- Email: [email protected]
Cutting nerves and saving lives
EDITORIAL COMMENTARY
Cutting nerves and saving lives Peter J. Schwartz, MD, FHRS From the Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy, Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy, and Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, South Africa. The management and prevention of life-threatening cardiac arrhythmias in clinical practice has always been a difficult task. It is exacerbated by the fact that “with sudden death there is no room for error,” as clearly stated by Lown.1 The problem is further compounded when the patients are young. With these patients, especially children and teenagers, the pressure to avoid an even small probability of error, which could result in a fatal cardiac arrest, becomes very high. When the right concerns for the life of the patient are complemented by the not-unfounded worries of possible medicolegal consequences, it may become difficult to resist the temptation of recommending implantable cardioverter-defibrillator (ICD) placement even when the indication is far from certain. This sad but understandable reality has contributed to the major increase in the use of ICDs, often but not always justified, in children and teenagers. The problem has become particularly important for patients affected by either congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT).2 The ventricular tachyarrhythmias of LQTS patients as well as those of CPVT patients are largely triggered by sudden increases in sympathetic activity.2– 4 This carries several implications. One is that either blockade of adrenergic receptors, especially beta-adrenergic receptors, or interference with norepinephrine release at the ventricular level can be expected to provide a significant degree of protection. Another is that whatever causes pain and fear can act as a trigger for life-threatening arrhythmias. ICDs save many lives, but they are not innocent devices. Besides the well-known high rate of complications (especially in the young) and the long-term consequences of many replacements of batteries and ventricular leads,5,6 even appropriate discharges often initiate those horror sequences called “electrical storms” in which the first shock restores sinus rhythm but the combination of pain and fear leads to further release of catecholamines, new arrhythmic episodes, and Address reprint requests and correspondence: Dr. Peter J. Schwartz, Department of Cardiology, University of Pavia, c/o Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy. E-mail address: [email protected].
new shocks. Sometimes this actually results in battery exhaustion and in the patient’s death.7 A multicenter study has concluded that the consequences, physical and psychological, of electrical storms can be devastating in children.8 The ensuing clinical problems are mainly twofold. One concerns patients with syncope only despite beta-blocker therapy, and the other concerns patients already implanted with an ICD who receive appropriate shocks. For the first group, strong evidence indicates that, with some gene-specific differences,9 –11 surgical antiadrenergic therapy effectively complements pharmacologic therapy and becomes sufficient for most patients12; appropriate risk stratification can help in dubious cases.4 For the second group, ICDs can interrupt life-threatening arrhythmias but cannot prevent them. Accordingly, a major effort is needed to reduce the probability of shocks. This can be done in two ways. As previously suggested,13 the first is by lengthening the ventricular tachycardia time, thus allowing brief self-terminating episodes of torsades de pointes to end spontaneously, a concept reinforced by Viskin and Halkin.12 The second is with a synergistic effect, by adding therapeutic measures capable of further reducing the probability of sustained ventricular tachyarrhythmias. The best way to accomplish this latter result is by performing left cardiac sympathetic denervation (LCSD), as described by Collura et al14 in this issue of Heart Rhythm.
