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Voltage and calcium dynamics both underlie cellular alternans in cardiac myocytes.

ABSTRACT: Cardiac alternans, a putative trigger event for cardiac reentry, is a beat-to-beat alternation in membrane potential and calcium transient. Alternans was originally attributed to instabilities in transmembrane ion channel dynamics (i.e., the voltage mechanism). As of this writing, the predominant view is that instabilities in subcellular calcium handling are the main underlying mechanism. That being said, because the voltage and calcium systems are bidirectionally coupled, theoretical studies have suggested that both mechanisms can contribute. To date, to our knowledge, no experimental evidence of such a dual role within the same cell has been reported. Here, a combined electrophysiological and calcium imaging approach was developed and used to illuminate the contributions of voltage and calcium dynamics to alternans. An experimentally feasible protocol, quantification of subcellular calcium alternans and restitution slope during cycle-length ramping alternans control, was designed and validated. This approach allows simultaneous illumination of the contributions of voltage and calcium-driven instability to total cellular instability as a function of cycle-length. Application of this protocol in in vitro guinea-pig left-ventricular myocytes demonstrated that both voltage- and calcium-driven instabilities underlie alternans, and that the relative contributions of the two systems change as a function of pacing rate.

SUBMITTER: Groenendaal W

PROVIDER: S-EPMC4052344 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Voltage and calcium dynamics both underlie cellular alternans in cardiac myocytes.

Groenendaal Willemijn W Ortega Francis A FA Krogh-Madsen Trine T Christini David J DJ

Biophysical journal 20140501 10

Cardiac alternans, a putative trigger event for cardiac reentry, is a beat-to-beat alternation in membrane potential and calcium transient. Alternans was originally attributed to instabilities in transmembrane ion channel dynamics (i.e., the voltage mechanism). As of this writing, the predominant view is that instabilities in subcellular calcium handling are the main underlying mechanism. That being said, because the voltage and calcium systems are bidirectionally coupled, theoretical studies ha ...[more]

PMID: 24853751

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Project description:Cardiac repolarization alternans is an arrhythmogenic rhythm disturbance, manifested in individual myocytes as a beat-to-beat alternation of action potential durations and intracellular calcium transient magnitudes. Recent experimental studies have reported "subcellular alternans," in which distinct regions of an individual cell are seen to have counterphase calcium alternations, but the mechanism by which this occurs is not well understood. Although previous theoretical work has proposed a possible dynamical mechanism for subcellular alternans formation, no direct evidence for this mechanism has been reported in vitro. Rather, experimental studies have generally invoked fixed subcellular heterogeneities in calcium-cycling characteristics as the mechanism of subcellular alternans formation.In this study, we have generalized the previously proposed dynamical mechanism to predict a simple pacing algorithm by which subcellular alternans can be induced in isolated cardiac myocytes in the presence or absence of fixed subcellular heterogeneity. We aimed to verify this hypothesis using computational modeling and to confirm it experimentally in isolated cardiac myocytes. Furthermore, we hypothesized that this dynamical mechanism may account for previous reports of subcellular alternans seen in statically paced, intact tissue.Using a physiologically realistic computational model of a cardiac myocyte, we show that our predicted pacing algorithm induces subcellular alternans in a manner consistent with theoretical predictions. We then use a combination of real-time electrophysiology and fluorescent calcium imaging to implement this protocol experimentally and show that it robustly induces subcellular alternans in isolated guinea pig ventricular myocytes. Finally, we use computational modeling to demonstrate that subcellular alternans can indeed be dynamically induced during static pacing of 1D fibers of myocytes during tissue-level spatially discordant alternans.Here we provide the first direct experimental evidence that subcellular alternans can be dynamically induced in cardiac myocytes. This proposed mechanism may contribute to subcellular alternans formation in the intact heart.

Project description:This study investigated the mechanisms underlying the propagation of cytoplasmic calcium waves and the genesis of systolic Ca(2+) alternans in cardiac myocytes lacking transverse tubules (t-tubules). These correspond to atrial cells of either small mammals or large mammals that have lost their t-tubules due to disease-induced structural remodeling (e.g., atrial fibrillation). A mathematical model was developed for a cluster of ryanodine receptors distributed on the cross section of a cell that was divided into 13 elements with a spatial resolution of 2 ?m. Due to the absence of t-tubules, L-type Ca(2+) channels were only located in the peripheral elements close to the cell-membrane surface and produced Ca(2+) signals that propagated toward central elements by triggering successive Ca(2+)-induced Ca(2+) release (CICR) via Ca(2+) diffusion between adjacent elements. Under control conditions, the Ca(2+) signals did not fully propagate to the central region of the cell. However, with modulation of several factors responsible for Ca(2+) handling, such as the L-type Ca(2+) channels (Ca(2+) influx), SERCA pumps (sarcoplasmic reticulum (SR) Ca(2+) uptake), and ryanodine receptors (SR Ca(2+) release), Ca(2+) wave propagation to the center of the cell could occur. These simulation results are consistent with previous experimental data from atrial cells of small mammals. The model further reveals that spatially functional heterogeneity in Ca(2+) diffusion within the cell produced a steep relationship between the SR Ca(2+) content and the cytoplasmic Ca(2+) concentration. This played an important role in the genesis of Ca(2+) alternans that were more obvious in central than in peripheral elements. Possible association between the occurrence of Ca(2+) alternans and the model parameters of Ca(2+) handling was comprehensively explored in a wide range of one- and two-parameter spaces. In addition, the model revealed a spontaneous second Ca(2+) release in response to a single voltage stimulus pulse with SR Ca(2+) overloading and augmented Ca(2+) influx. This study provides what to our knowledge are new insights into the genesis of Ca(2+) alternans and spontaneous second Ca(2+) release in cardiac myocytes that lack t-tubules.

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Voltage and calcium dynamics both underlie cellular alternans in cardiac myocytes.

Publications

Voltage and calcium dynamics both underlie cellular alternans in cardiac myocytes.

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