The relevance of sodium homeostasis for atrial myopathy in heart failure with preserved ejection fraction

• Applicant: Dr. Maximilian Trum
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 562070634

Patients with heart failure with preserved ejection fraction (HFpEF) often develop atrial myopathy, which frequently serves as the substrate for the onset of atrial fibrillation. Previous studies have shown that increased activity of the Ca/calmodulin-dependent kinase II (CaMKII) is associated with the development of atrial fibrillation in patients and animal models. CaMKII can be activated not only by autophosphorylation but also through oxidation by reactive oxygen species (ROS). Interestingly, we recently detected increased CaMKII activity in atrial tissue from patients with HFpEF, who did not have atrial fibrillation. This increased activity was associated with an increased sodium influx, which was partly due to a CaMKII-dependent enhancement of the late sodium current (late INa). In a mouse model with genetically increased late INa, it was shown that this can induce atrial remodeling via increased ROS production. The planned project aims to investigate, for the first time, the significance of the (CaMKII-dependent) increased sodium influx for the development and progression of atrial myopathy and the associated arrhythmogenesis in HFpEF. Therefor, a mouse model of HFpEF, as well as various genetic and (clinically approved) pharmacological interventions, will be used. The transferability of the findings obtained in the animal model will be tested through experiments on human atrial tissue from patients undergoing on-pump cardiac surgery. To enable mechanistic insights in addition to correlation analyses that account for clinical confounders, the oxidative activation of CaMKII will be prevented in human tissue using CRISPR-Cas9 base editing. This will allow investigation of the effects of oxCaMKII on atrial sodium influx and arrhythmogenesis in human HFpEF. Thus, the project aims to better understand the pathophysiological processes of atrial myopathy while also evaluating whether clinically approved medications can intervene in these processes, potentially preventing the development of atrial myopathy in at-risk patients or reducing the severity of established atrial myopathy.

• DFG Programme: Research Grants