Effects of the atrial fibrillation risk region on chromosome 4q25 and PITX2 on atrial metabolic and mitochondrial function

• Applicants: Professorin Dr. Friederike Cuello; Professor Dr. Paulus Kirchhof
• Subject Area: Pharmacology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 509167694

Atrial fibrillation (AF) affects at least 2% of the population in Germany. It is a highly prevalent risk factor for cardiovascular deaths, stroke, heart failure, and acute coronary syndromes in patients. Common gene variants on chromosome 4q25 show by far the strongest genomic association with AF risk in the population. These risk variants reside in an enhancer region controlling transcription of the Paired like Homeodomain 2 (PITX2) gene via long-range chromatin interactions. PITX2 expression is largely confined to the left atrium in the adult heart. Enhancer deletion including these risk variants leads to reduced atrial PITX2 expression in mice and in patients to recurrent AF after ablation, predisposition to AF by modifying electrical function of the atria and alterations in atrial electrical and contractile function. To understand the molecular mechanisms of this atrial disease phenotype, the present project aims to characterize the electrophysiological and metabolic consequences of enhancer deletion in a knockin-in mouse and in genetically-engineered enhancer deleted human induced pluripotent stem cell-derived atrial cardiomyocyte (atrial hiPSC-EHTs) model cultured in a three-dimensional tissue culture format. Experiments will involve echocardiography and optical pacing in mice as well as contractile analysis during nutrient-restriction in atrial hiPSC-EHTs combined with unbiased transcriptomic and metabolic analysis. The results are anticipated to enhance our understanding of underlying AF disease mechanisms and might inspire novel treatment strategies.

• DFG Programme: Research Grants