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Zhilin Qu

Publications and source records attributed to Zhilin Qu.

35 records · Page 2Linked to original sources
PubMed2004

Dynamical effects of diffusive cell coupling on cardiac excitation and propagation: a simulation study.

Cell coupling is considered to be important for cardiac action potential propagation and arrhythmogenesis. We carried out computer simulations to investigate the effects of stimulation strength and cell-to-cell coupling on action potential duration (APD) restitution, APD alternans, and stability of reentry in models of isolated cell, one-dimensional cable, and two-dimensional tissue. Phase I formulation of the Luo and Rudy action potential model was used. We found that stronger stimulation resulted in a shallower APD restitution curve and onset of APD alternans at a faster pacing rate. Reducing diffusive coupling between cells prolonged APD. Weaker diffusive currents along the direction of propagation steepened APD restitution and caused APD alternans to occur at a slower pacing rate in tissue. Diffusive current due to curvature changed APD but had little effect on APD restitution slope and onset of instability. Heterogeneous cell coupling caused APD inhomogeneities in space. Reduction in coupling strength either uniformly or randomly had little effect on the rotation period and stability of a reentry, but random cell decoupling slowed the rotation period and, thus, stabilized the reentry, preventing it from breaking up into multiple waves. Therefore, in addition to its effects on action potential conduction velocity, diffusive cell coupling also affects APD in a rate-dependent manner, causes electrophysiological heterogeneities, and thus modulates the dynamics of cardiac excitation. These effects are brought about by the modulation of ionic current activation and inactivation.

Action Potentials↗
PubMed2004

Intracellular Ca dynamics in ventricular fibrillation.

In the heart, membrane voltage (Vm) and intracellular Ca (Cai) are bidirectionally coupled, so that ionic membrane currents regulate Cai cycling and Cai affects ionic currents regulating action potential duration (APD). Although Cai reliably and consistently tracks Vm at normal heart rates, it is possible that at very rapid rates, sarcoplasmic reticulum Cai cycling may exhibit intrinsic dynamics. Non-voltage-gated Cai release might cause local alternations in APD and refractoriness that influence wavebreak during ventricular fibrillation (VF). In this study, we tested this hypothesis by examining the extent to which Cai is associated with Vm during VF. Cai transients were mapped optically in isolated arterially perfused swine right ventricles using the fluorescent dye rhod 2 AM while intracellular membrane potential was simultaneously recorded either locally with a microelectrode (5 preparations) or globally with the voltage-sensitive dye RH-237 (5 preparations). Mutual information (MI) is a quantitative statistical measure of the extent to which knowledge of one variable (Vm) predicts the value of a second variable (Cai). MI was high during pacing and ventricular tachycardia (VT; 1.13 +/- 0.21 and 1.69 +/- 0.18, respectively) but fell dramatically during VF (0.28 +/- 0.06, P < 0.001). Cai at sites 4-6 mm apart also showed decreased MI during VF (0.63 +/- 0.13) compared with pacing (1.59 +/- 0.34, P < 0.001) or VT (2.05 +/- 0.67, P < 0.001). Spatially, Cai waves usually bore no relationship to membrane depolarization waves during nonreentrant fractionated waves typical of VF, whereas they tracked each other closely during pacing and VT. The dominant frequencies of Vm and Cai signals analyzed by fast Fourier transform were similar during VT but differed significantly during VF. Cai is closely associated with Vm closely during pacing and VT but not during VF. These findings suggest that during VF, non-voltage-gated Cai release events occur and may influence wavebreak by altering Vm and APD locally.

Animals↗
PubMed2004

A simulation study of the effects of cardiac anatomy in ventricular fibrillation.

