Institute of Experimental Cardiology, Heidelberg University, Heidelberg and DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany.
Department of General Internal Medicine and Psychosomatics, University of Heidelberg, Heidelberg, Germany.
Basic Res Cardiol. 2022 Sep 6;117(1):44. doi: 10.1007/s00395-022-00951-6.
Myocardial infarction (MI) with subsequent depression is associated with increased cardiac mortality. Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR/GR signaling is causative for a poor outcome after MI in mice. Mice with an inducible forebrain-specific MR/GR knockout (MR/GR-KO) underwent baseline and follow-up echocardiography every 2 weeks after MI or sham operation. Behavioral testing at 4 weeks confirmed significant depressive-like behavior and, strikingly, a higher mortality after MI, while cardiac function and myocardial damage remained unaffected. Telemetry revealed cardiac autonomic imbalance with marked bradycardia and ventricular tachycardia (VT) upon MI in MR/GR-KO. Mechanistically, we found a higher responsiveness to atropine, pointing to impaired parasympathetic tone of 'depressive' mice after MI. Serum corticosterone levels were increased but-in line with the higher vagal tone-plasma and cardiac catecholamines were decreased. MR/GR deficiency in the forebrain led to significant depressive-like behavior and a higher mortality after MI. This was accompanied by increased vagal tone, depleted catecholaminergic compensatory capacity and VTs. Thus, limbic MR/GR disequilibrium may contribute to the impaired outcome of depressive patients after MI and possibly explain the lack of anti-depressive treatment benefit.
心肌梗死（MI）后继发抑郁与心脏死亡率增加有关。中枢矿物质皮质激素（MR）和糖皮质激素受体（GR）平衡受损被认为是人类抑郁症发病机制中的关键机制。在这里，我们研究了中枢 MR/GR 信号传导缺陷是否是 MI 后小鼠预后不良的原因。具有可诱导的大脑特异性 MR/GR 敲除（MR/GR-KO）的小鼠在 MI 或假手术后每 2 周进行基线和随访超声心动图检查。4 周时的行为测试证实了明显的抑郁样行为，令人惊讶的是，MI 后的死亡率更高，而心脏功能和心肌损伤仍未受影响。遥测显示，在 MI 后，心脏自主神经失衡导致明显的心动过缓和室性心动过速（VT）。在机制上，我们发现对阿托品的反应性更高，表明 MI 后“抑郁”小鼠的副交感神经张力受损。血清皮质酮水平升高，但与较高的迷走神经张力一致，血浆和心脏儿茶酚胺水平降低。大脑前脑的 MR/GR 缺乏导致 MI 后出现明显的抑郁样行为和更高的死亡率。这伴随着迷走神经张力增加、儿茶酚胺能代偿能力耗尽和 VT。因此，边缘 MR/GR 失衡可能导致抑郁患者 MI 后预后不良，并可能解释抗抑郁治疗益处缺乏的原因。
