Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models.

VILIP-1 was significantly upregulated in atrial tissues from AF patients and pacing-induced rat AF models.

• Upregulation was identified through integrated bulk RNA sequencing and single-cell transcriptomics from human AF patients and rodent AF models.
• Enhanced membrane localization of VILIP-1 was observed in cardiomyocytes in AF conditions.
• Both human AF patient samples and pacing-induced rat AF models showed consistent upregulation.

Atrial cardiomyocyte-specific overexpression of VILIP-1 led to pathological Ca2+ leakage and promoted delayed afterdepolarizations (DADs) and action potential duration (APD) alternans.

• VILIP-1 overexpression was achieved in an atrial cardiomyocyte-specific manner.
• Pathological Ca2+ leakage was observed following VILIP-1 overexpression.
• DADs and APD alternans were promoted, fostering AF substrate formation and increased arrhythmia susceptibility.
• These electrophysiological abnormalities were identified through electrophysiological profiling.

VILIP-1 augmented the surface abundance of sodium-calcium exchanger 1 (NCX-1) via a myristoylation-dependent trafficking mechanism.

• The mechanistic link between VILIP-1 and NCX-1 was identified as a myristoylation-dependent trafficking pathway.
• Increased NCX-1 surface expression disrupted Ca2+ handling and initiated AF.
• This mechanism represents a novel upstream modulator of atrial Ca2+ homeostasis.

Repaglinide and desloratadine, two FDA-approved drugs identified to target VILIP-1 or its myristoylation, attenuated AF susceptibility.

• Both drugs were identified pharmacologically as targeting VILIP-1 or its myristoylation process.
• The drugs reduced NCX-1 surface expression and restored intracellular Ca2+ homeostasis.
• Efficacy was validated in both human and rodent models.
• Both repaglinide and desloratadine are existing FDA-approved drugs, representing drug repurposing candidates.

VILIP-1 was newly identified as expressed in cardiomyocytes and has a role in modulating Ca2+ signaling relevant to AF.

• VILIP-1 was described as 'newly identified in cardiomyocytes' prior to this study.
• Its role in AF had been undefined before this investigation.
• The study establishes VILIP-1 as 'a critical upstream modulator of atrial Ca2+ homeostasis.'
• Integration of bulk RNA sequencing, single-cell transcriptomics, and electrophysiological profiling was used to identify VILIP-1 as a key mediator of Ca2+ dysregulation in AF.

VILIP-1 is established as a promising therapeutic target for AF based on findings validated in human and rodent models.

• The study collectively defines VILIP-1 as 'a critical upstream modulator of atrial Ca2+ homeostasis.'
• Therapeutic targeting of VILIP-1 and its myristoylation pathway was validated in both human and rodent models.
• The findings span from mechanistic discovery to pharmacological validation with existing approved drugs.