperglycemic conditions contributes to severity of ischemic heart disease. Method and Results: To address our hypothesis, we have determined the levels of m 6 A mRNA methylation in NRVM, NRVF and HUVEC, HMVE and mouse primary endothelial cells under hypoxic and hyperglycemic conditions. We also examined the m 6 A levels in mice hearts post 5 days of MI. m 6 A mRNA methylation was significantly upregulated both in human and mouse ischemic hearts. Furthermore, hypoxia and hyperglycemia significantly induced m 6 A methylation in neonatal rat cardiomyocytes, fibroblasts, and mouse primary endothelial cells (isolated from WT and db/db mice). Next, we measured the methylation machinery both at RNA and protein levels. Interestingly, in corroboration with our methylation data, the expression of both m 6 A writers (Mettl3 and WTAP) and Readers (YTHDF2) was significantly increased. To determine the target transcripts which were highly methylated post-ischemia, we performed deep sequencing of methylated RNA after their immunoprecipitation using MeRIP-sequencing protocol. Our MeRIP-seq data has suggested a differentially m 6 A methylated targets both in-vitro and in-vivo ischemic sample. Conclusion: Over all, for the first time our data showed that hypoxia and hyperglycemia alters m 6 A mRNA methylation which may contribute to enhance the severity of cardiovascular diseases under hyperglycemic conditions. Further understanding of the mechanisms, may present a novel approach to potentially regulate m 6 A methylation, which may help in preventing/reducing heart failure in diabetic patients.

Funding: This research was financially supported by the European Research Council under the European Union’s Horizon 2020 Framework Programme (FP/2014-2020)/ERC grant agreement no. 640012 (ABLASE), by EPSRC (grant no. EP/P030017/1) and by the RS Macdonald Charitable Trust. S.J.P. acknowledges funding by the Royal Society of Edinburgh (Biomedical Fellowship) and the British Heart Foundation (grant no. FS/17/9/32676). S.J.P. and G.B.R. acknowledge support from The Wellcome Trust Institutional Strategic Support Fund to the University of St Andrews (grant no. 204821/Z/16/A). M.S. acknowledges funding by the European Commission (Marie Skłodowska-Curie Individual Fellowship, 659213) and the Royal Society (Dorothy Hodgkin Fellowship, DH160102; grant no. RGF\R1\180070). The contractility of cardiac cells is a key parameter that describes the biomechanical characteristics of the beating heart, but functional monitoring of three-dimensional cardiac tissue with single-cell resolution remains a major challenge. Here, we introduce microscopic whispering-gallery-mode lasers into cardiac cells to realize all-optical recording of transient cardiac contraction profiles with cellular resolution. The brilliant emission and high spectral sensitivity of microlasers to local changes in refractive index enable long-term tracking of individual cardiac cells, monitoring of drug administration, accurate measurements of organ-scale contractility in live zebrafish, and robust contractility sensing through hundreds of micrometres of rat heart tissue. Our study reveals changes in sarcomeric protein density as an underlying factor to cardiac contraction. More broadly, the use of novel micro- and nanoscopic lasers as non-invasive, biointegrated optical sensors brings new opportunities to monitor a wide range of physiological parameters with cellular resolution. Postprint

Rationale: Efficient communication between heart cells is vital to ensure the anisotropic propagation of electrical impulses, a function mainly accomplished by gap junctions (GJ) composed of Cx43 (connexin 43). Although the molecular mechanisms remain unclear, altered distribution and function of gap junctions have been associated with acute myocardial infarction and heart failure. Objective: A recent proteomic study from our laboratory identified EHD1 (Eps15 [endocytic adaptor epidermal growth factor receptor substrate 15] homology domain-containing protein 1) as a novel interactor of Cx43 in the heart. Methods and Results: In the present work, we demonstrate that knockdown of EHD1 impaired the internalization of Cx43, preserving gap junction-intercellular coupling in cardiomyocytes. Interaction of Cx43 with EHD1 was mediated by Eps15 and promoted by phosphorylation and ubiquitination of Cx43. Overexpression of wild-type EHD1 accelerated internalization of Cx43 and exacerbated ischemia-induced lateralization of Cx43 in isolated adult cardiomyocytes. In addition, we show that EHDs associate with Cx43 in human and murine failing hearts. Conclusions: Overall, we identified EHDs as novel regulators of endocytic trafficking of Cx43, participating in the pathological remodeling of gap junctions, paving the way to innovative therapeutic strategies aiming at preserving intercellular communication in the heart.

