Thesis Defense: The Impact of Tamoxifen on Cardiac Electrophysiology in the Context of the Tamoxifen-Inducible Cre-Loxp System in Mice

About this Dissertation

Sudden cardiac death is one of the leading causes of death worldwide, with lethal ventricular arrhythmias being likely responsible for most incidents. The frequency of sudden cardiac death is increasing, presenting the need for more research into the causes and treatments of these deadly arrhythmias. As arrhythmia research increases to meet the need for more effective treatments, there is a distinct need for increased scrutiny into the possible confounding variables present in current models of arrhythmogenic disease. One of the most common and effective models for arrhythmia research is mice, utilizing the tamoxifen-inducible cardiac specific Cre-loxp system. In this system, tamoxifen is used to activate the Cre recombinase protein, made to express only in the heart. This protein targets and removes two inserted artificial loxp sites and the sequence between them, resulting in a gene knockout or other manipulation. This system can be used to target specific proteins known to contribute to arrhythmia formation, while avoiding developmental complications common in constitutive knockouts of cardiac proteins. The cardiac-specific Cre-loxp system is known to have off-target effects, including inflammation, fibrosis, and reduced cardiac performance. Tamoxifen also has effects on cardiac electrophysiology, with the ability to block sodium channels, which can slow conduction and promote arrhythmias. As many studies focus on tamoxifen in the context of its use in human patients, it is unknown whether tamoxifen on its own, as used in the mouse Cre-loxp system, can create an arrhythmogenic phenotype. Albrecht, mentored by Steven Poelzing, conducted studies to determine how tamoxifen impacts cardiac electrophysiology and the expression of key proteins responsible for conduction in an ex vivio mouse model. Albrecht found that tamoxifen could slow conduction, and change action potential duration characteristics, particularly at shorter paced cycle lengths. This indicates that tamoxifen can interfere with cardiac electrophysiology, and that these effects needs to be controlled for in arrhythmia research using models which are exposed to tamoxifen.

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