Abstract
BackgroundHypercholesterolemia 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.MethodsLeft 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.ResultsIntrinsic 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.ConclusionDiet-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.
Highlights
Hypercholesterolemia plays an important role in the occurrence of atherosclerosis [1] and is a major risk factor for ischemic heart disease [2]
Intrinsic left ventricular (LV) function eight weeks after myocardial infarction (MI)-R was significantly impaired in HC-MI compared to NC-MI mice as assessed by end-systolic pressure, dP/dtMAX, and -dP/dtMIN
Diet-induced hypercholesterolemia caused impaired LV function eight weeks after myocardial ischemia-reperfusion (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
Summary
Hypercholesterolemia plays an important role in the occurrence of atherosclerosis [1] and is a major risk factor for ischemic heart disease [2]. Experimental MI studies have reported controversial findings regarding the effect of dietinduced hypercholesterolemia on cardiac function following myocardial-ischemia reperfusion (MI-R). Prolonged exposure to diet-induced hypercholesterolemia, during up to 20 weeks, followed by MI-R injury with reperfusion periods up to 24 hours showed a reduced hemodynamic performance [9] and a negative inotropic effect in animals [10]. Hypercholesterolemia is a major risk factor for ischemic heart disease including acute myocardial infarction. 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
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