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Sequence-Dependent Repolarization Is Modulated by Endogenous Action Potential Duration Gradients Rather Than
Grace A Blair1,2, Madeline Depman1,2, William P Adams2
1Graduate Program in Translational Biology Medicine and Health, Virginia Tech Roanoke VA USA.
Insights
Electrical coupling does not significantly impact action potential duration (APD) heterogeneity. Instead, endogenous gradients and stimulus artifacts are the primary drivers of APD variability in cardiac tissue.
Area of Science:
- Cardiac Electrophysiology
- Computational Biology
- Pharmacology
Background:
- Previous research suggests electrotonic coupling influences the relationship between activation time (AT) and action potential duration (APD).
- However, direct experimental evidence testing this hypothesis and its impact on APD heterogeneity is lacking.
Purpose of the Study:
- To investigate whether acute alterations in electrical coupling affect APD heterogeneity.
- To determine the influence of other factors, such as conduction and repolarization dynamics, on APD heterogeneity.
Main Methods:
- Langendorff-perfused guinea pig hearts were optically mapped after epicardial pacing.
- Hearts were treated with agents affecting gap junction (carbenoxolone), ephaptic coupling (mannitol, dextran), sodium channels (flecainide), or potassium channels (E4031).
- Metrics quantifying APD heterogeneity included standard deviation of APD and the AT-APD relationship.
Main Results:
- Standard deviation of APD increased with carbenoxolone, mannitol, and altered activation sequences.
- The AT-APD slope was largely insensitive to pharmacological interventions but varied with activation sequence.
- APD heterogeneity measurements were influenced by the chosen metric, stimulus artifacts, and endogenous APD gradients, with simulations suggesting the latter are stronger determinants than AT.
Conclusions:
- The dependence of APD on conduction is minimal.
- APD heterogeneity is primarily determined by endogenous gradients and stimulus artifacts, not electrical coupling.
- Experimental approaches and inherent tissue properties play a more significant role in observed APD heterogeneity than direct electrical coupling modulation.
Background:
Previous studies suggest the relationship between activation time (AT) and action potential duration (APD) in the heart is dependent on electrotonic coupling, but this has not been directly tested. This study assessed whether acute changes in electrical coupling, or other determinants of conduction or repolarization, modulate APD heterogeneity.
Methods And Results:
Langendorff-perfused guinea pig hearts were epicardially paced and optically mapped after treatment with the gap junction uncoupler carbenoxolone, ephaptic uncoupler mannitol, ephaptic enhancer dextran 2MDa, sodium channel inhibitor flecainide, or rapid component of the delayed rectifier potassium channel inhibitor E4031. SD of APD and the AT-APD slope and coefficient of determination were quantified as metrics of APD heterogeneity. SD of APD increased with carbenoxolone, mannitol, and altered activation sequence. The AT-APD slope was insensitive to carbenoxolone, mannitol, dextran, flecainide, or E4031 but changed in response to activation sequence. The coefficient of determination did not change with carbenoxolone; decreased with mannitol, E4031, and activation sequence; but increased with dextran and flecainide. APD heterogeneity changes were dependent on whether the estimation used SD of APD or the AT-APD relationship. The pacing stimulus increased APD at the site of stimulation, revealing a confounding stimulus effect on APD within the measurement area. Simulations predict that the stimulus artifact and endogenous APD gradients are stronger determinants of APD heterogeneity than AT.
Conclusions:
APD dependence on conduction is relatively small. Furthermore, APD heterogeneity within a mapping field of view is dependent on endogenous gradients, the stimulus artifact, and the experimental approach, rather than electrical coupling.
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