James N Weiss

Publications (163)850.81 Total impact

• Article: Oxidative Stress in Atrial Fibrillation: An Emerging Role of NADPH Oxidase.

  Ji-Youn Youn, Jun Zhang, Yixuan Zhang, Houzao Chen, Depei Liu, Peipei Ping, James N Weiss, Hua Cai
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  ABSTRACT: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Patients with AF have up to seven-fold higher risk of suffering from ischemic stroke. Better understanding of etiologies of AF and its thromboembolic complications are required for improved patient care, as current anti-arrhythmic therapies have limited efficacy and off target effects. Accumulating evidence has implicated a potential role of oxidative stress in the pathogenesis of AF. Excessive production of reactive oxygen species (ROS) is likely involved in the structural and electrical remodeling of the heart, contributing to fibrosis and thrombosis. In particular, NADPH oxidase (NOX) has emerged as a potential enzymatic source for ROS production in AF based on growing evidence from clinical and animal studies. Indeed, NOX can be activated by known upstream triggers of AF such as angiotensin II and atrial stretch. In addition, treatments such as Statins, antioxidants, ACEI or AT1RB have been shown to prevent post-operative AF; among which ACEI/AT1RB and Statins can attenuate NOX activity. On the other hand, detailed molecular mechanisms by which specific NOX isoform(s) are involved in the pathogenesis of AF and the extent to which activation of NOX plays a causal role in AF development remains to be determined. The current review discusses causes and consequences of oxidative stress in AF with a special focus on the emerging role of NOX pathways.
  Journal of Molecular and Cellular Cardiology 05/2013; · 5.17 Impact Factor
• Article: Early Afterdepolarizations in Cardiac Myocytes: Beyond Reduced Repolarization Reserve.

  Zhilin Qu, Lai-Hua Xie, Riccardo Olcese, Hrayr S Karagueuzian, Peng-Sheng Chen, Alan Garfinkel, James N Weiss
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  ABSTRACT: Early afterdepolarizations (EADs) are secondary voltage depolarizations during the repolarizing phase of the action potential, which can cause lethal cardiac arrhythmias. The occurrence of EADs requires a reduction in outward current and/or an increase in inward current, a condition called reduced repolarization reserve. However, this generalized condition is not sufficient for EAD genesis and does not explain the voltage oscillations manifesting as EADs. Here we summarize recent progress that uses dynamical theory to build on and advance our understanding of EADs beyond the concept of repolarization reserve, towards the goal of developing a holistic and integrative view of EADs and their role in arrhythmogenesis. We first introduce concepts from nonlinear dynamics that are relevant to EADs, namely, Hopf bifurcation leading to oscillations and basin of attraction of an equilibrium or oscillatory state. We then present a theory of phase-2 EADs in nonlinear dynamics, which includes the formation of quasi-equilibrium states at the plateau voltage, their stabilities, and the bifurcations leading to and terminating the oscillations. This theory shows that the L-type calcium channel plays a unique role in causing the nonlinear dynamical behaviors necessary for EADs. We also summarize different mechanisms of phase-3 EADs. Based on the dynamical theory, we discuss the roles of each of the major ionic currents in the genesis of EADs, and potential therapeutic targets.
  Cardiovascular research 04/2013; · 5.80 Impact Factor
• Article: Apamin Sensitive Potassium Current Modulates Action Potential Duration Restitution and Arrhythmogenesis of Failing Rabbit Ventricles.

  Yu-Cheng Hsieh, Po-Cheng Chang, Chia-Hsiang Hsueh, Young Soo Lee, Changyu Shen, James N Weiss, Zhenhui Chen, Tomohiko Ai, Shien-Fong Lin, Peng-Sheng Chen
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  ABSTRACT: BACKGROUND: -Apamin-sensitive K currents (I(KAS)) are upregulated in heart failure (HF). We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and reduce ventricular fibrillation (VF) duration in failing ventricles. METHODS AND RESULTS: -We simultaneously mapped membrane potential and intracellular Ca (Ca(i)) in 7 rabbits hearts with pacing-induced HF and in 7 normal hearts. A dynamic pacing protocol was used to determine APDR at baseline and after apamin (100 nM) infusion. Apamin did not change APD(80) in normal ventricles, but prolonged APD(80) in failing ventricles at either long (≥300 ms) or short (≤170 ms) pacing cycle length (PCL), but not at intermediate PCL. The maximal slope of APDR curve was 2.03 [95% CI, 1.73 to 2.32] in failing ventricles and 1.26 [95% CI, 1.13 to 1.40] in normal ventricles at baseline (p=0.002). After apamin administration, the maximal slope of APDR in failing ventricles decreased to 1.43 [95% CI, 1.01 to 1.84] (p=0.018) whereas no significant changes were observed in normal ventricles. During VF in failing ventricles, the number of phase singularities (baseline vs apamin, 4.0 vs 2.5), dominant frequency (13.0 Hz vs 10.0 Hz), and VF duration (160 s vs 80 s) were all significantly (p<0.05) decreased by apamin. CONCLUSIONS: -Apamin prolongs APD at long and short, but not at intermediate PCL in failing ventricles. I(KAS) upregulation may be antiarrhythmic by preserving the repolarization reserve at slow heart rate, but is proarrhythmic by steepening the slope of APDR curve which promotes the generation and maintenance of VF.
  Circulation Arrhythmia and Electrophysiology 02/2013; · 6.46 Impact Factor
• Article: Oxidative stress, fibrosis, and early afterdepolarization-mediated cardiac arrhythmias.

