Estimation of Cardiac Bidomain Parameters from Extracellular Measurement: Two Dimensional Study

Cardiac tissue conductivity measurements can be used to assess the electrical substrate underlying normal and abnormal wavefront propagation. We describe a method of solving the inverse cardiac bidomain model to estimate average longitudinal and transverse intra and extra-cellular conductivities and fiber angle relative to an electrode array placed arbitrarily on the epi- or endocardial surface. A Newton–Raphson reconstruction method and two Tikhonov-type regularizations were able to stably identify conductivities and fiber angles in tissue models having anisotropies similar to those in real cardiac tissue. The reconstruction methods were tested with data from increasingly realistic two dimensional cardiac bidomain models and performed well both when measurement noise was added, and when simulated experimental and forward model matching was diminished. This approach may be a suitable basis for continuous monitoring of myocardial condition in-vivo via a catheter based electrode array.     

心肌细胞动作电位数学模型及其计算机仿真研究

恶性心律失常和室颤是心血管疾病中造成人类死亡的主要原因之一。建立在Hodgkin-Huxley方程基础上的心肌细胞动作电位数学模型由离子通道、泵及交换体电流组成,与细胞内外离子浓度、通道状况、神经递质和药物影响密切相关,可使细胞电生理和临床病理生理间建立确切的联系。基于这种模型的计算机仿真研究可以通过改变细胞内外环境,观察心肌组织乃至整个心脏电生理功能的变化,探讨和揭示心律失常或心源性猝死的机制。本文重点阐述了心肌细胞动作电位数学模型的构成及其计算机仿真研究的概况。     

采用灌注生物反应器构建的心肌组织中氧分布的数值模拟

目的　建立灌注生物反应器和心肌组织构建物中流体流动及氧传递和反应的稳态数学模型。方法　以工程化心肌组织体外多通道灌注培养系统为研究对象,利用计算流体力学方法,通过商业软件来求解数学模型,并考察两种细胞密度下灌注速率对氧分布的影响。结果　通过多通道灌注生物反应器模仿毛细血管,能部分提高及改善支架材料内的氧浓度分布。在细胞密度较低时多通道灌注方式可以满足细胞生长的需要;但由于通道的数目较少以及形状简单,在细胞密度较高时,仍无法满足细胞对氧的需求。结论　该模型能够用于优化支架材料的几何尺寸以及灌注速率等流动参数。     

Micro-Perfusion for Cardiac Tissue Engineering: Development of a Bench-Top System for the Culture of Primary Cardiac Cells

Tissue-engineered constructs have high metabolic requirements during in vitro culture necessitating the development of micro-perfusion systems to maintain high functional performance. In this study, we describe the design, fabrication, and testing of a novel micro-perfusion system to support the culture of primary cardiac cells. Our system consists of a micro-incubator with independent stages for 35-mm tissue culture plates with inflow/outflow manifolds for fluid delivery and aspiration. A peristaltic pump is utilized for fluid delivery and vacuum for fluid aspiration. Oxygen saturation, pH, and temperature are regulated for the media while temperature is regulated within the micro-incubator, fluid reservoir, and oxygenation chamber. Validation of the perfusion system was carried out using primary cardiac myocytes, isolated from 2- to 3-day-old neonatal rat hearts, plated on collagen-coated tissue culture plates. Two million cells/plate were used and the perfusion system was run for 1 h (without the need for a cell culture incubator) while controls were maintained in a standard cell culture incubator. We evaluated the cell viability, cell adhesion, total protein, total RNA, and changes in the expression of SERCA2 and phospholamban using RT-PCR, with N = 6 for each group. We found that there was no significant change in any variable during the 1-h run in the perfusion system. These studies served to demonstrate the compatibility of the perfusion system to support short-term culture of primary cardiac cells.     

Role of intracellular calcium dynamics in the short-term memory in CVM model: a simulation study

Many experimental studies claimed that, short-term memory, an intrinsic property of paced cardiac myocytes, has been regulated by either intracellular calcium cycling or membrane ionic currents, manifested by a time constant of cellular action potential duration (APD) restitution. Although both factors play important roles in short-term memory, their respective effects have not been well understood currently. In this study, we used an ionic model of canine ventricular myocytes (CVM) to investigate the effect of calcium release from the sacroplasm reticulum (SR), as well as the effect of L-type calcium current, on cardiac short-term memory. We calculated short-term memory response by testing the time to reach steady-state APD after an abrupt shortening of basic cycling length (BCL) in pacing protocol. Our results indicated that as the release of calcium from SR was gradually prevented, short-term memory response decreased, while the blockade of L-type calcium channel had little effect on short-term memory. Finally, we declared that the amount of intracellular calcium released from SR affected short-term memory of cardiac tissues more than that of L-type calcium channel.     

