DOI: 10.1161/CIRCULATIONAHA.115.017174
Sympathectomy for CPVT Patients: Should We Have the Nerve?
Running title: Narayanan et al.; Sympathectomy for CPVT
Kumar Narayanan, MD; Sumeet S. Chugh, MD
The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA A
A dd dress for Correspondence: Corrres Co rr spond pond nden nce ce:: Address Sum Su meet S. Ch hughh MD D Sumeet Chugh Thee He Hear artt In ar Instit ittut utee Heart Institute Advanced Health Sciences Pavilion Suite A3100 Cedars-Sinai Medical Center 127 S. San Vicente Blvd Los Angeles, CA 90048 Tel: 310-423-1206 Fax: 310-423-3522 E-mail: [email protected]
Journal Subject Code: Treatment:[27] Other treatment
Key words: sympathectomy, Editorial, catecholaminergic polymorphic ventricular tachycardia
1 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
Since the early descriptions almost four decades ago1, 2, there has been considerable expansion in the knowledge base for catecholaminergic polymorphic ventricular tachycardia (CPVT), with identification of underlying genetic mutations3, 4 and a better understanding of mechanisms leading to ventricular arrhythmias5, 6. However, as a malignant entity predisposing mostly young, apparently healthy individuals to sudden cardiac arrest (SCA), CPVT continues to pose a management challenge to the clinical cardiologist, often compounded by emotionally fraught situations. Risk stratification for CPVT remains problematic, particularly since long-term followup data in adequate numbers of patients is hard to obtain in this rare entity; yet clinical experience suggests fairly high event rates in diagnosed subjects7. The therapeutic approach to CPVT relies mainly on countering sympathetic stimulation as the key trigger of aarrhythmia rrhy rr hyth hy thmi th miaa in mi this his syndrome. Beta blockers have conventionally been the cornerstone of management with sizeable izeeab able le reductions red educ u tioons uc ons in arrhythmia burden; unfortunately unforttun unat a ely breakthrough eevents veents despite beta blocker therapy herrapy are nott uncommon unccomm mmon on8. Side Sidde Si de effects eff ffec ff ecctss suc such ucch as lethargy lettharg rgyy related rg rela re lateed to bbeta-blockade la eta--bloc et occka kade de aalso l o re ls resu result sult su lt iin n non-compliance no onn-co c mplian ance inn thi an this is yyoung oung ng ppopulation oppul ulatiionn9. Calcium Calciu Ca um ch channel han nneel bl bloc blockers occkers kerss su such uch aass vverapamil erapa pam pa mill hhave ave imi mite tedd ef te effi fica fi cacy ca cy10 aand nd tthe he cclass lass la ss IIcc ag agen agent entt fl en flec flecainide ecaain ec inid idee has id has shown show sh ownn some some promise pro romi mise mi se11 tthough houg ho ugh gh long-term long lo ng-ter ter erm m limited efficacy data are lacking. At the present time, implantable cardioverter defibrillators (ICDs) are advocated for those with sustained VT/syncope or aborted cardiac arrest despite beta blockers12. However, concerns have been raised about the possibility of VT storm and death due to the sympathetic surge following ICD shocks13 as well as the relatively high rate of inappropriate shocks and device complications in these young patients14. Left cardiac sympathetic denervation (LCSD) has emerged as an alternative approach to sympathetic blockade and has been effectively used in other inherited arrhythmia syndromes such as the long QT syndrome15. While scattered reports of the success of LCSD in abolishing arrhythmia in CPVT exist16, 17, recommendation for its
2 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
adoption as standard therapy has been hampered by lack of data on long-term efficacy. In the current issue of Circulation De Ferrari and colleagues aim their paper18 at this important knowledge gap. Using clinical data gathered from multiple leading centers over several years, they present a retrospective analysis of 63 patients who underwent LCSD for CPVT. Patients were mostly symptomatic, i.e. they had a major cardiac event (MCE) arrhythmic syncope, aborted cardiac arrest or appropriate ICD shocks. All therapy, including LCSD was at the discretion of treating physicians. LCSD was considered complete if the lower half of the stellate ganglion (T1) plus T2-T4 were ablated; if either T1 or T4 was spared, it was considered incomplete. A significant reduction in the percentage of patients with MCEs was seen ymp mpto toma to mati ma ticc prior ti pr post LCSD, from 86% to 21%. It is noteworthy that 9 of the 63 patients were asy asymptomatic too LCSD and continued to be so. Additionally, 16 patients had been symptom-free on medical herrap apyy al alon onee prio on iorr to LCSD. Therefore, the mai io in re esults of this study pe pert r ain to the 38 patients therapy alone prior main results pertain whoo had breakthrough breaktthro hrough gh M CEss de CE desp spit sp ite me it m ediical ca ther rapy w ithh m it axi xima xi mall ma