  Hrayr S Karagueuzian, Thao P Nguyen, Zhilin Qu, James N Weiss
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  ABSTRACT: Animal and clinical studies have demonstrated that oxidative stress, a common pathophysiological factor in cardiac disease, reduces repolarization reserve by enhancing the L-type calcium current, the late Na, and the Na-Ca exchanger, promoting early afterdepolarizations (EADs) that can initiate ventricular tachycardia and ventricular fibrillation (VT/VF) in structurally remodeled hearts. Increased ventricular fibrosis plays a key facilitatory role in allowing oxidative-stress induced EADs to manifest as triggered activity and VT/VF, since normal non-fibrotic hearts are resistant to arrhythmias when challenged with similar or higher levels of oxidative stress. The findings imply that antifibrotic therapy, in addition to therapies designed to suppress EAD formation at the cellular level, may be synergistic in reducing the risk of sudden cardiac death.
  Frontiers in physiology. 01/2013; 4:19.
• Article: Pro- and anti-arrhythmic effects of ATP-sensitive potassium current activation on reentry during early afterdepolarization-mediated arrhythmias.

  Marvin G Chang, Enno de Lange, Guillaume Calmettes, Alan Garfinkel, Zhilin Qu, James N Weiss
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  ABSTRACT: BACKGROUND: Under conditions promoting early afterdepolarizations (EADs), ventricular tissue can become bi-excitable, i.e. capable of wave propagation mediated by either the Na current (INa)or the L-type calcium current (ICa,L),raising the possibility that ICa,L- mediated reentry may contribute to polymorphic ventricular tachycardia (PVT) and Torsade de Pointes (TdP). ATP-sensitive K current (IKATP)activation suppresses EADs, but the effects on ICa,L-mediatedreentry are unknown. OBJECTIVE: To investigate the effects of IKATPactivation on ICa,L-mediated reentry. METHODS: We performed optical voltage mapping in cultured neonatal rat ventricular myocytemonolayers exposed to BayK4688 and isoproterenol.The effects of pharmacologically activating IKATPwith pinacidil were analyzed. RESULTS: In 13 monolayers with anatomic ICa,L-mediatedreentry around a central obstacle, pinacidil (50 µM) converted ICa,L-mediatedreentry to INa-mediatedreentry. In 33 monolayers with functional ICa,L-mediatedreentry (spiral waves), pinacidil terminated reentry in 17, converted reentry into more complex INa-mediatedreentry resembling fibrillation in 12, and had no effect in 4. In simulated 2D bi-excitable tissue in which ICa,L-and INa-mediated wavefronts coexisted, slow IKATPactivation (over minutes) reliably terminated rotors, but rapid IKATPactivation (over seconds) often converted ICa,L-mediatedreentry to INa-mediatedreentry resembling fibrillation. CONCLUSIONS: IKATPactivation can have pro-arrhythmic effects on EAD-mediated arrhythmias if ICa,L-mediatedreentry is present.
  Heart rhythm: the official journal of the Heart Rhythm Society 12/2012; · 4.56 Impact Factor
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  Available from: Zhilin Qu

  Article: Calcium Alternans in Cardiac Myocytes: Order From Disorder.

