Cardiac Electrophysiological Activity Research Articles

A simulation study of the impact of drug-IKr binding mechanisms on biomarkers of proarrhythmic risk reveals a crucial role in reverse use-dependence of action potential duration and a marked influence on the vulnerable window.

In silico human models are being used more and more to predict the potential proarrhythmic risk of compounds. It has been shown that incorporation of the dynamics of drug-hERG channel interactions can have an important impact on the action potential duration (APD) at normal heart rates. Our aim is to investigate the relevance of drug dynamics on other important biomarkers of proarrhythmic risk. We use the state-of-the-art mathematical models of the cardiac electrophysiological activity to simulate TRIaD biomarkers, namely Triangulation, Reverse use-dependency, electrical Instability of the action potential and Dispersion, together with the vulnerable window to unidirectional block. They were simulated in control conditions and in the presence of an extensive set of 114 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and 10 well-known real IKr blockers at the concentration leading to a 25 % prolongation of the APD. Our results show that drug binding dynamics to hERG are crucial for the reverse use-dependence of APD, the slope of the APD restitution curve as a function of the root square of the cycle length ranging from 0 to 5.6 ms/ms (2.1 ms/ms in control conditions). The vulnerable window for unidirectional block and the transmural action potential duration dispersion markedly depended on the drug binding mechanisms and kinetics, although to a lesser extent. Virtual drugs led to increments of these two biomarkers from 25 % to 200 %. On the contrary, temporal instability and, beat-to-beat instability, are less dependent on the dynamics of drug binding. The results obtained with the models of real IKr blockers are in line with those obtained with the virtual drugs. Our study highlights the importance of considering the drug binding mechanism, as well as the kinetics, to assess the effects of IKr blockers. Moreover, adoption of in silico models mimicking these characteristics would contribute to the improvement of the prediction of the proarrhythmic risk of new compounds.

Combined in silico model of cardiac electrophysiological activity and modulation by the autonomic nervous system

Combined in silico model of cardiac electrophysiological activity and modulation by the autonomic nervous system

Virtual blebbistatin: A robust and rapid software approach to motion artifact removal in optical mapping of cardiomyocytes

Fluorescent reporters of cardiac electrophysiology provide valuable information on heart cell and tissue function. However, motion artifacts caused by cardiac muscle contraction interfere with accurate measurement of fluorescence signals. Although drugs such as blebbistatin can be applied to stop cardiac tissue from contracting by uncoupling calcium-contraction, their usage prevents the study of excitation-contraction coupling and, as we show, impacts cellular structure. We therefore developed a robust method to remove motion computationally from images of contracting cardiac muscle and to map fluorescent reporters of cardiac electrophysiological activity onto images of undeformed tissue. When validated on cardiomyocytes derived from human induced pluripotent stem cells (iPSCs), in both monolayers and engineered tissues, the method enabled efficient and robust reduction of motion artifact. As with pharmacologic approaches using blebbistatin for motion removal, our algorithm improved the accuracy of optical mapping, as demonstrated by spatial maps of calcium transient decay. However, unlike pharmacologic motion removal, our computational approach allowed direct analysis of calcium-contraction coupling. Results revealed calcium-contraction coupling to be more uniform across cells within engineered tissues than across cells in monolayer culture. The algorithm shows promise as a robust and accurate tool for optical mapping studies of excitation-contraction coupling in heart tissue.

Three-Dimensional Cardiomyocyte-Nanobiosensing System for Specific Recognition of Drug Subgroups.

