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Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for
A O Verkerk1, M W Veldkamp, R Coronel
1Department of Physiology, Cardiovascular Research Institute Amsterdam, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. a.o.verkerk@amc.uva.nl
Insights
Cell uncoupling during acute ischemia promotes afterdepolarizations, contributing to phase-1b arrhythmias. Norepinephrine further increases this risk, highlighting the role of triggered activity in cardiac events.
Area of Science:
- Cardiac Electrophysiology
- Arrhythmia Mechanisms
- Ischemic Heart Disease
Background:
- Phase-1b arrhythmias during acute ischemia are linked to catecholamine depletion and cell uncoupling.
- Understanding the interplay between cell uncoupling and catecholamines is crucial for elucidating arrhythmia development.
Purpose of the Study:
- To investigate the effects of cell uncoupling and catecholamines on the development of proarrhythmic afterdepolarizations.
- To determine the role of triggered activity in phase-1b arrhythmias.
Main Methods:
- Simulated a depressed, depolarized ischemic region using an electronic circuit with varying potentials.
- Employed patch-clamp methodology to couple sheep Purkinje and ventricular cells to the simulated region.
- Varied coupling conductance to study the effects of different degrees of cell uncoupling.
Main Results:
- Progressive uncoupling increased cell excitability, action potential duration, and resting potential.
- A critical range of uncoupling induced early afterdepolarizations in ventricular and Purkinje cells at -13 mV.
- Norepinephrine induced afterdepolarizations during uncoupling at -33 mV or more positive potentials.
Conclusions:
- Afterdepolarizations occurred within a critical range of uncoupling when the simulated ischemic region potential was -33 or -13 mV.
- These findings suggest triggered activity contributes to phase-1b arrhythmias.
- Cellular uncoupling from a depolarized ischemic region is a key factor in arrhythmia generation.
Objective:
The delayed phase of ventricular arrhythmias during acute ischemia (phase-1b arrhythmia) is associated with depletion of catecholamines and cell-to-cell uncoupling between depressed depolarized intramural ischemic region and surviving cells in subepicardium and subendocardium. In the present study we determined the effects of uncoupling and catecholamines on development of proarrhythmic afterdepolarizations.
Methods:
Depressed depolarized ischemic region was simulated by a passive electronic circuit with a potential of -73, -53, -33 or -13 mV. Using patch-clamp methodology, single sheep Purkinje and ventricular cells were coupled to the simulated ischemic region via a variable conductance. By varying coupling conductance, we were able to selectively study the effects of various degrees of uncoupling.
Results:
At strong coupling, cells were inexcitable and depolarized to potentials near those of the simulated ischemic region. Excitability, action potential duration and resting potential increased with progressive uncoupling. In a critical range of uncoupling, ventricular and "high-plateau" Purkinje cells developed early afterdepolarizations when the potential of the simulated ischemic region was -13 mV. Norepinephrine (1 microM) frequently induced early and delayed afterdepolarizations in both ventricular and Purkinje cells, but these afterdepolarizations were only present during uncoupling when the potential of the simulated ischemic region was -33 mV or more positive.
Conclusions:
In a critical range of uncoupling, afterdepolarizations were present when the potential of the simulated ischemic region was -33 or -13 mV, suggesting that triggered activity plays a role in phase-1b arrhythmias when surviving layers uncouple from a highly depolarized intramural ischemic region.