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  • Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing.

    12 December 2017

    Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.

  • Spontaneous initiation and termination of complex rhythms in cardiac cell culture.

    8 December 2017

    INTRODUCTION: Complex cardiac arrhythmias often start and stop spontaneously. These poorly understood behaviors frequently are associated with pathologic modification of the structural heterogeneity and functional connectivity of the myocardium. To evaluate underlying mechanisms, we modify heterogeneity by varying the confluence of embryonic chick monolayer cultures that display complex bursting behaviors. A simple mathematical model was developed that reproduces the experimental behaviors and reveals possible generic mechanisms for bursting dynamics in heterogeneous excitable systems. METHODS AND RESULTS: Wave propagation was mapped in embryonic chick myocytes monolayers using calcium-sensitive dyes. Monolayer confluence was varied by plating cultures with different cell densities and by varying times in culture. At high plating densities, waves propagate without breaks, whereas monolayers plated at low densities display spirals with frequent breaks and irregular activation fronts. Monolayers at intermediate densities display bursting rhythms in which there is paroxysmal starting and stopping of spiral waves of activity. Similar spatiotemporal patterns of activity were also observed as a function of the time in culture; irregular activity dominates the first 30 hours, followed by repetitive bursting dynamics until 54 hours, after which periodic target patterns or stable spirals prevail. In some quiescent cultures derived from older embryos, it was possible to trigger pacemaker activity following a single activation. We are able to reproduce all of these behaviors by introducing spatial heterogeneity and varying neighborhood size, equivalent to cell connectivity, in a spontaneous cellular automaton model containing a rate-dependent fatigue term. CONCLUSION: We observe transitions from irregular propagating waves, to spiral waves that spontaneously start and stop, to target waves originating from localized pacemakers in cell culture and a simple theoretical model of heterogeneous excitable media. The results show how physiologic properties of spontaneous activity, heterogeneity, and fatigue can give rise to a wide range of different complex dynamic behaviors similar to clinically observed cardiac arrhythmias.

  • Early voltage/calcium uncoupling predestinates the duration of ventricular tachyarrhythmias during ischemia/reperfusion.

    12 December 2017

    BACKGROUND: Abnormal intracellular calcium (Ca(i)) kinetics during ischemia/reperfusion (I/R) can alter membrane voltage (V(m)) and destabilize wavefront propagation. OBJECTIVE: We used optical mapping to investigate the hypothesis that early V(m)/Ca(i) uncoupling during a ventricular tachyarrhythmia (VT) can play a primary role in perpetuation of VT episodes. METHODS: Seventeen Langendorff-perfused guinea pig hearts were subjected to 15 min I/15 min R. Simultaneous optical recordings of V(m) and Ca(i) signals were obtained using a dual-photodiode array. Spatiotemporal entropy (E) was used to quantify differences in V(m)/Ca(i) kinetics during VT and compare wavefront topology during the first 500 ms of a VT episode. RESULTS: A total of 39 episodes of VT were analyzed; VT was classified as self-terminating (ST, n = 28) and non-self-terminating (NST, n = 11). The ST/VTs were further classified into short ST/VT (1 to 5 s in duration; n = 16) and long ST/VT (>5 s, n = 12). E values for NST/VTs were significantly higher than E values for both short and long ST/VTs separately as well as E values for ST/VTs as a group. Further, E values for long ST/VTs were significantly higher than E values for short ST/VTs. Wave breaks were consistently identified during periods of high E. CONCLUSION: High E during the first 500 ms of the onset of VT (the first 2 to 3 beats) is significantly correlated with long ST or NST episodes. This may be related to destabilization of wave propagation that helps to perpetuate VT. Early V(m)/Ca(i) uncoupling can predestinate the development of a malignant NST/VT.

  • Reentrant waves in a ring of embryonic chick ventricular cells imaged with a Ca2+ sensitive dye.

    8 December 2017

    According to the classic model initially formulated by Mines, reentrant cardiac arrhythmias may be associated with waves circulating in a ring geometry. This study was designed to study the dynamics of reentry in a ring geometry of cardiac tissue culture. Reentrant calcium waves in rings of cultured embryonic chick cardiac myocytes were imaged using a macroscope to monitor the fluorescence of intracellular Calcium Green-1 dye. The rings displayed a variety of stable rhythms including pacemaker activity and spontaneous reentry. Waves originating from a localized pacemaker could lead to reentry as a consequence of unidirectional block. In addition, more complex patterns were observed due to the interactions between reentrant and pacemaker rhythms. These rhythms included instances in which pacemakers accelerated the reentrant rhythm, and instances in which the excitation was blocked in the vicinity of pacemakers. During reentrant activity an appropriately timed electrical stimulus could induce resetting of activity or cause complete annihilation of the propagating waves. This experimental preparation reveals many spontaneously occuring complex rhythms. These complex rhythms are hypothesized to reflect interactions between spontaneous pacemakers, wave propagation, refractory period, and overdrive suppression. This preparation may serve as a useful model system to further investigate complex dynamics arising during reentrant rhythms in cardiac tissue.

  • Propagation through heterogeneous substrates in simple excitable media models.