Origins of Spiral Wave Meander and Breakup in a Two-Dimensional Cardiac Tissue Model

We studied the stability of spiral waves in homogeneous two-dimensional cardiac tissue using phase I of the Luo–Rudy ventricular action potential model. By changing the conductance and the relaxation time constants of the ion channels, various spiral wave phenotypes, including stable, quasiperiodically meandering, chaotically meandering, and breakup were observed. Stable and quasiperiodically meandering spiral waves occurred when the slope of action potential duration (APD) restitution was <1 over all diastolic intervals visited during reentry; chaotic meander and spiral wave breakup occurred when the slope of APD restitution exceeded 1. Curvature of the wave changes both conduction velocity and APD, and their restitution properties, thereby modulating local stability in a spiral wave, resulting in distinct spiral wave phenotypes. In the LR1 model, quasiperiodic meander is most sensitive to the Na⁺ current, whereas chaotic meander and breakup are more dependent on the Ca²⁺ and K⁺ currents. © 2000 Biomedical Engineering Society. PAC00: 8719Hh, 8717Nn, 8717Aa, 8716Uv     

Bistability and Correlation with Arrhythmogenesis in a Model of the Right Atrium

Rapid pacing is an important tool for understanding cardiac arrhythmias. A recent experiment involving rapid pacing of sheep atria indicated that the initiation of atrial arrhythmias may be related to the 1:1/2:1 bistability. To elucidate the mechanism of this relation, this study applied the pacing protocol from the sheep study to an idealized model of the right atrium. The model included all major anatomical features, the sino-atrial node, and the regional differences in the action potential duration (APD). A pacing protocol was applied, in which the basic cycle length (BCL) was decreased in steps of 10 ms until the response switched to 2:1, then BCL was increased. The 1:1-to-2:1 transitions occurred at shorter BCLs than the 2:1-to-1:1 transitions yielding a global bistability window of 60 ms. As in the sheep study, idiopathic waves were observed at BCLs within or near the bistability window. The model was used to quantify the types, prevalence, and persistence of idiopatic waves, study their initiation and termination, and relate them to the model components. The results demonstrate that idiopatic waveforms move with the shift of the bistability window and that they disappear when bistability is eliminated. Thus, this modeling study supports causal relationship between the 1:1/2:1 bistability and the initiation of arrhythmias.     

Facts and Artifacts in Cardiac Cycle Time Analysis: A Simple Model of Vagal Control

Cardiac cycle time effects occur when stimuli or responses presented at different times within the cardiac cycle induce differential changes in the same or following interbeat interval (IBI). Two related problems regarding cardiac cycle time effects are discussed. One problem concerns how to separate anticipatory from stimulus-induced changes in interbeat intervals that occur around the time of presentation of an expected stimulus. The other problem is an anomalous finding in reaction time tasks: prestimulus interbeat intervals are longer when they precede stimuli presented early, rather than late, in the cardiac cycle. These two problems can be understood if some simple assumptions are made about anticipatory and stimulus-induced vagal excitation. If vagal excitation regularly increases prior to an expected event, the anomalous effect of stimulus delay in the cardiac cycle on preceding interbeat intervals can be explained. The presentation of events and IBI times on an ordinal IBI axis induces an inappropriate time shift. Furthermore, estimates of maximal anticipatory deceleration at stimulus onset in the interbeat interval of the stimulus and of subsequent stimulus-induced vagal changes can be inferred. The relevance of this analysis to earlier experimental results is discussed.     