Abnormal cardiac electrophysiological activities significantly contribute to the incidence of cardiovascular diseases. Therefore, it is crucial to recognize effective drugs, which require an accurate, stable, and sensitive platform. Although conventional extracellular recordings offer a non-invasive and label-free manner to monitor the electrophysiological state of cardiomyocytes, the misrepresented and low-quality extracellular action potentials are difficult to provide accurate and high-content information for drug screening. This study presents the development of a three-dimensional cardiomyocyte-nanobiosensing system that can specifically recognize drug subgroups. The nanopillar-based electrode is manufactured by template synthesis and standard microfabrication technology on a porous polyethylene terephthalate membrane. Based on the cardiomyocyte-nanopillar interface, high-quality intracellular action potentials can be recorded by the minimally invasive electroporation. We validate the performance of a cardiomyocyte-nanopillar-based intracellular electrophysiological biosensing platform by two subclasses of sodium channel blockers, quinidine and lidocaine. The recorded intracellular action potentials accurately reveal the subtle differences between these drugs. Our study indicates that high-content intracellular recordings utilizing nanopillar-based biosensing can provide a promising platform for the electrophysiological and pharmacological investigation of cardiovascular diseases.

Cardiomyocyte electrophysiology and its modulation: current views and future prospects.

Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca2+ homeostasis, excitation-contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in this Phil. Trans. B theme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Artificial Intelligence-Enabled Electrocardiography Predicts Left Ventricular Dysfunction and Future Cardiovascular Outcomes: A Retrospective Analysis.

BACKGROUND: The ejection fraction (EF) provides critical information about heart failure (HF) and its management. Electrocardiography (ECG) is a noninvasive screening tool for cardiac electrophysiological activities that has been used to detect patients with low EF based on a deep learning model (DLM) trained via large amounts of data. However, no studies have widely investigated its clinical impacts. OBJECTIVE: This study developed a DLM to estimate EF via ECG (ECG-EF). We further investigated the relationship between ECG-EF and echo-based EF (ECHO-EF) and explored their contributions to future cardiovascular adverse events. METHODS: There were 57,206 ECGs with corresponding echocardiograms used to train our DLM. We compared a series of training strategies and selected the best DLM. The architecture of the DLM was based on ECG12Net, developed previously. Next, 10,762 ECGs were used for validation, and another 20,629 ECGs were employed to conduct the accuracy test. The changes between ECG-EF and ECHO-EF were evaluated. The primary follow-up adverse events included future ECHO-EF changes and major adverse cardiovascular events (MACEs). RESULTS: The sex-/age-matching strategy-trained DLM achieved the best area under the curve (AUC) of 0.9472 with a sensitivity of 86.9% and specificity of 89.6% in the follow-up cohort, with a correlation of 0.603 and a mean absolute error of 7.436. In patients with accurate prediction (initial difference < 10%), the change traces of ECG-EF and ECHO-EF were more consistent (R-square = 0.351) than in all patients (R-square = 0.115). Patients with lower ECG-EF (≤35%) exhibited a greater risk of cardiovascular (CV) complications, delayed ECHO-EF recovery, and earlier ECHO-EF deterioration than patients with normal ECG-EF (>50%). Importantly, ECG-EF demonstrated an independent impact on MACEs and all CV adverse outcomes, with better prediction of CV outcomes than ECHO-EF. CONCLUSIONS: The ECG-EF could be used to initially screen asymptomatic left ventricular dysfunction (LVD) and it could also independently contribute to the predictions of future CV adverse events. Although further large-scale studies are warranted, DLM-based ECG-EF could serve as a promising diagnostic supportive and management-guided tool for CV disease prediction and the care of patients with LVD.

B-AB01-04 INTERACTION BETWEEN ISCHEMIA AND SYMPATHETIC ACTIVITY ON CARDIAC ELECTROPHYSIOLOGY AND ARRHYTHMIA IN THE INNERVATED LANGENDORFF-PERFUSED MOUSE HEART

