Research Article: Hypercholesterolemia affects cardiac function, infarct size and inflammation in APOE*3-Leiden mice following myocardial ischemia-reperfusion injury

Date Published: June 14, 2019

Publisher: Public Library of Science

Author(s): Niek J. Pluijmert, Melina C. den Haan, Vanessa L. van Zuylen, Paul Steendijk, Hetty C. de Boer, Anton J. van Zonneveld, Willem E. Fibbe, Martin J. Schalij, Paul H. A. Quax, Douwe E. Atsma, Vincenzo Lionetti.

http://doi.org/10.1371/journal.pone.0217582

Abstract

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.

Partial Text

Hypercholesterolemia plays an important role in the occurrence of atherosclerosis [1] and is a major risk factor for ischemic heart disease [2]. Several clinical studies demonstrated an adverse effect of hypercholesterolemia on coronary heart disease events and left ventricular (LV) systolic function after suffering a myocardial infarction (MI) [3,4] and reported positive effects of lipid lowering therapies [5,6].

A schematic overview of the complete study protocol shown as a timeline can be found as a supplemental figure online (S1 Fig).

Key findings of the present study are that diet-induced hypercholesterolemia in APOE*3-Leiden mice caused a pre-ischemic peripheral monocytosis, in particular of the Ly-6Chi pro-inflammatory monocytes, and impaired intrinsic LV function eight weeks after acute MI-R. Paradoxically, this was accompanied by a reduced infarct size and a suppressed accumulation of infiltrated inflammatory cells in the ischemic-reperfused myocardium after eight weeks. To our knowledge this study is the first to extend follow-up after MI-R to a period of eight weeks regarding the effects of hypercholesterolemia. Furthermore, 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 aiming for improved translation into the complex clinical reality of reperfused STEMI patients in the end as was also suggested in a recent ESC position paper [18].

 

Source:

http://doi.org/10.1371/journal.pone.0217582

 

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