Kidney Injury and Heat Shock Protein Modulate the Atrial Electrophysiological Characterisitcs

Atrial fibrillation (AF) is the commonest sustained arrhythmia, and it increases the risk of stroke, heart failure, and mortality. Chronic kidney disease (CKD), defined as reduced kidney function is associated with a higher risk of AF. However, the mechanisms of AF occurrence in patients with CKD are not really clear. The animal study of CKD due to partial nephronectomy has been shown to increase atrial fibrosis with more AF occurrences. Pulmonary veins (PV) and left atrium (LA) are the most important AF initiator and substrate with a high AF arrhythmogenesis. However, limited information is available for the electrophysiological effects of CKD on LA and PVs. Uremic toxins contribute to the genesis of cardiovascular disease. Their effects on cardiac arrhythmia is still unclear. Uremic toxin, especially protein-bound compounds, such as P-cresol and Indoxyl sulfate plays an important role in oxidative stress, inflammation, atherosclerosis and endothelial dysfunction, which have been shown to significantly contribute to the genesis of AF. In the results of our study supported by the grant of National Science Council in 2013, Indoxyl sulfate would increase the incidence of pulmonary veins burst firing, reduce the action potential duration of the left atrium and reduce the sinoatrial node spontaneous firing rate. The above effects were eliminated by ascorbic acid, making oxidative stress as a possible mechanism. Besides, after pretreatment of Indoxyl sulfate and isoproterenol, burst pacing would induce sustained atrial contraction, which was not noted after pretreatment of isoproterenol alone. Moreover, heat shock protein can reduce cell oxidative stress and apotosis and attenuate the AF occurrences due to ischemia or rapid atrial pacing. It is possible that heat shock protein can reduce the AF risks in CKD. Based on our preliminary results and the protective effects of heat shock protein, we designed a two-year study. In the first year study, we will study the neomycin-induced CKD to evaluate the effects of CKD on atrial electrophysiology and calcium regulations. In the second year study, we will investigate whether and how the heat shock protein can reduce the arrhythmogenesis in CKD. Methods: In the first year study, high density mapping, convention electrodes, western blot analysis, patch clamp and iodo-1 fluoresce were used to study the conduction properties, action potential, ion channel proteins, ionic currents and calcium image in neomycin (100 mg/kg/day, intraperitoneum)-induced CKD rabbit with and without intraperitoneal injection of Indoxyl sulfate (100 mg/kg/day, intraperitoneum). In the second year, high density mapping, convention electrodes, western blot analysis, patch clamp and iodo-1 fluoresce were used to study the conduction properties, action potential, ion channel proteins, ionic currents and calcium image in neomycin (100 mg/kg/day, intraperitoneum)-induced CKD rabbit with and without heat shock protein induction from Geranylgeranylacetone (GGA) (120 mg/kg/day, oral).