Taufiq Fikri, Li Peili, Miake Junichiro, Hisatome Ichiro
Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science Yonago Japan.
Department of Physiology, Faculty of Medicine Sultan Agung Islamic University Semarang Indonesia.
Circ Rep. 2019 Nov 1;1(11):469-473. doi: 10.1253/circrep.CR-19-0088.
Among the several independent risk factors for atrial fibrillation (AF), hyperuricemia has been widely accepted as associated with the incidence of paroxysmal or persistent AF, as well as with the risk of AF in patients undergoing cardiovascular surgery. The electrophysiological mechanism of AF involves electrical remodeling of the arrhythmogenic substrate and abnormal automaticity as trigger. Both electrical and structural remodeling mediated by oxidative stress derived from either xanthine oxidoreductase (XOR), soluble uric acid (UA) or monosodium urate (MSU) crystals might be plausible explanations for the association of AF with hyperuricemia. XOR generates reactive oxygen species (ROS) that lead to atrial structural remodeling via inflammation. Soluble UA accumulates intracellularly through UA transporters (UAT), shortening the atrial action potential via enhanced expression and activity of Kv1.5 channel proteins. Intracellular accumulation of soluble UA generates ROS in atrial myocytes via nicotinamide adenine dinucleotide phosphate oxidase, which phosphorylates ERK/Akt and heat shock factor 1 (HSF1), thereby increasing transcription and translation of Hsp70, which stabilizes Kv1.5. In macrophages, MSU activates the NLRP3 inflammasome and proteolytic processing mediated by caspase-1 with enhanced interleukin (IL)-1β and IL-18 secretion. Use of an XOR inhibitor, antioxidants, a UAT inhibitor such as a uricosuric agent, and an NLRP3 inflammasome inhibitor, might become a potential strategy to reduce the risk of hyperuricemia-induced AF, and control serum UA level.
在心房颤动（AF）的多种独立危险因素中，高尿酸血症已被广泛认为与阵发性或持续性AF的发生率相关，也与心血管手术患者发生AF的风险相关。AF的电生理机制涉及致心律失常基质的电重构和作为触发因素的异常自律性。由黄嘌呤氧化还原酶（XOR）、可溶性尿酸（UA）或尿酸钠（MSU）晶体产生的氧化应激介导的电和结构重构，可能是AF与高尿酸血症之间关联的合理原因。XOR产生活性氧（ROS），通过炎症导致心房结构重构。可溶性UA通过UA转运体（UAT）在细胞内蓄积，通过增强Kv1.5通道蛋白的表达和活性缩短心房动作电位。可溶性UA在细胞内的蓄积通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶在心房肌细胞中产生活性氧，该酶使ERK/Akt和热休克因子1（HSF1）磷酸化，从而增加Hsp70的转录和翻译，Hsp70可稳定Kv1.5。在巨噬细胞中，MSU激活NLRP3炎性小体，并通过半胱天冬酶-1介导的蛋白水解过程增强白细胞介素（IL）-1β和IL-18的分泌。使用XOR抑制剂、抗氧化剂、UAT抑制剂（如促尿酸排泄剂）和NLRP3炎性小体抑制剂，可能成为降低高尿酸血症诱导的AF风险和控制血清UA水平的潜在策略。
