Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na⁺ channels

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• 作者：Brian L. Henry ; MD ; PhD^* ; Beth Gabris^* ; Qiao Li^* ; Brian Martin^&dagger ; ; Marianna Giannini^* ; Ashish Parikh ; PhD^&dagger ; ; Divyang Patel ; MD^* ; Jamie Haney ; PhD^&dagger ; ; David S. Schwartzman ; MD ; FHRS^* ; Sanjeev G. Shroff ; PhD^&dagger ; ; Guy Salama ; PhD ; FHRS^* ; ^&dagger ; ; ^{gsalama@pitt.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Atrial fibrillation ; Relaxin ; Fibrosis ; Sodium channel ; Aging
• 刊名：Heart Rhythm
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：13
• 期：4
• 页码：983-991
• 全文大小：4692 K

文摘

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.

Objective

To test the ability of relaxin to reverse age-dependent atrial fibrosis and suppress AF.

Methods

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 (I_Na) were measured by tissue immunofluorescence and whole-cell patch clamp technique.

Results

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 < .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 < .05) and decreased collagen I and III and TGF-β1 mRNA (P < .05). Voltage-clamp experiments demonstrated that relaxin treatment (100 nM for 2 days) increased atrial I_Na by 46% ± 4% (n = 12–13/group, P < .02).

Conclusion

Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing I_Na. These data provide compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents.