Atrial fibrillation is associated with atrial remodeling, in which connexin 43 (Cx43) and cell hypertrophy play important roles. In this study, apelin-13, an aliphatic peptide, was used to explore the protective effects of the adenosine monophosphate-activated protein kinase (AMPK)/mTOR signaling pathway on Cx43 expression and autophagy, using murine atrial HL-1 cells. The expression of Cx43, AMPK, B-type natriuretic peptide (BNP) and pathway-related proteins was detected by Western blot analysis. Cellular fluorescence imaging was used to visualize Cx43 distribution and the cytoskeleton. Our results showed that the Cx43 expression was significantly decreased in HL-1 cells treated with angiotensin II but increased in cells additionally treated with apelin-13. Meanwhile, apelin-13 decreased BNP expression and increased AMPK expression. However, the expression of Cx43 and LC3 increased by apelin-13 was inhibited by treatment with compound C, an AMPK inhibitor. In addition, rapamycin, an mTOR inhibitor, promoted the development of autophagy, further inhibited the protective effect on Cx43 expression and increased cell hypertrophy. Thus, apelin-13 enhances Cx43 expression and autophagy via the AMPK/mTOR signaling pathway, and serving as a potential therapeutic target for atrial fibrillation.

Biallelic variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to DEE52, a developmental and epileptic encephalopathy with a high risk of Sudden Unexpected Death in Epilepsy (SUDEP). DEE52 patients present clinically with Dravet syndrome or the more severe early infantile DEE. SCN1B is expressed in brain and heart in humans and in mice. Thus, we have proposed that, in addition to generalized seizures, cardiac arrhythmia may play a role in SUDEP. Mice with homozygous expression of the DEE52 variant Scn1b-c.265C>T, predicting p.R89C, have spontaneous and hyperthermia-induced generalized seizures and SUDEP. Here we conducted cardiac characterization of Scn1b-c.265C>T mice and studied induced pluripotent stem cell cardiomyocytes (iPSC-CMs) derived from two SCN1B-c.265C>T DEE52 patients. Scn1b^C89/C89 mouse CMs showed increased transient outward potassium current (Ito) density and heart sections revealed ventricular fibrosis. Scn1b^C89/C89 mice were susceptible to pacing-induced cardiac arrhythmias. Patient-derived iPSC-CMs with biallelic SCN1B-c.265C>T variant expression showed increased sodium current (I_Na), late I_NaL, and I_to current densities. We conclude that, while mouse and human cardiac AP waveforms have critical differences, increased Ito is common to both models of DEE52. Overall, our data suggest that electrical and structural substrates may lead to arrhythmias and contribute to SUDEP in DEE52.