The main purpose of the review article is to assess the contributions of telomere length and telomerase activity to the cardiac function at different stages of development and clarify their role in cardiac disorders. It has been shown that the telomerase complex and telomeres are of great importance in many periods of ontogenesis due to the regulation of the proliferative capacity of heart cells. The review article also discusses the problems of heart regeneration and the identification of possible causes of dysfunction of telomeres and telomerase.

The main function of the heart is pumping blood, which is performed by contraction of the cardiac cells (red).

Experiment was performed to study the effect of Aeromonas hydrophila MTCC 646 on the heart of Cirrhinus mrigala (Hamilton, 1822) . The in vivo innate immune response was also monitored in these fishes. Fishes were inoculated with 3 asymptomatic doses (2x105, 2x106 and 2x107 CFU ml-1) intraperitoneally (i.p.) @ 0.5 ml 100 g-1. Dose dependent pattern of change was observed in the immune biomarkers chosen for the study. Histopathology revealed endocarditis and cell death identified as apoptosis. The percentage contribution of late apoptotic cells was 0.36% after 7 days in fish heart exposed to the highest dose of bacteria which was reduced to 0.01% after 30 days. Oxidative stress and dosage were directly proportional. The oxidised dichloro fluorescein peak was about 4.05 fold more than the control samples, after 7 days with respect to the highest dose and immune responses helped to decrease the mean peak to 1.02 after 30 days, signifying recovery of phagocytic activity, which is a part of the reticulo-endothelial system. This work presents an insight into the immune response and the results analysed statistically show that there was significant difference between percent population of early apoptotic cells (p

In the lab of biomedical engineer Nenad Bursac of Duke University, patches of human heart tissue beat rhythmically on their own accord. Each translucent patch—on some days up to about 15 patches, 4 centimeters by 4 centimeters each—sits suspended in its own dish on a gently rocking platform. A red broth washes over the cells as the tissues strengthen. If these patches can get strong enough, and functional enough, they may just revolutionize heart repair. Heart tissue is challenging to generate in the lab but even more so in the adult body. During a heart attack, as many as one billion contracting heart cells known as cardiomyocytes can be lost (1). Those cells do not regenerate. Instead, the heart forms scar tissue that cannot transmit electrical signals or contract, putting patients at risk of heart failure. Researchers are using a diverse array of tools, from rocking dishes to 3D bioprinters, to engineer tissues that could one day help replace the cells lost during a heart attack. Image courtesy of Shutterstock/Petrafler. According to the CDC, about 790,000 Americans have a heart attack each year (2). Because existing therapies cannot heal the heart and organ donations are scarce, patients are left with limited options. “If we could put back actively contracting cardiac muscle cells, then we believe we would be delivering the largest benefit,” Bursac says. Bursac and other researchers are racing to fabricate a cardiac patch with ingredients, ranging from heart cells to thigh-muscle cells, and tools as diverse as rocking dishes and 3D bioprinters. But before heart patches become a real option for patients, researchers must overcome challenges ranging from the logistical—how to mass produce and store them—to the biological—how to build a patch thick enough for powerful contractions and synchronize its rhythm with the heart’s own. There’s more than …

From fireflies to heart cells, many systems in Nature show the remarkable ability to spontaneously fall into synchrony. By imitating Nature's success at self-synchronizing, scientists have designed cost-effective methods to achieve synchrony in the lab, with applications ranging from wireless sensor networks to radio transmission. A similar story has occurred in the study of swarms, where inspiration from the behavior flocks of birds and schools of fish has led to low-footprint algorithms for multi-robot systems. Here, we continue this `bio-inspired' tradition, by speculating on the technological benefit of fusing swarming with synchronization. The subject of recent theoretical work, minimal models of so-called `swarmalator' systems exhibit rich spatiotemporal patterns, hinting at utility in `bottom-up' robotic swarms. We review the theoretical work on swarmalators, identify possible realizations in Nature, and discuss their potential applications in technology.

