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Atrial Fibrillation Burden Specifically Determines Human Ventricular Cellular Remodeling
Thomas Körtl1, Thea Stehle1, Dominic Riedl1
1Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.
Insights
Atrial fibrillation (AF) burden over 50% significantly impairs heart function at the cellular level, mirroring clinical findings in heart failure patients. This research explains why reducing AF burden is crucial for improving cardiac health.
Area of Science:
- Cardiology
- Biomedical Engineering
- Stem Cell Biology
Background:
- Atrial fibrillation (AF) is linked to left ventricular systolic dysfunction.
- The CASTLE-AF trial indicated benefits for AF burden <50% post-ablation in patients with LV dysfunction.
Purpose of the Study:
- To investigate the cellular mechanisms behind AF burden's impact on ventricular function.
- To provide a "back-to-bench" explanation for CASTLE-AF trial findings.
Main Methods:
- Human ventricular induced pluripotent stem cell-derived cardiomyocytes were used for in vitro AF simulation.
- Techniques included epifluorescence microscopy, action potential, and sarcomere regularity measurements.
Main Results:
- High AF burden (≥60%) induced heart failure hallmarks in cardiomyocytes.
- Reduced Ca2+ transient amplitude and prolonged action potential duration were observed.
- Decreased sarcomere regularity correlated with impaired contractility, worsening over 7 days.
Conclusions:
- Cellular damage thresholds align with the CASTLE-AF trial's ~50% AF burden finding.
- These results elucidate the cellular basis for AF burden's detrimental effects on the left ventricle.
Background:
Atrial fibrillation (AF) can either be a consequence or an underlying mechanism of left ventricular systolic dysfunction. Patients included in the CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF) trial who suffered from AF and left ventricular systolic dysfunction benefited from an AF burden <50% after catheter ablation compared with those patients with an AF burden >50%.
Objectives:
This analysis tried to explain the clinical findings of the CASTLE-AF trial regarding AF burden in a "back-to-bench" approach.
Methods:
To study the ventricular effects of different AF burdens, experiments were performed using human ventricular induced pluripotent stem cell-derived cardiomyocytes undergoing in vitro AF simulation. Epifluorescence microscopy, action potential measurements, and measurements of sarcomere regularity were conducted.
Results:
Induced pluripotent stem cell-derived cardiomyocytes stimulated with AF burden of 60% or higher displayed typical hallmarks of heart failure. Ca2+ transient amplitude was significantly reduced indicating negative inotropic effects. Action potential duration was significantly prolonged, which represents a potential trigger for arrhythmias. A significant decrease of sarcomere regularity could explain impaired cardiac contractility in patients with high AF burden. These effects were more pronounced after 7 days of AF simulation compared with 48 hours.
Conclusions:
Significant functional and structural alterations occurred at the cellular level at a threshold of ∼50% AF burden as it was observed to be harmful in the CASTLE-AF trial. Therefore, these translational results may help to understand the findings of the CASTLE-AF trial.
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