Nothing new under the sun LCSD is not a novel therapy. In this era of PubMed, people tend to ignore previous research, when “previous” means more than 30 to 40 years ago. The report by Collura et al amplifies a concept that has been present even in the recent cardiologic literature, but it may be useful to revisit how LCSD really started, developed, almost disappeared, and eventually was resurrected. In 1899, Francois-Frank,15 who was studying the transmission of sensory information from the aorta through the cervicothoracic sympathetic nervous system, suggested that removal of these nerves might be useful in patients with angina. His suggestion eventually was followed by Jonnesco16 who, in 1916, for the first time used a unilateral section of the left stellate ganglion in a patient affected by
1547-5271/$ -see front matter © 2009 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2009.04.009
Schwartz
Editorial Commentary
incapacitating angina accompanied by cardiac arrhythmias. Of relevance here, after surgery the arrhythmias disappeared, as did the attacks of angina. This truly pioneering surgical intervention by Jonnesco was severely criticized by Danielopolu,17 who defined it as “physiologically inadmissible” because it was severing the sympathetic fibers innervating the myocardium and the coronary arteries, where they were thought to have a vasodilating effect. Thus, according to Danielopolu, removal of the stellate ganglion or ganglia (in case of bilateral denervation) was producing an “anesthetic effect” without preventing the anginal episodes. He suggested a more extensive denervation from C5 to T6. In 1925 Jonnesco18 confirmed in a larger number of patients that stellate ganglionectomy represented a mainstay in the treatment for angina. In 1929 Leriche and Fontaine19 stated that the left stellate ganglion had a central role in the reflexes that initiate angina and, very importantly, that sympathetic nerves had a vasoconstrictive effect on the coronary arteries. They also regarded as exaggerated the warnings by Danielopolu about the side effects of stellectomy. Nonetheless, Danielopolu20 for several years went on claiming that the relief of pain during anginal episodes might have been detrimental by “removing the alarm signal which allows the patients to stop and put to rest their hearts.” These concerns proved to be unfounded, as a large series of studies in anginal patients treated with stellectomy, both in Europe and in the United States, were highly successful in preventing anginal attacks and improving performance during an exercise stress test.21–23 With the advent of betablockers, sympathectomy became superseded despite its clear efficacy. Progressively, however, interest developed for its antiarrhythmic potential, also on the basis of encouraging experimental results.24 –27 The first human studies, by Estes and Izlar28 and Zipes et al,29 focused primarily on ventricular tachycardia and were successful. However, the lack of a solid rationale prevented further clinical attempts. The tide began to turn when, in 1970, Moss and McDonald30 performed LCSD in a LQTS patient not protected by betablockers. Their rationale was provided by QT shortening following left stellectomy demonstrated in dogs by Yanowitz et al.31 The subsequent failures by others to shorten QTc by pharmacologic blockade of the left stellate ganglion, a naïve assumption,3 discouraged new interventions. Once more LCSD lost favor. In 1975 Schwartz and Malliani32 reported to have reproduced in cats by left stellate ganglion stimulation both QT prolongation and macroscopic T-wave alternans (another ECG feature typical of LQTS) and— based on their view of a major triggering role of sympathetic activity mediated by the left stellate ganglion3—to have performed in 1973 LCSD in a 9-year-old LQTS patient who continued to have syncope and cardiac arrest despite full-dose beta-blockade. The patient remained completely asymptomatic for the following 36 years. After this event, Schwartz embarked on a long series of experimental studies investigating the consequences of unilateral (right or left)
761 stellate ganglion ablation. Of the many effects,33,34 the two most relevant to patient management probably are the profound impact on the threshold for ventricular fibrillation,35 which increases by an average of 70%, and the lack of ensuing postdenervation supersensitivity.36 Thus, after LCSD it is more difficult to fibrillate and the effect is permanent because following preganglionic denervation there is no reinnervation. In 1991, Schwartz et al37 reported the first large series of LQTS patients treated with LCSD, and in 2004 they extended the number of patients treated to 147 and reported a very high success rate.38 These patients were regarded as very high risk: 99% were symptomatic, 75% had recurrences despite beta-blockers, and their mean QTc was extremely prolonged (543 ⫾ 65 ms). In 1992, Schwartz et al39 reported that in a multicenter clinical trial of postmyocardial infarction patients at high risk for lethal arrhythmias and randomized among placebo, beta-blocker therapy, and LCSD, the two antiadrenergic therapies resulted in a striking reduction of the 2-year incidence of sudden death from 22% to 3%. In 2008, Wilde and Schwartz40 with their associates reported for the first time that LCSD was extremely effective in patients affected by CPVT resistant to beta-blockers. This leads us directly to the study by Collura et al14 in this issue of the Heart Rhythm.