  Zhilin Qu, Michael Nivala, James N Weiss
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  ABSTRACT: Calcium alternans is associated with T-wave alternans and pulsus alternans, harbingers of increased mortality in the setting of heart disease. Recent experimental, computational, and theoretical studies have led to new insights into the mechanisms of Ca alternans, specifically how disordered behaviors dominated by stochastic processes at the subcellular level become organized into ordered periodic behaviors. In this article, we summarize the recent progress in this area, outlining a holistic theoretical framework in which the complex effects of Ca cycling proteins on Ca alternans are linked to three key properties of the cardiac Ca cycling network: randomness, refractoriness, and recruitment. We also illustrate how this '3R theory' can reconcile many seemingly contradictory experimental observations.
  Journal of Molecular and Cellular Cardiology 10/2012; · 5.17 Impact Factor
• Article: Loss of Function of hNav1.5 by a ZASP1 Mutation Associated With Intraventricular Conduction Disturbances in Left Ventricular Noncompaction.

  Yutao Xi, Tomohiko Ai, Enno De Lange, Zhaohui Li, Geru Wu, Luca Brunelli, W Buck Kyle, Isik Turker, Jie Cheng, Michael J Ackerman, Akinori Kimura, James N Weiss, Zhilin Qu, Jeffrey J Kim, Georgine Faulkner, Matteo Vatta
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  ABSTRACT: Background- Defects of cytoarchitectural proteins can cause left ventricular noncompaction, which is often associated with conduction system diseases. We have previously identified a p.D117N mutation in the LIM domain-binding protein 3-encoding Z-band alternatively spliced PDZ motif gene (ZASP) in a patient with left ventricular noncompaction and conduction disturbances. We sought to investigate the role of p.D117N mutation in the LBD3 NM_001080114.1 isoform (ZASP1-D117N) for the regulation of cardiac sodium channel (Na(v)1.5) that plays an important role in the cardiac conduction system. Methods and Results- Effects of ZASP1-wild-type and ZASP1-D117N on Na(v)1.5 were studied in human embryonic kidney-293 cells and neonatal rat cardiomyocytes. Patch-clamp study demonstrated that ZASP1-D117N significantly attenuated I(Na) by 27% in human embryonic kidney-293 cells and by 32% in neonatal rat cardiomyocytes. In addition, ZASP1-D117N rightward shifted the voltage-dependent activation and inactivation in both systems. In silico simulation using Luo-Rudy phase 1 model demonstrated that altered Na(v)1.5 function can reduce cardiac conduction velocity by 28% compared with control. Pull-down assays showed that both wild-type and ZASP1-D117N can complex with Na(v)1.5 and telethonin/T-Cap, which required intact PDZ domains. Immunohistochemical staining in neonatal rat cardiomyocytes demonstrates that ZASP1-D117N did not significantly disturb the Z-line structure. Disruption of cytoskeletal networks with 5-iodonaphthalene-1-sulfonyl homopiperazine and cytochalasin D abolished the effects of ZASP1-D117N on Na(v)1.5. Conclusions- ZASP1 can form protein complex with telethonin/T-Cap and Na(v)1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na(v)1.5, without significant alteration of the cytoskeletal protein complex. Our study suggests that electric remodeling can occur in left ventricular noncompaction subject because of a direct effect of mutant ZASP on Na(v)1.5.
  Circulation Arrhythmia and Electrophysiology 08/2012; 5(5):1017-1026. · 6.46 Impact Factor
• Article: "Good enough solutions" and the genetics of complex diseases.

  James N Weiss, Alain Karma, W Robb MacLellan, Mario Deng, Christoph D Rau, Colin M Rees, Jessica Wang, Nicholas Wisniewski, Eleazar Eskin, Steve Horvath, Zhilin Qu, Yibin Wang, Aldons J Lusis
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  ABSTRACT: In this Emerging Science Review, we discuss a systems genetics strategy, which we call gene module association study (GMAS), as a novel approach complementing genome-wide association studies (GWAS), to understand complex diseases by focusing on how genes work together in groups rather than singly. The first step is to characterize phenotypic differences among a genetically diverse population. The second step is to use gene expression microarray (or other high-throughput) data from the population to construct gene coexpression networks. Coexpression analysis typically groups 20 000 genes into 20 to 30 modules containing tens to hundreds of genes, whose aggregate behavior can be represented by the module's "eigengene." The third step is to correlate expression patterns with phenotype, as in GWAS, only applied to eigengenes instead of single nucleotide polymorphisms. The goal of the GMAS approach is to identify groups of coregulated genes that explain complex traits from a systems perspective. From an evolutionary standpoint, we hypothesize that variability in eigengene patterns reflects the "good enough solution" concept, that biological systems are sufficiently complex so that many possible combinations of the same elements (in this case eigengenes) can produce an equivalent output, that is, a "good enough solution" to accomplish normal biological functions. However, when faced with environmental stresses, some "good enough solutions" adapt better than others, explaining individual variability to disease and drug susceptibility. If validated, GMAS may imply that common polygenic diseases are related as much to group interactions between normal genes, as to multiple gene mutations.
  Circulation Research 08/2012; 111(4):493-504. · 9.49 Impact Factor
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  Available from: Zhilin Qu

  Article: Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers.

