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Updated: May 1, 2026
Programmed Electrical Stimulation in Mice
Published on: May 27, 2010
Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study
Kerstin Trappe1, Dierk Thomas, Olympia Bikou
1Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Aims:
Atrial fibrillation (AF) is linked to cardiomyocyte apoptosis, leading to atrial remodelling and reduction in electrical conduction velocity. We hypothesized that genetic suppression of an apoptotic key enzyme, caspase 3, would prevent the development of persistent AF by reducing apoptosis which may serve as an arrhythmogenic substrate.
Methods And Results:
Atrial fibrillation was induced in domestic pigs by atrial burst pacing via an implanted cardiac pacemaker. Study animals were then assigned to receive either Ad-siRNA-Cas3 gene therapy to inactivate caspase 3 or green fluorescent protein (Ad-GFP) as a control. Adenoviruses were applied using a hybrid technique employing right and left atrial virus injection followed by epicardial electroporation to increase expression of plasmid DNA. In pigs treated with Ad-siRNA-Cas3, the onset of AF was suppressed or significantly delayed compared with controls (10.3 ± 1.2 days vs. 6.0 ± 1.6 days; P= 0.04). Electrical mapping revealed prolonged atrial conduction in the control group that was prevented by Ad-siRNA-Cas3 gene therapy. On the molecular level, Ad-siRNA-Cas3 application resulted in down-regulation of caspase 3 expression and suppression of apoptotic activity.
Conclusion:
Knockdown of caspase 3 by atrial Ad-siRNA-Cas3 gene transfer suppresses or delays the onset of persistent AF by reduction in apoptosis and prevention of intra-atrial conduction delay in a porcine model. These results highlight the significance of apoptosis in the pathophysiology of AF and demonstrate short-term efficacy of gene therapy for suppression of AF.
Insights
Genetic suppression of caspase 3 via gene therapy delayed the onset of atrial fibrillation (AF) in pigs. This approach reduced apoptosis and prevented conduction delays, highlighting gene therapy
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Gene Therapy
Background:
- Atrial fibrillation (AF) is associated with cardiomyocyte apoptosis, leading to atrial remodeling and impaired electrical conduction.
- Apoptosis, a key process in cell death, contributes to the arrhythmogenic substrate in AF.
Purpose of the Study:
- To investigate if genetic suppression of caspase 3, a key apoptotic enzyme, could prevent persistent AF.
- To determine if reducing apoptosis through gene therapy mitigates AF development and atrial conduction delays.
Main Methods:
- Atrial fibrillation was induced in pigs using atrial burst pacing.
- Gene therapy with Ad-siRNA-Cas3 (to inactivate caspase 3) or Ad-GFP (control) was administered via viral injection and electroporation.
- Electrical mapping and molecular analysis were used to assess AF onset, conduction velocity, and caspase 3 expression.
Main Results:
- Ad-siRNA-Cas3 treatment significantly delayed the onset of AF compared to controls (10.3 days vs. 6.0 days).
- Gene therapy prevented the prolonged atrial conduction observed in the control group.
- Caspase 3 expression and apoptotic activity were significantly reduced in the Ad-siRNA-Cas3 treated group.
Conclusions:
- Atrial gene transfer of Ad-siRNA-Cas3 effectively suppresses or delays persistent AF in a porcine model.
- Reduction in apoptosis and prevention of intra-atrial conduction delay are key mechanisms underlying AF suppression.
- These findings underscore the role of apoptosis in AF pathophysiology and demonstrate the potential of gene therapy for AF suppression.