Understanding the implications Collura et al14 report on 20 patients (18 with LQTS and 2 with CPVT) in whom LCSD was performed for primary and secondary prevention of life-threatening arrhythmias. Except for two cases operated on according to traditional surgery,37,38 in the remaining 18 patients LCSD was performed by video-assisted thoracic surgery (VATS). The results were very successful. Especially impressive are the cases of patients whose tachyarrhythmias could be prevented by only continuous infusion of lidocaine and who, after LCSD, became arrhythmia-free. Their conclusion is that LCSD, in addition to beta-blocker therapy, may provide greater sudden death protection than beta-blockers alone, with less comorbidity than ICD therapy. LCSD by VATS for LQTS is not new. It was first reported by Li et al in 2003, and in 2008 the same group expanded their small series to 11 patients.41 In the same year, Atallah et al42 from Berul’s group in Boston provided additional encouraging data on nine patients with LQTS and CPVT. In 2009 Makanjee et al43 reported on a 10-year successful follow-up with LCSD in a CPVT patient with recurrent ICD shocks despite -blockers. So why is the study by Collura et al important? Because, in my opinion, this represents the final rainfall that will take the water over the levees and initiate the flood. With 20 patients, the study is relatively large and, despite the rather short follow-up, the results are impressive given the previously very serious clinical manifestations. Also of importance is the fact that this is largely a pediatric population, with a mean age of 9 years and including a 2-month-old patient. Finally, the study comes from the group led by Ackerman at Mayo, a group
762 with a very large experience in the management of young patients affected by life-threatening arrhythmias of genetic origin. For too long it seemed that LCSD was a single group trip, with too few cases performed outside Italy. The appearance within 12 months of four different reports dealing with the high success rate of LCSD14,41,42,43 and thus confirming the main message of both our large38 and small40 series on LQTS and on CPVT should remove the existing hesitations and convince cardiologists all over the world about the necessity to always consider the option of LCSD when dealing with high-risk patients, especially those who are young. Collura et al used VATS instead of traditional surgery, and they discuss at length all the possible advantages of this approach. My only concern with VATS is the possibility of bleeding from the stellate ganglion artery. When bleeding occurs with traditional surgery, the open field allows the surgeon to clamp the bleeding artery without difficulty. If bleeding occurs during thoracoscopy, the surgeon probably will be forced to make a quick opening, but identification of the small culprit artery may be complex because of the ongoing bleeding. In my view, the best surgical approach (VATS or traditional38) is the one preferred by the local surgeon. At the end of the day, what matters is that the lower half of the left stellate ganglion is removed together with the first four thoracic ganglia. The upper half of the stellate ganglion should remain intact in order to avoid Horner syndrome. It is objectively difficult not to share Collura’s et al expectation that LCSD, by whatever approach, may provide a “near-ICD level of protection with less co-morbidity than ICD therapy” for patients with either LQTS or CPVT. The two reports from the Children’s Hospital in Boston and from the Mayo Clinic offer U.S. physicians caring for patients with LQTS or CPVT who are not fully protected by beta-blockers a practical option for the performance of LCSD, if not available in their centers. There should be no more excuses for not considering, whenever appropriate, this important therapeutic option. It should not be forgotten that LCSD is a preganglionic denervation that precludes reinnervation. Thus, when dealing with a child or teenager, the consideration of a once for ever intervention versus the unavoidable multiple pulse generator and lead replacements should be kept in mind and placed in the proper context of the patient’s quality of life. In line with our previous conclusions,38 I believe that, when dealing with patients experiencing syncope despite beta-blocker therapy, the patients and their families have the right to be properly informed about the pros and cons of both ICD therapy and LCSD. This discussion will allow the family to make a reasoned choice after assessing the impact of the two therapeutic modalities on patient safety and quality of life.
