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Cellular basis for complex T waves and arrhythmic activity following combined I(Kr) and I(Ks) block
1Masonic Medical Research Laboratory, Utica, New York 13501-1787, USA.
Insights
Combined I(Kr) and I(Ks) channel block significantly alters cardiac electrophysiology, leading to complex T-wave changes and increased risk of ventricular tachycardia. This study reveals how blocking these channels impacts action potentials and ECG characteristics.
Area of Science:
- Cardiovascular Electrophysiology
- Cardiac Ion Channels
- Arrhythmia Mechanisms
Background:
- Cardiomyopathies often involve reduced I(Kr) and I(Ks) potassium currents.
- Electrophysiologic and ECG characteristics of combined I(Kr) and I(Ks) block are poorly understood.
Purpose of the Study:
- Investigate the electrophysiologic and ECG effects of combined I(Kr) and I(Ks) block.
- Characterize changes in action potential duration and transmural dispersion of repolarization.
- Determine the link between ion channel block, T-wave morphology, and ventricular arrhythmias.
Main Methods:
- Used arterially perfused canine left ventricular wedge preparations.
- Simultaneously recorded transmembrane action potentials (epicardial, M, endocardial) and transmural ECG.
- Applied combined block of I(Kr) (d-sotalol) and I(Ks) (chromanol 293B).
Main Results:
- Combined block induced complex T-wave morphologies (inverted, biphasic, triphasic).
- Action potentials in M and epicardial cells prolonged significantly, increasing transmural dispersion of repolarization (TDR) from 33±10 ms to 244±71 ms.
- Early afterdepolarizations (EADs) developed, triggering polymorphic ventricular tachycardia.
Conclusions:
- Combined I(Kr) and I(Ks) block causes significant T-wave abnormalities and increased TDR.
- EADs in epicardial and M cells are linked to triggered beats causing polymorphic ventricular tachycardia.
- Results offer insights for estimating TDR from complex T-waves on the surface ECG.
Introduction:
A growing number of cardiomyopathies have been shown to result in a reduction in both I(Kr) and I(Ks) yet little is known about the electrophysiologic and ECG characteristics of combined I(Kr) and I(Ks) block.
Methods And Results:
To address this gap in our knowledge, transmembrane action potentials (APs) from epicardial, M, and endocardial cells were recorded simultaneously, together with a transmural ECG from arterially perfused canine left ventricular wedge preparations exposed to combined I(Kr) (d-sotalol; 100 micromol/L) and I(Ks) (chromanol 293B; 30 to 60 micromol/L) block. Under baseline conditions, the T wave was typically upright; epicardium repolarized first, coinciding with the peak of the T wave, and the M cells repolarized last, coinciding with the end of the T wave (T(end)). Complex (inverted, biphasic, and triphasic) T waves developed following combined I(Kr) and I(Ks) block. M and epicardial APs prolonged dramatically, so that the endocardial AP was now the earliest to repolarize, coinciding with the first nadir of the complex T wave. In the case of biphasic/triphasic or inverted T waves, Tend coincided with repolarization of either M or epicardial cells, whichever was the last to repolarize. QT intervals prolonged from 286+/-13 msec up to 744+/-148 msec and transmural dispersion of repolarization (TDR) increased from 33+/-10 msec up to 244+/-71 msec. Early afterdepolarizations (EADs) developed in M and epicardial cells, evoking extrasystoles that precipitated polymorphic ventricular tachycardia. Acceleration-induced EADs and T wave alternans also were observed.
Conclusion:
Combined I(Kr) and I(Ks) block gives rise to inverted, biphasic, and triphasic T wave morphologies, a dramatic increase in TDR, and a high incidence of EADs. The diversity of T wave morphologies derives from a preferential AP prolongation of different transmural layers leading to variation in the predominance of voltage gradients on either side of the M cell region. Our study provides direct evidence linking EADs that arise in ventricular epicardial and M cells to the triggered beats that precipitate polymorphic ventricular tachycardia. Our results also suggest possible guidelines for the estimation of TDR from complex T waves appearing in the precordial leads of the surface ECG.