llyy to ll ttolerated leraate tedd be beta ta bblockers lock lo cker ck erss er who MCEs despite medical therapy with maximally an nd/ d/or o fleca ain inidee. E veen in thi his hi hi hhigh gh rrisk issk su ssubgroup, bgro bg oup, tthere herre wa as a si ssizeable zeab ze ab ble l re educ ucctiion o inn the th and/or flecainide. Even this was reduction perc pe rcen rc enta en tage ta ge of of symptomatic symp sy mpto mp toma to mati ma ticc patients ti pati pa tien ti ents en ts (100% (10 100% 0% to to 32%) 32%) as wel elll as iin el n th thee year ye ear arly ly eevent veent rrate vent atee (d at (dec ecre ec reas re ased as ed d percentage well yearly (decreased from 3.4 pre-, to 0.5 post-LCSD). Importantly, the time periods over which MCE data were gathered were similar pre- and post-LCSD. Even after exclusion of patients with very high event rates pre-LCSD, reduction in MCEs remained impressive. Furthermore, as potential proof of a dose-response relationship, subjects with incomplete LCSD were more likely to suffer recurrent events compared to those with complete denervation. What do these results mean for the clinician managing patients with CPVT? Clearly, the work of De Ferrari et al, following on earlier smaller reports16, 19 gives LCSD a much needed shot-in-the-arm. Is it time to include LCSD as standard therapy in the management of CPVT?
3 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
Impressive as the present results are, certain caveats should be considered. This was an observational, non-randomized study and the lack of a control group is an important limitation. While it is difficult to perform a randomized trial for a condition such as CPVT, perhaps a group of historical controls, albeit imperfect, could have further strengthened the results. LCSD was performed over 26 years in multiple centers, thus variations in standard of care and surgical expertise both region-wise and over time may have influenced results. Additionally, while beta blocker prescription was almost universal, only 24% of the study population was on flecainide. Flecainide, a drug that potentially directly targets the underlying molecular defect in RYR220, has generated considerable interest recently, with early reports of significant reductions in arrhythmia burden in CPVT over that conferred by beta blockers alone11, 21. A multi-center mu ult ltii-ce icent ce nter nt er randomized andomized controlled trial of flecainide in CPVT, currently under way (ClinicalTrials.gov Identifier: den nti tifi fier fi er:: NC er NCT0 NCT01117454), 011 1117454), will hopefully provide de m more ore definitive answ answers wer ers on the efficacy of flec fl flecainide. cainide. The Th he present preesen ent study en stud st udyy cannot ud cann ca nn not answer answer ns r the th he question quuestion on of of whether whet wh ettheer LCSD LCS LC SD is is supe ssuperior upe peri riorr tto ri o flecainide. trials, would important fl lecai ecai ainide. If the thee early eaarly y promise promi miisee of of this thiis drug th drug rug holds ho up up in n llarger a ge ar gerr tr riaalss, it i w ould d bbee im mpo portaantt forr clin cl clinicians inic in icia ic ians ia ns ttoo fa fact factor ctor ct or tthis his iin n th thee ma mana management nage na geme ge ment me nt sscheme chem ch emee as a de em desi desirable sira si rabl ra blee no bl non non-invasive n-in inva in vasi asi sive vee ooption ptio pt ionn co io comp compared mpar mp ared ar ed to LCSD. Surgical expertise to perform LCSD is currently available only in selected centers, representing a possible bottleneck to its widespread adoption. Also, whether LCSD can be “substituted” for an ICD when symptoms are refractory to medical therapy (as the authors suggest), may need further investigation. De Ferrari and colleagues are to be congratulated for their careful work which represents an important advance in the therapeutic options available for the difficult CPVT patient. For rare syndromes such as CPVT, randomized trials can be difficult to conduct and multicenter, longterm observational studies are a key resource in advancing the field. This useful cooperative
4 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
study also shows the way forward for clinicians to continue evaluating management options in CPVT. Considering the results of this study, we agree with the authors that it is reasonable to proceed with LCSD for the CPVT patient with recurrent ICD shocks, despite maximally tolerated beta blocker and/or flecainide therapy. It is not unreasonable to consider LCSD in the CPVT patient with OMT and recurrent syncope if a particular clinical situation demands it, but some residual risk will need to be factored in (9% major events in this study). Future studies should focus on whether LCSD can be universally moved up the management ladder in front of an ICD, and whether it affords any long-term benefit in the presently asymptomatic, genotypepositive patient.