  Marvin G Chang, Connie Y Chang, Enno de Lange, Linmiao Xu, Brian O'Rourke, Hrayr S Karagueuzian, Leslie Tung, Eduardo Marbán, Alan Garfinkel, James N Weiss, Zhilin Qu, M Roselle Abraham
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  ABSTRACT: Early afterdepolarizations (EADs) are voltage oscillations that occur during the repolarizing phase of the cardiac action potential and cause cardiac arrhythmias in a variety of clinical settings. EADs occur in the setting of reduced repolarization reserve and increased inward-over-outward currents, which intuitively explains the repolarization delay but does not mechanistically explain the time-dependent voltage oscillations that are characteristic of EADs. In a recent theoretical study, we identified a dual Hopf-homoclinic bifurcation as a dynamical mechanism that causes voltage oscillations during EADs, depending on the amplitude and kinetics of the L-type Ca(2+) channel (LTCC) current relative to the repolarizing K(+) currents. Here we demonstrate this mechanism experimentally. We show that cardiac monolayers exposed to the LTCC agonists BayK8644 and isoproterenol produce EAD bursts that are suppressed by the LTCC blocker nitrendipine but not by the Na(+) current blocker tetrodoxin, depletion of intracellular Ca(2+) stores with thapsigargin and caffeine, or buffering of intracellular Ca(2+) with BAPTA-AM. These EAD bursts exhibited a key dynamical signature of the dual Hopf-homoclinic bifurcation mechanism, namely, a gradual slowing in the frequency of oscillations before burst termination. A detailed cardiac action potential model reproduced the experimental observations, and identified intracellular Na(+) accumulation as the likely mechanism for terminating EAD bursts. Our findings in cardiac monolayers provide direct support for the Hopf-homoclinic bifurcation mechanism of EAD-mediated triggered activity, and raise the possibility that this mechanism may also contribute to EAD formation in clinical settings such as long QT syndromes, heart failure, and increased sympathetic output.
  Biophysical Journal 06/2012; 102(12):2706-14. · 3.65 Impact Factor
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  Available from: Zhilin Qu

  Article: Criticality in intracellular calcium signaling in cardiac myocytes.

  Michael Nivala, Christopher Y Ko, Melissa Nivala, James N Weiss, Zhilin Qu
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  ABSTRACT: Calcium (Ca) is a ubiquitous second messenger that regulates many biological functions. The elementary events of local Ca signaling are Ca sparks, which occur randomly in time and space, and integrate to produce global signaling events such as intra- and intercellular Ca waves and whole-cell Ca oscillations. Despite extensive experimental characterization in many systems, the transition from local random to global synchronous events is still poorly understood. Here we show that criticality, a ubiquitous dynamical phenomenon in nature, is responsible for the transition from local to global Ca signaling. We demonstrate this first in a computational model of Ca signaling in a cardiac myocyte and then experimentally in mouse ventricular myocytes, complemented by a theoretical agent-based model to delineate the underlying dynamics. We show that the interaction between the Ca release units via Ca-induced Ca release causes self-organization of Ca spark clusters. When the coupling between Ca release units is weak, the cluster-size distribution is exponential. As the interactions become strong, the cluster-size distribution changes to a power-law distribution, which is characteristic of criticality in thermodynamic and complex nonlinear systems, and facilitates the formation and propagation of Ca waves and whole-cell Ca oscillations. Our findings illustrate how criticality is harnessed by a biological cell to regulate Ca signaling via self-organization of random subcellular events into cellular-scale oscillations, and provide a general theoretical framework for the transition from local Ca signaling to global Ca signaling in biological cells.
  Biophysical Journal 06/2012; 102(11):2433-42. · 3.65 Impact Factor
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  Available from: Michael Nivala