References 1. Lown B. Sudden cardiac death: the major challenge confronting contemporary cardiology. Am J Cardiol 1979;43:313–328. 2. Schwartz PJ, Crotti L. Ion channel diseases in children: manifestations and management. Curr Opin Cardiol 2008;23:184 –191.
Heart Rhythm, Vol 6, No 6, June 2009 3. Schwartz PJ, Periti M, Malliani A. The long QT syndrome. Am Heart J 1975;89:378 –390. 4. Schwartz PJ, Crotti L. Long QT and short QT syndromes. In: Zipes DP, Jalife J, editors. Cardiac Electrophysiology: From Cell to Bedside. Fifth edition. Philadelphia: Elsevier/Saunders, 2009:731–734. 5. Link MS, Hill SL, Cliff DL, et al. Comparison of frequency complications of implantable cardioverter-defibrillators in children versus adults. Am J Cardiol 1999;83:263–266. 6. Ten Harkel AD, Blom NA, Reimer AG, et al. Implantable cardioverter defibrillator implantation in children in the Netherlands. Eur J Pediatr 2005; 164:436 – 441. 7. Mohamed U, Gollob MH, Gow RM, et al. Sudden cardiac death despite an implantable cardioverter-defibrillator in a young female with catecholaminergic ventricular tachycardia. Heart Rhythm 2006;3:1486 –1489. 8. Wolf MJ, Zeltser IJ, Salerno J, et al. Electrical storm in children with an implantable cardioverter defibrillator: clinical features and outcome. Heart Rhythm 2007;4(5 Suppl):S43. 9. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long QT syndrome. Gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89 –95. 10. Vincent GM, Schwartz PJ, Denjoy I, et al. High efficacy of beta-blockers in long QT syndrome type 1: contribution of non-compliance and QT prolonging drugs to the occurrence of beta-blocker treatment “failures.” Circulation 2009;119: 215–221. 11. Schwartz PJ, Spazzolini C, Crotti L. All LQT3 patients need an ICD. True or false? Heart Rhythm 2009;6:113–120. 12. Viskin S, Halkin A. Treating the long-QT syndrome in the era of implantable defibrillators. Circulation 2009;119:204 –206. 13. Schwartz PJ, Priori SG, Napolitano C. The long QT syndrome. In: Zipes DP, Jalife J, Cardiac Electrophysiology: From Cell to Bedside. Third edition. Philadelphia: WB Saunders, 2000:597– 615. 14. Collura CA, Johnson JN, Moir C, et al. Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery. Heart Rhythm 2009; 6:752–759. 15. Francois-Frank CA. Signification physiologique de la resection du sympathique dans la maladie de Basedow, l’epilepsie, l=idiotic et le glaucoma. Bull Acad Med Paris 1899;41:565–594. 16. Jonnesco T. Traitement chirurgical de l’angine de poitrine par la résection du sympathique cervico-thoracique. Presse Med 1921;20:221–230. 17. Danielopolu D. Le traitement chirurgical de I’angine de poitrine à la lumière des dernières recherches cliniques et expérimentales. C R Soc Biol Tome I 1925; 92:1157. 18. Jonnesco T. Heart function after sympathectomy. JAMA 1925;85:1921. 19. Leriche R, Fontaine R. Rôle du ganglion étoile gauche dans le déterminisme de la crise de l’angine de poitrine. C R Acad Sci 1929;188:279 –280. 20. Danielopolu D. L’infarctus du myocarde accident de la stellectomie dans l’angine de poitrine. Presse Med 1948;56:337–338. 21. Lindgren I, Olivecrona H. Surgical treatment of angina pectoris. J Neurosurg 1947;4:19 –39. 22. Burnett CF, Evans JA. Follow-up report on resection of the anginal pathway in thirty-three patients. JAMA 1956;162:709. 23. Cox WV. Influence of stellate ganglion block on angina pectoris and the post-exercise ECG. Am J Med 1966;252:289 –295. 24. Leriche R, Herman L, Fontaine R. Ligature de la coronaire gauche et fonction du coeur après enervation sympathique. C R Soc Biol 1931;107:547. 25. Cox WV, Robertson HF. The effect of stellate ganglionectomy on cardiac function of intact dogs. Am Heart J 1936;12:285. 26. McEachern G, Manning GW, Hall GE. Sudden occlusion of coronary arteries following removal of cardiosensory pathways: an experimental study. Arch Intern Med 1940;65:661. 27. Harris S, Estandia A, Tillotson RF. Ventricular ectopic rhythms and ventricular fibrillation following cardiac sympathectomy and coronary occlusion. Am J Physiol 1951;165:505. 28. Estes EH Jr, Izlar HR Jr. Recurrent ventricular tachycardia. A case successfully treated by bilateral cardiac sympathectomy. Am J Med 1961;31:493– 497. 29. Zipes DP, Festoff B, Schaal SF, et al. Treatment of ventricular arrhythmia by permanent atrial pacemaker and cardiac sympathectomy. Ann Intern Med 1968; 68:591–597. 30. Moss AJ, McDonald J. Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome. N Engl J Med 1971;285: 903–904.