In this study, we analyze a nonlinear map model of intracellular calcium (Ca) and voltage in cardiac cells. In this model, Ca release from the sarcoplasmic reticulum (SR) occurs at spatially distributed dyadic junctions that are diffusively coupled. At these junctions, release occurs with a probability that depends on key variables such as the SR load and the diastolic interval. Using this model, we explore how nonlinearity and stochasticity determine the spatial distribution of Ca release events within a cardiac cell. In particular, we identify a novel synchronization transition, which occurs at rapid pacing rates, in which the global Ca transient transitions from a period 2 response to a period 1 response. In the global period 2 response dyadic junctions fire in unison, on average, on alternate beats, while in the period 1 regime, Ca release at individual dyads is highly irregular. A close examination of the spatial distribution of Ca reveals that in the period 1 regime, the system coarsens into spatially out-of-phase regions with a length scale much smaller than the system size, but larger than the spacing between dyads.We have also explored in detail the coupling to membrane voltage. We study first the case of positive coupling, where a large Ca transient promotes a long action potential duration (APD). Here, the coupling to voltage synchronizes Ca release so that the system exhibits a robust period 2 response that is independent of initial conditions. On the other hand, in the case of negative coupling, where a large Ca transient tends to shorten the APD, we find a multitude of metastable states which consist of complex spatially discordant alternans patterns. Using an analogy to equilibrium statistical mechanics, we show that the spatial patterns observed can be explained by a mapping to the Potts model, with an additional term that accounts for a global coupling of spin states. Using this analogy, we argue that Ca cycling in cardiac cells exhibits complex spatiotemporal patterns that emerge via first or second order phase transitions. These results show that voltage and Ca can interact in order to induce complex subcellular responses, which can potentially lead to heart rhythm disorders.

An in vitro culture model mimicking the heart function can help in the search for effective treatments for cardiovascular diseases (CVDs). For this reason, Lab-on-a-chip systems are used to mimic various heart features and to create a cellular model. In this paper, we present a newly designed microfluidic system integrated with poly- l -lactic acid (PLLA) and polyurethane (PU) nanofibrous mats. Nanofibrous mats with aligned fibers, produced using a solution blow spinning (SBS) method, were used to create a parallel orientation of heart cells. Two types of cardiac cells were used in the research: rat cardiomyoblasts (H9C2) and human cardiomyocytes (HCM). The morphology, arrangement, and viability of the cells cultured on the nanofibrous mats in the designed microsystem were evaluated. The obtained results indicate that nanofibrous mats are a suitable surface for cardiac cell culture and they enhance the parallel orientation of the cells. The main aim of the research was to create a cellular model of hypoxic myocardial tissue (as a disease state) under flow conditions, useful for further studies under heart regeneration. Hypoxia was simulated using a biochemical method (cyanide p-trifluoromethoxyphenylhydrazone, FCCP). The effectiveness of the hypoxic agent was assessed by quantifying adenosine triphosphate (ATP) molecules using a bioluminescence-based test. We proved that it is possible to simulate hypoxia of cardiac cells cultured on nanofibrous mats in the developed microfluidic system. In the future, the designed microsystem can become an useful tool for testing new drugs or developing new treatments for heart failure based on stem cells.

Cardio-protection includes” all mechanism and means that contribute to the preservation of the heart by reducing or even preventing Myocardial damage. Cardiovascular disease (CVD) remains the principle cause of death in both developed and developing countries. It may present as a typical heart attack, a sudden death or it may be detected at an advanced stage and be described as a silent infarct. CVD includes high blood pres-sure, coronary heart disease, congestive heart failure, stroke and accounts Myocardial infarction is the interruption of blood supply to part of the heart, causing heart cells to die, commonly due to blockage of coronary artery. Herbal drugs are known to exhibit creditable medicinal properties for the treatment of heart ailments and need to be explored to identify their po-tential application in prevention and therapy of human ailments. Cardio-vas-cular disease remains a leading cause of death in India. Therefore, finding ways to reduce the mortality of cardiovascular disease remains an impor-tant health goal. This review deals with medicinal plants possessing cardio-protective and cardio tonic activity. Cardiovascular disease is the number one cause of death globally and is projected to remain the leading cause of death. This review work explains chemical and pharmacological status of various cardio-protective plants including phyto constituents responsible for cardio-protection, extract employed, dosage, pharmacological screen-ing model and mechanism involved in cardio-protection. This review work definitely helps in enlisting the Indian plants having cardioprotective activ-it y. How to Cite this Article Pubmed Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara. Indian Plants with Cardioprotective Activity – A Review. SRP. 2017; 8(1): 8-12. doi:10.5530/srp.2017.1.3 Web Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara. Indian Plants with Cardioprotective Activity – A Review. http://www.sysrevpharm.org/?mno=302644557 [Access: March 28, 2021]. doi:10.5530/srp.2017.1.3 AMA (American Medical Association) Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara. Indian Plants with Cardioprotective Activity – A Review. SRP. 2017; 8(1): 8-12. doi:10.5530/srp.2017.1.3 Vancouver/ICMJE Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara. Indian Plants with Cardioprotective Activity – A Review. SRP. (2017), [cited March 28, 2021]; 8(1): 8-12. doi:10.5530/srp.2017.1.3 Harvard Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara (2017) Indian Plants with Cardioprotective Activity – A Review. SRP, 8 (1), 8-12. doi:10.5530/srp.2017.1.3 Turabian Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara. 2017. Indian Plants with Cardioprotective Activity – A Review. Systematic Reviews in Pharmacy, 8 (1), 8-12. doi:10.5530/srp.2017.1.3 Chicago Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara. "Indian Plants with Cardioprotective Activity – A Review." Systematic Reviews in Pharmacy 8 (2017), 8-12. doi:10.5530/srp.2017.1.3 MLA (The Modern Language Association) Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara. "Indian Plants with Cardioprotective Activity – A Review." Systematic Reviews in Pharmacy 8.1 (2017), 8-12. Print. doi:10.5530/srp.2017.1.3 APA (American Psychological Association) Style Amith Kumar, Gopala Krishna, Prabha Hullatti, Tanmoy, Akshara (2017) Indian Plants with Cardioprotective Activity – A Review. Systematic Reviews in Pharmacy, 8 (1), 8-12. doi:10.5530/srp.2017.1.3

