Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Hypertension. 2012 May;59(5):949-57. doi: 10.1161/HYPERTENSIONAHA.111.183913. Epub 2012 Apr 9.
To investigate whether heart rate reduction via I(f)-channel blockade and β-receptor blockade prevents left ventricular (LV) dysfunction, we studied ivabradine and metoprolol in angiotensin II-induced heart failure. Cardiac dysfunction in C57BL/6J mice was induced by implantation of osmotic pumps for continuous subcutaneous dosing of angiotensin II (1.8 mg/kg per day SC) over a period of 3 weeks. Ivabradine (10 mg/kg per day) and metoprolol (90 mg/kg per day), which resulted in similar heart rate reduction, or placebo treatments were simultaneously started with infusion of angiotensin II. After 3 weeks, LV function was estimated by conductance catheter technique, cardiac remodeling assessed by estimation of cardiac hypertrophy, fibrosis, and inflammatory stress response by immunohistochemistry or PCR, respectively. Compared with controls, angiotensin II infusion resulted in hypertension in impaired systolic (LV contractility, stroke volume, end systolic elastance, afterload, index of arterial-ventricular coupling, and cardiac output; P<0.05) and diastolic (LV relaxation, LV end diastolic pressure, τ, and stiffness constant β; P<0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased cardiac stress was also indicated by an increase in cardiac inflammation and apoptosis. Both ivabradine and metoprolol led to a similar reduction in heart rate. Metoprolol also reduced systolic blood pressure. Ivabradine led to a significant improvement in systolic and diastolic LV function (P<0.05). This was associated with less cardiac hypertrophy, fibrosis, inflammation, and cardiac apoptosis (P<0.05). Metoprolol treatment did not prevent the reduction in cardiac function and adverse remodeling, despite a reduction of the inflammatory stress response. Behind heart rate reduction, additional beneficial cardiac effects contribute to heart failure prevention with I(f)-channel inhibition.
为了研究通过 I(f)通道阻滞和β受体阻滞来降低心率是否能预防左心室（LV）功能障碍，我们在血管紧张素 II 诱导的心力衰竭中研究了伊伐布雷定和美托洛尔。通过在 3 周内持续皮下注射血管紧张素 II（1.8mg/kg/天），在 C57BL/6J 小鼠中诱导心脏功能障碍。伊伐布雷定（10mg/kg/天）和美托洛尔（90mg/kg/天），这两种药物都导致了相似的心率降低，或安慰剂治疗同时开始与血管紧张素 II 输注。3 周后，通过心导管技术评估 LV 功能，通过免疫组化或 PCR 分别评估心脏肥大、纤维化和炎症应激反应来评估心脏重构。与对照组相比，血管紧张素 II 输注导致收缩功能受损的高血压（LV 收缩性、每搏量、收缩末期弹性、后负荷、动静脉耦联指数和心输出量；P<0.05）和舒张功能受损（LV 舒张功能、LV 舒张末期压力、τ 和僵硬常数β；P<0.05）。这与心脏肥大和纤维化的显著增加有关。心脏应激的增加也表明心脏炎症和细胞凋亡的增加。伊伐布雷定和美托洛尔都导致心率的相似降低。美托洛尔还降低了收缩压。伊伐布雷定导致收缩和舒张 LV 功能的显著改善（P<0.05）。这与心脏肥大、纤维化、炎症和心脏凋亡减少有关（P<0.05）。尽管炎症应激反应减少，但美托洛尔治疗并不能预防心脏功能障碍和不良重构。在心率降低的背后，I(f)通道抑制的额外有益的心脏作用有助于预防心力衰竭。
