© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Life out of balance: The sympathetic nervous system and cardiac arrhythmias
Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853-6401, USA
accepted 5 July 2001
See article by Sosunov et al. [1] (pages 659–669) in this issue.
That the sympathetic nervous system has profound and recurrent effects on cardiac electrical activity has been an article of faith (amply supported by fact) for decades. However, our understanding of the role of sympathetic activity in the development of cardiac arrhythmias remains fragmented. In this issue of the journal, Sosunov and co-workers contribute an important piece to this puzzle [1]. They present a conceptually straightforward and technically demanding series of experiments that asks the question ‘what are the electrophysiological consequences of right stellectomy in the dog?’. In the process of answering that question, they have uncovered several interesting consequences of this type of denervation. However, they have also, as one might hope with any worthwhile study, raised more questions than they have answered.
One of the more intriguing unanswered questions relates to potential roles for the sympathetic nervous system in the development of ventricular arrhythmias in patients afflicted with the long QT syndrome (LQTS). In a recent editorial, Peter Schwartz revisited, with some circumspection, the now all but abandoned terrain of the ‘sympathetic imbalance’ hypothesis for that syndrome [2]. In his review of the theory, he emphasized the generally acknowledged triggering role of the sympathetic nervous system. Perhaps more importantly, he presented a cogent argument and brief outline of evidence for a role of sympathetic stimulation as a modifier of the arrhythmogenic substrate in patients with LQTS.
Sosunov et al. [1] provide additional support for a contribution of sympathetic innervation to the development of a permissive substrate for ventricular arrhythmias. In particular, they cite experimental evidence for a trophic effect of sympathetic neurotransmitters on the expression of certain cardiac ion channels, including repolarizing K+ current channels, and suggest that the absence of such effects in sympathetically denervated myocardium may account for some of their observations. Not only have such effects been demonstrated in normal myocardium [3], but there is evidence that the trophic effects of sympathetic neurotransmitters may alter the electrophysiologic substrate in diseased hearts as well [4–6].
Given the documented effects of sympathetic neurotransmitters on the expression of certain ion channels, perhaps a revisiting of the ‘sympathetic imbalance’ hypothesis is in order. The studies cited above would seem to suggest at least two additional ‘modifier’ roles for the sympathetic nervous system. Either may help to explain the routine clinical finding that groups of patients with a common genotype frequently exhibit a spectrum of phenotypes [7].
The first possibility is that an imbalance of sympathetic innervation (defined broadly to encompass different densities of sympathetic nerves, receptors, components of second messenger cascades, etc.) may result in non-uniform expression of errant genes in patients with LQTS. Consequently, the density of an abnormal ionic current might vary across different regions of the heart, in association with variation in the density of sympathetic innervation. The consequences arising from such heterogeneity of expression could include increased QT interval and QT dispersion, which could, in turn, increase susceptibility to the development of triggered activity, conduction block and reentrant excitation.
The second possibility is that sympathetic imbalance may alter ‘compensatory’ mechanisms set in motion by the presence of a mutant ion channel, particularly with respect to increased or decreased expression of complimentary or competing plateau currents. The possibility that a cardiac myocyte might monitor the currents being expressed at any given time and adjust its spectrum of ionic currents to satisfy an optimal setpoint with respect to the balance of currents, and that such a process might be modulated by the sympathetic nervous system, seems less like ‘sciencefaction’ than it might have even a few years ago, in light of the current fascination with ionic remodeling [8–10]. Such a mechanism might even help to explain the observation that in the present study right stellectomy initially was associated with prolongation of the QT interval, but that with time the QT prolongation abated.
The German shepherd model of inherited ventricular arrhythmias and sudden cardiac death [11], which motivated the experiments by Sosunov et al. [1], could provide a proving ground for tests of the hypothesis that sympathetic imbalance confers non-uniform gene expression. In these animals, sympathetic innervation of the left ventricle is significantly attenuated, compared to the right ventricle [12], and cellular electrophysiological abnormalities are largely restricted to denervated regions of tissue [5,13,14]. The German shepherds offer the additional advantage of exhibiting a naturally evolving syndrome complete with ventricular arrhythmias and sudden death [11], features not reproduced by right stellectomy alone, as reported by Sosunov et al. [1]. Perhaps the initial investigation could focus on the distribution of the transient outward current (Ito) and its channel proteins (primarily Kv 4.3 and its associated beta subunit [15,16]), recognizing that even in normally innervated canine ventricles distribution of Ito is not uniform [17].
A caveat regarding Ito, however: despite the numerous studies demonstrating an association between various forms of cardiac disease and a reduction of Ito density (e.g. see Refs. [5,18–21]), it still is unclear (at least to this observer) whether Ito is a canary in the mineshaft, in that its disappearance is a reliable harbinger of impending cardiac disease, or a red herring – an easily identified distraction whose disappearance merely reflects the fact that it is of so little importance to cell function that it is jettisoned at the first sign of trouble.