Sympathetic activation of the heart plays a key role in the modulation of cardiac electrophysiology and arrhythmogenesis. It is generally believed that sympathetic activation is proarrhythmic in the setting of cardiac ischemia. However, few studies have looked at the dynamic effects of physiological sympathetic nerve activation on cardiac electrophysiological activities during ischemia. To investigate the effects of sympathetic activation in the innervated Langendorff-perfused mouse heart subjected to acute ischemia. The heart and posterior thoracic cavity from mice (C57Bl6, N=4) were dissected and perfused through the descending aorta for dual optical mapping of transmembrane potential (Vm) and intracellular Ca2+ to study the effects of sympathetic nerve stimulation (SNS). SNS, achieved through spinal cord stimulation at T1-T3, was performed before, during and immediately after 5 min of low-flow ischemia (10% of pre-ischemic flow rate). Early afterdepolarizations (EADs) and ventricular tachycardia (VT) occurred in all 4 animals within 5 min of ischemia and immediately upon reperfusion. Both SNS and ventricular pacing, during either ischemia or reperfusion, completely abolished EADs and VT induced by global low-flow ischemia and reperfusion (Fig). In the isolated innervated mouse heart, we showed that sympathetic stimulation protects against ischemia-induced cardiac arrhythmias potentially by over-driving ventricular ectopic activity.

Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.

Drug‐mediated or medical condition‐mediated disruption of hERG function accounts for the main cause of acquired long‐QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG‐HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG) was measured by patch‐clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell‐based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after‐depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long‐term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.

When Does the IC50 Accurately Assess the Blocking Potency of a Drug?

Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-à-go-go-related gene (hERG) channels, which is currently quantified by the IC50. However, channel block depends on the experimental conditions. Our aim is to improve the evaluation of the blocking potency of drugs by designing experimental stimulation protocols to measure the IC50 that will help to decide whether the IC50 is representative enough. We used the state-of-the-art mathematical models of the cardiac electrophysiological activity to design three stimulation protocols that enhance the differences in the probabilities to occupy a certain conformational state of the channel and, therefore, the potential differences in the blocking effects of a compound. We simulated an extensive set of 144 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and we also experimentally validated our key predictions. Our results show that the IC50 protocol dependency relied on the tested compounds. Some of them showed no differences or small differences on the IC50 value, which suggests that the IC50 could be a good indicator of the blocking potency in these cases. However, others provided highly protocol dependent IC50 values, which could differ by even 2 orders of magnitude. Moreover, the protocols yielding the maximum IC50 and minimum IC50 depended on the drug, which complicates the definition of a “standard” protocol to minimize the influence of the stimulation protocol on the IC50 measurement in safety pharmacology. As a conclusion, we propose the adoption of our three-protocol IC50 assay to estimate the potency to block hERG in vitro. If the IC50 values obtained for a compound are similar, then the IC50 could be used as an indicator of its blocking potency, otherwise kinetics and state-dependent binding properties should be accounted.

Magnetocardiogram forward problem based on personalized three-dimensional heart-torso model

In order to simulate the distribution of magnetic field generated by cardiac electrophysiological activities, a three-dimensional (3D) computing framework of magnetocardiogram forward problem based on a finite element method (FEM) is proposed. First, the 3D heart-torso geometry model is established from the 3D reconstruction of magnetic resonance images. Then the modified FitzHugh-Nagumo (FHN) equation combined with 3D cardiac geometry is used to investigate the propagation of transmembrane potential (TMP). In the end, quasi-static Maxwell equations and 3D torso model are used to explore the propagation of the bioelectromagnetic field produced by TMP. In our calculation, the Galerkin finite element method is used. The results show that the FEM-model can simulate extracorporeal magnetic field. Further, numerical solutions of simplified models with the one-dimensional FHN equation and the straight wire are respectively consistent with the analytical solutions, which verifies the feasibility of the computing framework. In summary, this framework successfully simulates the cardiac TMP and extracorporeal magnetic field, which may conduce to the study of magnetocardiogram inverse problem.

Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative.

In 2005, the International Council for Harmonization (ICH) established cardiotoxicity assessment guidelines to identify the risk of Torsade de Pointes (TdP). It is focused on the blockade of the human ether-à-go-go-related gene (hERG) channel known to cause QT/QTc prolongation and the QT/QTc prolongation shown on the electrocardiogram. However, these biomarkers are not the direct risks of TdP with low specificity as the action potential is influenced by multiple channels along with the hERG channel. Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative emerged to address limitations of the current model. The objective of CiPA is to develop a standardized in silico model of a human ventricular cell to quantitively evaluate the cardiac response for the cardiac toxicity risk and to come up with a metric for the TdP risk assessment. In silico working group under CiPA developed a standardized and reliable in silico model and a metric that can quantitatively evaluate cellular cardiac electrophysiologic activity. The implementation mainly consists of hERG fitting, Hill fitting, and action potential simulation. In this review, we explained how the in silico model of CiPA works, and briefly summarized current overall CiPA studies. We hope this review helps clinical pharmacologists to understand the underlying estimation process of CiPA in silico modeling.

