Détrait Maximin, Gaucher Jonathan, Billoir Emma, Bouyon Sophie, Lemarié Emeline, Paradis Stéphanie, Vial Guillaume, Chuffart Florent, Pasqualin Côme, Hubert Fabien, Rochais Francesca, Doutreleau Stéphane, Pépin Jean-Louis, Godin-Ribuot Diane, Belaidi Elise, Arnaud Claire
Univ. Grenoble Alpes, Inserm, CHU Grenoble Alpes, HP2 Grenoble France.
Université Grenoble Alpes, INSERM U1209, CNRS UMR5309, IAB Grenoble France.
J Am Heart Assoc. 2025 Jun 3;14(11):e038781. doi: 10.1161/JAHA.124.038781. Epub 2025 May 23.
Ischemic cardiomyopathy with comorbid obstructive sleep apnea syndrome is associated with worse long-term outcomes. Intermittent hypoxia (IH), a key feature of obstructive sleep apnea, exacerbates sympathetic activity, hastening cardiac dysfunction and remodeling in ischemic cardiomyopathy rat models. This study explores whether targeted cardiac sympathetic denervation (CSD) can limit IH-induced progression of ischemic cardiomyopathy.
Male Wistar rats underwent CSD, through ablation of the left middle cervical and stellate ganglions, and simultaneously myocardial infarction, via permanent left coronary artery ligation. Three days post surgery, rats were exposed to IH (21%-5% fraction of inspired O, 60-second cycle, 8 hours/day) or normoxia. At 6 weeks, calcium transient, sarcomere shortening, and adrenergic reserve in response to isoproterenol (100 nmol/L) were assessed in isolated cardiomyocytes. At 14 weeks, sympathovagal balance, cardiac function, and remodeling were evaluated.
Post myocardial infarction, CSD prevented IH-induced blunting of cardiomyocyte response to isoproterenol challenge and reduced cardiac sympathetic activity. In hypoxic animals, CSD reduced post-myocardial infarction alterations in long-term ejection fraction and mitigated cardiomyocyte hypertrophy and apoptosis. Transcriptomic analysis unveiled that CSD triggered biological processes related to cardiac repair and regeneration. Immunohistochemistry further supported these findings, demonstrating increased cardiomyocyte proliferation in the hypoxic group, as indicated by elevated Ki67 expression colocalized with MF20 markers.
Our data demonstrate that CSD prevents IH-induced sympathetic hyperactivity, depletion of cardiac adrenergic reserve, and deterioration of cardiac function in a rat model of ischemic cardiomyopathy. This study highlights the intricate interplay between sympathetic activity and hypoxia in cardiac regeneration and underscores the importance of managing sympathetic hyperactivity in ischemic cardiomyopathy, particularly in the context of comorbid obstructive sleep apnea.
合并阻塞性睡眠呼吸暂停综合征的缺血性心肌病与更差的长期预后相关。间歇性缺氧（IH）是阻塞性睡眠呼吸暂停的一个关键特征，会加剧交感神经活动，加速缺血性心肌病大鼠模型中心脏功能障碍和重塑。本研究探讨靶向性心脏交感神经去支配术（CSD）是否能限制IH诱导的缺血性心肌病进展。
雄性Wistar大鼠通过切除左中颈神经节和星状神经节进行CSD，并通过永久性左冠状动脉结扎同时诱导心肌梗死。术后三天，将大鼠暴露于IH（吸入氧分数为21%-5%，60秒周期，每天8小时）或常氧环境。在6周时，评估分离的心肌细胞中钙瞬变、肌节缩短以及对异丙肾上腺素（100 nmol/L）的肾上腺素能储备。在14周时，评估交感迷走平衡、心脏功能和重塑情况。
心肌梗死后，CSD可防止IH诱导的心肌细胞对异丙肾上腺素刺激反应减弱，并降低心脏交感神经活动。在缺氧动物中，CSD减少了心肌梗死后长期射血分数的改变，并减轻了心肌细胞肥大和凋亡。转录组分析表明，CSD触发了与心脏修复和再生相关的生物学过程。免疫组织化学进一步支持了这些发现，显示缺氧组心肌细胞增殖增加，Ki67表达升高且与MF20标记物共定位。
我们的数据表明，在缺血性心肌病大鼠模型中，CSD可防止IH诱导的交感神经过度活跃、心脏肾上腺素能储备耗竭以及心脏功能恶化。本研究突出了交感神经活动与缺氧在心脏再生中的复杂相互作用，并强调了在缺血性心肌病中管理交感神经过度活跃的重要性，特别是在合并阻塞性睡眠呼吸暂停的情况下。