Schwartz
Editorial Commentary
31. Yanowitz F, Preston JB, Abildskov JA. Functional distribution of right and left stellate innervation to the ventricles: production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone. Circ Res 1966;18:416 – 428. 32. Schwartz PJ, Malliani A. Electrical alternation of the T wave. Clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long QT syndrome. Am Heart J 1975;89:45–50. 33. Schwartz PJ. The rationale and the role of left stellectomy for the prevention of malignant arrhythmias. Ann NY Acad Sci 1984;427:199 –221. 34. Schwartz PJ, Priori SG. Sympathetic nervous system and cardiac arrhythmias. In: Zipes DP, Jalife J, Cardiac Electrophysiology: From Cell to Bedside. Third edition. Philadelphia: WB Saunders, 2000:330 –343. 35. Schwartz PJ, Snebold NG, Brown AM. Effects of unilateral cardiac sympathetic denervation on the ventricular fibrillation threshold. Am J Cardiol 1976;37: 1034 –1040. 36. Schwartz PJ, Stone HL. Left stellectomy and denervation supersensitivity in conscious dogs. Am J Cardiol 1982;49:1185–1190. 37. Schwartz PJ, Locati EH, Moss AJ, et al. Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome: a worldwide report. Circulation 1991;84:503–511. 38. Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation
763
39.
40.
41.
42.
43.
in the management of high-risk patients affected by the long QT syndrome. Circulation 2004;109:1826 –1833. Schwartz PJ, Motolese M, Pollavini G, et al. and the Italian Sudden Death Prevention Group. Prevention of sudden cardiac death after a first myocardial infarction by pharmacologic or surgical antiadrenergic interventions. J Cardiovasc Electrophysiol 1992;3:2–16. Wilde AAM, Bhuiyan ZA, Crotti L, et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med 2008; 358:2024 –2029. Li J, Liu Y, Yang F, et al. Video-assisted thoracoscopic left cardiac sympathetic denervation: a reliable minimally invasive approach for congenital long-QT syndrome. Ann Thorac Surg 2008;86:1955–1958. Atallah J, Fynn-Thompson F, Cecchin F, et al. Video-assisted thorascopic cardiac denervation: a potential novel therapeutic option for children with intractable ventricular arrhythmias. Ann Thorac Surg 2008;86:1620 –1625. Makanjee B, Gollob MH, Klein GJ, et al. Ten-year follow up of cardiac sympathectomy in a young woman with Catecholaminergic Polymorphic Ventricular Tachycardia and an implantable cardioverter defibrillator. J Cardiovasc Electrophysiol. 2009 Feb 26. [Epub ahead of print].