A composite visualization method for electrophysiology-morphous merging of human heart

BackgroundElectrophysiological behavior is of great importance for analyzing the cardiac functional mechanism under cardiac physiological and pathological condition. Due to the complexity of cardiac structure and biophysiological function, visualization of a cardiac electrophysiological model compositively is still a challenge. The lack of either modality of the whole organ structure or cardiac electrophysiological behaviors makes analysis of the intricate mechanisms of cardiac dynamic function a difficult task. This study aims at exploring 3D conduction of stimulus and electrical excitation reactivity on the level of organ with the authentic fine cardiac anatomy structure.MethodsIn this paper, a cardiac electrical excitation propagation model is established based on the human cardiac cross-sectional data to explore detailed cardiac electrical activities. A novel biophysical merging visualization method is then presented for biophysical integration of cardiac anatomy and electrophysiological properties in the form of the merging optical model, which provides the corresponding position, spatial relationship and the whole process in 3D space with the context of anatomical structure for representing the biophysical detailed electrophysiological activity.ResultsThe visualization result present the action potential propagation of the left ventricle within the excitation cycle with the authentic fine cardiac organ anatomy. In the visualized images, all vital organs are identified and distinguished without ambiguity. The three dimensional spatial position, relation and the process of cardiac excitation conduction and re-entry propagation in the anatomical structure during the phase of depolarization and repolarization is also shown in the result images, which exhibits the performance of a more detailed biophysical understanding of the electrophysiological kinetics of human heart in vivo.ConclusionsResults suggest that the proposed merging optical model can merge cardiac electrophysiological activity with the anatomy structure. By specifying the respective opacity for the cardiac anatomy structure and the electrophysiological model in the merging attenuation function, the visualized images can provide an in-depth insight into the biophysical detailed cardiac functioning phenomena and the corresponding electrophysiological behavior mechanism, which is helpful for further speculating cardiac physiological and pathological responses and is fundamental to the cardiac research and clinical diagnoses.

Gastrodin Pretreatment Impact on Sarcoplasmic Reticulum Calcium Transport ATPase (SERCA) and Calcium Phosphate (PLB) Expression in Rats with Myocardial Ischemia Reperfusion.

BackgroundCalcium overload, inflammation, and apoptosis play important roles in myocardial ischemia-reperfusion injury (MIRI). Gastrodin pretreatment can alleviate MIRI. This study observed sarcoplasmic reticulum calcium transport ATPase (Ca2+-ATPase, SERCA) and calcium phosphate (PLB) protein expression in the ventricular remodeling process after myocardial infarction to explore the effect of gastrodin pretreatment on MIRI.Material/MethodsHealthy 7-week-old male SD rats were randomly divided into a sham group (A), a model group (B), and gastrodin pretreatment groups C, D, and E (100, 200, and 400 mg/kg, respectively) with 20 in each group. Anterior descending coronary artery ligation method was used to establish a rat MIRI model with 30-min ischemia and 120-min reperfusion. Cardiac electrophysiological activity was recorded. Serum IL-6 and IL10 levels were determined by ELISA. SERCA activity was tested by colorimetric phosphorus method. SERCA, PLB, and pSer-PLB protein expression were detected by Western blot.ResultsCompared with the sham group, IL-6 and IL-10 levels were elevated, SERCA2a expression was downregulated, and PLB protein was elevated in the model group (P<0.05). pSer16-PLB showed no significant difference among groups, and the ratio of pSer16-PLB/PLB obviously decreased (P<0.05). IL-6 level gradually declined and IL-10 increased in the gastrodin group following concentration elevation. SERCA 2a expression rose in the gastrodin group in a dose-dependent manner (P<0.05). Elevated PLB protein expression showed no significant difference, while pSer16-PLB protein increased (P<0.05), leading to elevated pSer16 PLB/PLB ratio (P<0.05).ConclusionsGastrodin pretreatment alleviates MIRI and inflammation injury by regulating SERCA and PLB expression to decrease calcium overload.

