Increasing gap junction coupling suppresses ibutilide-induced torsades de pointes.

Area of Science:

• Cardiovascular Pharmacology
• Electrophysiology
• Molecular Cardiology

Background:

• Drug-induced torsades de pointes (TdP) is a serious arrhythmia linked to increased transmural dispersion of repolarization (TDR).
• Gap junctions are crucial for regulating TDR and preventing arrhythmias like TdP, especially in conditions like Long QT syndrome.

Purpose of the Study:

• To investigate the effect of antiarrhythmic peptide 10 (AAP10), a gap junction enhancer, on ibutilide-induced TdP.
• To determine if AAP10 can mitigate TdP by modulating TDR and connexin 43 (Cx43) phosphorylation.

Main Methods:

• Utilized coronary-perfused rabbit ventricular wedge preparations to assess arrhythmia induction.
• Recorded transmural electrocardiograms and action potentials to evaluate TdP, early afterdepolarizations (EADs), and Tpeak-end (Tp-e) to QT ratio (Tp-e/QT).
• Measured non-phosphorylated connexin 43 (Cx43) levels via immunoblotting.

Main Results:

• Ibutilide administration, particularly under hypokalemia and hypomagnesemia, increased QT interval, Tp-e/QT, EADs, and TdP incidence, correlating with increased Cx43 dephosphorylation.
• Co-administration of AAP10 significantly reduced EADs and TdP incidence, lowered Tp-e/QT ratio, and decreased non-phosphorylated Cx43 levels.
• These effects suggest AAP10 mitigated TdP by reducing TDR, likely through preventing Cx43 dephosphorylation and enhancing gap junction communication.

Conclusions:

• AAP10 effectively suppresses ibutilide-induced TdP in a relevant preclinical model, even under conditions mimicking electrolyte imbalances.
• The mechanism involves reducing TDR by enhancing gap junction function, potentially via modulation of Cx43 phosphorylation.
• AAP10 represents a potential therapeutic strategy for preventing drug-induced arrhythmias associated with altered repolarization and gap junction function.