The hyperpolarization-activated inward cationic current ( Ih) is known to regulate the rhythmicity, excitability, and synaptic transmission in heart cells and many types of neurons across a variety of species, including some pyloric and gastric mill neurons in the stomatogastric ganglion (STG) in Cancer borealis and Panulirus interruptus. However, little is known about the role of Ih in regulating the gastric mill dynamics and its contribution to the dynamical bifurcation of the gastric mill and pyloric networks. We investigated the role of Ih in the rhythmic activity and cellular excitability of both the gastric mill neurons (medial gastric, gastric mill) and pyloric neurons (pyloric dilator, lateral pyloric) in Homarus americanus. Through testing the burst period between 5 and 50 mM CsCl, and elimination of postinhibitory rebound and voltage sag, we found that 30 mM CsCl can sufficiently block Ih in both the pyloric and gastric mill neurons. Our results show that Ih maintains the excitability of both the pyloric and gastric mill neurons. However, Ih regulates slow oscillations of the pyloric and gastric mill neurons differently. Specifically, blocking Ih diminishes the difference between the pyloric and gastric mill burst periods by increasing the pyloric burst period and decreasing the gastric mill burst period. Moreover, the phase-plane analysis shows that blocking Ih causes the trajectory of slow oscillations of the gastric mill neurons to change toward the pyloric sinusoidal-like trajectories. In addition to regulating the pyloric rhythm, we found that Ih is also essential for the gastric mill rhythms and differentially regulates these two dynamics.

The extracellular matrix (ECM) is needed to maintain the structural integrity of tissues and to mediate cellular dynamics. Its main components are fibrous proteins and glycosaminoglycans, which provide a suitable environment for biological functions. Thus, biomaterials with ECM-like properties have been extensively developed by modulating their key components and properties. In the field of cardiac tissue engineering, the use of biomaterials offers several advantages in that biophysical and biochemical cues can be designed to mediate cardiac cells, which is critical for maturation and regeneration. This suggests that understanding biomaterials and their use in vivo and in vitro is beneficial in terms of advancing cardiac engineering. The current review provides an overview of both natural and synthetic biomaterials and their use in cardiac engineering. In addition, we focus on different strategies to recapitulate the cardiac tissue in 2D and 3D approaches, which is an important step for the maturation of cardiac tissues toward regeneration of the adult heart.

Spontaneous local calcium releases (sparks) from sarcoplasmic reticulum (SR) in heart cell were modeled. We solved two-dimensional problem of Ca2+ diffusion along the dyadic space and “domino-like” activation of ryanodine receptors (RyRs) on the membrane of SR. We purpose results of the numerical experiments investigating sparks initiation, spread and termination. We discovered different regimes of the Ca2+ release unit behavior for different values of the release unit model and found out conditions for spark formation violations.

