Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Anesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
Int J Cardiol. 2019 Apr 15;281:99-104. doi: 10.1016/j.ijcard.2018.12.045. Epub 2018 Dec 21.
Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that is not caused by coronary artery occlusion. Exogenous as well as endogenous excess catecholamines can induce TS. The aim of this study was to explore the effects of pharmacological cardio-simulative and cardio-depressing drugs on the development of isoprenaline-induced takotsubo-like cardiac dysfunction, a rat model of TS.
We randomized 295 rats into twelve groups. The animals were randomized to pre-treatment with either a low or high dose of metoprolol, propranolol, ICI 118551 (beta-receptor antagonists), milrinone (phosphodiesterase inhibitor), levosimendan or saline (control) before induction of TS with isoprenaline. In one additional group, high dose of milrinone was administered alone. We measured invasively blood pressure and heart rate over a period of 90 min. Cardiac function and morphology were evaluated with high-resolution echocardiography.
Milrinone alone induced apical ballooning similar to isoprenaline. Pretreatment with propranolol and metoprolol but not with ICI 118551 attenuated takotsubo-like akinesia in a dose-dependent manner. Pretreatment with metoprolol decreased mortality. Pretreatment with levosimendan resulted in higher incidence of apical ballooning while pretreatment with milrinone did not change the degree of akinesia.
The phosphodiesterase inhibitor milrinone induces takotsubo-like dysfunction in the absence of exogenous catecholamines. This finding challenges the concept that high levels of circulating catecholamines or excessive stimulation of adrenergic receptors are necessary for the development of takotsubo syndrome. Our study provides experimental evidence for the concept of avoidance of inotropes and that selective beta-blockade may be beneficial in the treatment of TS-patients.
Takotsubo 综合征（TS）是一种以区域性心肌运动障碍为特征的急性心脏综合征，并非由冠状动脉阻塞引起。外源性和内源性儿茶酚胺过多均可诱导 TS 的发生。本研究旨在探讨药理学心脏刺激和心脏抑制药物对异丙肾上腺素诱导的 Takotsubo 样心功能障碍（TS 的大鼠模型）发展的影响。
我们将 295 只大鼠随机分为十二组。动物随机接受低剂量或高剂量美托洛尔、普萘洛尔、ICI 118551（β受体拮抗剂）、米力农（磷酸二酯酶抑制剂）、左西孟旦或生理盐水（对照组）预处理，然后用异丙肾上腺素诱导 TS。在另外一组中，单独给予高剂量米力农。我们在 90 分钟内通过有创方法测量血压和心率。通过高分辨率超声心动图评估心功能和形态。
单独使用米力农可诱导出类似于异丙肾上腺素的心尖球囊样扩张。普萘洛尔和美托洛尔预处理而非 ICI 118551 预处理可剂量依赖性地减轻 Takotsubo 样运动障碍。美托洛尔预处理可降低死亡率。左西孟旦预处理可增加心尖球囊样扩张的发生率，而米力农预处理不会改变运动障碍的程度。
磷酸二酯酶抑制剂米力农在没有外源性儿茶酚胺的情况下可诱导出 Takotsubo 样功能障碍。这一发现对高水平循环儿茶酚胺或肾上腺素能受体过度刺激是 Takotsubo 综合征发展所必需的这一概念提出了挑战。本研究为避免使用正性肌力药物的概念以及选择性β受体阻滞剂可能有益于 TS 患者的治疗提供了实验证据。