Electrophysiocardiogram: For the first time EPCG has been recorded on human body surface

Since ECG was invented in 1903, this is the first time in history that a full information multi-band and multi-linear electrophysiological cardiogram has been used to successfully scan and record on the human body surface. Since it is able to record various multi-band, multi-track linear electric signals of cardiac electrophysiological activities that correspond to different regions of the entire heart, it has thus been denominated as “electrophysiocardiogram” (EPCG). A traditional ECG is always represented by a characteristic wave form, which resembles a string. For a long period of time, ECG has had a lot of mysteries surrounding it, it maybe because ECG has a lot of mixed signals buried in such convolutionary forms, which limits the amount of the signals that are discernable and determinable. For the first time, the EPCG technology has allowed cardiac signals to be convoluted into the linear wave form, which is then processed through various new approaches featuring multiple frequency bands, multiple dimensions and multiple patterns, and consequentially recorded as the following types of signals within the ranges of P wave and T wave: multiple frequency band signals, signals of different regions and different locations, forward waves and negative waves. Therefore, EPCG may help to solve many puzzling scientific questions regarding heart, such as exactly how many electric signals are involved in heart excitation, pacing, conduction and action, as well as many other intriguing questions about heart, and thus would become a very helpful tool in clinical practice.

Depth Attenuation Degree Based Visualization for Cardiac Ischemic Electrophysiological Feature Exploration.

Although heart researches and acquirement of clinical and experimental data are progressively open to public use, cardiac biophysical functions are still not well understood. Due to the complex and fine structures of the heart, cardiac electrophysiological features of interest may be occluded when there is a necessity to demonstrate cardiac electrophysiological behaviors. To investigate cardiac abnormal electrophysiological features under the pathological condition, in this paper, we implement a human cardiac ischemic model and acquire the electrophysiological data of excitation propagation. A visualization framework is then proposed which integrates a novel depth weighted optic attenuation model into the pathological electrophysiological model. The hidden feature of interest in pathological tissue can be revealed from sophisticated overlapping biophysical information. Experiment results verify the effectiveness of the proposed method for intuitively exploring and inspecting cardiac electrophysiological activities, which is fundamental in analyzing and explaining biophysical mechanisms of cardiac functions for doctors and medical staff.

Alternans and Spiral Breakup in an Excitable Reaction-Diffusion System: A Simulation Study.

The determination of the mechanisms of spiral breakup in excitable media is still an open problem for researchers. In the context of cardiac electrophysiological activities, spiral breakup exhibits complex spatiotemporal pattern known as ventricular fibrillation. The latter is the major cause of sudden cardiac deaths all over the world. In this paper, we numerically study the instability of periodic planar traveling wave solution in two dimensions. The emergence of stable spiral pattern is observed in the considered model. This pattern occurs when the heart is malfunctioning (i.e., ventricular tachycardia). We show that the spiral wave breakup is a consequence of the transverse instability of the planar traveling wave solutions. The alternans, that is, the oscillation of pulse widths, is observed in our simulation results. Moreover, we calculate the widths of spiral pulses numerically and observe that the stable spiral pattern bifurcates to an oscillatory wave pattern in a one-parameter family of solutions. The spiral breakup occurs far below the bifurcation when the maximum and the minimum excited states become more distinct, and hence the alternans becomes more pronounced.

