Atrial Fibrillation Induces Sarcomere Remodeling, Enhanced Sarcomere Contractility, and Loss of Atrial Identity.

Atrial fibrillation (AF) is the most common arrhythmia, with few treatment options. To discover novel pathways, we performed mass spectrometry (MS) on atrial tissue from patients in Sinus Rhythm or with AF without heart failure. We identified changes in canonical AF pathways, although surprisingly, contractile proteins and specifically a loss of atrial isoforms. Functional remodeling was confirmed in AF cardiomyocytes, revealing increased contractility compared to SR. We performed MS analysis of human atrial and ventricular tissue and found that ~1/3 of proteomic remodeling in AF was associated with chamber identity. Using atrial hiPSC-CM Engineered Heart Tissues to model AF, we replicated proteomic and contractile remodeling observed in human tissue, indicating mechano-sensing likely drives these effects. Lastly, an integrative patient simulation suggests this cellular remodeling is likely maladaptive. Together, these results reveal a novel role for sarcomere remodeling and a loss of atrial identity in AF, representing potential new therapeutic targets.