Atrial fibrillation is the most common cardiac arrhythmia in adults, with a rapidly growing prevalence that is expected to double in the next 30 years. The consequences of atrial fibrillation include higher rates of stroke, dementia, and heart failure, and it is even associated with increased mortality. Basically, atrial fibrillation is a disease of the left atrium of the heart, and it is no longer considered a mere arrhythmia, but a manifestation of atrial cardiomyopathy syndrome. In this syndrome, there is increased scarring, as well as electrical and mechanical dysfunction in the atrium of the heart. Therapeutic options are limited, involve risks, and are unfortunately associated with an increased likelihood of recurrence. Thus, new therapeutic options, especially those with unique mechanisms of action, are needed to improve the management of patients with atrial fibrillation and atrial cardiomyopathy.
Large genetic studies have identified genetic variants that are strongly associated with atrial fibrillation and atrial cardiomyopathy, including a single nucleotide polymorphism in the promoter region of ZFHX3 which results in decreased gene expression. In my Gateway Fellowship project, I will investigate the impact of an atrial-specific ZFHX3 knockout on the development of atrial cardiomyopathy in a mouse model. We will also test whether these genetically modified mice can be rescued from atrial cardiomyopathy and atrial fibrillation. In particular, we will focus on the non-canonical WNT signaling pathway and its antagonists, which regulate various cellular processes and may represent a potential therapeutic target. I will start the project in early 2024 in the Ellinor Lab at Massachusetts General Hospital / Harvard Medical School in Boston under the supervision of Dr. Patrick Ellinor and Dr. Aneesh Bapat. The Ellinor Lab is one of the world's leading research groups in genetic and epigenetic studies of cardiovascular disease, particularly atrial fibrillation. There, I will have the opportunity to gain experience in a broad range of technical methods, including murine physiology, electrophysiology, biochemical assays, bulk RNA sequencing, as well as cutting-edge methods such as single-nuclear RNA sequencing.