Activation of proteolysis by calpains and structural changes in human paroxysmal and persistent atrial fibrillation

Objective: Atrial fibrillation (AF) is accompanied by electrical. structural and ion-channel protein remodeling. We tested if proteolysis by calpain and proteasome is activated during AF. and studied the relation with the remodeling processes. Methods: Right atrial appendages were obtained from patients with paroxysmal (n = 7) or persistent (n = 10) lone AF and compared to controls (n = 10) in sinus rhythm undergoing coronary artery bypass grafting (CABG). Proteolysis was measured using Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl-coumarin. Protein expression of calpain I and 11 was assessed by Western-blot and calpain I localization by immunohistochemistry. Structural changes were quantified by counting atrial myocytes with contraction bands or hibernation. Results: Calpain activity was significantly increased in paroxysmal AF (2-fold, P<0.001) and persistent AF (3-fold. P<0.001), mainly due to calpain I activation. Increased calpain I protein expression was found in AF with Western blot and immunohistochemistry. Myocytes from all AF groups showed increased contraction bands. whereas hibernation was only found in persistent AF. Calpain activity correlated with L-type Ca2+ channel and Kv1.5 protein amounts (r = -0.80, P<0.001 and r = -0.72, P<0.001. respectively), degree of structural changes (r = 0.90, P<0.001), shortening of atrial effective refractory period (AERP) (basic cycle length 500 ms, r = -0.60, P<0.001) and AERP rate adaptation (r = -0.80, P<0.001). Conclusions: Calpain activity is induced during AF and correlates with parameters of ion-channel protein, structural and electrical remodeling. The results suggest that calpain activation represents an important mechanism linking calcium overload to Cellular adaptation mechanisms in human AF. (C) 2002 Elsevier Science B.V. All rights reserved.