In ventricular fibrillation (VF), the principal cause of sudden cardiac death, waves of electrical excitation break up into turbulent and incoherent fragments. The causes of this breakup have been intensely debated. Breakup can be caused by fixed anatomical properties of the tissue, such as the biventricular geometry and the inherent anisotropy of cardiac conduction. However, wavebreak can also be caused purely by instabilities in wave conduction that arise from ion channel dynamics, which represent potential targets for drug action. To study the interaction between these two wave-breaking mechanisms, we used a physiologically based mathematical model of the ventricular cell, together with a realistic three-dimensional computer model of cardiac anatomy, including the distribution of fiber angles throughout the myocardium. We find that dynamical instabilities remain a major cause of the wavebreak that drives VF, even in an anatomically realistic heart. With cell physiology in its usual operating regime, dynamics and anatomical features interact to promote wavebreak and VF. However, if dynamical instability is reduced, for example by modeling of certain pharmacologic interventions, electrical waves do not break up into fibrillation, despite anatomical complexity. Thus, interventions that promote dynamical wave stability show promise as an antifibrillatory strategy in this more realistic setting.

Animals↗
PubMed2004

Multisite phosphorylation and network dynamics of cyclin-dependent kinase signaling in the eukaryotic cell cycle.

Multisite phosphorylation of regulatory proteins has been proposed to underlie ultrasensitive responses required to generate nontrivial dynamics in complex biological signaling networks. We used a random search strategy to analyze the role of multisite phosphorylation of key proteins regulating cyclin-dependent kinase (CDK) activity in a model of the eukaryotic cell cycle. We show that multisite phosphorylation of either CDK, CDC25, wee1, or CDK-activating kinase is sufficient to generate dynamical behaviors including bistability and limit cycles. Moreover, combining multiple feedback loops based on multisite phosphorylation do not destabilize the cell cycle network by inducing complex behavior, but rather increase the overall robustness of the network. In this model we find that bistability is the major dynamical behavior of the CDK signaling network, and that negative feedback converts bistability into limit cycle behavior. We also compare the dynamical behavior of several simplified models of CDK regulation to the fully detailed model. In summary, our findings suggest that multisite phosphorylation of proteins is a critical biological mechanism in generating the essential dynamics and ensuring robust behavior of the cell cycle.

Cell Cycle↗
PubMed2003

Effects of Na(+) channel and cell coupling abnormalities on vulnerability to reentry: a simulation study.

The role of dynamic instabilities in the initiation of reentry in diseased (remodeled) hearts remains poorly explored. Using computer simulations, we studied the effects of altered Na(+) channel and cell coupling properties on the vulnerable window (VW) for reentry in simulated two-dimensional cardiac tissue with and without dynamic instabilities. We related the VW for reentry to effects on conduction velocity, action potential duration (APD), effective refractory period dispersion and restitution, and concordant and discordant APD alternans. We found the following: 1). reduced Na(+) current density and slowed recovery promoted postrepolarization refractoriness and enhanced concordant and discordant APD alternans, which increased the VW for reentry; 2). uniformly reduced cell coupling had little effect on cellular electrophysiological properties and the VW for reentry. However, randomly reduced cell coupling combined with decoupling promoted APD dispersion and alternans, which also increased the VW for reentry; 3). the combination of decreased Na(+) channel conductance, slowed Na(+) channel recovery, and cellular uncoupling synergistically increased the VW for reentry; and 4) the VW for reentry was greater when APD restitution slope was steep than when it was flat. In summary, altered Na(+) channel and cellular coupling properties increase vulnerability to reentrant arrhythmias. In remodeled hearts with altered Na(+) channel properties and cellular uncoupling, dynamic instabilities arising from electrical restitution exert important influences on the VW for reentry.

Action Potentials↗
PubMed2003

Mechanism for spiral wave breakup in excitable and oscillatory media.

We study spiral wave breakup using a Fitzhugh-Nagumo-type system. We find that spiral wave breakup can occur near the core or far from it in both excitable and oscillatory regimes. There is a faraway breakup scenario in both excitable and oscillatory media that depends on long wavelength modulation modes. We observed three distinct scenarios, including one that involves breakup that does not develop into turbulence. However, we find that the mechanisms behind these three scenarios are the same: they are caused by the interaction between the dispersion relation and the asymptotic behavior of the modulation mode. The difference in phenomenology is due to the asymptotic behavior of the modulation mode.

