Mechanism for polarisation of cardiac tissue at a sealed boundary

If current is flowing in cardiac tissue, and if the myocardial fibres approach a sealed boundary at an angle, then the tissue within a few length constants of the boundary is polarised. This polarisation occurs when the cardiac tissue has different anisotropy ratios in the intracellular and extracellular spaces. This new mechanism of tissue polarisation is demonstrated using a simple, analytical model, and it is shown quantitatively that this polarisation can be nearly as large as that occurring near an electrode.     

A comparison of two boundary conditions used with the bidomain model of cardiac tissue

In the bidomain model, two alternative sets of boundary conditions at the interface between cardiac tissue and a saline bath have been used. It is shown that these boundary conditions are equivalent if the length constant of the tissue in the direction transverse to the fibers is much larger than the radius of the individual cardiac cells. If this is not the case, the relative merits of the two boundary conditions are closely related to the question of the applicability of a continuum model, such as the bidomain model, to describe a discrete multicellular tissue.     

Effect of a perfusing bath on the rate of rise of an action potential propagating through a slab of cardiac tissue

Experiments show that the rate of rise of the action potential depends on the direction of propagation in cardiac tissue. Two interpretations of these experiments have been presented: (i) the data are evidence of discrete propagation in cardiac tissue, and (ii) the data are an effect of the perfusing bath. In this paper we present a mathematical model that supports the second interpretation. We use the bidomain model to simulate action potential propagation through a slab of cardiac tissue perfused by a bath. We assume an intracellular potential distribution and solve the bidomain equations analytically for the transmembrane and extracellular potentials. The key assumption in our model is that the intracellular potential is independent of depth within the tissue. This assumption ensures that all three boundary conditions at the surface of a bidomain are satisfied simultaneously. One advantage of this model over previous numerical calculations is that we obtain an analytical solution for the transmembrane potential. The model predicts that the bath reduces the rate of rise of the transmembrane action potential at the tissue surface, and that this reduction depends on the direction of propagation. The model is consistent with the hypothesis that the perfusing bath causes the observed dependence of the action-potential rate of rise on the direction of propagation, and that this dependence has nothing to do with discrete properties of cardiac tissue.     

A microfabricated platform to measure and manipulate the mechanics of engineered cardiac microtissues

Engineered myocardial tissues can be used to elucidate fundamental features of myocardial biology, develop organotypic in vitro model systems, and as engineered tissue constructs for replacing damaged heart tissue in vivo. However, a key limitation is an inability to test the wide range of parameters (cell source, mechanical, soluble and electrical stimuli) that might impact the engineered tissue in a high-throughput manner and in an environment that mimics native heart tissue. Here we used microelectromechanical systems technology to generate arrays of cardiac microtissues (CMTs) embedded within three-dimensional micropatterned matrices. Microcantilevers simultaneously constrain CMT contraction and report forces generated by the CMTs in real time. We demonstrate the ability to routinely produce ~200 CMTs per million cardiac cells (<1 neonatal rat heart) whose spontaneous contraction frequency, duration, and forces can be tracked. Independently varying the mechanical stiffness of the cantilevers and collagen matrix revealed that both the dynamic force of cardiac contraction as well as the basal static tension within the CMT increased with boundary or matrix rigidity. Cell alignment is, however, reduced within a stiff collagen matrix; therefore, despite producing higher force, CMTs constructed from higher density collagen have a lower cross-sectional stress than those constructed from lower density collagen. We also study the effect of electrical stimulation on cell alignment and force generation within CMTs and we show that the combination of electrical stimulation and auxotonic load strongly improves both the structure and the function of the CMTs. Finally, we demonstrate the suitability of our technique for high-throughput monitoring of drug-induced changes in spontaneous frequency or contractility in CMTs as well as high-speed imaging of calcium dynamics using fluorescent dyes. Together, these results highlight the potential for this approach to quantitatively demonstrate the impact of physical parameters on the maturation, structure, and function of cardiac tissue and open the possibility to use high-throughput, low volume screening for studies on engineered myocardium.     

