© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Decrease of delayed rectifier currents in the subacute phase of infarction
Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
* Tel.: +31-20-566-3269; fax: +31-20-697-5458 m.w.veldkamp{at}amc.uva.nl
Received 1 August 2000; accepted 1 August 2000
See article by Jiang et al. [1] (pages 34–43) in this issue.
The paper of Jiang et al. [1] in this issue of Cardiovascular Research – ‘Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infarcted canine ventricle’ – forms the coping-stone in a long series of investigations into the mechanisms underlying arrhythmias post myocardial infarction (in terms of altered ionic currents). In this paper, delayed rectifier currents were characterized in ventricular myocytes isolated from the surviving layer of epicardium overlying a 5 day-old infarct, the epicardial borderzone (EBZ).
 |
1 The canine model of myocardial infarction |
|---|
 Top 1 The canine model... 2 Pathophysiological...References |
|---|
This canine model of myocardial infarction, caused by complete occlusion of the left anterior descending coronary artery, has been thoroughly studied over the past decades. It has been demonstrated that during the healing phase post infarction (days to weeks after coronary occlusion), inducible ventricular tachycardias are a consequence of reentrant excitation localized to this EBZ (see for review [2]). Previous experimental studies on whole hearts and multicellular preparations already indicated important changes in cellular electrophysiology in the EBZ besides changes in anatomy relevant for reentry. Electrophysiological properties of the surviving epicardial fibers 5 days after coronary occlusion are characterized by a reduction in resting membrane potential, action potential amplitude and Vmax of phase 0 (upstroke velocity), partly contributing to slowed conduction. Additionally, action potentials had a brief plateau phase and thereby action potential duration was decreased [2,3]. Despite the latter, prolonged effective and relative refractory periods were observed suggesting increase in postrepolarization refractoriness. The fact that single cells isolated from the EBZ in non-ischemic conditions displayed similar alterations in action potential configuration, except for having a normal resting membrane potential, suggested that changes in ion channel function were at the basis of these membrane abnormalities [4]. A second line of investigations concerned patch-clamp studies on myocytes from the epicardial borderzone to determine the properties of various ion current types important to the action potential configuration.
These studies show in general a reduction in membrane current densities, with normal or altered channel kinetics (see for review [5]). The main depolarizing currents, the sodium current (INa) and L-type calcium current (ICa,L), both show a significant reduction in peak current density with concomitant alterations in channel kinetics [6,7]. For INa these kinetic alterations concern a negative shift of the voltage dependence of inactivation and a reduction in the rate of recovery from inactivation. For ICa,L an accelaration of the time course of inactivation was demonstrated. Also the repolarizing currents, the 4-AP sensitive transient outward current (Ito1), the Ca-sensitive Chloride current (Ito2) and the inward rectifying K current (IK1), showed reduced current densities [4,8]. Finally, Jiang and collegues (1) have investigated another important repolarizing current, the delayed rectifier K current (IK). The authors demonstrate that in infarct zone myocytes (IZ's) isolated from the epicardial borderzone, the rapid (IKr) and slow (IKs) component of IK have reduced current densities compared to normal myocytes (NZ's) isolated from the corresponding region of control hearts. The reduction in total IK was about 75% of which the major part is due to the reduction in IKs. Analysis of current kinetics further revealed an acceleration of IKr activation and IKs deactivation. To shed light on the mechanism underlying the reduction in current density and function the investigators quantified mRNA levels of IKr and IKs channel subunits: dERG, dIsK, and dKvLQT1 at 2 and 5 days after coronary occlusion. It was established that at 2 days after coronary occlusion mRNA levels of dERG, dIsK, and dKvLQT11 were reduced by 48%, 68% and 45% respectively. By day 5, dERG and dIsK mRNA levels remained reduced, whereas dKvLQT1 mRNA levels had returned to control values again.
|
2 Pathophysiological significance of IKr/IKs reduction in EBZ |
|---|
|
Top1 The canine model...2 Pathophysiological...References |
|---|
IKs and IKr are involved in phase 3 and final repolarization. In normal ventricular myocardium, a reduction in IKr and/or IKs, will give rise to an action potential prolongation [9,10]. However, the action potential of myocytes from the EBZ is shortened, despite the fact that also the other repolarizing curents, Ito and IK1, are reduced in amplitude. Obviously, it is the balance between in- and outward plateau currents which ultimately determines whether repolarization is delayed or accelerated. Apparently, the reduction in ICa by far outweighs the reduction in outwards currents and may well be the dominant determinant of action potential duration in this setting. Nevertheless, the balance between in- and outward currents may change under other conditions like increase in heart rate or neurohumoral stimulation. The authors suggest that IKr becomes more important relative to IKs in action potential repolarization in IZs than in NZs, which may have an impact on the effects of β-adrenergic tone or changing heart rate on action potential duration in different regions of an infarcted heart [1]. However, for both conditions applies that the change in action potential duration will strongly depend on changes in other currents also, e.g. ICa. Therefore, taking β-adrenergic tone as an example, it would be worthwile to determine the extent of IKs increase on stimulation by catecholamines and how this compares to the increase in ICa,L. It has been shown that ICa,L increase by isoproterenol is attenuated in IZs [11], probably by reduced β-receptor density and impared activity of the signal transduction pathway involved. An attenuated increase in IKs by catecholamines might therefore also be expected. In a previous study on multicellular preparations from canine heart it was observed that epinephrine (3.10–5 M), hardly affected the action potential duration in the EBZ, although it increased action potentail duration in the non-ischemic area [12]. This might increase the dispersion in action potential duration and thereby the propensity to reentrant arrhythmias.