Complications of Cardiac Perforation and Lead Dislodgement with an MRI-Conditional Pacing Lead: a Korean Multi-Center Experience

Medtronic CapSureFix MRI 5086 pacing lead (5086; Medtronic, Inc., Minneapolis, MN, USA) has been reported to be associated with increased cardiac perforation and lead dislodgement. This study aimed to compare the incidence of cardiac perforation and lead dislodgement within 30 days after pacemaker implantation between 5086 MRI lead and previous Medtronic CapSureFix Novus 5076 non-MRI pacing lead. This was a nationwide, multicenter retrospective study in which we compared the incidence of adverse events between 277 patients implanted with 5086 lead and 205 patients implanted with 5076 lead between March 2009 and September 2014. Cardiac perforation within 30 days of pacemaker implantation occurred in 4 patients (1.4%) with the 5086 lead and in no patient with the 5076 lead (P = 0.084). Lead dislodgement occurred in 8 patients (2.9%) with the 5086 lead and in 5 patients (2.4%) with the 5076 lead (P = 0.764). On multivariate logistic regression analysis, age was significantly associated with cardiac perforation. Congestive heart failure and implantation of right atrial (RA) lead at RA free wall or septum were significant factors for the incidence of lead dislodgement and lead revision. The incidence of cardiac perforation and lead dislodgement were not statistically different between the patients with 5086 lead and the patients with 5076 lead. However, careful attention for cardiac perforation may be needed when using the 5086 MRI lead, especially in elderly patients.     

Analysis of Characteristics and Mortality in Cardiac Arrest Patients by Hospital Level: a Nationwide Population-based Study

BackgroundSurvival and post-cardiac arrest care vary considerably by hospital, region, and country. In the current study, we aimed to analyze mortality in patients who underwent cardiac arrest by hospital level, and to reveal differences in patient characteristics and hospital factors, including post-cardiac arrest care, hospital costs, and adherence to changes in resuscitation guidelines.MethodsWe enrolled adult patients (≥ 20 years) who suffered non-traumatic cardiac arrest from 2006 to 2015. Patient demographics, insurance type, admission route, comorbidities, treatments, and hospital costs were extracted from the National Health Insurance Service database. We categorized patients into tertiary hospital, general hospital, and hospital groups according to the level of the hospital where they were treated. We analyzed the patients'' characteristics, hospital factors, and mortalities among the three groups. We also analyzed post-cardiac arrest care before and after the 2010 guideline changes. The primary end-point was 30 days and 1 year mortality rates.ResultsThe tertiary hospital, general hospital, and hospital groups represented 32.6%, 49.6%, and 17.8% of 337,042 patients, respectively. The tertiary and general hospital groups were younger, had a lower proportion of medical aid coverage, and fewer comorbidities, compared to the hospital group. Post-cardiac arrest care, such as percutaneous coronary intervention, targeted temperature management, and extracorporeal membrane oxygenation, were provided more frequently in the tertiary and general hospital groups. After adjusting for age, sex, insurance type, urbanization level, admission route, comorbidities, defibrillation, resuscitation medications, angiography, and guideline changes, the tertiary and general hospital groups showed lower 1-year mortality (tertiary hospital vs. general hospital vs. hospital, adjusted odds ratios, 0.538 vs. 0.604 vs. 1; P < 0.001). After 2010 guideline changes, a marked decline in atropine use and an increase in post-cardiac arrest care were observed in the tertiary and general hospital groups.ConclusionThe tertiary and general hospital groups showed lower 30 days and 1 year mortality rates than the hospital group, after adjusting for patient characteristics and hospital factors. Higher-level hospitals provided more post-cardiac arrest care, which led to high hospital costs, and showed good adherence to the guideline change after 2010.     

Electroporation and Shock-Induced Transmembrane Potential in a Cardiac Fiber During Defibrillation Strength Shocks

Experimental studies have shown that the magnitude of the shock-induced transmembrane potential (V_m) saturates with increasing electric field strength. This study uses a mathematical model to investigate the effects of electroporation and membrane kinetics on V_m in a cardiac fiber. The model consists of the core conductor equation for a one-dimensional fiber, where excitability is represented by the Luo–Rudy dynamic model (1994–1995) and electroporation is described by a membrane conductance that increases exponentially with V_m squared. For shocks delivered during the plateau of an action potential, the model reproduces the experimentally observed saturation of V_m with a root mean square error of 4.27% and a correlation coefficient of 0.9992. For shocks delivered during diastole, the saturation of V_m is qualitatively reproduced even when the sodium and calcium channels are inactivated. Quantitative replication of the response to diastolic shocks is hindered by the choice of electroporation parameters (optimized for shocks delivered during the plateau) and differences in the membrane kinetics between model and experiment. The complex behavior of V_m during large shocks is due to a combination of electroporation, electrotonus, propagation, and active membrane kinetics. The modeling results imply that the experimentally observed saturation of V_m is due to electroporation of the lipid bilayer. © 1998 Biomedical Engineering Society. PAC98: 8722Fy, 8710+e, 8722Jb     