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels control electrical rhythmicity in specialized brain and heart cells. We quantitatively analysed voltage-dependent activation of homotetrameric HCN2 channels and its modulation by the second messenger cAMP using global fits of hidden Markovian models to complex experimental data. We show that voltage-dependent activation is essentially governed by two separable voltage-dependent steps followed by voltage-independent opening of the pore. According to this model analysis, the binding of cAMP to the channels exerts multiple effects on the voltage-dependent gating: It stabilizes the open pore, reduces the total gating charge from ~8 to ~5, makes an additional closed state outside the activation pathway accessible and strongly accelerates the ON-gating but not the OFF-gating. Furthermore, the open channel has a much slower computed OFF-gating current than the closed channel, in both the absence and presence of cAMP. Together, these results provide detailed new insight into the voltage- and cAMP-induced activation gating of HCN channels., Author summary Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetrameric voltage-controlled ion channels in the cell membrane of specialized nerve and heart cells. Their main function is to generate a so-called pacemaker current which plays a key role in the generation of electrical rhythmicity. A special messenger molecule, cAMP, synthesized within these cells at sympathetic stimulation, can bind to these channels, thereby enhancing channel opening evoked by voltage. The mechanism of this dual activation is still poorly understood. Here we quantified this duality of activation for HCN2 channels by globally fitting hidden Markovian state models to extensive sets of data. We propose that activation of this tetrameric channel requires for a full description only two voltage-dependent steps that are followed by a voltage-independent opening step of the channel pore. According to this model analysis cAMP exerts multiple effects on channel activation: It notably accelerates the charge movement of the voltage-dependent steps and reduces the number of the involved electrical charges. Furthermore, it introduces an additional closed state and stabilizes the open pore. Together, our results provide new insight into the duality of voltage- and cAMP-induced activation of HCN channels.

59 páginas. Maestría en Ingeniería de Procesos. En años recientes se ha verificado que el metabolismo mitocondrial y la dinámica de Ca2+ se encuentran acoplados de forma compleja, lo cual se debe a la capacidad de la mitocondria de captar, almacenar y liberar iones Ca2+, así como a la activación del metabolismo energético por el Ca2+ mitocondrial. En los cardiomiocitos (células cardiacas), la alta demanda energética y la regulación del Ca2+ sobre el acople excitacióncontracción, vuelven determinante la interrelación entre los procesos antes mencionados. Incluso, el problema de la dinámica de Ca2+ y el metabolismo mitocondrial se ha definido como uno de los campos centrales en la fisiología y patología cardiacas. En este sentido, los métodos experimentales han enfrentado grandes dificultades para medir Ca2+ mitocondrial dinámico dentro de la estructura celular de los cardiomiocitos, lo que ha llevado a resultados experimentales controversiales. En el presente trabajo, la relación entre la dinámica de Ca2+ y el metabolismo mitocondrial se abordó mediante un enfoque de modelado y simulación. Además, dado que los cardiomiocitos presentan incrementos de Ca2+ altamente heterogéneos, por su estructura celular, la investigación se centró en el aspecto espacial. Así, la hipótesis de investigación es que, en los miocitos cardiacos, la localización de la mitocondria con respecto al espacio diádico determina los cambios en la dinámica de calcio y el metabolismo mitocondrial. En una primera etapa, se utilizó un modelo recientemente publicado (Wacquier et al., 2016) que describe la interrelación entre la señalización del Ca2+ y el metabolismo mitocondrial en células no excitables para desarrollar un modelo mitocondrial (MM) capaz de reproducir las características particulares de la mitocondria en las células cardiacas. En la segunda etapa se utilizó un enfoque de modelado compartamental con el fin de tomar en cuenta los aspectos espaciales, y se obtuvo un modelo acoplado (CM) integrado por el MM y un modelo de miocito ventricular humano (Grandi, Pasqualini, and Bers, 2010). Finalmente, el nuevo modelo integral se utilizó para demostrar que la posición de la mitocondria tiene un efecto significativo en la dinámica del Ca2+ y el metabolismo mitocondrial, lo anterior se realizó mediante el análisis de tres escenarios que corresponden distribuciones e interacciones particulares entre la mitocondria y los compartimentos intracelulares del modelo de célula cardiaca. It is well known that mitochondrial metabolism is linked to Ca2+ dynamics in a complex manner. This relation underlies on the capacity of mitochondria to uptake, release and storage Ca2+ as well as on the activation of the energetic metabolism by mitochondrial Ca2+. In cardiomyocytes (cardiac cells) this interplay becomes very important because of both the high energy demand (tissue-characteristic) and the regulation of excitationcontraction coupling by Ca2+. Ca2+ dynamics and mitochondrial metabolism has been defined as a key issue in cardiac physiology and pathology. However, experimental methods have strong limitations due to the difficulties in measuring dynamic mitochondrial Ca2+ in the intricated cellular structure of cardiomyocytes, leading to controversial experimental results. In the present project the relationship between Ca2+ dynamics and mitochondrial metabolism was addressed by modelling and simulation approach. Since in cardiomyocytes, Ca2+ increases are highly heterogeneous due to the cell structure, spatial aspects are considered as a main aspect. In fact, the working hypothesis is that the location of mitochondria with respect to Ca2+ channels plays a crucial role in determining the kinetics of Ca2+ changes and metabolism. As a first step, a previous model that properly describes the coupling between Ca2+ signalling and mitochondrial metabolism in a non-excitable cells (Wacquier et al., 2016) was used as a base to develop a new mitochondrial model (MM) able to account for the particular features of mitochondria in cardiac cells. In a second step, a compartmental modelling approach was used to account for the spatial aspects, so a coupled model (CM) was developed with the MM inside a model of a human ventricular myocyte (Grandi, Pasqualini, and Bers, 2010). Finally, the whole new model was used to prove that mitochondrial position has significant effect on Ca2+ dynamics and mitochondrial metabolism through the design of three scenarios corresponding to particular distributions and interactions between mitochondria and other intracellular compartments of the cardiac cell model.