Controlling the contractile strength of engineered cardiac muscle by hierarchal tissue architecture

The heart is a muscular organ with a wrapping, laminar structure embedded with neural and vascular networks, collagen fibrils, fibroblasts, and cardiac myocytes that facilitate contraction. We hypothesized that these non-muscle components may have functional benefit, serving as important structural alignment cues in inter- and intra-cellular organization of cardiac myocytes. Previous studies have demonstrated that alignment of engineered myocardium enhances calcium handling, but how this impacts actual force generation remains unclear. Quantitative assays are needed to determine the effect of alignment on contractile function and muscle physiology. To test this, micropatterned surfaces were used to build 2-dimensional myocardium from neonatal rat ventricular myocytes with distinct architectures: confluent isotropic (serving as the unaligned control), confluent anisotropic, and 20?μm spaced, parallel arrays of multicellular myocardial fibers. We combined image analysis of sarcomere orientation with muscular thin film contractile force assays in order to calculate the peak sarcomere-generated stress as a function of tissue architecture. Here we report that increasing peak systolic stress in engineered cardiac tissues corresponds with increasing sarcomere alignment. This change is larger than would be anticipated from enhanced calcium handling and increased uniaxial alignment alone. These results suggest that boundary conditions (heterogeneities) encoded in the extracellular space can regulate muscle tissue function, and that structural organization and cytoskeletal alignment are critically important for maximizing peak force generation.     

Fully coupled fluid–structure interaction model of congenital bicuspid aortic valves: effect of asymmetry on hemodynamics

A bicuspid aortic valve (BAV) is a congenital cardiac disorder where the valve consists of only two cusps instead of three, as in a normal tricuspid valve (TAV). Although 97 % of BAVs include asymmetric cusps, little or no prior studies have investigated the blood flow through a three-dimensional BAV and root. The aim of the present study was to characterize the effect of asymmetric BAV on the blood flow using fully coupled fluid–structure interaction (FSI) models with improved boundary conditions and tissue properties. This study presents four FSI models, including a native TAV, asymmetric BAVs with or without a raphe, and an almost symmetric BAV. Cusp tissue is composed of hyperelastic finite elements with collagen fibres embedded in the elastin matrix. A full cardiac cycle is simulated by imposing the same physiological blood pressures for all the TAV and BAV models. The latter have significantly smaller opening areas compared with the TAV. Larger stress values were found in the cusps of BAVs with fused cusps, at both the systolic and diastolic phases. The asymmetric geometry caused asymmetric vortices and much larger flow shear stress on the cusps which could be a potential initiator for early valvular calcification of BAVs.     

Senile cardiac amyloidosis with myocardial dysfunction. Diagnosis by endomyocardial biopsy and immunohistochemistry

Senile cardiac amyloid discovered at autopsy is usually regarded as an incidental finding. However, in immunohistochemical studies of autopsy material, three distinct forms of senile cardiovascular amyloid have been characterized, including a systemic form that diffusely infiltrates the cardiac ventricles. The systemic form can be identified immunohistochemically with use of antiserum to human prealbumin. We diagnosed senile systemic amyloidosis causing cardiac dysfunction in five men (57 to 72 years old) by using antiserum to prealbumin in myocardial biopsy tissue. Clinically, the five patients were indistinguishable from patients with nonsecretory immunoglobulin-derived primary amyloidosis with cardiac involvement; only immunohistochemical staining of myocardial tissue distinguished between the two entities. This distinction is important, because the treatment and prognosis of the two disorders are different. We recommend immunohistochemical staining of myocardial tissue for prealbumin in patients with biopsy-proved cardiac amyloid in whom no monoclonal immunoglobulin light chain is detectable in the serum or urine.     

Primary nodular amyloidosis of the lung (author's transl)]

A 69-year old woman deceased from a pericardial tamponade following a myocardial infarction. In the autopsy, approximately 30 cherry-sized or smaller nodules, were unexpectedly found in the subpleural tissue. These nodules produced no clinical manifestations, however histological and polarisation optical investigations showed that they correspond to an isolated primary pericollagenous amyloidosis of the lung.     

