Copyright © 2005, European Society of Cardiology
Transmural dispersion in LQT3 and arrhythmogenesis
Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology, Münster, Germany
* Corresponding author. Medizinische Klinik und Poliklinik C, -Kardiologie und Angiologie-, Universitätsklinikum Münster, Albert-Schweitzer Str. 33, D-48149 Münster. Tel.: +49 251 834 5160; fax: +49 251 834 9943. Email address: milbergp{at}uni-muenster.de
We thank Dr. Opthof and Dr. Coronel for the interest in our recently published work [1] and appreciate their comments. We aimed at developing a novel intact heart model of LQT3 for a better understanding of the mechanisms by which functional electrical instability at the level of the whole heart leads to torsade de pointes (TdP). The potassium concentration was repeatedly lowered to design an experimental setup that reproduced conditions and circumstances that are clinically known to be associated with an increased propensity to the development of TdP [2]. The low potassium concentration of 1.5 mM results in a markedly reduced repolarization reserve, which, in combination with bradycardia and a QT-prolonging agent, reproducibly causes TdP. Under baseline conditions (without inhibiting sodium channel inactivation or blocking IKr) TdP do not occur. With higher potassium concentrations, e.g. 2.0 mM [3] up to 3.0 mM (data not published), TdP do also occur in some hearts (fewer hearts, less episodes as compared to the low concentration of 1.5 mM).
Dispersion in repolarization is caused by the combined differences in activation times between the RV (pacing site) and the LV, and by the local MAP. We agree that the term "dispersion of repolarization of MAP90" would be more correct than just "dispersion of repolarization". However, several groups [4,5], including Dr. Coronel's group [6], use the two terms as synonyms. In previous studies, we observed only insignificant changes in local activation time even in the presence of amiodarone [7]. Thus, it is unlikely that the main message of our study is due to changes in activation pattern.
Veratridine led to a marked increase in transmural dispersion of MAP90 mainly due to excessive prolongation of left endocardial MAP90 in contrast to epicardial recorded action potentials. This indicates that action potential differences across the ventricular myocardium may be of particular importance for the increased arrhythmia susceptibility. Transmural action potential heterogeneity may support reentrant mechanisms responsible for the perpetuation of TdP, after being initiated by early afterdepolarizations. Dr. Opthof and Dr. Coronel make the valid point that a clear distinction between endocardial cells and subendocardial "M cells" is not possible with our setup. Therefore, the combined use of simultaneous microelectrode and contact MAP electrode catheter recordings would be of additional value. Anyhow, it is apparent in cases of mixed cell population that the MAP duration reflects the average duration of the underlying cell population. If this is or is not a so-called M cell region remains an open issue. However, an "insignificant" role of M cells in the human heart is far from being proven [8,9] with regard to the conditions under which the recordings of the quoted study [10] were obtained. The discussion on the existence of M cells and their contribution to arrhythmogenesis in experimental intact heart models as well as the human heart awaits further investigations, and the extent to which transmural heterogeneity exists within the human heart remains to be definitely determined.
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- Milberg P., Reinsch N., Wasmer W., Mönnig G., Stypmann J., Osada N., et al. Transmural dispersion of repolarization as a key factor of arrhythmogenicity in a novel intact heart model of LQT3. Cardiovasc Res (2005) 65:397–404.
[Abstract/Free Full Text] - Eckardt L., Haverkamp W., Borggrefe M., Breithardt G. Experimental models of torsade de pointes. Cardiovasc Res (1998) 39:178–193.
[Abstract/Free Full Text] - Johna R., Mertens H., Haverkamp W., Eckardt L., Niederbröker T., Borggrefe M., et al. Clofilium in the isolated perfused rabbit heart: a new model to study proarrhythmia induced by class III antiarrhythmic drugs. Basic Res Cardiol (1998) 93:127–135.[CrossRef][Web of Science][Medline]
- Verduyn S.C., Vos M.A., van der Zande J., van der Huls F.F., Wellens H.J. Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium. Cardiovasc Res (1997) 34:453–463.
[Abstract/Free Full Text] - Zabel M., Hohnloser S.H., Behrens S., Yi-Gang L., Woosley R.L., Franz M.R. Electrophysiologic features of torsade de pointes: insights from a new isolated rabbit heart model. J Cardiovasc Electrophysiol (1997) 8:1148–1158.[Web of Science][Medline]
- de Groot J.R., Schumacher C.A., Verkerk A.O., Baartscheer A., Fiolet J.W.T., Coronel R. Intrinsic heterogeneity in repolarization is increased in isolated failing rabbit cardiomyocytes during simulated ischemia. (2003) vol. 59:705–714.
- Kirchhof P., Degen H., Franz M.R., Eckardt L., Fabritz L., Milberg P., et al. Amiodarone-induced postrepolarization refractoriness suppresses induction of ventricular fibrillation. J Pharmacol Exp Ther (2003) 305:257–263.
[Abstract/Free Full Text] - Vos M., Jungschleger J. Transmural repolarization gradients in vivo: the flukes and falls of the endocardium. Cardiovasc Res (2001) 50:423–425.
[Free Full Text] - Antzelevitch C. Transmural dispersion of repolarization and the T wave. Cardiovasc Res (2001) 50:426–431.
[Free Full Text] - Taggart P., Sutton P.M.I., Opthof T., Coronel R., Trimlett R., Pugsley W., et al. Transmural repolarization in the left ventricle in humans during normoxia and ischaemia. Cardiovasc Res (2001) 50:454–462.
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