Validation of a 1D patient-specific model of the arterial hemodynamics in bypassed lower-limbs: Simulations against in vivo measurements

The validation of a coupled 1D–0D model of the lower-limb arterial hemodynamics is presented. This study focuses on pathological subjects (6 patients, 72.7 ± 11.1 years) suffering from atherosclerosis who underwent a femoro-popliteal bypass surgery. The 1D model comprises four vessels from the upper-leg, peripheral networks are modeled with three-element windkessels and in vivo velocity is prescribed at the inlet.The model is patient-specific: its parameters reflect the physiological condition of the subjects. In vivo data are acquired invasively during bypass surgery using B-mode ultrasonography and catheter.Simulations from the model compare well with measured velocity (u) and pressure (p) waveforms: average relative root-mean-square error between numerical and experimental waveforms are limited to ?_p = 9.6%, ?_u = 16.0%. The model is able to reproduce the intensity and shape of waveforms observed in different clinical cases. This work also details the introduction of blood leakages along the pathological arterial network, and the sensitivity of the model to its parameters.This study constitutes a first validation of a patient-specific numerical model of a pathological arterial network. It presents an efficient tool for engineers and clinicians to help them improve their understanding of the hemodynamics in diseased arteries.     

Cardiac papillary fibroelastoma: Retrospective clinicopathologic study of 17 tumors with resection at a single institution and literature review

Cardiac papillary fibroelastomas (PFEs), which are mainly found in the valves, are rare benign tumors that can cause embolism. Single-center surgical experience in the treatment of this tumor is uncommon.     

米利酮和哇巴因对心衰模型狗心功能效应的比较观察

米利酮和哇巴因均能改善心衰模型狗的心功能，在相近剂量，米利酮和哇巴因均能减轻心脏负荷，但其作用各有特点，结果表明，米利酮和哇巴因作和机制和作用方式肯定不尽相同。     

Mechanoelectric Feedback in a Model of the Passively Inflated Left Ventricle

Mechanoelectric feedback has been described in isolated cells and intact ventricular myocardium, but the mechanical stimulus that governs mechanosensitive channel activity in intact tissue is unknown. To study the interaction of myocardial mechanics and electrophysiology in multiple dimensions, we used a finite element model of the rabbit ventricles to simulate electrical propagation through passively loaded myocardium. Electrical propagation was simulated using the collocation-Galerkin finite element method. A stretch-dependent current was added in parallel to the ionic currents in the Beeler–Reuter ventricular action potential model. We investigated different mechanical coupling parameters to simulate stretch-dependent conductance modulated by either fiber strain, cross-fiber strain, or a combination of the two. In response to pressure loading, the conductance model governed by fiber strain alone reproduced the epicardial decrease in action potential amplitude as observed in experimental preparations of the passively loaded rabbit heart. The model governed by only cross-fiber strain reproduced the transmural gradient in action potential amplitude as observed in working canine heart experiments, but failed to predict a sufficient decrease in amplitude at the epicardium. Only the model governed by both fiber and cross-fiber strain reproduced the epicardial and transmural changes in action potential amplitude similar to experimental observations. In addition, dispersion of action potential duration nearly doubled with the same model. These results suggest that changes in action potential characteristics may be due not only to length changes along the long axis direction of the myofiber, but also due to deformation in the plane transverse to the fiber axis. The model provides a framework for investigating how cellular biophysics affect the function of the intact ventricles. © 2001 Biomedical Engineering Society. PAC01: 8716Uv, 8719Nn, 8719Hh, 8719Rr, 8718Bb, 8710+e, 0270Dh, 8717Aa     

Cardiac troponins and autoimmunity: Their role in the pathogenesis of myocarditis and of heart failure