Cutting nerves and saving lives Peter J. Schwartz, MD, FHRS From the Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy, Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy, and Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, South Africa. The management and prevention of life-threatening cardiac arrhythmias in clinical practice has always been a difficult task. It is exacerbated by the fact that “with sudden death there is no room for error,” as clearly stated by Lown.1 The problem is further compounded when the patients are young. With these patients, especially children and teenagers, the pressure to avoid an even small probability of error, which could result in a fatal cardiac arrest, becomes very high. When the right concerns for the life of the patient are complemented by the not-unfounded worries of possible medicolegal consequences, it may become difficult to resist the temptation of recommending implantable cardioverter-defibrillator (ICD) placement even when the indication is far from certain. This sad but understandable reality has contributed to the major increase in the use of ICDs, often but not always justified, in children and teenagers. The problem has become particularly important for patients affected by either congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT).2 The ventricular tachyarrhythmias of LQTS patients as well as those of CPVT patients are largely triggered by sudden increases in sympathetic activity.2– 4 This carries several implications. One is that either blockade of adrenergic receptors, especially beta-adrenergic receptors, or interference with norepinephrine release at the ventricular level can be expected to provide a significant degree of protection. Another is that whatever causes pain and fear can act as a trigger for life-threatening arrhythmias. ICDs save many lives, but they are not innocent devices. Besides the well-known high rate of complications (especially in the young) and the long-term consequences of many replacements of batteries and ventricular leads,5,6 even appropriate discharges often initiate those horror sequences called “electrical storms” in which the first shock restores sinus rhythm but the combination of pain and fear leads to further release of catecholamines, new arrhythmic episodes, and Address reprint requests and correspondence: Dr. Peter J. Schwartz, Department of Cardiology, University of Pavia, c/o Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy. E-mail address: [email protected].
new shocks. Sometimes this actually results in battery exhaustion and in the patient’s death.7 A multicenter study has concluded that the consequences, physical and psychological, of electrical storms can be devastating in children.8 The ensuing clinical problems are mainly twofold. One concerns patients with syncope only despite beta-blocker therapy, and the other concerns patients already implanted with an ICD who receive appropriate shocks. For the first group, strong evidence indicates that, with some gene-specific differences,9 –11 surgical antiadrenergic therapy effectively complements pharmacologic therapy and becomes sufficient for most patients12; appropriate risk stratification can help in dubious cases.4 For the second group, ICDs can interrupt life-threatening arrhythmias but cannot prevent them. Accordingly, a major effort is needed to reduce the probability of shocks. This can be done in two ways. As previously suggested,13 the first is by lengthening the ventricular tachycardia time, thus allowing brief self-terminating episodes of torsades de pointes to end spontaneously, a concept reinforced by Viskin and Halkin.12 The second is with a synergistic effect, by adding therapeutic measures capable of further reducing the probability of sustained ventricular tachyarrhythmias. The best way to accomplish this latter result is by performing left cardiac sympathetic denervation (LCSD), as described by Collura et al14 in this issue of Heart Rhythm.
