Role of the extracellular matrix in myocardial remodeling441Late blockade of the Wnt/frizzled signaling prevents further left ventricular dilatation following myocardial infarction

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Abstract

Purpose

Current pharmacotherapy can not stop the left ventricular (LV) dilatation that occurs after myocardial infarction (MI), although this would be highly clinically relevant. We showed previously that blocking of Wnt/frizzled signaling immediately after MI attenuates LV dilatation, but whether this intervention can also stop the progressive dilatation of an already dilated LV is the subject of the present study.

Methods

Twenty three Swiss mice were subjected to MI by occlusion of the LAD. At 2 weeks post-MI, administration of the frizzled antagonist UM206 (Alzet osmotic minipump, 6μg/kg/day) was started until sacrifice at 5 weeks post-MI (late treatment). The results were compared with saline-treated animals that were sacrificed at 2 (n=8) and 5 (n=23) weeks post-MI.

Results

The progressive increase of end-diastolic volume could effectively be stopped by UM206 treatment starting at week 3 after MI. This was accompanied by a doubling of the myofibroblast content of the infarct area. Ejection Fraction (EF) and dP/dt increased significantly in the late UM206 treatment group compared to saline.

Conclusions

Late Wnt/frizzled blocking after MI stops further LV dilatation, resulting in improved cardiac function. This may be explained by the increased myofibroblast numbers in the infarct area, as the contractile properties of these cells are likely to reduce dilatation of the infarct.

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