Biophysics↗
PubMed2003

Dynamics of the cell cycle: checkpoints, sizers, and timers.

We have developed a generic mathematical model of a cell cycle signaling network in higher eukaryotes that can be used to simulate both the G1/S and G2/M transitions. In our model, the positive feedback facilitated by CDC25 and wee1 causes bistability in cyclin-dependent kinase activity, whereas the negative feedback facilitated by SKP2 or anaphase-promoting-complex turns this bistable behavior into limit cycle behavior. The cell cycle checkpoint is a Hopf bifurcation point. These behaviors are coordinated by growth and division to maintain normal cell cycle and size homeostasis. This model successfully reproduces sizer, timer, and the restriction point features of the eukaryotic cell cycle, in addition to other experimental findings.

Animals↗
PubMed2003

Understanding biological complexity: lessons from the past.

Advances in molecular biology now permit complex biological systems to be tracked at an exquisite level of detail. The information flow is so great, however, that using intuition alone to draw connections is unrealistic. Thus, the need to integrate mathematical biology with experimental biology is greater than ever. To achieve this integration, obstacles that have traditionally prevented effective communication between theoreticians and experimentalists must be overcome, so that experimentalists learn the language of mathematics and dynamical modeling and theorists learn the language of biology. Fifty years ago Alan Hodgkin and Andrew Huxley published their quantitative model of the nerve action potential; in the same year, Alan Turing published his work on pattern formation in activator-inhibitor systems. These classic studies illustrate two ends of the spectrum in mathematical biology: the detailed model approach and the minimal model approach. When combined, they are highly synergistic in analyzing the mechanisms underlying the behavior of complex biological systems. Their effective integration will be essential for unraveling the physical basis of the mysteries of life.

Animals↗
PubMed2002

Regulation of the mammalian cell cycle: a model of the G1-to-S transition.

We have formulated a mathematical model for regulation of the G(1)-to-S transition of the mammalian cell cycle. This mathematical model incorporates the key molecules and interactions that have been identified experimentally. By subdividing these critical molecules into modules, we have been able to systematically analyze the contribution of each to dynamics of the G(1)-to-S transition. The primary module, which includes the interactions between cyclin E (CycE), cyclin-dependent kinase 2 (CDK2), and protein phosphatase CDC25A, exhibits dynamics such as limit cycle, bistability, and excitable transient. The positive feedback between CycE and transcription factor E2F causes bistability, provided that the total E2F is constant and the retinoblastoma protein (Rb) can be hyperphosphorylated. The positive feedback between active CDK2 and cyclin-dependent kinase inhibitor (CKI) generates a limit cycle. When combined with the primary module, the E2F/Rb and CKI modules potentiate or attenuate the dynamics generated by the primary module. In addition, we found that multisite phosphorylation of CDC25A, Rb, and CKI was critical for the generation of dynamics required for cell cycle progression.

Animals↗
PubMed2002

Frequency analysis of ventricular fibrillation in Swine ventricles.