Despite the widespread use of cardiac troponins as biomarkers for the diagnosis and quantitation of cardiac injury, the effect of troponin release and a possible autoimmune response to the troponins is unknown. Other investigators reported that programmed cell death-1 (PD-1)-receptor deficient mice developed severe cardiomyopathy with autoantibodies to troponin I. We found that immunization of genetically susceptible mice with troponin I but not troponin T induced a robust autoimmune response leading to marked inflammation and fibrosis in the myocardium. At later times, antibodies to cardiac myosin were detected in troponin-immunized mice. The severity of inflammation correlated with expression of chemokines RANTES, MIP-2, IP-10 and MCP-1 in the myocardium. Prior immunization with troponin I increased the severity of experimental infarctions, indicating that an autoimmune response to troponin I aggravates acute cardiac damage. Cardiac inflammation, fibrosis and functional impairment were transferred from immunized to naive recipients by CD4⁺ T cells, and the cytokine profile suggested both Th2 and Th17 profiles in A/J mice. Finally we identified an 18-mer of troponin I containing an immuno-dominant epitope.     

The Immunomodulating Effects of Thalidomide and Dexamethasone in a Murine Cardiac Allograft Transplantation Model

PurposeThe immunomodulatory effects of thalidomide (TM) and dexamethasone (DX) on immune cells and their co-stimulatory, co-inhibitory molecules in vitro and in vivo have been previously reported. The current study investigated the effects of TM and the combinatorial treatment with DX on immune cells using a murine cardiac allograft transplantation model.Materials and MethodsIntraabdominal transplant of cardiac allografts from BALB/c (H-2^d) donors to C57BL/6 (H-2^b) recipients was performed. After transplantation, mice were injected daily with TM or DX or a combination of both TM and DX (TM/DX) by intraperitoneal route until the time of graft loss. CD4⁺ T cell subsets and CD11c⁺ cells in the peripheral blood mononuclear cells and spleen were examined and quantified with flow cytometry. Serum IL-6 levels were measured by enzyme-linked immunosorbent assay on day 7.ResultsThe mean graft survivals were 6.86 days in the untreated group, and 10.0 days in the TM/DX group (p<0.001). The TM/DX treatment affected the CD4⁺ T cell subsets without suppressing the total CD4⁺ T cell population. The CD4⁺FOXP3⁺/CD4⁺CD44^hi T cell ratio increased. Increase in cell counts and median fluorescence intensity on CD11c⁺CD85k⁺ with TM/DX were observed. The inhibition of pro-inflammatory cytokine interleukin-6 was also observed.ConclusionThese outcomes suggest the immunomodulating effect of the TM/DX combinatorial treatment. In conclusion, TM/DX combination may be a promising immunomodulatory approach for preventing allograft rejection and improving graft survival by inducing tolerance in transplantation.     

Tamarind Multifunctional Protein: Safety and Anti-Inflammatory Potential in Intestinal Mucosa and Adipose Tissue in a Preclinical Model of Diet-Induced Obesity

IntroductionObesity has emerged as one of the main public health problems. This condition triggers a series of hormonal and metabolic changes related to a low-grade chronic inflammatory condition. The trypsin inhibitor purified from tamarind (TTIp) seeds is a promising anti-inflammatory molecule, but its safety needs to be evaluated. This study aimed to evaluate TTIp bioactive dose effects on organs involved in its metabolism (liver and pancreas) and affected tissues (small intestine and perirenal adipose tissue) in an obesity model.MethodsThree groups of adult male Wistar rats were used (n = 5). Two of these groups had diet-induced obesity, and a third group was eutrophic. TTIp was administered by gavage in one of the obese groups for 10 days, while the remaining groups received a vehicle. The chromatographic profile and the inhibition assay corroded the purification of the inhibitor. Physical and behavioral changes, liver enzymes, and stereological and histopathological analyses of tissues were evaluated.ResultsTTIp did not cause visible signs of toxicity, nor caused changes in liver enzymes, the liver, and pancreatic tissues. TTIp did not cause changes in the intestinal mucosa, showing improvement in the villi''s histopathological characteristics compared to the group of animals with obesity without treatment with TTIp (p = 0.004). The analysis of perirenal adipose tissue showed that the average sectional area of animals with obesity that received TTIp did not differ from the control. There was a difference between the high glycemic load diet group and the group treated with the inhibitor (351.8 ± 55.5) (p = 0.016). In addition, the group that received TTIp had no inflammatory infiltrates.ConclusionBased on histological and stereological analysis, the use of TTIp is potentially safe and anti-inflammatory in the evaluated obesity model and can be investigated as a possible adjuvant in obesity therapy.