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

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

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

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

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) TdP Proarrhythmia Models

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

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

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

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

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

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