Sequence-Dependent Repolarization Is Modulated by Endogenous Action Potential Duration Gradients Rather Than...

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.