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bioRxiv · 10.1101/2023.11.05.565691

Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation

Cizauskas, H.·Burnham, H.·Panni, A.·Pena, A.·Alvarez-Arce, A.·Davis, M. T.·Araujo, K.·Delligatti, C.·Edaserry, S.·Kirk, J.·Arora, R.·Barefield, D.
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Abstract

(ii) ABSTRACTO_ST_ABSAimsC_ST_ABSAtrial fibrillation (AFib) is the most common cardiac rhythm disturbance. Treatment of AFib involves restoration of the atrial electrical rhythm. Following rhythm restoration, a period of depressed mechanical function known as atrial stunning occurs that involves decreased blood flow velocity and reduced atrial contractility. This suggests that defects in contractility occur in AFib and are revealed upon restoration of rhythm. The aim of this project is to define the contractile remodeling that occurs in AFib Methods and ResultsTo assess contractile function, we used a canine atrial tachypacing model of induced AFib. Mass spectrometry analysis showed dysregulation of contractile proteins in samples from AFib compared to sinus rhythm atria. Atrial cardiomyocytes showed reduced force of contraction in skinned single cardiomyocyte calcium-force studies. There were no significant differences in myosin heavy chain isoform expression. Resting tension is decreased in the AFib samples correlating with reduced full-length titin in the sarcomere. We measured degradation of other myofilament proteins including cMyBP-C, actinin, and cTnI, showing significant degradation in the AFib samples compared to sinus rhythm atria. Many of the protein degradation products appeared as discrete cleavage products that are generated by calpain proteolysis. We assessed calpain activity and found it to be significantly increased. Skinned cardiomyocytes from AFib atria showed decreased troponin I phosphorylation, consistent with the increased calcium sensitivity that was found within these cardiomyocytes. ConclusionsWith these results it can be concluded that AFib causes alterations in contraction that can be explained by both molecular changes occurring in myofilament proteins and overall myofilament protein degradation. These results provide an understanding of the contractile remodeling that occurs in AFib and provides insight into the molecular explanation for atrial stunning and the increased risk of atrial thrombus and stroke in AFib.

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Cizauskas, H., Burnham, H., Panni, A., Pena, A., Alvarez-Arce, A., Davis, M. T., Araujo, K., Delligatti, C., Edaserry, S., Kirk, J., Arora, R., Barefield, D.. 2023-11-05. Proteolytic degradation of atrial sarcomere proteins underlies contractile defects in atrial fibrillation. https://doi.org/10.1101/2023.11.05.565691

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