Introduction:
Atrial fibrillation (AF) can cause left ventricular (LV) dysfunction and heart failure (HF). However, whereas the pathogenesis of AF has been broadly studied in the atria, the effects of AF on LV function are yet limited. The aim of this study is to understand the molecular mechanisms leading to cardiomyocyte dysfunction in LV from AF patients.

Methods and results:
Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm (SR) or rate-controlled AF was studied. LV myocardium from patients with SR and patients with AF showed no differences in fibrosis. LV cardiomyocyte from AF patients showed increased Ca²⁺ sensitivity and titin-based cardiomyocyte stiffness and reduced maximum Ca²⁺-activated tension of isolated permeabilized cardiomyocyte compared to cardiomyocyte from SR patients. The altered cardiomyocyte mechanics in AF patients was associated with phosphorylation deficit and increased oxidation of sarcomeric proteins including cardiac troponin I (cTnI), myosin binding protein C (cMyBP-C) and titin, in addition to phosphorylation deficit and increased oxidation of calcium handling proteins sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), phospholamban (PLB), and ryanodine receptor (RyR). This was also accompanied with impaired signalling pathways involved in phosphorylation of these sarcomeric and calcium handling proteins such as Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinases (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase G (PKG) in AF patients compared to SR patients. Impaired protein phosphorylation status and dysregulated signalling pathways were associated with significant alterations in expression, phosphorylation, or the oxidative status of these kinases contributing therefore to the elevated Ca²⁺ sensitivity and titin-based cardiomyocyte stiffness and reduced maximum Ca²⁺-activated tension. The cardiomyocyte dysfunction was reversible upon administration in ex-vivo of these kinases and in particular CaMKII and PKG.

Conclusion:
Our study showed that AF patients have LV cardiomyocyte dysfunction which is associated with impaired signalling pathways involved in the phosphorylation of sarcomeric and calcium handling proteins, in addition to oxidation status of these proteins.

 
KEYWORDS 

Atrial fibrillation, left ventricular, cardiomyocyte, sinus rhythm, heart failure, phosphorylation, oxidation, signalling pathways, sarcomeric proteins, calcium handling proteins, fibrosis, Ca²⁺ sensitivity, protein kinases.