Arrhythmogenic mechanisms of sleep-disordered breathing

• Applicant: Professor Dr. Stefan Wagner
• Subject Area: Cardiology, Angiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440975675

Patients with sleep-disordered breathing (SDB) are at increased risk for the development of atrial fibrillation (AF). Beside positive pressure ventilation, there are no specific pharmacological treatment options available. Preliminary experiments in patients and animal models have revealed that AF may be associated with increased atrial activity of Ca/Calmodulin-abhängigen Proteinkinase II (CaMKII). Interestingly, a major mechanism of CaMKII activation is reactive oxygen-species(ROS)-mediated CaMKII oxidation and CaMKII autophosphorylation. The present proposal wants to prove the mechanistic link between increased SDB-dependent CaMKII activation and enhanced atrial arrhythmogenesis by investigation of detailed mechanisms of CaMKII activation but also CaMKII-dependent regulation of excitation-contraction coupling and their consequences for arrhythmias. Current animal models are insufficient to investigate all aspects of the clinical disease. Thus, we have developed and will apply a novel mouse model of spontaneous sleep apnea by increases airway resistance as a consequence of increased tongue diameters. Moreover, we will accompany animal experiments by data from a clinical observational study that enrolls patients that undergo CABG and are screened for SDB. We will make use of atrial biopsies that become available upon surgery and correlate laboratory findings with clinical variables. Unique for this type of research, we will perform multivariate linear regression analysis to account for multiple clinical co-variates that may confound our lab results. If successful, our project could identify CaMKII inhibition as a potential novel pharmacological treatment option to reduce the incidence of AF in patients with SDB.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Michael Arzt