Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
PLoS One. 2019 Jun 14;14(6):e0217582. doi: 10.1371/journal.pone.0217582. eCollection 2019.
Hypercholesterolemia is a major risk factor for ischemic heart disease including acute myocardial infarction. However, long-term effects of hypercholesterolemia in a rodent myocardial ischemia-reperfusion injury model are unknown. Therefore, the effects of diet-induced hypercholesterolemia on cardiac function and remodeling were investigated up to eight weeks after myocardial ischemia-reperfusion (MI-R) injury which was induced in either normocholesterolemic (NC-MI) or hypercholesterolemic (HC-MI) APOE*3-Leiden mice.
Left ventricular (LV) dimensions were serially assessed using parasternal long-axis echocardiography followed by LV pressure-volume measurements. Subsequently, infarct size and the inflammatory response were analyzed by histology and fluorescence-activated cell sorting (FACS) analysis.
Intrinsic LV function eight weeks after MI-R was significantly impaired in HC-MI compared to NC-MI mice as assessed by end-systolic pressure, dP/dtMAX, and -dP/dtMIN. Paradoxically, infarct size was significantly decreased in HC-MI compared to NC-MI mice, accompanied by an increased wall thickness. Hypercholesterolemia caused a pre-ischemic peripheral monocytosis, in particular of Ly-6Chi monocytes whereas accumulation of macrophages in the ischemic-reperfused myocardium of HC-MI mice was decreased.
Diet-induced hypercholesterolemia caused impaired LV function eight weeks after MI-R injury despite a reduced post-ischemic infarct size. This was preceded by a pre-ischemic peripheral monocytosis, while there was a suppressed accumulation of inflammatory cells in the ischemic-reperfused myocardium after eight weeks. This experimental model using hypercholesterolemic APOE*3-Leiden mice exposed to MI-R seems suitable to study novel cardioprotective therapies in a more clinically relevant animal model.
高胆固醇血症是缺血性心脏病（包括急性心肌梗死）的一个主要危险因素。然而，在啮齿动物心肌缺血再灌注损伤模型中，高胆固醇血症的长期影响尚不清楚。因此，本研究旨在探讨饮食诱导的高胆固醇血症对心肌缺血再灌注（MI-R）损伤后 8 周内心脏功能和重构的影响，该损伤在正常胆固醇血症（NC-MI）或高胆固醇血症（HC-MI）APOE*3-Leiden 小鼠中诱导。
使用胸骨旁长轴超声心动图连续评估左心室（LV）尺寸，然后进行 LV 压力-容积测量。随后，通过组织学和荧光激活细胞分选（FACS）分析分析梗死面积和炎症反应。
与 NC-MI 小鼠相比，HC-MI 小鼠在 MI-R 后 8 周时的固有 LV 功能明显受损，表现为收缩末期压力、dP/dtMAX 和-dP/dtMIN 降低。矛盾的是，与 NC-MI 小鼠相比，HC-MI 小鼠的梗死面积显著减小，同时伴有壁厚度增加。高胆固醇血症导致缺血前外周单核细胞增多，特别是 Ly-6Chi 单核细胞，而 HC-MI 小鼠缺血再灌注心肌中巨噬细胞的积累减少。
尽管缺血后梗死面积减小，但饮食诱导的高胆固醇血症导致 MI-R 损伤后 8 周时 LV 功能受损。这之前是缺血前外周单核细胞增多，而 8 周后缺血再灌注心肌中炎症细胞的积累受到抑制。该实验模型使用了高胆固醇血症 APOE*3-Leiden 小鼠和 MI-R，似乎适合在更具临床相关性的动物模型中研究新型心脏保护治疗方法。
