Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels.
Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels.
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DOI：
10.1016/j.hrthm.2015.12.030
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发表时间：
2016-04
期刊：
影响因子：
5.5
通讯作者：
Salama G
中科院分区：
文献类型：
--
作者：
Henry BL;Gabris B;Li Q;Martin B;Giannini M;Parikh A;Patel D;Haney J;Schwartzman DS;Shroff SG;Salama G
心房颤动（AF）是老年患者发病率和死亡率的重要因素，并与年龄依赖性心房纤维化增强相关。为了测试松弛素逆转年龄依赖性心房纤维化和抑制AF的能力，已经提出了心房纤维化的抑制作为治疗策略，以抑制AF。老年F-344大鼠（24个月大）进行治疗与皮下注射的车辆或松弛素（0.4毫克/公斤/天）2周。切除大鼠心脏，在Langendorff装置上灌注，并用电压和Ca 2+指示剂染料染色。光学标测和程控电刺激用于测试心律失常脆弱性和电生理特征的变化。采用组织免疫荧光和全细胞膜片钳技术检测蛋白表达和Na+电流密度（INa）的变化。在老年大鼠中，持续性AF容易由过早脉冲（n=7/8）诱导，松弛素治疗抑制了由过早脉冲或短阵起搏引起的持续性AF（n=1/6）（p<0.01）。松弛素显著增加心房动作电位传导速度，减少心房纤维化。松弛素治疗增加老年心房Nav1.5表达（n=6; 36±10%），降低总胶原和胶原I（n=5-6; 55-66±15%）（p<0.05），降低胶原I和III以及TGF-β1 mRNA（p<0.05）。电压钳实验表明，松弛素治疗（100 nM，持续2天）使心房INa增加46±4%（n=12-13/组，p<0.02）。松弛素通过减少心房纤维化和增加INa增加心房传导速度来抑制AF。这些数据提供了令人信服的证据，松弛素可作为一种有效的治疗方法，通过逆转纤维化和调节心脏离子电流来管理老年患者的AF。
Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. To test the ability of relaxin to reverse aged-dependent atrial fibrosis and suppress AF. Aged F-344 rats (24-months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2-weeks. Rat hearts were excised, perfused on a Langendorff apparatus and stained with voltage and Ca2+ indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na+-current density (INa) were measured by tissue immunofluorescence and whole-cell patch clamp technique. In aged rats, sustained AF was readily induced with a premature pulse (n=7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n=1/6) (p<0.01). Relaxin significantly increased atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin-treatment increased Nav1.5 expression (n=6; 36±10%) and decreased total collagen and collagen I (n=5–6; 55–66±15%) in aged atria (p<0.05) and decreased collagen I&III and TGF-β1 mRNA (p<0.05). Voltage-clamp experiments demonstrated that relaxin-treatment (100nM for 2 days) increased atrial INa by 46±4% (n=12–13/group, p<0.02). Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing INa. This data provides compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents.