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Session III – Models of TdP Proarrhythmia

Moving Towards Better Predictors of Drug-Induced Torsade de Pointes (TdP) Workshop. Session III – Models of TdP Proarrhythmia. Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach. Presented data. J. Kramer, ChanTest: added MAPD-wave

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Session III – Models of TdP Proarrhythmia

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  1. Moving Towards Better Predictors of Drug-Induced Torsade de Pointes (TdP) Workshop Session III – Models of TdP Proarrhythmia Co-Chairs: Wilhelm Haverkamp and Marc Vos Rapporteurs: Chris Lawrence, Hal Feldman and Alexander Breidenbach

  2. Presented data • J. Kramer, ChanTest: added MAPD-wave • alternans as parameter • C. Antzelevitch: spatial dispersion emphasized • as important parameter • B. Hamlin: heart failure rabbit model • S. Moise: inherited German shephard sudden • death dog model

  3. Breakout Session III Report • Identification of consensus issues • Development of priorities for next steps

  4. Identification of consensus issues • There is a need for in-vitro and in-vivo TdP • proarrhythmia models • A multi-faceted testing strategy that incorporates several parameters simultaneously is proposed that includes data derived from increasingly complex structures (ie. single cells to intact animal and pathological models) • Agreement that a multi-center validation study • is needed (eg: each model / method is to be tested in more than 1 laboratory) • At least two species needed for validation • purposes

  5. TdP Proarrhythmia Models • Strategic Approach • A useful model should possess the following properties: • Provide adequate testing throughput to meet the users needs (e.g., in-vitro throughput comparable to manual patch-clamp techniques and in-vivo comparable to non-rodent telemetry studies) • Intact animal model should employ a conscious animal • Animal model should reproducibly develop spontaneous TdP • High sensitivity at clinical therapeutic dose (and • beyond)

  6. There is a need for in-vitro and in-vivo TdP proarrhythmia models • Increase knowledge of arrhythmogenic • mechanisms (helps to identify new parameters of proarrhythmia) • Validated parameters might help to add value to • the QT (weak surrogate) parameter by • improving clinical prediction of proarrhythmia

  7. A multi-faceted testing strategy employing test systems of increasing complexity (addressing several parameters) is proposed • Diseased animal model • Intact animal • Isolated heart • Isolated tissue and/or wedge • Single cells Complexity

  8. Parameters to be recorded include: • Repolarization times (local and global) • including rate dependence • Spatial dispersion • Temporal dispersion • EADs • Arrhythmias Complexity

  9. Agreement that multi-center validation study is needed • International • Blinded, standardized, reproducible based on preliminary investigations • (qualified locations) • Subcommittee appointed to coordinate with special attention to sensitivity and specificity, and selection of drugs

  10. At least two species needed for validation purposes • Rabbit as species of choice • Dogs proposed as second speciesNon human primates may be considered when metabolically closer related to humans

  11. We like to thank the session III participants for their contributions and enthusiastic discussions.

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