Na+ channel mutation that causes both Brugada and long-QT syndrome phenotypes - A simulation study of mechanism

Article

关键词: ST-SEGMENT ELEVATION;    EARLY AFTERDEPOLARIZATIONS;    CARDIAC-ARRHYTHMIA;    RATE DEPENDENCE;    MYOCYTES;    DURATION;   

DOI  :  10.1161/hc1002.105183

来源: SCIE

【 摘 要 】

Background-Complex physiological interactions determine the functional consequences of gene abnormalities and make mechanistic interpretation of phenotypes extremely difficult. A recent example is a single mutation in the C terminus of the cardiac Na+ channel. 1795insD. The mutation causes two distinct clinical syndromes, long QT (LQT) and Brugada. leading to life-threatening cardiac arrhythmias. Coexistence of these syndromes is seemingly paradoxical; LQT is associated with enhanced Na+ channel function, and Brugada with reduced function. Methods and Results-Using a computational approach, we demonstrate that the 1795insD mutation exerts variable effects depending on the myocardial substrate. We develop Markov models of the wild-type and 1795insD cardiac Na+ channels. By incorporating the models into a virtual transgenic cell, we elucidate the mechanism by which 1795insD differentially disrupts cellular electrical behavior in epicardial and midmyocardial cell types. We provide a cellular mechanistic basis for the ECG abnormalities observed in patients carrying the 1795insD gene mutation. Conclusions-We demonstrate that the 1795insD mutation call cause both LQT and Brugada syndromes through interaction with the heterogeneous myocardium in a rate-dependent manner. The results highlight the complexity and multiplicity of genotype-phenotype relationships, and the usefulness of computational approaches in establishing a mechanistic link between genetic defects and functional abnormalities.

【 授权许可】

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