  Article: Criticality in Intracellular Calcium Signaling in Cardiac Myocytes

  Michael Nivala, Christopher Y Ko, Melissa Nivala, James N Weiss, Zhilin Qu
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  ABSTRACT: Calcium (Ca) is a ubiquitous second messenger that regulates many biological functions. The elementary events of local Ca signaling are Ca sparks, which occur randomly in time and space, and integrate to produce global signaling events such as intra-and intercellular Ca waves and whole-cell Ca oscillations. Despite extensive experimental characterization in many systems, the transition from local random to global synchronous events is still poorly understood. Here we show that criticality, a ubiquitous dynamical phenomenon in nature, is responsible for the transition from local to global Ca signaling. We demonstrate this first in a computational model of Ca signaling in a cardiac myocyte and then experimentally in mouse ventricular myocytes, complemented by a theoretical agent-based model to delineate the underlying dynamics. We show that the interaction between the Ca release units via Ca-induced Ca release causes self-organization of Ca spark clusters. When the coupling between Ca release units is weak, the cluster-size distribution is exponential. As the interactions become strong, the cluster-size distribution changes to a power-law distribution, which is characteristic of criticality in thermodynamic and complex nonlinear systems, and facilitates the formation and propagation of Ca waves and whole-cell Ca oscillations. Our findings illustrate how criticality is harnessed by a biological cell to regulate Ca signaling via self-organization of random subcellular events into cellular-scale oscillations, and provide a general theoretical framework for the transition from local Ca signaling to global Ca signaling in biological cells.
  Biophysical Journal 06/2012; · 3.65 Impact Factor
• Article: Enhanced sensitivity of aged fibrotic hearts to angiotensin II- and hypokalemia-induced early afterdepolarization-mediated ventricular arrhythmias.

  Aneesh Bapat, Thao P Nguyen, Jong-Hwan Lee, Ali A Sovari, Michael C Fishbein, James N Weiss, Hrayr S Karagueuzian
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  ABSTRACT: Unlike young hearts, aged hearts are highly susceptible to early afterdepolarization (EAD)-mediated ventricular fibrillation (VF). This differential may result from age-related structural remodeling (fibrosis) or electrical remodeling of ventricular myocytes or both. We used optical mapping and microelectrode recordings in Langendorff-perfused hearts and patch-clamp recordings in isolated ventricular myocytes from aged (24-26 mo) and young (3-4 mo) rats to assess susceptibility to EADs and VF during either oxidative stress with ANG II (2 μM) or ionic stress with hypokalemia (2.7 mM). ANG II caused EAD-mediated VF in 16 of 19 aged hearts (83%) after 32 ± 7 min but in 0 of 9 young hearts (0%). ANG II-mediated VF was suppressed with KN-93 (Ca(2+)/calmodulin-dependent kinase inhibitor) and the reducing agent N-acetylcysteine. Hypokalemia caused EAD-mediated VF in 11 of 11 aged hearts (100%) after 7.4 ± 0.4 min. In 14 young hearts, however, VF did not occur in 6 hearts (43%) or was delayed in onset (31 ± 22 min, P < 0.05) in 8 hearts (57%). In patch-clamped myocytes, ANG II and hypokalemia (n = 6) induced EADs and triggered activity in both age groups (P = not significant) at a cycle length of >0.5 s. When myocytes of either age group were coupled to a virtual fibroblast using the dynamic patch-clamp technique, EADs arose in both groups at a cycle length of <0.5 s. Aged ventricles had significantly greater fibrosis and reduced connexin43 gap junction density compared with young hearts. The lack of differential age-related sensitivity at the single cell level in EAD susceptibility indicates that increased ventricular fibrosis in the aged heart plays a key role in increasing vulnerability to VF induced by oxidative and ionic stress.
  AJP Heart and Circulatory Physiology 03/2012; 302(11):H2331-40. · 3.71 Impact Factor
• Article: Shaping a new Ca²⁺ conductance to suppress early afterdepolarizations in cardiac myocytes.

