This is a readme file for the models associated with the paper:

Clancy CE and Rudy Y. Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation 2002;105:1208-13.

Abstract: BACKGROUND: Complex physiological interactions determine the functional consequences of gene abnormalities and make mechanistic interpretation of phenotypes extremely difficult. A recent example is a single mutation in the C terminus of the cardiac Na(+) channel, 1795insD. The mutation causes two distinct clinical syndromes, long QT (LQT) and Brugada, leading to life-threatening cardiac arrhythmias. Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced Na(+) channel function, and Brugada with reduced function. METHODS AND RESULTS: Using a computational approach, we demonstrate that the 1795insD mutation exerts variable effects depending on the myocardial substrate. We develop Markov models of the wild-type and 1795insD cardiac Na(+) channels. By incorporating the models into a virtual transgenic cell, we elucidate the mechanism by which 1795insD differentially disrupts cellular electrical behavior in epicardial and midmyocardial cell types. We provide a cellular mechanistic basis for the ECG abnormalities observed in patients carrying the 1795insD gene mutation. CONCLUSIONS: We demonstrate that the 1795insD mutation can cause both LQT and Brugada syndromes through interaction with the heterogeneous myocardium in a rate-dependent manner. The results highlight the complexity and multiplicity of genotype-phenotype relationships, and the usefulness of computational approaches in establishing a mechanistic link between genetic defects and functional abnormalities.

The state diagram for this Markovian model (model.jpg): was shown in figure 1A of the paper. Model parameters are available in the Appendix file at: http://circ.ahajournals.org/cgi/content/full/105/10/1208/DC1

Parts of the results were shown in figure 3B of the paper. Current-voltage relation of this current can also be constructed.

To run the models:

XPP: start with the command xpp Ina_Mar.ode Mouse click on "Initialconds", and then "(G)o".

Regarding xpp program, please contact with Bard Ermentrout's website: http://www.pitt.edu/~phase/ Here describes the details in how to get and use xpp.

To run a series of voltage-clamp studies shown in result.jpg, click "Range over", change to 'vtest_1', and then select voltage protocol from Steps (12), Start (-60) and End (+60). and press (G)o, This makes traces

similar to fig 3A of the paper by Makita et al (2002). Makita N et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation 2002;106:1269-74.

The model files were submitted by: Jiun-Shian Wu, Sheng-Nan Wu, Ruey J. Sung, Han-Dong Chang National Cheng Kung University Medical College Tainan 70101, Taiwan e-mail: snwu@mail.ncku.edu.tw