Chronic changes in channel density/function in heart disease may occur at the level of gene transcription, mRNA processing, protein transport, post-translational modification, assembly with other proteins, and degradation (see for review [13]). In the study of Jiang et al. [1] mRNA levels of the IKr and IKs subunits, dERG, dIsK and dKvLQT1, were determined. At two days after coronary occlusion, mRNA levels of all three subunits were greatly reduced, probably leading to a decreased translation of these channel proteins and their expression in the membrane. Intriguingly, while dIsK and dERG mRNA levels remain decreased, dKvLQT1 mRNA returns to normal levels again at day 5. Still, IKs amplitude is greatly depressed at day 5. It may be that IKs amplitude strongly depends on the amount of IsK subunit. Or, as the authors further suggest, changes in mRNA levels at day 2 only become manifest at the level of functional membrane channels at day 5. Since mRNA levels not necessarily reflect the amount of channel proteins in the membrane [14], as the authors appreciate, measurement of protein levels of the different subunits are required to provide further insight. By and large, the study by Jiang and collegues shows that functional changes in membrane currents are not easily understood from changes at the level of gene transcription.
|
References |
|---|
|
Top1 The canine model...2 Pathophysiological...References |
|---|
- Jiang M., Cabo C., Yao J.-A., Boyden P.A., Tseng G.-N. Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infarcted canine ventricle. Cardiovasc Res (2000) 48:34–43.
[Abstract/Free Full Text] - Janse M.J., Wit A.L. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiological Reviews (1989) 69:1049–1169.
[Free Full Text] - Ursell P.C., Gardner P.I., Albala A., Fenoglio J.J., Wit A.L. Structural and electrophysiological changes in the epicardial border zone of canine myocardial infarcts during infarct healing. Circ Res (1985) 56:436–451.
[Abstract/Free Full Text] - Lue W.-M., Boyden P.A. Abnormal electrical properties of myocytes from chronically infarcted canine heart. Alterations in Vmax and the transient outward current. Circulation (1992) 85:1175–1188.
[Abstract/Free Full Text] - Pinto J.M.B., Boyden P.A. Electrical remodeling in ischemia and infarction. Cardiovasc Res (1999) 42:284–297.
[Abstract/Free Full Text] - Pu J., Boyden P.A. Alterations of Na+ currents in myocytes from epicardial border zone of the infarcted heart. A possible ionic mechanism for reduced excitability and postrepolarization refractoriness. Circ Res (1997) 81:110–119.
[Abstract/Free Full Text] - Aggarwal R., Boyden P.A. Dimished calcium and barium currents in myocytes surviving in the epicardial border zone of the 5 day infarcted canine heart. Circ Res (1995) 77:1180–1191.
[Abstract/Free Full Text] - Aggarwal R., Pu J., Boyden P.A. Ca2+ dependent outward currents in myocytes from the epicardial border zone of the 5 day infarcted heart. Am J Physiol (1997) 273:H1386–H1394.[Web of Science][Medline]
- Bosch R.F., Gaspo R., Busch A.E., Lang H.J., Li G.R., Nattel S. Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc Res (1998) 38:441–450.
[Abstract/Free Full Text] - Jurkiewicz N.K., Sanguinetti M.C. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res (1993) 72:75–83.
[Abstract/Free Full Text] - Aggarwal R., Boyden P.A. Diminished Ca2+ and Ba2+ currents in myocytes surviving in the epicardial border zone of the 5-day infarcted canine heart. Circ Res (1995) 77:1180–1191.
[Abstract/Free Full Text] - Action potentials of cardiac muscle in healing infarcts. Response to norepinephrine and caffeine. Boyden P.A. Gardner P.I. Wit A.L. J Mol Cell Cardiol 1988;20:525-537.
- Roden D.M., Kupershmidt S. From genes to channels: normal machanisms. Cardiovasc Res (1999) 42:318–326.
[Abstract/Free Full Text] - Linck B., Boknik P., Eschenhagen T., Muller F.U., Neumann J., Nose M., Jones L.R., Schmitz W., Scholz H. Messenger RNA expression and immunological quantification of phospholamban and SR-Ca2+-ATPase in failing and nonfailing human hearts. Cardiovasc Res (1996) 31:625–632.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||