Indoxyl Sulfate, Chronic Kidney Disease and Heat Shock Protein Modulate the Atrial Electrophysiological Characteristics

Project: A - Government Institutionb - Ministry of Science and Technology

Description

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. Calcium dysregulation plays a critical role in the genesis of AF and PV or LA arrhythmogenesis. Therefore, CKD may enhance PV or LA arrhythmogenesis due to abnormal calcium regulation. Moreover, it is not clear whether different etiology of CKD may produce abnormal AF propensity. Uremic toxins contributes 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 inflammation, atherosclerosis and endothelial dysfunction, which have been shown to significantly contribute to the genesis of AF. Nevertheless, the effects of Indoxyl sulfate on atrial electrophysiology are not elucidated. 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. In the first year study, we will evaluate the effects of Indoxyl sulfate on atrial and PV electrophysiological characteristics and arrhythmogenesis. In the second year study, we will study the neomycin-induced CKD to evaluate the effects of CKD on atrial electrophysiology and calcium regulations. In the third year study, we will investigate whether and how the heat shock protein can reduce the arrhythmogenesis in CKD. Methods: In the first year study, convention electrodes, patch clamp and iodo-1 fluoresce were used to record action potential, ionic currents (fast and late sodium currents, L type calcium currents, and ultra-rapid potassium current, transient outward potassium current, slow conductance potassium currents and inward rectifier potassium current) and calcium image in rabbit LA and PV tissue preparations and isolated single cardiomycytes before and after Indoxyl sulfate (0.1 nM, 1nM, 10 nM and 100 nM). 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 intraperitoneal injection of Indoxyl sulfate (100 mg/kg/day, intraperitoneum). In the third 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). Preliminary results: Indoxyl sulfate (10nM and 100nM) increased burst beats in PVs, which may contribute to the occurrence of AF.
StatusFinished
Effective start/end date8/1/137/31/14