G-Heart: A GPU-based System for Electrophysiological Simulation and Multi-modality Cardiac Visualization

Cardiac electrophysiological simulation and multi-modality visualization are computationally intensive and valuable in studying the structure, mechanism, and dynamics of heart. The existing multi-CPU based approaches can reduce the calculation time, but suffer from the hardware and communication cost problems and are inefficient for 3D data visualization. Compared with multi-CPU, the highly parallel and multi-core properties of GPU make it a suitable alternative for accelerating cardiac simulation and visualization. In this paper, we develop a G-Heart system where GPU-based acceleration technologies are adopted for both the simulation of cardiac electrophysiological activities and the online illustration 3D multi-modality (anatomical and electrophysiological) data. In the simulation stage, a phase-field method is employed to cope with the no-flux boundary condition. For heart geometrical structure illustration, a GPU-based ray-casting volume rendering algorithm is implemented and an improved context-preserving model with user interaction is integrated into the proposed framework. Finally, a fusion visualization method is proposed, which can provide 3D visualization results for both the simulation data and the anatomical data simultaneously.

Abstract 450: Cardiac Electrophysiological Changes Linked to Vitamin D Receptors Deficiency in Obstructive Nephropathy

Background: Chronic kidney disease is highly prevalent and is associated with cardiovascular disease. Paricalcitol protects individuals from some of the renal and cardiovascular complications associated with kidney disease. However, its electrophysiological effect during myocardial ischemia-reperfusion is currently unknown. Aims: Using an obstructive nephropathy (ON) model, we plan to investigate the potential, structural, and functional changes of the heart that are linked to vitamin D deficiency. Methods: The ureters of adult rats (n = 10) were unilaterally obstructed. An inductor of the vitamin D receptor (VDR) was administered for 15 days (30ng/Kg/day, ip). We evaluated histological, molecular, and biochemical parameters, as well, cardiac electrophysiological activity with ischemia-reperfusion protocol. Results: we found changes in the action potential duration (APD) at 90% (* P&lt;0.05 vs. C, +P&lt;0.05 vs. O). The analysis revealed arrhythmias, ventricular tachycardia (VT), and ventricular fibrillation (VF). Arrhythmias were quantified in the following ways: 0 − sinus rhythm, 1 – premature ventricular complex, 2 - salvos, 3 - no sustained VT, and 4 – sustained VT or VF (&gt;30 seconds). * P&lt;0.05 vs. C, +P&lt;0.05 vs. O. Of interest was the finding that appears to prolong Pari ischemia DPA in both the controls and the obstructed animals. Also, a significant bradycardia was established in the ischemic phase of the animals obstructed with Pari, which reversed completely during reperfusion. In hearts from ON model animals, we found high AT 1 expression and marked low VDR expression; these changes were reversed by paricalcitol treatment. Conclusions: The reduction of VDR expression in ON hearts could be related to increased arrhythmogenesis. The recovery induced by paricalcitol could protect against ventricular fibrillation by the lengthening of the action potential. Further studies will be necessary to elucidate these interesting kidney-heart interactions.

Progress on correlation between connexin 43 and cardiovascular disease

As the most important gap junction protein, connexin 43 ( Cx43 ) is the most important connexin in the mammalian heart. Recent studies suggest that it plays an important role in heart development, cardiac electrophysiological activity and cell repair after myocardial ischemia. Cx43 abnormity is an important cause of many cardiovascular diseases including congenital heart disease, ischemic heart disease, arrhythmias and hypertension. The expression of Cx43 is regulated by various factors, including methylation, histone modification and non-coding RNA regulation, etc. These abnormal regulations may be important for the development of diseases. Key words: Connexin; Cardiovascular diseases; Expression regulation

Inverse computation for cardiac sources using single current dipole and current multipole models

Two cardiac functional models are constructed in this paper. One is a single current model and the other is a current multipole model. Parameters denoting the properties of these two models are calculated by a least-square fit to the measurements using a simulated annealing algorithm. The measured signals are detected at 36 observation nodes by a superconducting quantum interference device (SQUID). By studying the trends of position, orientation and magnitude of the single current dipole model and the current multipole model in the QRS complex during one time span and comparing the reconstructed magnetocardiography (MCG) of these two cardiac models, we find that the current multipole model is a more appropriate model to represent cardiac electrophysiological activity.