Nothing new under the sun LCSD is not a novel therapy. In this era of PubMed, people tend to ignore previous research, when “previous” means more than 30 to 40 years ago. The report by Collura et al amplifies a concept that has been present even in the recent cardiologic literature, but it may be useful to revisit how LCSD really started, developed, almost disappeared, and eventually was resurrected. In 1899, Francois-Frank,15 who was studying the transmission of sensory information from the aorta through the cervicothoracic sympathetic nervous system, suggested that removal of these nerves might be useful in patients with angina. His suggestion eventually was followed by Jonnesco16 who, in 1916, for the first time used a unilateral section of the left stellate ganglion in a patient affected by
1547-5271/$ -see front matter © 2009 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2009.04.009
Schwartz
Editorial Commentary
incapacitating angina accompanied by cardiac arrhythmias. Of relevance here, after surgery the arrhythmias disappeared, as did the attacks of angina. This truly pioneering surgical intervention by Jonnesco was severely criticized by Danielopolu,17 who defined it as “physiologically inadmissible” because it was severing the sympathetic fibers innervating the myocardium and the coronary arteries, where they were thought to have a vasodilating effect. Thus, according to Danielopolu, removal of the stellate ganglion or ganglia (in case of bilateral denervation) was producing an “anesthetic effect” without preventing the anginal episodes. He suggested a more extensive denervation from C5 to T6. In 1925 Jonnesco18 confirmed in a larger number of patients that stellate ganglionectomy represented a mainstay in the treatment for angina. In 1929 Leriche and Fontaine19 stated that the left stellate ganglion had a central role in the reflexes that initiate angina and, very importantly, that sympathetic nerves had a vasoconstrictive effect on the coronary arteries. They also regarded as exaggerated the warnings by Danielopolu about the side effects of stellectomy. Nonetheless, Danielopolu20 for several years went on claiming that the relief of pain during anginal episodes might have been detrimental by “removing the alarm signal which allows the patients to stop and put to rest their hearts.” These concerns proved to be unfounded, as a large series of studies in anginal patients treated with stellectomy, both in Europe and in the United States, were highly successful in preventing anginal attacks and improving performance during an exercise stress test.21–23 With the advent of betablockers, sympathectomy became superseded despite its clear efficacy. Progressively, however, interest developed for its antiarrhythmic potential, also on the basis of encouraging experimental results.24 –27 The first human studies, by Estes and Izlar28 and Zipes et al,29 focused primarily on ventricular tachycardia and were successful. However, the lack of a solid rationale prevented further clinical attempts. The tide began to turn when, in 1970, Moss and McDonald30 performed LCSD in a LQTS patient not protected by betablockers. Their rationale was provided by QT shortening following left stellectomy demonstrated in dogs by Yanowitz et al.31 The subsequent failures by others to shorten QTc by pharmacologic blockade of the left stellate ganglion, a naïve assumption,3 discouraged new interventions. Once more LCSD lost favor. In 1975 Schwartz and Malliani32 reported to have reproduced in cats by left stellate ganglion stimulation both QT prolongation and macroscopic T-wave alternans (another ECG feature typical of LQTS) and— based on their view of a major triggering role of sympathetic activity mediated by the left stellate ganglion3—to have performed in 1973 LCSD in a 9-year-old LQTS patient who continued to have syncope and cardiac arrest despite full-dose beta-blockade. The patient remained completely asymptomatic for the following 36 years. After this event, Schwartz embarked on a long series of experimental studies investigating the consequences of unilateral (right or left)
761 stellate ganglion ablation. Of the many effects,33,34 the two most relevant to patient management probably are the profound impact on the threshold for ventricular fibrillation,35 which increases by an average of 70%, and the lack of ensuing postdenervation supersensitivity.36 Thus, after LCSD it is more difficult to fibrillate and the effect is permanent because following preganglionic denervation there is no reinnervation. In 1991, Schwartz et al37 reported the first large series of LQTS patients treated with LCSD, and in 2004 they extended the number of patients treated to 147 and reported a very high success rate.38 These patients were regarded as very high risk: 99% were symptomatic, 75% had recurrences despite beta-blockers, and their mean QTc was extremely prolonged (543 ⫾ 65 ms). In 1992, Schwartz et al39 reported that in a multicenter clinical trial of postmyocardial infarction patients at high risk for lethal arrhythmias and randomized among placebo, beta-blocker therapy, and LCSD, the two antiadrenergic therapies resulted in a striking reduction of the 2-year incidence of sudden death from 22% to 3%. In 2008, Wilde and Schwartz40 with their associates reported for the first time that LCSD was extremely effective in patients affected by CPVT resistant to beta-blockers. This leads us directly to the study by Collura et al14 in this issue of the Heart Rhythm.
