Analysis of a case of Brugada Syndrome through Numerical Simulation of Ventricular Action Potential

Giulia Guidi1, Chiara Bartolucci1, Anthony Frosio2, Procolo Marchese3, Annalisa Bucchi2, Mirko Baruscotti2, Stefano Severi1
1University of Bologna, 2University of Milano, 3Mazzoni Hospital


Brugada syndrome (BrS) is a disorder characterized by cardiac conduction system dysfunctions, which increases the risk of sudden cardiac death, without heart structural alterations. The diagnosis is based on the ECG tracing analysis: BrS patients have common anomalies. The typical ECG pattern, however, can remain latent and patients can be asymptomatic: the first symptom often coincides with death. Recently, a new mutation associated with BrS has been identified and characterized by HEK 293 cells. The study aims to analyse, through numerical simulation of the O’Hara-Rudy (ORd) model, the mutation effects on the ventricular action potential (AP). The O’Hara-Rudy human ventricular AP model was chosen to reproduce both wild-type and mutant action potential. In the mutant model the maximum conductance of the fast component of sodium current was reduced by 35%, and the half inactivation voltage of the current was positively shifted by 3.6 mV. The results suggest that the two opposite effects of the mutation, i) gain of function due to increased maximal conductance and ii) loss of function due to positive shift of the steady-state inactivation curve, largely compensate each other so that the overall impact on the sodium current under AP is quite limited (-8% peak current). Such decrease is not likely to provoke arrhythmic episodes. The occasional occurrence of the Brugada event may depend on other transient factors. In particular, the hypothesis which arises is that the loss of function of I_Na might be intensified by the hyperpolarization of the resting potential. This could happen because when moving to more negative potentials, the gap between the WT and mutated inactivation curve decreases. As a consequence, the effect of gain of function decreases, giving way to the loss of function, which might become the dominant effect. This hypothesis definitely deserves to be further investigated.