L-type Ca2+ channel mutations and T-wave alternans: A model study

Zheng I. Zhu, Colleen E Clancy

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

A number of mutations have been linked to diseases for which the underlying mechanisms are poorly understood. An example is Timothy Syndrome (TS), a multi-system disorder that includes severe cardiac arrhythmias. Here we employ theoretical simulations to examine the effects of a TS mutation in the L-type Ca2+ channel on cardiac dynamics over multiple scales, from a gene mutation to protein, cell, tissue, and finally the ECG, to connect a defective Ca2+ channel to arrhythmia susceptibility. Our results indicate that 1) the TS mutation disrupts the rate-dependent dynamics in a single cardiac cell and promotes the development of alternans; 2) in coupled tissue, concordant alternans is observed at slower heart rates in mutant tissue than in normal tissue and, once initiated, rapidly degenerates into discordant alternans and conduction block; and 3) the ECG computed from mutant-simulated tissue exhibits prolonged QT intervals at physiological rates and with small increases in pacing rate, T-wave alternans, and alternating T-wave inversion. At the cellular level, enhanced Ca2+ influx due to the TS mutation causes electrical instabilities. In tissue, the interplay between faulty Ca2+ influx and steep action potential duration restitution causes arrhythmogenic discordant alternans. The prolongation of action potentials causes spatial dispersion of the Na+ channel excitability, leading to inhomogeneous conduction velocity and large action potential spatial gradients. Our model simulations are consistent with the ECG patterns from TS patients, which suggest that the TS mutation is sufficient to cause the clinical phenotype and allows for the revelation of the complex interactions of currents underlying it.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number6
DOIs
StatePublished - Dec 2007
Externally publishedYes

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Keywords

  • Modeling
  • Timothy Syndrome

ASJC Scopus subject areas

  • Physiology

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