The stimulation of the cardiac differentiation of mesenchymal stem cells in tissue constructs that mimic myocardium structure and biomechanics

We investigated whether tissue constructs resembling structural and mechanical properties of the myocardium would induce mesenchymal stem cells (MSCs) to differentiate into a cardiac lineage, and whether further mimicking the 3-D cell alignment of myocardium would enhance cardiac differentiation. The tissue constructs were generated by integrating MSCs with elastic polyurethane nanofibers in an electrical field. Control of processing parameters resulted in tissue constructs recapitulating the fibrous and anisotropic structure, and typical stress-strain response of native porcine myocardium. MSCs proliferated in the tissue constructs when cultured dynamically, but retained a round morphology. mRNA expression demonstrated that cardiac differentiation was significantly stimulated. Enhanced cardiac differentiation was achieved by 3-D alignment of MSCs within the tissue constructs. Cell alignment was attained by statically stretching tissue constructs during culture. Increasing stretching strain from 25% to 75% increased the degree of 3-D cell alignment. Real time RT-PCR results showed that when cells assuming a high degree of alignment (with application of 75% strain), their expression of cardiac markers (GATA4, Nkx2.5 and MEF2C) remarkably increased. The differentiated cells also developed calcium channels, which are required to have electrophysiological properties. This report to some extent explains the outcome of many in?vivo studies, where only a limited amount of the injected MSCs differentiated into cardiomyocytes. It is possible that the strain of the heartbeat (～20%) cannot allow the MSCs to have an alignment high enough for a remarkable cardiac differentiation. This work suggests that pre-differentiation of MSCs into cardiomyocytes prior to injection may result in a greater degree of cardiac regeneration than simply injecting un-differentiated MSCs into heart.     

B型超声心动图中心脏组织及结构的识别

本文描述了一种从B型超声心动图识别心脏组织及结构的方法。该方法融合了空间特征信息及纹理特征信息，并经神经网络进行识别进而给出心脏组织及结构的类别标号图象，在空间特征提取中，采用了基于模糊的模型分割方法，该方法可将各类组织交界附近隶属度带识别过程中并融保纹理特征，因而有较好的识别率，该方法已在一台PentiumⅡPC机上进行了模拟，并获得了较好的实验结果。     

Perspectives in endoscopic cardiac surgery

Surgical telemanipulators are obviously used in cardiac surgery to provide the surgeon in a confined space the same stereoscopic vision, full dexterity, unimpaired hand-eye alignment and tactile feedback as in open surgery. This is the basic concept that enables the controlled fine soft tissue manipulation that is needed in bypass grafting and valve surgery. In 2005, a total of 2984 cardiac procedures were performed worldwide using the da Vinci system. This includes totally endoscopic coronary artery bypass grafting (TECAB), mitral valve repair (MVR) procedures, ASD closure and cardiac tissue ablation for atrial fibrillation.     

The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction

Regeneration of the damaged myocardium is one of the most challenging fronts in the field of tissue engineering due to the limited capacity of adult heart tissue to heal and to the mechanical and structural constraints of the cardiac tissue. In this study we demonstrate that an engineered acellular scaffold comprising type I collagen, endowed with specific physiomechanical properties, improves cardiac function when used as a cardiac patch following myocardial infarction. Patches were grafted onto the infarcted myocardium in adult murine hearts immediately after ligation of left anterior descending artery and the physiological outcomes were monitored by echocardiography, and by hemodynamic and histological analyses four weeks post infarction. In comparison to infarcted hearts with no treatment, hearts bearing patches preserved contractility and significantly protected the cardiac tissue from injury at the anatomical and functional levels. This improvement was accompanied by attenuated left ventricular remodeling, diminished fibrosis, and formation of a network of interconnected blood vessels within the infarct. Histological and immunostaining confirmed integration of the patch with native cardiac cells including fibroblasts, smooth muscle cells, epicardial cells, and immature cardiomyocytes. In summary, an acellular biomaterial with specific biomechanical properties promotes the endogenous capacity of the infarcted myocardium to attenuate remodeling and improve heart function following myocardial infarction.     