Heart is the first mesodermal organ to develop and is sensitive to life-threatening toxic effects of drugs during development. A number of methods have been devised to study developmental cardiotoxic effects of drugs including micromass system. The micromass system involves the culture of primary embryonic cells and reestablishment of tissue system in vitro. In chick embryonic cardiomyocyte micromass system the chick heart cells are cultured in a small volume at a very high cell density. These cells form synchronized contracting foci. Addition of drugs to this system allows us to study the developmental cardiotoxic effects at molecular level. Using appropriate end points and molecular marker or adopting high-throughput screening, this method can further help to identify and avoid the use of cardiotoxic compounds during development.

Cardiomyocyte contractility is essential to maintaining proper cardiac output and blood flow throughout the circulatory system. This action is dependent upon proper G protein-coupled receptor (GPCR) signaling. Previous studies showed G-protein dysregulation due to the loss of regulator of G protein signaling (RGS) 2 and 5, separately, impairs cardiac structure and function, including hypertrophy and arrhythmia. RGS2 and 5 are GTPase activating proteins (GAPs) that accelerate the hydrolysis of GTP by G proteins, resulting in a rapid signaling termination. We examined how the dual absence of Rgs2 and 5 (Rgs2/5 dbKO) affects cardiac function. We found that Rgs2/5 dbKO mice showed cardiac hypertrophy and a dilated left ventricle at baseline. Cardiac contractile response to a dobutamine stress test was sex-dependently reduced in male Rgs2/5 dbKO relative to WT mice. In addition, chronic systemic infusion of the [beta]-adrenergic receptor agonist, isoproterenol, led to marked exacerbation of cardiac hypertrophy in Rgs2/5 dbKO mice. When subjected to surgery-induced stress, male Rgs2/5 dbKO mice showed 80% mortality within 72 – 96 hours after surgery, accompanied by extreme hypertension and decreased cardiac contractile function. At the cellular level, cardiomyocytes from Rgs2/5 dbKO mice showed reduced contractile response to electrical pacing and exhibited irregular excitation-contraction coupling and death in response to increasing concentrations of different [beta]-adrenergic agonists. We conclude that RGS2 and 5 act synergistically within the heart to regulate signaling mechanisms that mediate cardiac structure and function. Thus, a thorough understanding of the G protein signaling regulation by multiple RGS proteins is key to identifying novel therapeutic targets for heart disease.

If blood flow from the heart is impeded, the pressure created causes tissue dysfunction. It emerges that different signals converge on the TSC2 and mTOR proteins to fine-tune the response of heart cells to stress. Disparate pathways converge in heart cells responding to stress.

Heart failure (HF) is a multifactorial disorder and is usually the end stage of many cardiovascular diseases (CVD). HF presents one of the highest morbidity and mortality indices worldwide and high costs to public health organizations. Myocardial infarction (MI) is the most prevalent CVD in the Western world and leads to HF when its management is inadequate. It has a destructive potential for heart cells and abruptly reduces the cardiac output, a clinical condition known as heart dysfunction that might progress to HF. Many acute and chronic adaptations occur due to MI that progress to HF, e.g., neurohumoral hyperactivity, inflammatory response and cardiac remodeling. Herein, we reviewed in simplistic manner the processes involved in setting of MI until the establishment of HF.

