CDR1as promotes arrhythmias in myocardial infarction via targeting the NAMPT-NAD⁺ pathway

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Acute myocardial infarction (AMI) frequently triggers cardiac ventricular arrhythmias, a leading cause of sudden cardiac death.
• Elevated serum levels of circular RNA CDR1as have been identified as a potential biomarker for AMI.
• The specific role of CDR1as in the development of post-infarct arrhythmias remains largely unknown.

Purpose of the Study:

• To investigate the functional role of CDR1as in ventricular arrhythmias following myocardial infarction (MI) in a mouse model.
• To elucidate the underlying molecular mechanisms by which CDR1as contributes to ischemic arrhythmias.

Main Methods:

• Myocardial infarction (MI) was induced in mice.
• CDR1as was knocked down using specific inhibitors.
• Cardiac electrophysiology was assessed using optical mapping to measure QRS and QTc intervals, conduction velocity, and repolarization dispersion.
• Cellular mechanisms involving NAD+ levels, mitochondrial function, and ion channel expression (NaV1.5, Kir6.2) were analyzed.
• NAMPT protein expression was evaluated.

Main Results:

• Knockdown of CDR1as significantly shortened prolonged QRS and QTc intervals and reduced susceptibility to ventricular arrhythmias.
• Optical mapping revealed that CDR1as inhibition improved conduction velocity and decreased repolarization dispersion, thereby reducing post-infarct arrhythmias.
• Mechanistically, CDR1as depletion of NAD+ led to mitochondrial dysfunction by directly targeting and repressing NAMPT expression.
• CDR1as aggravated the dysregulation of NaV1.5 and Kir6.2 channels, which was reversed by NAD+ replenishment.

Conclusions:

• CDR1as plays a critical role in promoting ventricular arrhythmias after myocardial infarction.
• The pro-arrhythmic effects of CDR1as are mediated through NAD+ depletion, mitochondrial dysfunction, and ion channel dysregulation.
• Targeting CDR1as with anti-CDR1as therapies presents a promising therapeutic strategy for managing ischemic arrhythmias.