Tumor necrosis factor-α alters calcium handling and increases arrhythmogenesis of pulmonary vein cardiomyocytes

Inflammation and abnormal calcium homeostasis play important roles in atrial fibrillation. Tumor necrosis factor-alpha. (TNF alpha), a proinflammatory cytokine, can induce cardiac arrhythmias. Pulmonary veins (PVs) are critical in initiating paroxysmal atrial fibrillation. This study was designed to investigate whether TNFa may change the calcium handling and arrhythmogenic activity of PV cardiomyocytes. We used whole-cell patch clamp and indo-I fluorimetric ratio technique to investigate the action potentials, ionic currents and intracellular calcium in isolated rabbit single PV cardiomyocytes with and without (control) incubation with TNF alpha (25 ng/ml) for 7-10 h. The expression of sarcoplasmic reticulum ATPase in the control and TNF alpha-treated PV cardiomyocytes was evaluated by confocal micrographs and Western blot. We found that the spontaneous beating rates were similar between the control (n = 45) and TNF alpha-treated (n = 28) PV cardiomyocytes. Compared with the control PV cardiomyocytes, the TNF alpha-treated PV cardiomyocytes had significantly a larger amplitude of the delayed afterdepolarizations (6.0 +/- 1.7 vs. 2.6 +/- 0.8 mV, P<0.05), smaller L-type calcium currents, larger transient inward currents, larger Na+-Ca2+ exchanger currents, a smaller intracellular calcium transient, smaller sarcoplasmic reticulum calcium content, larger diastolic intracellular calcium, a longer decay portion of the calcium transient (Tau), and a decreased sarcoplasmic reticulum ATPase expression. In conclusion, TNF alpha can increase the PV arrhythmogenicity and induce an abnormal calcium homeostasis, thereby causing inflammation-related atrial fibrillation. (C) 2007 Elsevier Inc. All rights reserved.