  Roshni V Madhvani, Yuanfang Xie, Antonios Pantazis, Alan Garfinkel, Zhilin Qu, James N Weiss, Riccardo Olcese
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  ABSTRACT: Sudden cardiac death (SCD) due to ventricular fibrillation (VF) is a major world-wide health problem. A common trigger of VF involves abnormal repolarization of the cardiac action potential causing early afterdepolarizations (EADs). Here we used a hybrid biological-computational approach to investigate the dependence of EADs on the biophysical properties of the L-type Ca(2+) current (I(Ca,L)) and to explore how modifications of these properties could be designed to suppress EADs. EADs were induced in isolated rabbit ventricular myocytes by exposure to 600 μmol l(-1) H(2)O(2) (oxidative stress) or lowering the external [K(+)] from 5.4 to 2.0-2.7 mmol l(-1) (hypokalaemia). The role of I(Ca,L) in EAD formation was directly assessed using the dynamic clamp technique: the paced myocyte's V(m) was input to a myocyte model with tunable biophysical parameters, which computed a virtual I(Ca,L), which was injected into the myocyte in real time. This virtual current replaced the endogenous I(Ca,L), which was suppressed with nifedipine. Injecting a current with the biophysical properties of the native I(Ca,L) restored EAD occurrence in myocytes challenged by H(2)O(2) or hypokalaemia. A mere 5 mV depolarizing shift in the voltage dependence of activation or a hyperpolarizing shift in the steady-state inactivation curve completely abolished EADs in myocytes while maintaining a normal Ca(i) transient. We propose that modifying the biophysical properties of I(Ca,L) has potential as a powerful therapeutic strategy for suppressing EADs and EAD-mediated arrhythmias.
  The Journal of Physiology 12/2011; 589(Pt 24):6081-92. · 4.72 Impact Factor
• Article: Linking flickering to waves and whole-cell oscillations in a mitochondrial network model.

  Melissa Nivala, Paavo Korge, Michael Nivala, James N Weiss, Zhilin Qu
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  ABSTRACT: It has been shown that transient single mitochondrial depolarizations, known as flickers, tend to occur randomly in space and time. On the other hand, many studies have shown that mitochondrial depolarization waves and whole-cell oscillations occur under oxidative stress. How single mitochondrial flickering events and whole-cell oscillations are mechanistically linked remains unclear. In this study, we developed a Markov model of the inner membrane anion channel in which reactive-oxidative-species (ROS)-induced opening of the inner membrane anion channel causes transient mitochondrial depolarizations in a single mitochondrion that occur in a nonperiodic manner, simulating flickering. We then coupled the individual mitochondria into a network, in which flickers occur randomly and sparsely when a small number of mitochondria are in the state of high superoxide production. As the number of mitochondria in the high-superoxide-production state increases, short-lived or abortive waves due to ROS-induced ROS release coexist with flickers. When the number of mitochondria in the high-superoxide-production state reaches a critical number, recurring propagating waves are observed. The origins of the waves occur randomly in space and are self-organized as a consequence of random flickering and local synchronization. We show that at this critical state, the depolarization clusters exhibit a power-law distribution, a signature of self-organized criticality. In addition, the whole-cell mitochondrial membrane potential changes from exhibiting small random fluctuations to more periodic oscillations as the superoxide production rate increases. These simulation results may provide mechanistic insight into the transition from random mitochondrial flickering to the waves and whole-cell oscillations observed in many experimental studies.
  Biophysical Journal 11/2011; 101(9):2102-11. · 3.65 Impact Factor
• Article: Arrhythmogenic consequences of myofibroblast-myocyte coupling.

  Thao P Nguyen, Yuanfang Xie, Alan Garfinkel, Zhilin Qu, James N Weiss
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  ABSTRACT: Fibrosis is known to promote cardiac arrhythmias by disrupting myocardial structure. Given recent evidence that myofibroblasts form gap junctions with myocytes at least in co-cultures, we investigated whether myofibroblast-myocyte coupling can promote arrhythmia triggers, such as early afterdepolarizations (EADs), by directly influencing myocyte electrophysiology. Using the dynamic voltage clamp technique, patch-clamped adult rabbit ventricular myocytes were electrotonically coupled to one or multiple virtual fibroblasts or myofibroblasts programmed with eight combinations of capacitance, membrane resistance, resting membrane potential, and gap junction coupling resistance, spanning physiologically realistic ranges. Myocytes were exposed to oxidative (1 mmol/L H(2)O(2)) or ionic (2.7 mmol/L hypokalaemia) stress to induce bradycardia-dependent EADs. In the absence of myofibroblast-myocyte coupling, EADs developed during slow pacing (6 s), but were completely suppressed by faster pacing (1 s). However, in the presence of myofibroblast-myocyte coupling, EADs could no longer be suppressed by rapid pacing, especially when myofibroblast resting membrane potential was depolarized (-25 mV). Analysis of the myofibroblast-myocyte virtual gap junction currents revealed two components: an early transient-outward I(to)-like current and a late sustained current. Selective elimination of the I(to)-like component prevented EADs, whereas selective elimination of the late component did not. Coupling of myocytes to myofibroblasts promotes EAD formation as a result of a mismatch in early vs. late repolarization reserve caused by the I(to)-like component of the gap junction current. These cellular and ionic mechanisms may contribute to the pro-arrhythmic risk in fibrotic hearts.
  Cardiovascular research 11/2011; 93(2):242-51. · 5.80 Impact Factor
• Article: Spontaneous atrial fibrillation initiated by tyramine in canine atria with increased sympathetic nerve sprouting.

