Computational Study on Effect of KCNQ1 P535T Mutation in a Cardiac Ventricular Tissue.

Heart diseases such as arrhythmia are the main causes of sudden death. Arrhythmias are typically caused by mutations in specific genes, damage in the cardiac tissue, or due to some chemical exposure. Arrhythmias caused due to mutation is called inherited arrhythmia. Induced arrhythmias are caused due to tissue damage or chemical exposure. Mutations in genes that encode ion channels of the cardiac cells usually result in (dysfunction) improper functioning of the channel. Improper functioning of the ion channel may lead to major changes in the action potential (AP) of the cardiac cells. This further leads to distorted electrical activity of the heart. Distorted electrical activity will affect the ECG that results in arrhythmia. KCNQ1 P535T mutation is one such gene mutation that encodes the potassium ion channel (KV7.1) of the cardiac ventricular tissue. Its clinical significance is not known. This study aims to perform a simulation study on P535T mutation in the KCNQ1 gene that encodes the potassium ion channel KV7.1 in the ventricular tissue grid. The effect of P535T mutation on transmural tissue grids for three genotypes (wild type, heterozygous, and homozygous) of cells are studied and the generated pseudo-ECGs are compared. Results show the delayed repolarization in the cells of ventricular tissue grid. Slower propagation of action potential in the transmural tissue grid is observed in the mutated (heterozygous and homozygous) genotypes. Longer QT interval is also observed in the pseudo-ECG of heterozygous and homozygous genotype tissue grids. From the pseudo-ECGs, it is observed that KCNQ1 P535T mutation leads to Long QT Syndrome (LQTS) which may result in life-threatening arrhythmias, such as Torsade de Pointes (TdP), Jervell and Lange-Nielsen syndrome (JLNS), and Romano-Ward syndrome (RWS).

Reentry in cardiac ventricular epicardial tissue due to SCN5A L812Q gene mutation: a computational study.

Cardiovascular diseases are the major cause of sudden death. Brugada syndrome is an inherited rare disease, that leads to death due to ventricular fibrillation (VF). Brugada Syndrome is related to mutations in the genes that encode SCN5A, a subunit of sodium ion channel (NaV). This computational study investigates the mechanism of loss of function gene mutation (SCN5A L812Q) in sodium ion channel that leads to spiral wave and further develops into VF in an epicardial tissue with homozygous condition. Study was made on wild type, L812Q heterozygous mutated and homozygous mutated ventricular tissues. Ten Tusscher human ventricular cell model (TP06) was used for the simulation study. VF is developed when a spiral wave that causes ventricular arrhythmia breaks. This leads to the formation of multiple spiral waves that are activated on different regions of the ventricles called wave break. This is observed in the epicardial tissue with homozygous condition as the effect of SCN5A L812Q gene mutation. This indicates that VF occurs in the SCN5A L812Q gene mutated homozygous ventricular epicardial tissue that may further lead to Brugada syndrome.

A Simulation Study on Electrical Activity of Ventricular Endocardial Tissue due to SCN5A L812Q Mutation.

Brugada Syndrome is a rare arrhythmia, hereditary in nature. It is caused due to mutation in genes that encodes sodium ion channels and it results sudden cardiac death in young adults. This paper aims to model a two dimensional SCN5A L812Q mutated endocardial tissue by modifying the model equations for sodium ion channel in the Ten Tusscher model for human ventricular tissue. Results show that the propagation of electrical activity in the mutated cells is slower when compared to the normal cells of the endocardial tissue. From this it is concluded that there is a large reduction of sodium current in the mutated region of the endocardial tissue. This leads to reduction in the total ionic current as well and further reduces the membrane potential. It also leads to the slower propagation of action potential in the mutated region when compared to the normal endocardial tissue.Clinical Relevance- This establishes the propagation of electrical activity in endocardial tissue for SCN5A L812Q gene mutation that results in arrhythmia called Brugada Syndrome.