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A ROS-Responsive Doxorubicin-Loaded Liposomal Strategy Reduces Postablation Electrical Conduction Recovery in a
Ying Zhuge1, Liping Yang2, Yulong Ge1
1Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200800, China.
Abstract:
Assessment of nanoplatform efficacy in reducing postablation electrical conduction recovery remains a major challenge in the development of controllable adjunctive therapies for radiofrequency catheter ablation (RFCA). Herein, we established a minimally invasive CARTO-guided canine model of right atrial postablation conduction recovery for mechanistic and pharmacodynamic evaluation. Here, a doxorubicin (DOX)-loaded and reactive oxygen species (ROS)-responsive liposome (DOX@rNP) was constructed to respond to high ROS levels, leading to the high local DOX concentration in the right atrium after ablation, which was 2.8-fold higher than that of the healthy group. Subsequently, released DOX induced apoptosis at the ablation site and modulated the Bax/Bcl-2 pathway, with associated effects on cleaved caspase-3, γ-H2AX, and fibrosis-related remodeling. CARTO-based voltage mapping and pacing assessment showed that DOX@rNP helped maintain postablation conduction block in both the short-term (30 days) and long-term (180 days). Additionally, in vivo electrocardiographic results showed that DOX@rNP treatment was associated with a lower observed electrical conduction recurrence rate than RFCA alone at 180 days (20.0% vs 80.0%), with a significant difference based on binary conduction-outcome analysis using a one-tailed Welch's t-test. This study establishes a large-animal model of postablation electrical conduction recovery and supports a ROS-responsive liposomal strategy for reinforcing ablation-site injury and suppressing lesion reconnection.
Insights
A novel nanoplatform effectively reduced electrical conduction recovery after radiofrequency catheter ablation (RFCA) in a canine model. This liposomal therapy enhanced ablation site injury, preventing lesion reconnection and improving long-term outcomes.
Area of Science:
- Biomedical Engineering
- Cardiovascular Research
- Nanomedicine
Background:
- Radiofrequency catheter ablation (RFCA) efficacy is challenged by postablation electrical conduction recovery.
- Developing controllable adjunctive therapies is crucial for improving RFCA outcomes.
- Current methods lack effective strategies to prevent lesion reconnection.
Purpose of the Study:
- To establish a large-animal model for evaluating nanoplatforms in preventing postablation conduction recovery.
- To assess the efficacy of a doxorubicin-loaded, ROS-responsive liposome (DOX@rNP) as an adjunctive therapy for RFCA.
- To investigate the mechanisms underlying DOX@rNP's effect on ablation site remodeling and conduction block.
Main Methods:
- A CARTO-guided canine model of right atrial postablation conduction recovery was established.
- Doxorubicin (DOX)-loaded, reactive oxygen species (ROS)-responsive liposomes (DOX@rNP) were developed.
- CARTO-based voltage mapping, pacing, and in vivo electrocardiography were used for assessment.
Main Results:
- DOX@rNP achieved a 2.8-fold higher local DOX concentration at the ablation site.
- DOX@rNP induced apoptosis, modulated the Bax/Bcl-2 pathway, and reduced fibrosis.
- DOX@rNP maintained conduction block short-term (30 days) and long-term (180 days).
- The electrical conduction recurrence rate was significantly lower with DOX@rNP (20.0%) compared to RFCA alone (80.0%) at 180 days.
Conclusions:
- A ROS-responsive liposomal strategy effectively reinforces ablation-site injury.
- DOX@rNP suppresses lesion reconnection, maintaining long-term conduction block after RFCA.
- This study supports the use of nanoplatforms as adjunctive therapies to improve RFCA efficacy.