  Ayaka Numata, Yasushi Miyauchi, Norihiko Ono, Michael C Fishbein, William J Mandel, Shien-Fong Lin, James N Weiss, Peng-Sheng Chen, Hrayr S Karagueuzian
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  ABSTRACT: Chronic left ventricular myocardial infarction (LVMI) promotes atrial and pulmonary veins (PV) sympathetic nerve sprouting. To test the hypothesis that sympathetic stimulation with tyramine initiates atrial fibrillation (AF) by early after depolarization (EAD)-mediated triggered activity at the left atrial PV (LAPV) junction. LVMI was created in 6 dogs and 6 dogs served as controls. Six to 8 weeks later the activation pattern of the isolated LAPV was optically mapped using dual voltage and intracellular Ca(+2) (Ca(i) (2+) )-sensitive epifluorescent dyes before and after tyramine (5 μM) perfusion. Tyramine initiated spontaneous AF in 5 of 6 atria but none in the control group (P < 0.01). The AF was initiated by late phase 3 EAD-mediated triggered activity that arose from the LAPV junction causing functional conduction block in LA, reentry, and AF. The AF was subsequently maintained by mixed reentrant and focal mechanisms. The EADs arose during the late phase 3, when the Ca(i) (2+) level was 64 ± 12% of the peak systolic Ca(i) (2+) transient amplitude, a property caused by tyramine's simultaneous shortening of the action potential duration and lengthening of the Ca(i) (2+) transient duration in the LVMI group but not in the control. Tyrosine hydroxylase and growth associated protein 43 positive nerve sprouts were significantly increased in the sinus node, LAA, and the LSPV in the LVMI group compared to control (P < 0.01). Increased atrial sympathetic nerve sprouts after LVMI makes the LAPV junction susceptible to late phase 3 EAD-mediated triggered and AF during sympathetic stimulation with tyramine.
  Journal of Cardiovascular Electrophysiology 10/2011; 23(4):415-22. · 3.06 Impact Factor
• Article: Protective role of transient pore openings in calcium handling by cardiac mitochondria.

  Paavo Korge, Ling Yang, Jun-Hai Yang, Yibin Wang, Zhilin Qu, James N Weiss
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  ABSTRACT: Long-lasting mitochondrial permeability transition pore (mPTP) openings damage mitochondria, but transient mPTP openings protect against chronic cardiac stress. To probe the mechanism, we subjected isolated cardiac mitochondria to gradual Ca(2+) loading, which, in the absence of BSA, induced long-lasting mPTP opening, causing matrix depolarization. However, with BSA present to mimic cytoplasmic fatty acid-binding proteins, the mitochondrial population remained polarized and functional, even after matrix Ca(2+) release caused an extramitochondrial free [Ca(2+)] increase to >10 μM, unless mPTP openings were inhibited. These findings could be explained by asynchronous transient mPTP openings allowing individual mitochondria to depolarize long enough to flush accumulated matrix Ca(2+) and then to repolarize rapidly after pore closure. Because subsequent matrix Ca(2+) reuptake via the Ca(2+) uniporter is estimated to be >100-fold slower than matrix Ca(2+) release via mPTP, only a tiny fraction of mitochondria (<1%) are depolarized at any given time. Our results show that transient mPTP openings allow cardiac mitochondria to defend themselves collectively against elevated cytoplasmic Ca(2+) levels as long as respiratory chain activity is able to balance proton influx with proton pumping. We found that transient mPTP openings also stimulated reactive oxygen species production, which may engage reactive oxygen species-dependent cardioprotective signaling.
  Journal of Biological Chemistry 08/2011; 286(40):34851-7. · 4.77 Impact Factor
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  Available from: Zhilin Qu

  Article: Bi-stable wave propagation and early afterdepolarization-mediated cardiac arrhythmias.

