Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation

• Published in: Circulation (New York, N.Y.) N.Y.), 2014-01, Vol.129 (2), p.145-156
• Main Authors: Voigt, Niels, Heijman, Jordi, Wang, Qiongling, Chiang, David Y, Li, Na, Karck, Matthias, Wehrens, Xander H.T, Nattel, Stanley, Dobrev, Dobromir
• Format: Article
• Language: English
• Subjects: Aged; Arrhythmias, Cardiac - physiopathology; Atrial Appendage - pathology; Atrial Appendage - physiopathology; Atrial Fibrillation - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Calcium - physiology; Calcium Signaling - physiology; Calcium-Binding Proteins - physiology; Cardiac dysrhythmias; Cardiology. Vascular system; Case-Control Studies; Cells, Cultured; Computer Simulation; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Heart; Heart Atria - physiopathology; Humans; Male; Medical sciences; Membrane Potentials - physiology; Models, Cardiovascular; Myocytes, Cardiac - pathology; Myocytes, Cardiac - physiology; Patch-Clamp Techniques; Ryanodine Receptor Calcium Release Channel - physiology; Sarcoplasmic Reticulum - physiology; Sarcoplasmic Reticulum Calcium-Transporting ATPases - physiology; Sodium-Calcium Exchanger - physiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.006641

BACKGROUND—Electrical, structural, and Ca-handling remodeling contribute to the perpetuation/progression of atrial fibrillation (AF). Recent evidence has suggested a role for spontaneous sarcoplasmic reticulum Ca-release events in long-standing persistent AF, but the occurrence and mechanisms of sarcoplasmic reticulum Ca-release events in paroxysmal AF (pAF) are unknown. METHOD AND RESULTS—Right-atrial appendages from control sinus rhythm patients or patients with pAF (last episode a median of 10–20 days preoperatively) were analyzed with simultaneous measurements of [Ca]i (fluo-3-acetoxymethyl ester) and membrane currents/action potentials (patch-clamp) in isolated atrial cardiomyocytes, and Western blot. Action potential duration, L-type Ca current, and Na/Ca-exchange current were unaltered in pAF, indicating the absence of AF-induced electrical remodeling. In contrast, there were increases in SR Ca leak and incidence of delayed after-depolarizations in pAF. Ca-transient amplitude and sarcoplasmic reticulum Ca load (caffeine-induced Ca-transient amplitude, integrated Na/Ca-exchange current) were larger in pAF. Ca-transient decay was faster in pAF, but the decay of caffeine-induced Ca transients was unaltered, suggesting increased SERCA2a function. In agreement, phosphorylation (inactivation) of the SERCA2a-inhibitor protein phospholamban was increased in pAF. Ryanodine receptor fractional phosphorylation was unaltered in pAF, whereas ryanodine receptor expression and single-channel open probability were increased. A novel computational model of the human atrial cardiomyocyte indicated that both ryanodine receptor dysregulation and enhanced SERCA2a activity promote increased sarcoplasmic reticulum Ca leak and sarcoplasmic reticulum Ca-release events, causing delayed after-depolarizations/triggered activity in pAF. CONCLUSIONS—Increased diastolic sarcoplasmic reticulum Ca leak and related delayed after-depolarizations/triggered activity promote cellular arrhythmogenesis in pAF patients. Biochemical, functional, and modeling studies point to a combination of increased sarcoplasmic reticulum Ca load related to phospholamban hyperphosphorylation and ryanodine receptor dysregulation as underlying mechanisms.