Evaluation of cardiac arrhythmic risks using a rabbit model of left ventricular systolic dysfunction

Area of Science:

• Cardiology
• Pharmacology
• Preclinical Research

Background:

• Patients with heart disease are susceptible to drug-induced cardiac arrhythmias.
• Myocardial infarction (MI) and left ventricular systolic dysfunction (LVSD) increase this risk.
• Evaluating drug safety in at-risk populations is crucial.

Purpose of the Study:

• To establish a rabbit model of MI with LVSD for preclinical drug safety assessment.
• To investigate the pro-arrhythmic potential of flecainide in this model.
• To evaluate the predictive value of the iCEB biomarker for drug-induced arrhythmias.

Main Methods:

• Induction of MI and LVSD in New Zealand White rabbits via coronary artery ligation.
• Administration of escalating doses of flecainide or solvent.
• Continuous electrocardiogram (ECG) monitoring and calculation of the iCEB (QT/QRS ratio).

Main Results:

• Rabbits with MI and LVSD did not exhibit spontaneous arrhythmias.
• Flecainide administration induced ventricular arrhythmias in MI rabbits (2/5 moderate LVSD).
• A significant decrease in iCEB preceded arrhythmia onset; atrioventricular block and death occurred in some MI rabbits.

Conclusions:

• The developed rabbit model effectively simulates MI and LVSD, suitable for preclinical drug risk evaluation.
• Flecainide demonstrated pro-arrhythmic effects in this model, particularly in rabbits with LVSD.
• The iCEB biomarker shows potential for predicting flecainide-induced cardiac arrhythmias in at-risk models.