Arrhythmogenic Cardiomyopathy (ACM) is an inherited disease characterized by life-threatening abnormal heart rhythm (arrhythmias) up to sudden cardiac death especially in young athletes. The disease is mainly caused by genetic mutations in components of cell-cell junctions, which are important for the connection of cardiac muscle cells. Typical symptoms include palpitations, arrhythmic syncope and sudden cardiac arrest. Until today, the disease is not well understood, and therapeutic options are only limited to management of symptoms. Only by knowing more about the origin of the disease, it may be possible to develop an effective treatment one day. Therefore, Camilla Schinner and her team aimed to better understand the mechanisms leading to ACM to support the identification of new therapeutic targets.

In the Cell Adhesion lab at the DBM, University of Basel, they investigated the relevance of insufficient cell-cell connection for the development of the disease. To approach this, the research team introduced a specific gene mutation into a mouse model to disrupt the connection of cardiac muscle cells. Analyses of the diseased hearts revealed that disruption of the cell-cell connection leads to changes in the connection of cardiac muscle cells to the surrounding tissue. Importantly, this is contributing to cardiac scar formation. The resulting heart fibrosis could be prevented by blocking the identified pathway with a chemical compound.

This study shows that impaired cell-cell connection can lead to the development of symptoms characteristic to ACM. With the newly generated mouse model, Camilla Schinner and her team were able to identify a novel pathway promoting scar formation in the heart. This is important, as it helps to better understand the mechanisms causing the disease. Moreover, they tested a first approach to target these changes therapeutically. This highlights the high value of the new model to discern mechanisms of ACM to identify novel treatment strategies for this cardiac disorder.

Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVβ6/TGF-β Signaling Cascade. Camilla Schinner, Lifen Xu, Henriette Franz, Aude Zimmermann, Marie-Therès Wanuske, Maitreyi Rathod, Pauline Hanns, Florian Geier, Pawel Pelczar, Yan Liang, Vera Lorenz, Chiara Stüdle, Piotr I. Maly, Silke Kauferstein, Britt M. Beckmann, Farah Sheikh, Gabriela M. Kuster and Volker Spindler. Circulation. 2022 Nov 22;146(21):1610-1626