Nucleic Acids Research, 37 (4), ISSN:1362-4962, ISSN:0301-5610

Mitochondrial flashes have a central role in ensuring that ATP levels remain constant in heart cells.

The research on heart cells have attracted broad attention for the development of either heart disease therapy or muscle cell-based actuation for bio-syncretic robots. In order to study the mechanism and dynamics of beating activity of cardiomyocytes, many research methods have been proposed, such as the measurement of contractility and action potential of the cells. However, few of them has focused on the effect from the mechanical properties of sub-cell elements on the contraction performance of heart cells. In this work, a mechanical model of single heart cell was proposed based on the sub-cell structures, to study and control the contraction of the cardiomyocytes. The parameters of the parts in the theoretical model were identified with the cellular beating data obtained using Scanning Ion Conductance Microscopy (SICM) based on the derived mathematic model. Therefore, the contraction performance and the mechanical properties of sub-cell elements associated with the mechanical properties of parts in the model can be obtained for the further analysis of the relationship between the cell activity and sub-cell structures. This work is fundamental and meaningful for the research on cytobiology, heart mechanism and bio-syncretic robotics.

Scalable units for building cardiac tissue are fabricated from biodegradable elastomeric polymers by pairwise stacking of heart-cell scaffolds with sinusoidal internal pore architectures and dedicated perfusable microvessels with rapidly degrading porous interfaces in a parallel flow configuration. This platform supports viable heart cells in vitro and, if validated in vivo, may aid in the regenerative repair of vascularized tissues.

As a boy in suburban Los Angeles, Mark Sussman’s mother used to tell him that scientists saved more lives than physicians because they were the ones who developed the treatments that doctors used. He has taken her words to heart. By deploying a wide range of tools gathered throughout a diverse 25-year career, Sussman is pursuing novel ways to encourage the replacement and repair of damaged tissue in heart failure, the leading cause of hospitalization in the elderly. After a postdoctoral fellowship in cytoskeletal biology, Sussman joined the molecular genetics laboratory of Larry Kedes, at the University of Southern California. There, he characterized the role of the tropomodulin, a protein that caps and regulates the length of actin fibers, in the heart.1 In his first faculty position, at the Cincinnati Children’s Hospital Medical Center, he created a transgenic mouse model of dilated cardiomyopathy resulting from the cardiac-specific overexpression of tropomodulin.2 Sussman’s research in the area of signaling networks in the heart led to the discovery of the role of Pim-1 kinase as a mediator of cardiomyocyte survival and proliferation.3 Using cells from patients with severe heart failure undergoing left ventricular assist device implantation, Sussman’s laboratory at the San Diego State University Heart Research Institute recently demonstrated that stem cells engineered with Pim-1 kinase can enhance the repair of damaged myocardium.4 In a recent interview with Circulation Research , Sussman described how a successful career can be like a pinball machine: you ricochet from one thing to another, accumulating skills and ideas, and by making the most of each opportunity, end up doing something valuable that you never anticipated. Mark Sussman My father was an accountant who had little interest in science. On the contrary, my mother almost died of polio as a teenager and she always …

Spontaneously beating engineered heart tissue (EHT) represents an advanced in vitro model for drug testing and disease modeling, but cardiomyocytes in EHTs are less mature and generate lower forces than in the adult heart. We devised a novel pacing system integrated in a setup for videooptical recording of EHT contractile function over time and investigated whether sustained electrical field stimulation improved EHT properties. EHTs were generated from neonatal rat heart cells (rEHT, n=96) or human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hEHT, n=19). Pacing with biphasic pulses was initiated on day 4 of culture. REHT continuously paced for 16–18 days at 0.5Hz developed 2.2× higher forces than nonstimulated rEHT. This was reflected by higher cardiomyocyte density in the center of EHTs, increased connexin-43 abundance as investigated by two-photon microscopy and remarkably improved sarcomere ultrastructure including regular M-bands. Further signs of tissue maturation include a rightward shift (to more physiological values) of the Ca2+-response curve, increased force response to isoprenaline and decreased spontaneous beating activity. Human EHTs stimulated at 2Hz in the first week and 1.5Hz thereafter developed 1.5× higher forces than nonstimulated hEHT on day 14, an ameliorated muscular network of longitudinally oriented cardiomyocytes and a higher cytoplasm-to-nucleus ratio. Taken together, continuous pacing improved structural and functional properties of rEHTs and hEHTs to an unprecedented level. Electrical stimulation appears to be an important step toward the generation of fully mature EHT.

