Modelling the Ionic Mechanisms Underlying Brugada Syndrome
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Status
This model is valid CellML but can not be integrated.
Model Structure
Of the 300,000 sudden deaths that occur in America each year, 5 to 12 percent are due to polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) developing in patients with structurally normal hearts. About half of these cases are attributed to the Brugada syndrome, which is characterised by an ST-segment elevation in V1 through V3 and a rapid VT that can degenerate into VF. The disease has been linked to mutations in the SCN5A gene, which encodes the alpha subunit of the cardiac sodium channel. This temperature dependent mutation appears to change the gating kinetics of the sodium channel, such that the net outward current is augmented during the early phases of the right ventricular action potential.
In their 1999 study, Dumaine et al. tested this temperature dependence hypothesis. They studied cardiac action potentials by using a modified version of the Luo-Rudy II model. The modification involved adding a transient outward potassium current (Ito
) to the original model, and reducing the conductance of the L-type calcium channel by 20 to 50 percent. For a diagram of the model, please see the figure below.
The results of their study showed that this mutation is only expressed at physiological temperatures. This explained why the mutation phenotype had not been observed in previous experiments which had been carried out at room temperature. Their findings also suggest that some patients may be more at risk during febrile states when their body temperature is elevated.
The complete original paper reference is cited below:
Ionic Mechanisms Responsible for the Electrocardiographic Phenotype of the Brugada Syndrome Are Temperature Dependent, Robert Dumaine, Jeffrey A. Towbin, Pedro Brugada, Matteo Vatta, Dmitri V. Nesterenko, Vladislav V. Nesterenko, Josep Brugada, Ramon Brugada, and Charles Antzelevitch, 1999,
Circulation Research
, 85, 803-809. PubMed ID: 10532948
cell diagram
A schematic diagram describing the ionic currents, pumps and exchangers that are captured in the Dumaine et al. 1999 model. The intracellular compartment is the sarcoplasmic reticulum (SR), which is divided into the two subcompartments, the network SR (NSR) and the junctional SR (JSR). Ca2+ buffers are present in both the cytoplasm and the JSR.
cardiac
ventricular myocyte
electrophysiology
Ventricular Myocyte
brugada
Circulation Research
Ionic mechanisms responsible for the electrocardiographic phenotype
of the Brugada Syndrome are temperature dependent
85
803
809
This is the CellML description of Dumaine et al.'s 1999 mathematical
model of ventricular action potentials in Brugada syndrome. The model is derived from the Luo-Rudy II (1994) mathematical model of the
mammalian cardiac ventricular action potential.
Jeffrey
Towbin
A
Vladislav
Nesterenko
V
Charles
Antzelevitch
Robert
Dumaine
Catherine Lloyd
Dmitri
Nesterenko
V
The University of Auckland
The Bioengineering Institute
The University of Auckland, The Bioengineering Institute
10532948
Ramon
Brugada
keyword
Pedro
Brugada
1999-10
Matteo
Vatta
Catherine
Lloyd
May
Dumaine et al.'s 1999 mathematical model of ventricular action
potentials in Brugada syndrome.
Ventricular Myocyte
Mammalia
2003-08-20
Josep
Brugada
c.lloyd@auckland.ac.nz