What is the clinical evidence from this study?

Study design: Other. Population: Myocardial ischemia-reperfusion injury (n=34). Intervention: Cholesterol-enriched diet vs. Normal chow diet. Primary outcome: Infarct size at 8 weeks (p=0.017).

June 14, 2019PLoS ONE17 citationsOpen Access

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

NPNiek J. Pluijmert MHMelina C. den Haan VZVanessa L. van Zuylen

Key Result

Diet-induced hypercholesterolemia impaired intrinsic left ventricular function eight weeks after myocardial ischemia-reperfusion injury in mice, despite paradoxically reducing infarct size from 22.2% to 12.7%.

Structured PICO

Does diet-induced hypercholesterolemia affect cardiac function, infarct size, and inflammation in APOE*3-Leiden mice following myocardial ischemia-reperfusion injury?

Population

34 female APOE*3-Leiden mice subjected to myocardial ischemia-reperfusion injury and followed for 8 weeks to assess the effects of hypercholesterolemia.

Intervention

Semisynthetic Western-type diet supplemented with 0.4% cholesterol (hypercholesterolemic diet) started 4 weeks prior to surgery and continued for 8 weeks post-MI-R.

Comparator

Normal chow diet (normocholesterolemic diet).

Outcome

Left ventricular (LV) dimensions and intrinsic function serially assessed using echocardiography and LV pressure-volume measurements at 8 weeks post-MI-R.surrogate

In a mouse model of ischemia-reperfusion, diet-induced hypercholesterolemia impaired long-term left ventricular function despite paradoxically reducing infarct size and myocardial inflammation.

Main Result

Absolute Event Rate: 12.7% vs 22.2%

p-value: p=0.017

Limitations

Animal model differs from the human situation due to the absence of coronary atherosclerosis resulting in plaque rupture and thrombus formation.
Only female mice were used in the experiment.
Absence of coronary atherosclerosis resulting in coronary plaque formation and lack of rupture followed by thrombus formation (differs from the human situation)

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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