Adult progenitor cells reside in specialized microenvironments which maintain their undifferentiated cell state and trigger regenerative responses following injury. Although these environments are well described in several tissues, the cellular components that comprise the cardiac environment where progenitor cells are located remain unknown. Here we use Bmi1CreERT and Bmi1GFP mice as genetic tools to trace cardiac damage-responsive cells throughout the mouse lifespan. In adolescent mice, Bmi1+ damage-responsive cells are broadly distributed throughout the myocardium. In adult mice, however, Bmi1+ cells are confined predominately in perivascular areas with low levels of reactive oxygen species (ROS) and their number decline in an age-dependent manner. In vitro co-culture experiments with endothelial cells supported a regulatory role of the endothelium in damage-responsive cell behavior. Accordingly, in vivo genetic decrease of ROS levels in adult heart disengaged Bmi1+ cells from the cardiovascular network, recapitulating an adolescent-like Bmi1 expression profile. Thus, we identify cardiac perivascular regions as low-stress microenvironments that favor the maintenance of adult damage-responsive cells. Keywords: Bmi1, Damage-responsive cell, Vasculature, Oxidative damage, Reactive oxygen species

Numerous studies have employed mathematical modeling to quantitatively understand release of Ca 2 + from the sarcoplasmic reticulum (SR) in the heart. Models have been used to investigate physiologically important phenomena such as triggering of SR Ca 2 + release by Ca 2 + entry across the cell membrane and spontaneous leak of Ca 2 + from the SR in quiescent heart cells. In this review we summarize studies that have modeled myocardial Ca 2 + at different spatial scales: the sub-cellular level, the cellular level, and the multicellular level. We discuss each category of models from the standpoint of parameter sensitivity analysis, a common simulation procedure that can generate quantitative, comprehensive predictions about how changes in conditions influence model output. We propose that this is a useful perspective for conceptualizing models, in part because a sensitivity analysis requires the investigator to define the relevant parameters and model outputs. This procedure therefore helps to illustrate the capabilities and limitations of each model. We further suggest that in future studies, sensitivity analyses will aid in simplifying complex models and in suggesting experiments to differentiate between competing models built with different assumptions. We conclude with a discussion of unresolved questions that are likely to be addressed over the next several years. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.

Summary Embryonic gene expression intricately reflects anatomical context, developmental stage, and cell type. To address whether the precise spatial origins of cardiac cells can be deduced solely from their transcriptional profiles, we established a genome-wide expression database from 118, 949, and 1,166 single murine heart cells at embryonic day 8.5 (e8.5), e9.5, and e10.5, respectively. We segregated these cells by type using unsupervised bioinformatics analysis and identified chamber-specific genes. Using a random forest algorithm, we reconstructed the spatial origin of single e9.5 and e10.5 cardiomyocytes with 92.0% ± 3.2% and 91.2% ± 2.8% accuracy, respectively (99.4% ± 1.0% and 99.1% ± 1.1% if a ±1 zone margin is permitted) and predicted the second heart field distribution of Isl-1-lineage descendants. When applied to Nkx2-5 −/− cardiomyocytes from murine e9.5 hearts, we showed their transcriptional alteration and lack of ventricular phenotype. Our database and zone classification algorithm will enable the discovery of novel mechanisms in early cardiac development and disease.

Type 2 ryanodine receptors (RyR2) are large (mass=2.2 MegaDalton) proteins expressed in heart cells that mediate the release of calcium ions (Ca2+) that, in turn, modulate contraction of the heart. In this work, we analyze the sub-cellular spatial distribution of RyR2 using data from superresolution microscopy, an imaging technique that allows highly accurate positioning ( 95% at proximity thresholds 200 and 250 nm). Our findings may help in better understanding Ca2+ signaling during contraction and give insight into the changes that underlie its regulation.

Theory predicts that a stimulus delivered to an excitation wave circulating on a ring of excitable media will either have no effect, or it will reset or annihilate the excitation depending on the phase and magnitude of the stimulus. We summarize the basis for these theoretical predictions and demonstrate these phenomena in an experimental system consisting of a tissue culture of embryonic chick heart cells cultured in the shape of a ring.