    12 December 2017

    The interaction of waves and obstacles is simulated by adding heterogeneities to a FitzHugh-Nagumo model and a cellular automata model. The cellular automata model is formulated to account for heterogeneities by modelling the interaction between current sources and current sinks. In both models, wave fronts propagate if the size of the heterogeneities is small, and block if the size of the heterogeneities is large. For intermediate values, wave fronts break up into numerous spiral waves. The theoretical models give insights concerning spiral wave formation in heterogeneous excitable media. (c) 2002 American Institute of Physics.

  • Temporal pixel multiplexing for simultaneous high-speed, high-resolution imaging.

    12 December 2017

    We introduce an imaging modality that, by offsetting pixel-exposure times during capture of a single image frame, embeds temporal information in each frame. This allows simultaneous acquisition of full-resolution images at native detector frame rates and high-speed image sequences at reduced resolution, without increasing bandwidth requirements. We demonstrate this method using macroscopic and microscopic examples, including imaging calcium transients in heart cells at 250 Hz using a 10-Hz megapixel camera.

  • The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis.

    12 December 2017

    Peristaltic waves of the ureteric smooth muscles move urine down from the kidney, a process that is commonly defective in congenital diseases. To study the mechanisms that control the initiation and direction of contractions, we used video microscopy and optical mapping techniques and found that electrical and contractile waves began in a region where the renal pelvis joined the connective tissue core of the kidney. Separation of this pelvis-kidney junction from more distal urinary tract segments prevented downstream peristalsis, indicating that it housed the trigger for peristalsis. Moreover, cells in the pelvis-kidney junction were found to express isoform 3 of the hyperpolarization-activated cation on channel family known to be required for initiating electrical activity in the brain and heart. Immunocytochemical and real-time PCR analyses found that hyperpolarization-activated cation-3 is expressed at the pelvis-kidney junction where electrical excitation and contractile waves originate. Inhibition of this channel caused a loss of electrical activity at the pelvis-kidney junction and randomized the origin of electrical activity in the urinary tract, thus markedly perturbing contractions. Collectively, our study demonstrates that hyperpolarization-activated cation-3 channels play a fundamental role in coordinating proximal-to-distal peristalsis of the upper urinary tract. This provides insight into the genetic causes of common inherited urinary tract disorders such as reflux and obstruction.

  • The kinetics of spontaneous calcium oscillations and arrhythmogenesis in the in vivo heart during ischemia/reperfusion.

    12 December 2017

    BACKGROUND: The correlation between spontaneous calcium oscillations (S-CaOs) and arrhythmogenesis has been investigated in a number of theoretical and experimental in vitro models. There is an obvious lack of studies that directly investigate how the kinetics of S-CaOs correlates with a specific arrhythmia in the in vivo heart. OBJECTIVES: The purpose of the study is to investigate the correlation between the kinetics of S-CaOs and arrhythmogenesis in the intact heart using an experimental model of ischemia/reperfusion (I/R). METHODS: Perfused Langendorff guinea pig (GP) hearts were subjected to global I/R (10-15 minutes/10-15 minutes). The heart was stained with a voltage-sensitive dye (RH237) and loaded with a Ca2+ indicator (Rhod-2 AM). Membrane voltage (Vm) and intracellular calcium transient (Ca(i)T) were simultaneously recorded with an optical mapping system of two 16 x 16 photodiode arrays. S-CaOs were considered to arise from a localized focal site within the mapped surface when these preceded the associated membrane depolarizations by 2-15 ms. RESULTS: In 135 episodes of ventricular arrhythmias from 28 different GP experiments, 23 were linked to S-CaOs that were considered to arise from or close to the mapped epicardial window. Self-limited or sustained S-CaOs had a cycle length of 130-430 ms and could trigger propagated ventricular depolarizations. Self-limited S-CaOs that followed the basic beat action potential (AP)/Ca(i)T closely resembled phase 3 early afterdepolarizations. Fast S-CaOs could remain confined to a localized site (concealed) or exhibit varying conduction patterns. This could manifest as (1) an isolated premature beat (PB), bigeminal, or trigeminal rhythm; (2) ventricular tachycardia (VT) when a regular 2:1 conduction from the focal site develops; or (3) ventricular fibrillation (VF) when a complex conduction pattern results in wave break and reentrant excitation. CONCLUSIONS: The study examined, for the first time in the intact heart, the correlation between the kinetics of focal S-CaOs during I/R and arrhythmogenesis. S-CaOs may remain concealed or manifest as PBs, VT, or VF. A "benign looking" PB during I/R may represent "the tip of the iceberg" of an underlying potentially serious arrhythmic mechanism.

  • Sparrow Group

    22 October 2015

    Investigating the Genetic and Environmental Causes of Congenital Heart Disease

  • Hens Group

    16 September 2013

  • Patton Group

    28 April 2014

    Nanodiamond as a sensor for biologically generated electric and magnetic fields

  • Garcia-Moreno Group

    19 December 2013

    Forebrain Evolution Research laboratory

  • Zifarelli Group

    5 February 2015

    CLC chloride channels and transporters