Disturbed cardiac sodium homeostasis as a mechanism of ethanol-induced atrial arrhythmias

• Applicants: Privatdozent Dr. Julian Mustroph; Dr. Stefan Neef
• Subject Area: Cardiology, Angiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455425596

Ethanol abuse is a serious medical and social problem worldwide. Excessive drinking is an important risk factor for atrial and ventricular arrhythmias, as well as contractile dysfunction. 20 30% of hospitalized patients are considered alcohol abusers. 24% of Americans partake in “binge drinking” (blood alcohol contents of 0.8‰ [=0.08%] or higher). It has long been established that alcohol can acutely induce arrhythmias (especially atrial fibrillation in terms of the “holiday heart” syndrome). The mechanisms of these acute ethanol-induced cardiac arrhythmias are, however, insufficiently understood. An important enzyme in myocardial arrhythmogenesis is the Ca2+/calmodulin-dependent kinase II (CaMKII). We could show in cellular experiments that ethanol induces reactive oxygen species via NADPH-Oxidase II in isolated cardiomyocytes, which then activate CaMKII via oxidation. In these experiments we could show that increased CaMKII-activity leads to increased diastolic sarcoplasmic reticulum Ca2+-leak, which in consequence leads to cellular arrhythmias.In current preliminary experiments we could show that ethanol also induces cytosolic Na+-overload in atrial cardiomyocytes.The aim of the current project is to mechanistically investigate proarrhythmic mechanisms of cardiac Na+-overload upon acute ethanol exposure and to develop new therapeutic concepts.The central hypotheses are:1) Cytosolic Na+-overload is a thus far unrecognized mechanism of ethanol-induced arrhythmogenesis. It is dependent on a CaMKII-induced late Na+-influx current (late INa).2) There is positive feedback between ethanol-induced Na+-overload, Ca2+-homeostasis and Ca2+-leak, CaMKII activity, and reactive oxygen species.3) The prevention of cardiomyocyte Na+-overload is a novel translational concept to treat ethanol-induced atrial arrhythmias.These investigations can yield new therapeutic approaches, which can be rapidly translated into clinical practice and would - in the light of the high prevalence of ethanol-induced arrhythmias - be of high clinicial relevance.

• DFG Programme: Research Grants