Cardiac tamponade and pericardial disorders in connective tissue diseases: case report and literature review.

Pericardial disorders occurring in connective tissue diseases are not uncommon and may present as acute or chronic pericarditis with or without an effusion. In many instances, a diagnosis of pericardial involvement is not found until autopsy. Echocardiography and other currently employed radiographic techniques have enhanced the ability to make a diagnosis. Approximate frequencies of common connective tissue disorders with pericardial involvement include scleroderma (59%), systemic lupus erythematosus (44%), mixed connective tissue disease (30%), rheumatoid arthritis (24%), and polymyositis/dermatomyositis (11%). Cardiac tamponade or constriction is rare. This article describes a patient with clinical features consistent with mixed connective tissue disease that presented with a pericardial effusion and cardiac tamponade. In addition, a review of pericardial involvement in connective tissue diseases and the occurrence of cardiac tamponade or constriction is included.     

Measurements on glassy-carbon electrodes in saline

Results of measurements on glassy carbon used as physiological measuring electrodes and as stimulating electrodes are presented. The frequency dependence of the electrode impedance is shown to be comparable with that of metallic electrodes. Because of its inertness to body tissue, the glassy carbon electrode appears to have favourable properties for long-term implantation. When used with short current pulses, the glassy-carbon stimulating electrode shows a dominant ohmic polarisation similar to that of a silver anode; this holds for both the glassy-carbon anode and the cathode.     

Myocardial engineering in vivo: formation and characterization of contractile, vascularized three-dimensional cardiac tissue

Engineering cardiac tissue in three dimensions is limited by the ability to supply nourishment to the cells in the center of the construct. This limits the radius of an in vitro engineered cardiac construct to approximately 40 microm. This study describes a method of engineering contractile three-dimensional cardiac tissue with the incorporation of an intrinsic vascular supply. Neonatal cardiac myocytes were cultured in vivo in silicone chambers, in close proximity to an intact vascular pedicle. Silicone tubes were filled with a suspension of cardiac myocytes in fibrin gel and surgically placed around the femoral artery and vein of adult rats. At 3 weeks, the tissues in the chambers were harvested for in vitro contractility evaluation and processed for histologic analysis. By 3 weeks, the chambers had become filled with living tissue. Hematoxylin and eosin staining showed large amounts of muscle tissue situated around the femoral vessels. Electron micrographs revealed well-organized intracellular contractile machinery and a high degree of intercellular connectivity. Immunostaining for von Willebrand factor demonstrated neovascularization throughout the constructs. With electrical stimulation, the constructs were able to generate an average active force of 263 microN with a maximum of 843 microN. Electrical pacing was successful at frequencies of 1 to 20 Hz. In addition, the constructs exhibited positive inotropy in response to ionic calcium and positive chronotropy in response to epinephrine. As engineering of cardiac replacement tissue proceeds, vascularization is an increasingly important component in the development of three-dimensional structures. This study demonstrates the in vivo survival, vascularization, organization, and functionality of transplanted myocardial cells.     

Chondroitin sulfate expression is required for cardiac atrioventricular canal formation

