Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death

Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death

Model Status

This model is unsuitably constrained and is not able to be solved.

ValidateCellML verifies this model as valid CellML, but detects unit inconsistencies.

Model Structure

In 2001, Colleen E. Clancy and Yoram Rudy published a paper which investigated the cellular consequences of mutations in the HERG gene in the congenital Long-QT syndrome and how such mutations can lead to sudden cardiac death. Their model was based on the dynamic Luo-Rudy model of the cardiac ventricular action potential (1994) with modifications described in later publications (see Luo-Rudy II model). However, the traditional Hodgkin-Huxley formulation for the fast sodium current (INa) and the rapid, time-dependent potassium current (IKr)were replaced by a Markovian approach. Clancy and Rudy had recently reformulated INa in an earlier paper (Nature, 1999) and the current paper reference (cited below) develops Markovian models of wild-type and mutant Ikr.

The use of Markovian models to represent INa and Ikr deviates from the traditional Hodgkin-Huxley formulation, and it allows the modellers to define distinct channel states. The model for cardiac INa includes three closed states (C3, C2 and C1), an open, conducting state (O) and fast and slow inactivation states (IF and Is, respectively). IKr has three closed states (C3, C2 and C1), an open, conducting state (O) and a single inactivation states (I).

The complete original paper reference is cited below:

Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death, Colleen E. Clancy and Yoram Rudy, 2001, Cardiovascular Research , 50, 301-313. PubMed ID: 11334834

The raw CellML description of the Clancy-Rudy model can be downloaded in various formats as described in . For an example of a more complete documentation for an electrophysiological model, see The Hodgkin-Huxley Squid Axon Model, 1952.

A schematic diagram describing the current flows across the cell membrane that are captured in the Clancy-Rudy model.
The network defined in the CellML description of the Clancy-Rudy model. A key describing the significance of the shapes of the components and the colours of the connections between them is in the notation guide. For simplicity, not all the variables are shown.