Department of Bioengineering, Medicine, University of Pittsburgh Medical Center Heart and Vascular Institute, and Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Circ Res. 2013 Jul 19;113(3):313-21. doi: 10.1161/CIRCRESAHA.113.301646. Epub 2013 Jun 7.
Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy.
To evaluate the efficacy of the antifibrotic hormone relaxin (RLX) in suppressing AF in spontaneously hypertensive rats (SHR).
Normotensive Wistar-Kyoto (WKY) and SHR were treated for 2 weeks with vehicle (WKY+V and SHR+V) or RLX (0.4 mg/kg per day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations, intracellular Ca²⁺ transients, and restitution kinetics, and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV; P<0.01 versus WKY), steeper CV restitution kinetics, greater collagen deposition, higher levels of transcripts for transforming growth factor-β, metalloproteinase-2, metalloproteinase-9, collagen I/III, and reduced connexin 43 phosphorylation (P<0.05 versus WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5) and SHR+V (n=4/4), but not in WKY (n=0/5) and SHR+RLX (n=1/8; P<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV restitution kinetics, reduced action potential duration at 90% recovery to baseline, increased CV (P<0.01), and reversed atrial hypertrophy (P<0.05). Independent of antifibrotic actions, RLX (0.1 µmol/L) increased Na⁺ current density, INa (≈2-fold in 48 hours) in human cardiomyocytes derived from inducible pluripotent stem cells (n=18/18; P<0.01).
RLX treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and by increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis and hypertrophy and by modulating cardiac ionic currents.
心房颤动（AF）会显著增加老年和高血压患者的发病率和死亡率，并与增强的心房纤维化相关。尽管缺乏纤维化导致 AF 的直接证据，但逆转纤维化被认为是一种合理的治疗方法。
评估抗纤维化激素松弛素（RLX）抑制自发性高血压大鼠（SHR）中 AF 的疗效。
使用植入式微型泵，用载体（WKY+V 和 SHR+V）或 RLX（每天 0.4mg/kg，SHR+RLX）对正常血压的 Wistar-Kyoto（WKY）和 SHR 进行 2 周的治疗。对心脏进行灌流，通过光学映射分析动作电位持续时间、细胞内 Ca²⁺瞬变和恢复动力学，并测试 AF 易感性。SHR 心脏的传导速度（CV）较慢（P<0.01 与 WKY 相比），CV 恢复动力学更陡峭，胶原沉积更多，转化生长因子-β、金属蛋白酶-2、金属蛋白酶-9、胶原 I/III 的转录水平更高，连接蛋白 43 磷酸化水平降低（P<0.05 与 WKY 相比）。程控刺激在 SHR（n=5/5）和 SHR+V（n=4/4）中引发持续性 AF，但在 WKY（n=0/5）和 SHR+RLX（n=1/8；P<0.01）中未引发。RLX 治疗逆转了纤维化的转录物，使 CV 恢复动力学变平，将 90%恢复时的动作电位持续时间降低到基线，增加了 CV（P<0.01），并逆转了心房肥厚（P<0.05）。RLX（0.1µmol/L）在源自诱导多能干细胞的人心肌细胞中增加 Na⁺电流密度 INa（在 48 小时内增加约 2 倍，n=18/18；P<0.01），独立于抗纤维化作用。
RLX 通过逆转纤维化和肥厚以及增加 INa 来增加 CV，从而抑制 SHR 心脏中的 AF。该研究提供了令人信服的证据，表明 RLX 可能通过逆转纤维化和肥厚以及调节心脏离子电流，为人类 AF 的管理提供一种新的治疗方法。