Understanding the implications Collura et al14 report on 20 patients (18 with LQTS and 2 with CPVT) in whom LCSD was performed for primary and secondary prevention of life-threatening arrhythmias. Except for two cases operated on according to traditional surgery,37,38 in the remaining 18 patients LCSD was performed by video-assisted thoracic surgery (VATS). The results were very successful. Especially impressive are the cases of patients whose tachyarrhythmias could be prevented by only continuous infusion of lidocaine and who, after LCSD, became arrhythmia-free. Their conclusion is that LCSD, in addition to beta-blocker therapy, may provide greater sudden death protection than beta-blockers alone, with less comorbidity than ICD therapy. LCSD by VATS for LQTS is not new. It was first reported by Li et al in 2003, and in 2008 the same group expanded their small series to 11 patients.41 In the same year, Atallah et al42 from Berul’s group in Boston provided additional encouraging data on nine patients with LQTS and CPVT. In 2009 Makanjee et al43 reported on a 10-year successful follow-up with LCSD in a CPVT patient with recurrent ICD shocks despite -blockers. So why is the study by Collura et al important? Because, in my opinion, this represents the final rainfall that will take the water over the levees and initiate the flood. With 20 patients, the study is relatively large and, despite the rather short follow-up, the results are impressive given the previously very serious clinical manifestations. Also of importance is the fact that this is largely a pediatric population, with a mean age of 9 years and including a 2-month-old patient. Finally, the study comes from the group led by Ackerman at Mayo, a group
762 with a very large experience in the management of young patients affected by life-threatening arrhythmias of genetic origin. For too long it seemed that LCSD was a single group trip, with too few cases performed outside Italy. The appearance within 12 months of four different reports dealing with the high success rate of LCSD14,41,42,43 and thus confirming the main message of both our large38 and small40 series on LQTS and on CPVT should remove the existing hesitations and convince cardiologists all over the world about the necessity to always consider the option of LCSD when dealing with high-risk patients, especially those who are young. Collura et al used VATS instead of traditional surgery, and they discuss at length all the possible advantages of this approach. My only concern with VATS is the possibility of bleeding from the stellate ganglion artery. When bleeding occurs with traditional surgery, the open field allows the surgeon to clamp the bleeding artery without difficulty. If bleeding occurs during thoracoscopy, the surgeon probably will be forced to make a quick opening, but identification of the small culprit artery may be complex because of the ongoing bleeding. In my view, the best surgical approach (VATS or traditional38) is the one preferred by the local surgeon. At the end of the day, what matters is that the lower half of the left stellate ganglion is removed together with the first four thoracic ganglia. The upper half of the stellate ganglion should remain intact in order to avoid Horner syndrome. It is objectively difficult not to share Collura’s et al expectation that LCSD, by whatever approach, may provide a “near-ICD level of protection with less co-morbidity than ICD therapy” for patients with either LQTS or CPVT. The two reports from the Children’s Hospital in Boston and from the Mayo Clinic offer U.S. physicians caring for patients with LQTS or CPVT who are not fully protected by beta-blockers a practical option for the performance of LCSD, if not available in their centers. There should be no more excuses for not considering, whenever appropriate, this important therapeutic option. It should not be forgotten that LCSD is a preganglionic denervation that precludes reinnervation. Thus, when dealing with a child or teenager, the consideration of a once for ever intervention versus the unavoidable multiple pulse generator and lead replacements should be kept in mind and placed in the proper context of the patient’s quality of life. In line with our previous conclusions,38 I believe that, when dealing with patients experiencing syncope despite beta-blocker therapy, the patients and their families have the right to be properly informed about the pros and cons of both ICD therapy and LCSD. This discussion will allow the family to make a reasoned choice after assessing the impact of the two therapeutic modalities on patient safety and quality of life.
References 1. Lown B. Sudden cardiac death: the major challenge confronting contemporary cardiology. Am J Cardiol 1979;43:313–328. 2. Schwartz PJ, Crotti L. Ion channel diseases in children: manifestations and management. Curr Opin Cardiol 2008;23:184 –191.
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