Computer simulation of wild-type and mutant human cardiac Na+ current

Stefania Vecchietti, Ilaria Rivolta, Stefano Severi, Carlo Napolitano, Silvia G. Priori, Silvio Cavalcanti

Research output: Contribution to journalArticle

Abstract

Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited diseases predisposing to ventricular arrhythmias and sudden death. Genetic studies linked LQTS and BrS to mutations in genes encoding for cardiac ion channels. Recently, two novel missense mutations at the same codon in the gene encoding the cardiac Na+ channel (SCN5A) have been identified: Y1795C (causing the LQTS phenotype) and Y1795H (causing the BrS phenotype). Functional studies in HEK293 cells showed that both mutations alter the inactivation of Na+ current and cause a sustained Na+ current upon depolarisation. In this paper, a nine state Markov model was used to simulate the Na+ current in wild-type Na+ cardiac channel and the current alterations observed in Y1795C and Y1795H mutant channels. The model includes three distinct closed states, a conducting open state and five inactivation states (one fast-, two intermediate- and two closed-inactivation). Transition rates between these states were identified on the basis of previously published voltage-clamp experiments. The model was able to reproduce the experimental Na+ current in mutant channels just by altering the assignment of model parameters with respect to wild-type case. Parameter assignment was validated by performing action potential clamp experiments and comparing experimental and simulated INa current. The Markov model was subsequently introduced in the Luo-Rudy model of ventricular myocyte to investigate "in silico" the consequences on the ventricular cell action potential of the two mutations. Coherently with their phenotypes, the Y1795C mutation prolongs the action potential, while the Y1795H mutation causes only negligible changes in action potential morphology.

Original languageEnglish
Pages (from-to)35-44
Number of pages10
JournalMedical and Biological Engineering and Computing
Volume44
Issue number1-2
DOIs
Publication statusPublished - Mar 2006

Keywords

  • Action potential
  • Computer simulation
  • Functional proteomic
  • Inherited cardiac disorders
  • Na channel

ASJC Scopus subject areas

  • Biomedical Engineering
  • Health Informatics
  • Health Information Management
  • Computer Science Applications
  • Computational Theory and Mathematics

Fingerprint Dive into the research topics of 'Computer simulation of wild-type and mutant human cardiac Na+ current'. Together they form a unique fingerprint.

  • Cite this