  Marvin G Chang, Daisuke Sato, Enno de Lange, Jong-Hwan Lee, Hrayr S Karagueuzian, Alan Garfinkel, James N Weiss, Zhilin Qu
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  ABSTRACT: In normal atrial and ventricular tissue, the electrical wavefronts are mediated by the fast sodium current (I(Na)), whereas in sinoatrial and atrioventricular nodal tissue, conduction is mediated by the slow L-type calcium current (I(Ca,L)). However, it has not been shown whether the same tissue can exhibit both the I(Na)-mediated and the I(Ca,L)-mediated conduction. This study sought to test the hypothesis that bi-stable cardiac wave conduction, mediated by I(Na) and I(Ca,L), respectively, can occur in the same tissue under conditions promoting early afterdepolarizations (EADs), and to study how this novel wave dynamics is related to the mechanisms of EAD-mediated arrhythmias. Computer models of two-dimensional (2D) tissue with a physiologically detailed action potential model were used to study the bi-stable wave dynamics. Theoretical predictions were tested experimentally by optical mapping in neonatal rat ventricular myocyte monolayers. In the same 2D homogeneous tissue, we could induce spiral waves that are mediated by either I(Na) or I(Ca,L) under conditions in which the action potential model exhibited EADs. This bi-stable wave propagation behavior was similar to bi-stability shown in many other nonlinear systems. Because the bi-stable states are also excitable, we call this novel behavior bi-excitability. In a 2D heterogeneous tissue, the I(Ca,L)-mediated spiral wave meanders, giving rise to a twisting electrocardiographic QRS axis, resembling torsades de pointes, whereas the coexistence and interplay between the I(Na)-mediated wavefronts and I(Ca,L)-mediated wavefronts give rise to polymorphic ventricular tachycardia. We also present experimental evidence for bi-excitability under EAD-promoting conditions in neonatal rat ventricular myocyte monolayers exposed to BayK8644 and isoproterenol. Under EAD-prone conditions, both I(Na)-mediated conduction and I(Ca,L)-mediated conduction can occur in the same tissue. These novel wave dynamics may be responsible for certain EAD-mediated arrhythmias, such as torsades de pointes and polymorphic ventricular tachycardia.
  Heart rhythm: the official journal of the Heart Rhythm Society 08/2011; 9(1):115-22. · 4.56 Impact Factor
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  Available from: PubMed Central

  Article: Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes.

  Patima Sdek, Peng Zhao, Yaping Wang, Chang-Jiang Huang, Christopher Y Ko, Peter C Butler, James N Weiss, W Robb Maclellan
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  ABSTRACT: The mammalian heart loses its regenerative potential soon after birth. Adult cardiac myocytes (ACMs) permanently exit the cell cycle, and E2F-dependent genes are stably silenced, although the underlying mechanism is unclear. Heterochromatin, which silences genes in many biological contexts, accumulates with cardiac differentiation. H3K9me3, a histone methylation characteristic of heterochromatin, also increases in ACMs and at E2F-dependent promoters. We hypothesize that genes relevant for cardiac proliferation are targeted to heterochromatin by retinoblastoma (Rb) family members interacting with E2F transcription factors and recruiting heterochromatin protein 1 (HP1) proteins. To test this hypothesis, we created cardiac-specific Rb and p130 inducible double knockout (IDKO) mice. IDKO ACMs showed a decrease in total heterochromatin, and cell cycle genes were derepressed, leading to proliferation of ACMs. Although Rb/p130 deficiency had no effect on total H3K9me3 levels, recruitment of HP1-γ to promoters was lost. Depleting HP1-γ up-regulated proliferation-promoting genes in ACMs. Thus, Rb and p130 have overlapping roles in maintaining the postmitotic state of ACMs through their interaction with HP1-γ to direct heterochromatin formation and silencing of proliferation-promoting genes.
  The Journal of Cell Biology 08/2011; 194(3):407-23. · 10.26 Impact Factor
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  Available from: Zhilin Qu

  Article: Multi-scale modeling in biology: how to bridge the gaps between scales?

  Zhilin Qu, Alan Garfinkel, James N Weiss, Melissa Nivala
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  ABSTRACT: Human physiological functions are regulated across many orders of magnitude in space and time. Integrating the information and dynamics from one scale to another is critical for the understanding of human physiology and the treatment of diseases. Multi-scale modeling, as a computational approach, has been widely adopted by researchers in computational and systems biology. A key unsolved issue is how to represent appropriately the dynamical behaviors of a high-dimensional model of a lower scale by a low-dimensional model of a higher scale, so that it can be used to investigate complex dynamical behaviors at even higher scales of integration. In the article, we first review the widely-used different modeling methodologies and their applications at different scales. We then discuss the gaps between different modeling methodologies and between scales, and discuss potential methods for bridging the gaps between scales.
  Progress in Biophysics and Molecular Biology 06/2011; 107(1):21-31. · 3.20 Impact Factor