Key result
EPAC1 inhibition reverses AF susceptibility in HF mice by modulating L-type calcium channels.
Why the study?
AF and HF frequently coexist with complex structural and neurohormonal interactions, but the underlying molecular mechanisms remain unclear.
Does EPAC1 inhibition with CE3F4 reduce atrial fibrillation susceptibility in an isoproterenol-induced heart failure model?
Does EPAC1 inhibition with CE3F4 reduce atrial fibrillation susceptibility in an isoproterenol-induced heart failure model?
EPAC1 inhibition reduces atrial fibrillation susceptibility in a heart failure model by modulating L-type calcium channels, suggesting a potential therapeutic target.
May identify novel AF-HF molecular targets in animals; leaves open human translation and clinical relevance.
OBJECTIVE: Both atrial fibrillation (AF) and heart failure (HF) are increasingly prevalent and related to high hospitalization rate and mortality. AF is a cause as well as a consequence of HF, with complicated interactions resulting in impairment of cardiac systolic and diastolic function. Conversely, the complex structural and neurohormonal alterations in HF contribute to the occurrence and development of AF. However, the molecular mechanism remains unclear. This study aims to explore the effect of Exchange-protein activated by cAMP 1 (EPAC1) on AF in isoproterenol (ISO)-induced HF and the potential molecular mechanism. MATERIALS AND METHODS: Mice and cultured isolated adult cardiomyocytes were treated with ISO and or not EPAC1 inhibitor CE3F4. Programmed electrical stimulation (PES) was performed to induce AF. EPAC1 expression was determined by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Western blot. Cellular electrophysiology was examined by whole cell patch clamp. RESULTS: Both mRNA and protein levels of EPAC1 were upregulated in HF mice. ISO increased the AF susceptibility, and the negative effect was deteriorated by CE3F4. ISO mediated high AF susceptibility of HF via prolonging action potential and exciting L-type calcium channel (LTCC). These could also be reversed by CE3F4 treatment. CONCLUSIONS: EPAC1 increased the AF susceptibility in ISO-induced HF mouse model via alternating LTCC.
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Mx et al. (2019) studied Atrial fibrillation and heart failure. EPAC1 inhibitor CE3F4 vs. Isoproterenol alone (no CE3F4) was evaluated on Atrial fibrillation susceptibility and cellular electrophysiology (action potential and L-type calcium channel excitation). EPAC1 inhibition with CE3F4 reversed isoproterenol-induced high atrial fibrillation susceptibility in a heart failure mouse model by modulating L-type calcium channels.
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