Sarcomere remodeling of left atrial myocytes in non-failing atrial fibrillation patients.

Abstract

Atrial fibrillation (AF) significantly contributes to adverse cardiac events like stroke. To identify novel pathways to target therapeutically, we performed mass spectrometry on left atrial (LA) tissue from patients in Sinus Rhythm (SR, n = 3) or with AF (n = 3), with no other cardiovascular disease that could confound interpretation. Pathway analysis identified inflammatory, metabolic, and extracellular matrix pathways as highly altered in AF, all of which are currently active areas of AF research. However, contractile proteins were also significantly altered, and the role of the sarcomere in AF remains mostly unstudied. To understand the functional impact of AF on the sarcomere, we measured force-calcium relationships in single cardiomyocytes from LA and left ventricular (LV) tissue from SR (n = 6) and AF (n = 3) patients. Surprisingly, maximal calcium-activated force (Fmax) was almost doubled in AF compared to SR patients. This result contradicts previous work which observed depressed contractile function in AF patients; however, these patients had heart failure and valve disease. Ventricular cells from these patients showed no change in Fmax (expected in non-failing patients), but a slight calcium sensitization in AF due to decreased troponin I (TnI) phosphorylation, possibly in compensation for elevated heart rate. Mass spec analysis showed that AF atria had decreased myosin-binding protein H-like, slow skeletal TnI, and increased alpha tropomyosin and beta-MHC (confirmed by gel electrophoresis). These changes suggest that AF drives a more “ventricular-like” or mature sarcomere in atrial myocytes, resulting in increased force production that is also similar to ventricular myocytes. Together, these data provide insight into the development and outcomes of atrial fibrillation in absence of other cardiovascular conditions in humans and suggests that the sarcomere may be a feasible therapeutic target in atrial fibrillation.