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

    2 July 2018

    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.

    2 July 2018

    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.

    2 July 2018

    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.

    3 July 2018

    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.

    2 July 2018

    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.

    2 July 2018

    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.

  • Contrasting effects of ischemia on the kinetics of membrane voltage and intracellular calcium transient underlie electrical alternans.

    2 July 2018

    Repolarization alternans has been considered a strong marker of electrical instability. The objective of this study was to investigate the hypothesis that ischemia-induced contrasting effects on the kinetics of membrane voltage and intracellular calcium transient (Ca(i)T) can explain the vulnerability of the ischemic heart to repolarization alternans. Ischemia-induced changes in action potential (AP) and Ca(i)T resulting in alternans were investigated in perfused Langendorff guinea pig hearts subjected to 10-15 min of global no-flow ischemia followed by 10-15 min of reperfusion. The heart was stained with 100 microl of rhod-2 AM and 25 microl of RH-237, and AP and Ca(i)T were simultaneously recorded with an optical mapping system of two 16 x 16 photodiode arrays. Ischemia was associated with shortening of AP duration (D) but delayed upstroke, broadening of peak, and slowed decay of Ca(i)T resulting in a significant increase of Ca(i)T-D. The changes in APD were spatially heterogeneous in contrast to a more spatially homogeneous lengthening of Ca(i)T-D. Ca(i)T alternans could be consistently induced with the introduction of a shorter cycle when the upstroke of the AP occurred before complete relaxation of the previous Ca(i)T and generated a reduced Ca(i)T. However, alternans of Ca(i)T was not necessarily associated with alternans of APD, and this was correlated with the degree of spatially heterogeneous shortening of APD. Sites with less shortening of APD developed alternans of both Ca(i)T and APD, whereas sites with greater shortening of APD could develop a similar degree of Ca(i)T alternans but slight or no APD alternans. This resulted in significant spatial dispersion of APD. The study shows that the contrasting effects of ischemia on the duration of AP and Ca(i)T and, in particular, on their spatial distribution explain the vulnerability of ischemic heart to alternans and the increased dispersion of repolarization during alternans.

  • Global organization of dynamics in oscillatory heterogeneous excitable media.

    2 July 2018

    An oscillatory heterogeneous excitable medium undergoes a transition from periodic target patterns to a bursting rhythm driven by the spontaneous initiation and termination of spiral waves as coupling or density is reduced. We illustrate these phenomena in monolayers of chick embryonic heart cells using calcium-sensitive fluorescent dyes. These results are modeled in a heterogeneous cellular automaton in which the neighborhood of interaction and cell density is modified. Parameters that give rise to bursting rhythms are organized in distinct zones in parameter space, leading to a global organization that should be applicable to the dynamics in a large class of excitable media.

  • The role of photon scattering in voltage-calcium fluorescent recordings of ventricular fibrillation.

    3 July 2018

    Recent optical mapping studies of cardiac tissue suggest that membrane voltage (V(m)) and intracellular calcium concentrations (Ca) become dissociated during ventricular fibrillation (VF), generating a proarrhythmic substrate. However, experimental methods used in these studies may accentuate measured dissociation due to differences in fluorescent emission wavelengths of optical voltage/calcium (V(opt)/Ca(opt)) signals. Here, we simulate dual voltage-calcium optical mapping experiments using a monodomain-Luo-Rudy ventricular-tissue model coupled to a photon-diffusion model. Dissociation of both electrical, V(m)/Ca, and optical, V(opt)/Ca(opt), signals is quantified by calculating mutual information (MI) for VF and rapid pacing protocols. We find that photon scattering decreases MI of V(opt)/Ca(opt) signals by 23% compared to unscattered V(m)/Ca signals during VF. Scattering effects are amplified by increasing wavelength separation between fluorescent voltage/calcium signals and respective measurement-location misalignment. In contrast, photon scattering does not affect MI during rapid pacing, but high calcium dye affinity can decrease MI by attenuating alternans in Ca(opt) but not in V(opt). We conclude that some dissociation exists between voltage and calcium at the cellular level during VF, but MI differences are amplified by current optical mapping methods.