What is the clinical evidence from this study?

Study design: Other. Population: Myocardial infarction (n=54). Intervention: UM206 vs. Saline. Primary outcome: Survival at 5 weeks after myocardial infarction (p=<0.001).

September 20, 2011Circulation143 citationsOpen Access

Blocking of Frizzled Signaling With a Homologous Peptide Fragment of Wnt3a/Wnt5a Reduces Infarct Expansion and Prevents the Development of Heart Failure After Myocardial Infarction

Q: What are the key findings of this study?

Administration of the Frizzled antagonist UM206 for 5 weeks after myocardial infarction in mice completely prevented mortality, compared to 35% mortality in saline-treated mice.

HLHilde Laeremans THTilman M. Hackeng MZMarc A. M. J. van Zandvoort

Key Result

Administration of the Frizzled antagonist UM206 for 5 weeks after myocardial infarction in mice completely prevented mortality, compared to 35% mortality in saline-treated mice.

Structured PICO

Does UM206 (a Frizzled antagonist) reduce infarct expansion and prevent heart failure in a mouse model of myocardial infarction?

Population

Male Swiss mice (10-12 weeks of age) with induced myocardial infarction (n=18 per group for survival analysis).

Intervention

UM206 (Frizzled antagonist peptide) 6 µg/kg per day administered subcutaneously via osmotic minipump for up to 5 weeks, starting immediately or 2 weeks after myocardial infarction.

Comparator

Saline administered via osmotic minipump, or an inactive analog of UM206 (CNKASEAMACEL) at the same dosage.

Outcome

Infarct expansion, cardiac function (ejection fraction, end-diastolic volume, hemodynamics), and survival at 5 weeks post-myocardial infarction.surrogate

Blocking Frizzled signaling with the UM206 peptide reduces infarct expansion, preserves cardiac function, and prevents heart failure in a mouse model of myocardial infarction.

Main Result

Absolute Event Rate: 100% vs 65%

p-value: p=<0.001

Limitations

In vitro experiments used immortalized cardiac fibroblast cell line CFIT rather than primary cultures
In vitro experiments with HUVEC used untransfected cells
Cannot rule out an effect of UM206 on the inflammatory response after MI

Abstract

BACKGROUND: The molecular pathways that control the wound healing after myocardial infarction (MI) are not completely elucidated. One of these pathways is the Wnt/Frizzled pathway. In this study, we evaluated Frizzled as a novel therapeutic target for MI. These Frizzled proteins act as receptors for Wnt proteins and were previously shown to be expressed in the healing infarct. METHODS AND RESULTS: Wnt/Frizzled signaling has been studied for decades, but synthetic ligands that interfere with the interaction between Wnts and Frizzled have not been described to date. Here we report the selection of 3 peptides derived from regions of high homology between Wnt3a and Wnt5a that act as antagonists for Frizzled proteins. UM206, the peptide with the highest affinity, antagonized the effect of Wnt3a and Wnt5a in different in vitro assays. Administration of UM206 to mice for 5 weeks, starting immediately after the induction of MI, reduced infarct expansion and increased the numbers of capillaries and myofibroblasts in the infarct area. Moreover, heart failure development was inhibited by this therapy. CONCLUSIONS: Blocking of Frizzled signaling reduces infarct expansion and preserves cardiac function after MI. Our findings underscore the potential of Frizzled receptors as a target for pharmacotherapy of cardiac remodeling after MI.

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