FHF2 SAFEGUARDS THE HEART AGAINST REDUCTIONS IN JUNCTIONAL CONDUCTANCE [Meeting Abstract]
Background: Deficits in myocardial conduction velocity (CV) are associated with ventricular arrhythmias and conduction block. Abnormal organization and expression of cardiac sodium channel NaV1.5 and gap junction protein Cx43, key determinants of myocardial CV, are known features of arrhythmogenic heart disease. We previously identified fibroblast growth factor homologous factor 2 (FHF2) as a modulator of CV through its effects on NaV1.5. The aim of this study was to investigate whether modulating junctional conductance synergizes with loss of FHF2 to create conduction reserve deficits and susceptibility for arrhythmias. Method(s): ECGs were acquired to characterize conduction intervals of 2-3 month old wildtype (WT), cardiomyocyte-specific Cx43 heterozygous (Cx43 cHet), FHF2 KO, and FHF2 KO/Cx43 cHet mice. ECGs were then acquired with increasing doses of a gap junction channel blocker, carbenoxolone (CBX). Result(s): WT, Cx43 cHet, and FHF2 KO mice had normal conduction while FHF2 KO/Cx43 cHet mice showed ventricular conduction slowing at baseline. FHF2 KO and FHF2 KO/Cx43 cHet mice showed ventricular conduction slowing with CBX in a dose dependent fashion. Lethal conduction slowing was observed in FHF2 KO/Cx43 cHet mice given 120mg/kg CBX. Conclusion(s): These results identify a key role for FHF2 in maintaining myocardial conduction reserve which protects against stressors that depress junctional conductance (aging, pharmacologic blockade, genetic deficiency) and subsequent arrhythmias. [Figure presented]2019 American College of Cardiology Foundation. All rights reserved
[4+2] Cycloadditions of Seven-Membered-Ring trans-Alkenes: Decreasing Reactivity with Increasing Substitution of the Seven-Membered Ring
The reactivity of trans-oxasilacycloheptenes in [4+2] cycloadditions depends on the substitution pattern on the seven-membered ring. Unhindered trans-alkenes undergo [4+2] cycloadditions with 1,3-diphenylisobenzofuran faster than the most reactive trans-cyclooctene. Increasing the substitution of the seven-membered ring or increasing the electron density of the trans-alkene decreases reactivity with 1,3-dienes in concerted cycloaddition reactions. Although highly substituted trans-alkenes are unreactive in concerted cycloaddition reactions, these alkenes react rapidly in stepwise reactions with diethyl azodicarboxylate (DEAD), an electrophilic diene.