Life out of balance: the sympathetic nervous system and cardiac arrhythmias.

See article by Sosunov et al. [1] (pages 659 –669) in effects in sympathetically denervated myocardium may this issue. account for some of their observations. Not only have such effects been demonstrated in normal myocardium [3], but That the sympathetic nervous system has profound and there is evidence that the trophic effects of sympathetic recurrent effects on cardiac electrical activity has been an neurotransmitters may alter the electrophysiologic subarticle of faith (amply supported by fact) for decades. strate in diseased hearts as well [4–6]. However, our understanding of the role of sympathetic Given the documented effects of sympathetic neuroactivity in the development of cardiac arrhythmias remains transmitters on the expression of certain ion channels, fragmented. In this issue of the journal, Sosunov and perhaps a revisiting of the ‘sympathetic imbalance’ hyco-workers contribute an important piece to this puzzle [1]. pothesis is in order. The studies cited above would seem to They present a conceptually straightforward and technicalsuggest at least two additional ‘modifier’ roles for the ly demanding series of experiments that asks the question sympathetic nervous system. Either may help to explain ‘what are the electrophysiological consequences of right the routine clinical finding that groups of patients with a stellectomy in the dog?’. In the process of answering that common genotype frequently exhibit a spectrum of question, they have uncovered several interesting consephenotypes [7]. quences of this type of denervation. However, they have The first possibility is that an imbalance of sympathetic also, as one might hope with any worthwhile study, raised innervation (defined broadly to encompass different denmore questions than they have answered. sities of sympathetic nerves, receptors, components of One of the more intriguing unanswered questions relates second messenger cascades, etc.) may result in non-unito potential roles for the sympathetic nervous system in the form expression of errant genes in patients with LQTS. development of ventricular arrhythmias in patients afflicted Consequently, the density of an abnormal ionic current with the long QT syndrome (LQTS). In a recent editorial, might vary across different regions of the heart, in Peter Schwartz revisited, with some circumspection, the association with variation in the density of sympathetic now all but abandoned terrain of the ‘sympathetic imbalinnervation. The consequences arising from such heteroance’ hypothesis for that syndrome [2]. In his review of the geneity of expression could include increased QT interval theory, he emphasized the generally acknowledged trigand QT dispersion, which could, in turn, increase suscepgering role of the sympathetic nervous system. Perhaps tibility to the development of triggered activity, conduction more importantly, he presented a cogent argument and block and reentrant excitation. brief outline of evidence for a role of sympathetic stimulaThe second possibility is that sympathetic imbalance tion as a modifier of the arrhythmogenic substrate in may alter ‘compensatory’ mechanisms set in motion by the patients with LQTS. presence of a mutant ion channel, particularly with respect Sosunov et al. [1] provide additional support for a to increased or decreased expression of complimentary or contribution of sympathetic innervation to the development competing plateau currents. The possibility that a cardiac of a permissive substrate for ventricular arrhythmias. In myocyte might monitor the currents being expressed at any particular, they cite experimental evidence for a trophic given time and adjust its spectrum of ionic currents to effect of sympathetic neurotransmitters on the expression satisfy an optimal setpoint with respect to the balance of 1 of certain cardiac ion channels, including repolarizing K currents, and that such a process might be modulated by current channels, and suggest that the absence of such the sympathetic nervous system, seems less like ‘science-