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      Abnormal Intracellular Calcium Handling Underlying T-Wave Alternans and Its Hysteresis

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          Abstract

          Aims: To investigate the mechanism underlying T-wave alternans (TWA) and its hysteresis under ischemia conditions. Methods: Transmembrane action potential (AP) from endocardial, M, and epicardial cells and monophasic AP (MAP) from four epicardial sites were recorded in ventricular wedge preparation and in isolated intact rabbit heart, respectively. The AP/MAP duration (APD/ MAPD), effective refractory period (ERP), activation time, and APD/MAPD restitution were determined under control and ischemia conditions. The effects of ryanodine (0.01 and 1 µmol·l<sup>–1</sup>) on TWA, and the effects of low extracellular Ca<sup>2+</sup> and 4-aminopyridine on its hysteresis were studied. Results: Ischemia shortened the APD/MAPD and effective refractory period of all recording sites symmetrically, except the APD of M cells, which shortened markedly. In the ischemia group, TWA was induced within a cycle length (CL) range from 160 to 250 ms, which corresponded to a diastolic interval region of 0–70 ms. In this diastolic interval region, the repolarization restitution curve was the steepest (slope > 1.0). All TWA were accompanied by repolarization alternations. Low concentration ryanodine (0.01 µmol·l<sup>–1</sup>) facilitated TWA, high concentration (1 µmol·l<sup>–1</sup>) abolished it. Alternans of calcium transient were observed in myocytes purfused with ischemia solution during rapid stimulation. Ryanodine (0.1 µmol·l<sup>–1</sup>) abolished alternans of calcium transient, and ryanodine (0.01 µmol·l<sup>–1</sup>) facilitated them. After 60 min pacing at a CL of 200 ms, TWA persisted until the initial several beats at a CL of 300 ms at which a TWA was exceptional. The suppression of hysteresis by low extracellular Ca<sup>2+</sup> and 4-aminopyridine indicated an underlying role of the intracellular Ca<sup>2+</sup> overload and transient outward current (I<sub>to</sub>). Conclusion: TWA is principally due to repolarization alternans, which is secondary to steep APD/MAPD restitution, and relates to intracellular calcium cycling. Hysteresis relates to intracellular Ca<sup>2+</sup> overload and I<sub>to</sub>.

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          Most cited references 9

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          Sarcoplasmic reticulum calcium content fluctuation is the key to cardiac alternans.

          The aim of this work was to investigate whether beat-to-beat alternation in the amplitude of the systolic Ca(2+) transient (Ca(2+) alternans) is due to changes of sarcoplasmic reticulum (SR) Ca(2+) content, and if so, whether the alternans arises due to a change in the gain of the feedback controlling SR Ca(2+) content. We found that, in rat ventricular myocytes, stimulating with small (20 mV) depolarizing pulses produced alternans of the amplitude of the Ca(2+) transient. Confocal measurements showed that the larger transients resulted from propagation of Ca(2+) waves. SR Ca(2+) content (measured from caffeine-evoked membrane currents) alternated in phase with the alternans of Ca(2+) transient amplitude. After a large transient, if SR Ca(2+) content was elevated by brief exposure of the cell to a Na(+)-free solution, then the alternans was interrupted and the next transient was also large. This shows that changes of SR Ca(2+) content are sufficient to produce alternans. The dependence of Ca(2+) transient amplitude on SR content was steeper under alternating than under control conditions. During alternation, the Ca(2+) efflux from the cell was also a steeper function of SR Ca(2+) content than under control. We attribute these steeper relationships to the fact that the larger responses in alternans depend on wave propagation and that wave propagation is a steep function of SR Ca(2+) content. In conclusion, alternans of systolic Ca(2+) appears to depend on alternation of SR Ca(2+) content. This, in turn results from the steep dependence on SR Ca(2+) content of Ca(2+) release and therefore Ca(2+) efflux from the cell as a consequence of wave propagation.
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            Role of calcium cycling versus restitution in the mechanism of repolarization alternans.

            T-wave alternans, a powerful marker of arrhythmic events, results from alternation in action potential duration (APD). The underlying cellular mechanism of APD alternans is unknown but has been attributed to either intracellular calcium (Ca2+) cycling or membrane ionic currents, manifested by a steep slope of cellular APD restitution. To address these mechanisms, high-resolution optical mapping techniques were used to measure action potentials and Ca2+ transients simultaneously from hundreds of epicardial sites in the guinea pig model of pacing-induced T-wave alternans (n=7). The pacing rates (ie, alternans threshold) at which T-wave (369+/-11 bpm), APD (369+/-21 bpm), and Ca2+ (371+/-29 bpm) alternans first appeared were comparable. Importantly, the site of origin of APD alternans and Ca2+ alternans consistently occurred together near the base of the left ventricle, not where APD restitution was steepest. In addition, APD and Ca2+ alternans were remarkably similar both spatially and temporally during discordant alternans. In conclusion, the mechanism underlying T-wave alternans in the intact heart is more closely associated with intracellular Ca2+ cycling rather than APD restitution.
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              Ryanodine receptors/calcium release channels in heart failure and sudden cardiac death.

               Andrew Marks (2001)
              Calcium (Ca2+) ions are second messengers in signaling pathways in all types of cells. They regulate muscle contraction, electrical signals which determine the cardiac rhythm and cell growth pathways in the heart. In the past decade cDNA cloning has provided clues as to the molecular structure of the intracellular Ca2+ release channels (ryanodine receptors, RyR, and inositol 1,4,5-trisphosphate receptors, IP3R) on the sarcoplasmic and endoplasmic reticulum (SR/ER) and an understanding of how these molecules regulate Ca2+ homeostasis in the heart is beginning to emerge. The intracellular Ca2+ release channels form a distinct class of ion channels distinguished by their structure, size, and function. Both RyRs and IP3Rs have gigantic cytoplasmic domains that serve as scaffolds for modulatory proteins that regulate the channel pore located in the carboxy terminal 10% of the channel sequence. The channels are tetramers comprised of four RyR or IP3R subunits. RyR2 is required for excitation-contraction (EC) coupling in the heart. Using co-sedimentation and co-immunoprecipitation we have defined a macromolecular complex comprised of RyR2, FKBP12.6, PKA, the protein phosphatases PP1 and PP2A, and an anchoring protein mAKAP. We have shown that protein kinase A (PKA) phosphorylation of RyR2 dissociates FKBP12.6 and regulates the channel open probability (P(o)). In failing human hearts RyR2 is PKA hyperphosphorylated resulting in defective channel function due to increased sensitivity to Ca2+-induced activation.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2007
                September 2007
                03 November 2006
                : 108
                : 3
                : 147-156
                Affiliations
                aDepartment of Cardiology, Renmin Hospital of Wuhan University, and bWuhan General Hospital of PLA, Wuhan, Hubei, China
                Article
                96566 Cardiology 2007;108:147–156
                10.1159/000096566
                17085935
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 7, Tables: 1, References: 33, Pages: 10
                Categories
                Original Research

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