Abstract 18704: Late Blockade of Wnt/frizzled Signaling Pathway with UM206 Halts Further Dilatation of the Left Ventricle Following Myocardial Infarction
Purpose: Current pharmacotherapy cannot stop left ventricular (LV) dilatation that occurs after myocardial infarction (MI). Recently we have shown that in the MI mouse model, LV dilatation can be prevented by pharmacological blockade of Wnt/frizzled signaling with UM206. In these studies UM206 treatment was started immediately after induction of MI. The subject of the current study was to investigate if similar beneficial effects could be obtained with UM206 when treatment was started 3 weeks after the MI induction, when adverse LV dilatation has become manifest.
Methods: Swiss male mice were subjected to MI by occlusion of the left anterior descending artery. At 3 weeks post-MI, UM206 administration (Alzet osmotic minipump, 6µg/kg/day) was initiated and animals were sacrificed at 8 weeks post-MI. The results were compared with vehicle (saline)-treated animals (treatment between weeks 3-8) that were also sacrificed at weeks 8 post-MI. Cardiac geometry and function parameters were obtained using 3D-echocardiography (Vevo 2100, Visualsonics, Toronto, Canada).
Results: UM206 late treatment had a beneficial effect on both End diastolic volume (EDV, saline: 278 ± 24 mm3, UM206: 202 ± 13 mm3; p<0.01) and End systolic volume (ESV, saline: 250 ± 27 mm3, UM206: 151 ± 15 mm3; p<0.01). Ejection Fraction (EF) was also improved in UM206-treated animals (saline: 11.0 ± 3.2 %, UM206: 23.2 ± 2.6 %; p<0.05), while increased lung weights (an indication of heart failure development) were found in the saline-treated animals only (saline: 319 ± 42 mg, UM206: 214 ± 6 mg, p<0.01).
Conclusion: In the MI mouse model, administration of UM206 starting at week 3 post-MI, halts further increases in EDV and ESV while preserving the EF, resulting in improved overall cardiac function and prevention of heart failure development. The results show that pharmacotherapy targeting the Wnt/frizzled signaling can be beneficial in preventing heart failure after MI, even after adverse LV remodeling has been initiated.
- © 2012 by American Heart Association, Inc.