That issue aside, studies of Ito and other repolarizing currents may provide important clues to the relationship between sympathetic innervation and ion channel gene expression. Investigations of that type promise to build on the observations of Sosunov et al., hopefully to the point where we have a sufficiently clear understanding of the role of sympathetic activity in the genesis of cardiac arrhythmias to more effectively manage patients at risk for such arrhythmias.
 |
References |
|---|
 Top References |
|---|
- Sosunov E.A., Anyukhovsky E.P., Gainullin R.Z., et al. Long-term electrophysiological effects of regional cardiac sympathetic denervation of the neonatal dog. Cardiovasc Res (2001) 51:659–669.
[Abstract/Free Full Text] - Schwartz P.J. Another role for the sympathetic nervous system in the long QT syndrome? J Cardiovasc Electrophysiol (2001) 12:500–502.[CrossRef][Web of Science][Medline]
- Liu Q.-Y., Rosen M.R., McKinnon D., Robinson R.B. Sympathetic innervation modulates repolarizing K+ currents in rat epicardial myocytes. Am J Physiol. (1998) 274:H915–H922.[Web of Science][Medline]
- Han W.-P., Barr S.C., Pacioretty L.M., Gilmour R.F. Jr. Restoration of the transient outward potassium current by norepinephrine in chagasic canine epicardium. J Physiol (Lond) (1997) 500(1):75–83.
[Abstract/Free Full Text] - Freeman L.C., Pacioretty L.M., Moïse N.S., Kass R.S., Gilmour R.F. Jr. Decreased density of Ito in left ventricular myocytes from German shepherd dogs with inherited arrhythmias. J Cardiovasc Electrophysiol (1997) 8:872–883.[Web of Science][Medline]
- Pacioretty L.M., Gilmour R.F. Jr. Restoration of the transient outward current by norepinephrine in cultured canine cardiac myocytes. Am J Physiol (1998) 44:H1599–H1605.
- Moss A.J., Zareba W., Benhorin J., et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation (1995) 92:2929–2934.
[Abstract/Free Full Text] - Wijifels M.C., Kirchhof C.J., Dorland R., Power J., Allessie M.A. Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch and high rate of electrical activation. Circulation (1997) 96:3710–3720.
[Abstract/Free Full Text] - Yue L., Feng J., Gaspo R., Li G., Wang Z., Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res (1997) 81:512–525.
[Abstract/Free Full Text] - Winslow R.L., Rice J., Jafri S., Marban B., O'Rourke B. Mechanisms of altered excitation–contraction coupling in canine tachycardia-induced heart failure II. Model studies. Circ Res (1999) 84:571–586.
[Abstract/Free Full Text] - Moïse N.S., Meyers-Wallen V., Flahive W.J., et al. Inherited ventricular arrhythmias and sudden death in German shepherd dogs. J Am Coll Cardiol (1994) 24:233–243.[Abstract]
- Dae M.W., Lee R.I., Ursell P.C., et al. Heterogenous sympathetic innervation in German shepherd dogs with inherited ventricular arrhythmias and sudden cardiac death. Circulation (1997) 96:1337–1342.
[Abstract/Free Full Text] - Gilmour R.F. Jr., Moïse N.S. Triggered activity as a mechanism for inherited ventricular arrhythmias and sudden cardiac death. J Am Coll Cardiol (1996) 27:1526–1533.[Abstract]
- Sosunov B.A., Anyukhovsky E.P., Shvilkin A., et al. Abnormal cardiac repolarization and impulse initiation in German shepherd dogs with inherited ventricular arrhythmias and sudden cardiac death. Cardiovasc Res (1999) 42:65–79.
[Abstract/Free Full Text] - Dixon J.E., Shi W., Wang H.-S., et al. Role of the Kv 4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circ Res (1996) 79:659–668.
[Abstract/Free Full Text] - Zhang M, Jiang M, Tseng G-N. MinK-related peptide 1 associates with Kv 4.2 and modulates its gating function. Circ Res 2001;102–1019.
- Di Diego J.M., Sun Z.Q., Antzelevitch C. I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol (1996) 271:H548–H561.[Web of Science][Medline]
- Näbauer M., Beuckelmann D.J., Erdmann B. Characterization of transient outward current in human ventricular myocytes from patients with terminal heart failure. Circ Res (1993) 73:386–394.
[Abstract/Free Full Text] - Pacioretty L.M., Cooper B.J., Gilmour R.F. Jr. Reduction of the transient outward potassium current in canine X-linked muscular dystrophy. Circulation (1994) 90:1350–1356.
[Abstract/Free Full Text] - Pacioretty L.M., Barr S.C., Han W.-P., Gilmour R.F. Jr. Reduction of the transient outward potassium current in a canine model of Chagas’ disease. Am J Physiol (1995) 268:H1258–H1264.[Web of Science][Medline]
- Kääb S., Nuss H.B., Chiamvimonvat N., et al. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res (1996) 78:262–273.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||