Defects in cardiac valvulogenesis are a common cause of congenital heart disease, and the study of this process promises to provide mechanistic insights and lead to novel therapeutics. Normal valve development involves multiple signaling pathways, and recently roles have been identified for extracellular matrix components, including glycosaminoglycans. We, therefore, explored the role of the glycosaminoglycan chondroitin sulfate during zebrafish cardiac development. Beginning at 33 hr, there is a distinct zone of chondroitin sulfate expression in the atrioventricular (AV) boundary, in the cardiac jelly between the endocardium and myocardium. This expression is both spatially and temporally restricted, and is undetectable after 48 hr. Chemical as well as genetic inhibition of chondroitin synthesis results in AV canal (AVC) defects, including loss of the atrioventricular constriction, blood regurgitation, and failure of circulation. Lack of chondroitin disrupts a marker of cell migration, results in a loss of myocardial and endothelial markers of valvulogenesis, and misregulates bone morphogenetic protein expression, supporting an early role in AVC development. In summary, we have defined a requirement for chondroitin sulfate expression in the normal patterning of the AV boundary, suggesting that this component of the cardiac jelly provides a necessary signal in this critical transition in vertebrate cardiogenesis. Developmental Dynamics 238:3103–3110, 2009. © 2009 Wiley‐Liss, Inc.     

A critique of impedance measurements in cardiac tissue

The specific impedance of cardiac tissue cannot be measured directly. Instead, the investigator obtains voltage and current measurements and places them into a model of the tissue's structure to infer the impedances of elements of the model. If the model fails to describe major aspects of the real tissue, the results may be worthless, although possibly self-consistent. In the literature of impedance measurement in cardiac tissue, only rarely is the model explicitly described; more commonly, the tissue model is adopted implicitly when equations giving the impedance in terms of voltage and current measurements are adopted. This paper examines the series of models that have been used in specific impedance measurements of cardiac tissue and shows how the same or similar measurements can accurately describe tissue impedivity or can lead to significant errors when inadequate models such as isotropic and anisotropic monodomains (although a part of work of historical merit) are used.     

A Mathematical Model for the Diffusion of Tumour Angiogenesis Factor into the Surrounding Host Tissue

Unless they are furnished with an adequate blood supply anda means of disposing of their waste products by a mechanismother than diffusion, solid tumours cannot grow beyond a fewmillimetres in diameter. It is now a well-established fact that,in order to accomplish this neovascularization, solid tumourssecrete a diffusable chemical compound known as turnour angiogenesisfactor (TAF) into the surrounding tissue. This stimulates nearbyblood vessels to migrate towards and finally penetrate the tumour.Once provided with the new supply of nutrient, rapid growthtakes place. In this paper, a mathematical model is presentedfor the diffusion of TAF into the surrounding tissue. The completeprocess of angiogenesis is made up of a sequence of severaldistinct events and the model is an attempt to take into accountas many of these as possible. In the diffusion equation forthe TAF, a decay term is included which models the loss of thechemical in the surrounding tissue itself. A threshold distancefor the TAF is incorporated in an attempt to reflect the resultsfrom experiments of corneal implants in test animals. By formulatingthe problems in terms of a free boundary problem, the extentof the diffusion of TAF into the surrounding tissue can be monitored.Finally, by introducing a sink term representing the actionof proliferating endothelial cells, the boundary of the TAFis seen to recede, and hence the position and movement of thecapillaries can be indirectly followed. The changing concentrationgradient observed as the boundary recedes may offer a possibleexplanation for the initiation of anastomosis. Several functionsare considered as possible sink terms and numerical resultsare presented. The situation where the turnour. (i.e. the sourceof TAF) is removed is also considered.     

Cardiac Tissue Structure,Properties, and Performance: A Materials Science Perspective

From an engineering perspective, many forms of heart disease can be thought of as a reduction in biomaterial performance, in which the biomaterial is the tissue comprising the ventricular wall. In materials science, the structure and properties of a material are recognized to be interconnected with performance. In addition, for most measurements of structure, properties, and performance, some processing is required. Here, we review the current state of knowledge regarding cardiac tissue structure, properties, and performance as well as the processing steps taken to acquire those measurements. Understanding the impact of these factors and their interactions may enhance our understanding of heart function and heart failure. We also review design considerations for cardiac tissue property and performance measurements because, to date, most data on cardiac tissue has been obtained under non-physiological loading conditions. Novel measurement systems that account for these design considerations may improve future experiments and lead to greater insight into cardiac tissue structure, properties, and ultimately performance.