It has been suggested from frequency analysis that cardiac fibrillation is driven by stable intramural reentry, with wavebreak occurring due to failure of 1:1 propagation. We tested this hypothesis with a combined experimental and theoretical approach. Optical mapping was performed on epicardial, endocardial, and transmural cut surfaces of fibrillating swine ventricles. Wavelets were characterized, the frequency content of optical signals analyzed, and space-time plots (STPs) constructed to detect Wenckebach-like conduction. The findings were compared with simulations in 2D and 3D cardiac tissue using the Luo-Rudy action potential model. The incidence of reentry in the cut transmural surface (11.8% in right ventricle, 14.3% in left ventricle) was similar to that on the endocardial surface (13.1%, P=NS) but greater than on the epicardial surface (7.7%, P<0.01). Frequency spectra of optically recorded membrane voltage were organized into spatial domains with the same dominant frequency, but these domains were nonstationary. In STPs, pseudo-2:1 conduction block was caused by double potentials arising when reentry occurred on the recording site rather than true Wenckebach conduction. The latter was observed in 11 of 166 STPs but did not occur at borders of high-to-low frequency domains. In simulations, similar findings were obtained when action potential duration (APD) restitution slope was steep. Stationary dominant frequency domains with Wenckebach conduction patterns were observed only in the presence of shallow APD restitution slope and marked nonuniform tissue heterogeneity. In conclusion, stable intramural reentry as the engine of fibrillation was not observed. Our findings support the idea that dynamic wavebreak plays a fundamental role in the generation and maintenance of ventricular fibrillation.

Action Potentials↗
PubMed2002

Electrical restitution and cardiac fibrillation.

Combined experimental and theoretical work has shown that restitution properties of the cardiac action potential duration and conduction velocity contribute to breakup of reentrant wavefronts during cardiac fibrillation independent of preexisting electrophysiologic heterogeneities in the tissue. Developing therapies that favorably alter these cardiac electrical restitution properties are a promising new approach to preventing fibrillation.

Electrophysiology↗
PubMed2002

Action potential duration restitution and ventricular fibrillation due to rapid focal excitation.

The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 microg) into normal isolated perfused swine right ventricles (RVs) stained with 4-[beta-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 +/- 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 +/- 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10-20 mM, n = 6), bretylium (10-20 microg/ml, n = 3), and verapamil (2-4 microg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the "aconitine" site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.

Aconitine↗
PubMed2002

Electrical refractory period restitution and spiral wave reentry in simulated cardiac tissue.

Theoretical and experimental studies have shown that restitution of the cardiac action potential (AP) duration (APD) plays a major role in predisposing ventricular tachycardia to degenerate to ventricular fibrillation, whereas its role in atrial fibrillation is unclear. We used the Courtemanche human atrial cell model and the Luo-Rudy guinea pig ventricular model to compare the roles of electrical restitution in destabilizing spiral wave reentry in simulated two-dimensional homogeneous atrial and ventricular tissue. Because atrial AP morphology is complex, we also validated the usefulness of effective refractory period (ERP) restitution. ERP restitution correlated best with APD restitution at transmembrane potentials greater than or equal to -62 mV, and its steepness was a reliable predictor of spiral wave phenotype (stable, meandering, hypermeandering, and breakup) in both atrial and ventricular tissue. Spiral breakup or single hypermeandering spirals occurred when the slope of ERP restitution exceeded 1 at short diastolic intervals. Thus ERP restitution, which is easier to measure clinically than APD restitution, is a reliable determinant of spiral wave stability in simulated atrial and ventricular tissue.

Animals↗
PubMed2002

Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol.

We hypothesized that partial cellular uncoupling produced by low concentrations of heptanol increases the vulnerability to inducible atrial fibrillation (AF). The epicardial surface of 12 isolated-perfused canine left atria was optically mapped before and after 1-50 microM heptanol infusion. At baseline, no sustained (>30 s) AF could be induced in any of the 12 tissues. However, after 2 microM heptanol infusion, sustained AF was induced in 9 of 12 tissues (P < 0.001). Heptanol >5 microM caused loss of 1:1 capture during rapid pacing, causing no AF to be induced. AF was initiated by conduction block across the fiber leading to reentry, which broke up after one to two rotations into two to four independent wavelets that sustained the AF. Heptanol at 2 microM had no effect on the cellular action potential duration restitution or on the maximal velocity rate over time of the upstroke. The effects of heptanol were reversible. We conclude that partial cellular uncoupling by heptanol without changing atrial active membrane properties promotes wavebreak, reentry, and AF during rapid pacing.

Action Potentials↗