Background-FrzA/sFRP-1, a secreted, frizzled-related protein and antagonist for the wnt/frizzled pathway, is expressed in the heart and vessels during mouse embryogenesis and adulthood. FrzA is involved in cell cycle control of vascular cells and angiogenesis. We assessed the hypothesis that FrzA could control the healing process after myocardial infarction (MI Early leukocyte infiltration had decreased in Tg mice during the first week. Apoptotic index was decreased by 50% in Tg mice at day 7. Matrix metalloproteinase-2 and -9 activity was reduced in Tg mice at day 4, and collagen deposition in the scar was increased in Tg mice. Capillary density in the scar was higher in Tg mice (290Ϯ103 vessels/mm 2 versus 104Ϯ43 in controls at day 15; PϽ0.001). Vessels were more muscularized, and mean lumen area was 3-fold higher in Tg animals. Conclusions-Overexpression

The FRANCE TAVI registry provided reassuring data regarding trends in TAVR performance in an all-comers population on a national scale. Nonetheless, given that TAVR indications are likely to expand to patients at lower surgical risk, concerns remain regarding potentially life-threatening complications and pacemaker implantation. (Registry of Aortic Valve Bioprostheses Established by Catheter [FRANCE TAVI]; NCT01777828).

These data usher in a new era of tissue-specific, ultrarapid ablation of atrial fibrillation.

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Background-Left ventricular assist devices (LVADs) are increasingly used as a bridge to cardiac transplantation or as destination therapy. Patients with LVADs are at high risk for ventricular arrhythmias. This study describes ventricular arrhythmia characteristics and ablation in patients implanted with a Heart Mate II device. Methods and Results-All patients with a Heart Mate II device who underwent ventricular arrhythmia catheter ablation at 9 tertiary centers were included. Thirty-four patients (30 male, age 58±10 years) underwent 39 ablation procedures. The underlying cardiomyopathy pathogenesis was ischemic in 21 and nonischemic in 13 patients with a mean left ventricular ejection fraction of 17%±5% before LVAD implantation. One hundred and ten ventricular tachycardias (VTs; cycle lengths, 230-740 ms, arrhythmic storm n=28) and 2 ventricular fibrillation triggers were targeted (25 transseptal, 14 retrograde aortic approaches). Nine patients required VT ablation <1 month after LVAD implantation because of intractable VT. Only 10/110 (9%) of the targeted VTs were related to the Heart Mate II cannula. During follow-up, 7 patients were transplanted and 10 died. Of the remaining 17 patients, 13 were arrhythmia-free at 25±15 months. In 1 patient with VT recurrence, change of turbine speed from 9400 to 9000 rpm extinguished VT. Conclusions-Catheter ablation of VT among LVAD recipients is feasible and reasonably safe even soon after LVAD implantation. Intrinsic myocardial scar, rather than the apical cannula, seems to be the dominant substrate.

Abstract-Phosphorylation and subsequent inactivation of glycogen synthase kinase (GSK)-3␤ via the Akt/PI3-Kinase pathway during ischemic preconditioning (PC) has been shown to be cardioprotective. As FrzA/sFRP-1, a secreted antagonist of the Wnt/Frizzled pathway, is expressed in the heart and is able to decrease the phosphorylation of GSK-3␤ in vitro on vascular cells, we examined its effect during PC using transgenic mouse overexpressing FrzA in cardiomyocytes (␣-MHC promoter) under a conditional transgene expression approach (tet-off system). Overexpression of FrzA inhibited the increase in GSK-3␤ phosphorylation as well as protein kinase C (PKC) epsilon activation in transgenic mice after PC as compared with littermates. Phospho-Akt (P-Akt), phospho-JNK, or the cytoplasmic ␤-catenin levels were not modified, phospho-p38 (P-p38) was slightly increased in transgenic mice after PC as compared with littermates. FrzA transgenic mice displayed a larger infarct size and a greater worsening of cardiac function compared with littermates. All these differences were reversed by the addition of doxycycline. This study demonstrates for the first time that disruption of a ␤-catenin independent Wnt/Frizzled pathway induces the activation of GSK-3␤ and reverses the benefit of preconditioning. Key Words: animal models of human disease Ⅲ cell signaling/signal transduction Ⅲ genetically-altered mice Ⅲ ischemia Ⅲ heart B rief episodes of ischemia/reperfusion, termed ischemic preconditioning (PC), protect the myocardium from the damage induced by subsequent and more prolonged ischemia. 1 PC has proved crucial in the protection of surviving cells, resulting in a reduction of infarct size, arrhythmias, and postischemic contractile dysfunction in all species tested so far. There is also evidence that it might be operative in man. 2,3 The different signaling pathways involved in PC result in protein kinase C (PKC) activation and in phosphatidylinositol-3-kinase (PI3-kinase) activation and translocation. 2,4 Downstream targets of PKC include the mitogen-activated protein kinase pathway, the activation of the mitochondrial ATPsensitive potassium channel, 5 and the modulation of energy and substrate metabolism. 6 Downstream targets of PI3-kinase in PC include the phosphorylation of the PKB/Akt pathway and the phosphorylation of glycogen synthase kinase-3␤ (GSK-3␤). 4 Phosphorylation at serine-9 residue (Ser9) and subsequent inactivation of GSK-3␤ has recently been demonstrated to play an important role in the protection and enhanced cell survival afforded by PC in the heart. 7 Multiple pathways other than the PI3-kinase-PKB/Akt-dependent pathway regulate the activity of GSK-3␤, eg, the Wnt signaling pathway. Wnt can inactivate GSK-3␤ through 2 distinct pathways. 8,9 In the Wnt canonical pathway, phosphorylation of GSK-3␤ (at a residue different from Ser9) results in increased ␤-catenin levels and its translocation to the nucleus. 10 Additionally, PKC could be involved in Wnt-induced GSK-3␤ inhibition by a phosphorylation at Ser9. [11][1...

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Objective-The inflammatory response after myocardial infarction plays a crucial role in the healing process. Lately, there is accumulating evidence that the Wnt/Frizzled pathway may play a distinct role in inflammation. We have shown that secreted frizzled-related protein-1 (sFRP-1) overexpression reduced postinfarction scar size, and we noticed a decrease in neutrophil infiltration in the ischemic tissue. We aimed to further elucidate the role of sFRP-1 in the postischemic inflammatory process. Methods and Results-We found that in vitro, sFRP-1 was able to block leukocyte activation and cytokine production. We transplanted bone marrow cells (BMCs) from transgenic mice overexpressing sFRP-1 into wild-type recipient mice and compared myocardial healing with that of mice transplanted with wild-type BMCs. These results were compared with those obtained in transgenic mice overexpressing sFRP-1 specifically in endothelial cells or in cardiomyocytes to better understand the spatiotemporal mechanism of the sFRP-1 effect. Our findings indicate that when overexpressed in the BMCs, but not in endothelial cells or cardiomyocytes, sFRP-1 was able to reduce neutrophil infiltration after ischemia, by switching the balance of pro-and antiinflammatory cytokine expression, leading to a reduction in scar formation and better cardiac hemodynamic parameters. Conclusion-sFRP-1 impaired the loop of cytokine amplification and decreased neutrophil activation and recruitment into the scar, without altering the neutrophil properties. These data support the notion that sFRP-1 may be a novel antiinflammatory factor protecting the heart from damage after myocardial infarction. (Arterioscler Thromb Vasc Biol. 2011;31:e80-e87.)