Disclosures: None.
References: Re efe ferrences re es es:: Reid Tynan Braidwood L,, F Fitzgerald GR. Bidirectional tachycardia child. study 11.. R eid DS, Tyna naan M,, B r id ra idwo w odd L wo itzzgerralld G R. Bi idireectiionaal tachyc ycardi diaa in a chi di h ld d. A st tud dy using bundle electrography. us sin ng his bund ndle el nd lectro rograp phy hy. Br Heart Hea art J. J 1975;37:339-344 19975;377:33399-34 3444 34 2. Coumel P FJ,, Lucet V,, Attuel P,, Bouvrain Y. Catecholamine-induced severe ventricular 1978;40:28-37. arrhythmias with adam-stokes in children: Report of four cases. cases Br Heart J. J 1978;40:28-37 3. Medeiros-Domingo A, Bhuiyan ZA, Tester DJ, Hofman N, Bikker H, van Tintelen JP, Mannens MM, Wilde AA, Ackerman MJ. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: A comprehensive open reading frame mutational analysis. J Am Coll Cardiol. 2009;54:2065-2074. 4. di Barletta MR, Viatchenko-Karpinski S, Nori A, Memmi M, Terentyev D, Turcato F, Valle G, Rizzi N, Napolitano C, Gyorke S, Volpe P, Priori SG. Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2006;114:1012-1019. 5. Lehnart SE, Wehrens XH, Laitinen PJ, Reiken SR, Deng SX, Cheng Z, Landry DW, Kontula K, Swan H, Marks AR. Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation. 2004;109:3208-3214. 6. Liu N, Rizzi N, Boveri L, Priori SG. Ryanodine receptor and calsequestrin in
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arrhythmogenesis: What we have learnt from genetic diseases and transgenic mice. J Mol Cell Cardiol. 2009;46:149-159. 7. Hayashi M, Denjoy I, Extramiana F, Maltret A, Buisson NR, Lupoglazoff JM, Klug D, Hayashi M, Takatsuki S, Villain E, Kamblock J, Messali A, Guicheney P, Lunardi J, Leenhardt A. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation. 2009;119:2426-2434. 8. van der Werf C, Zwinderman AH, Wilde AA. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: State of the art and future developments. Europace. 2012;14:175-183. 9. Roston TM, Vinocur JM, Maginot KR, Mohammed S, Salerno JC, Etheridge SP, Cohen M, Hamilton RM, Pflaumer A, Kanter RJ, Potts JE, LaPage MJ, Collins KK, Gebauer RA, Temple JD, Batra AS, Erickson C, Miszczak-Knecht M, Kubus P, Bar-Cohen Y, Kantoch M, Thomas VC, Hessling G, Anderson C, Young ML, Cabrera Ortega M, Lau YR, Johnsrude CL, Fournier A, Kannankeril PJ, Sanatani S. Catecholaminergic polymorphic ventricular tachycardia in multicenter children: An analysis of therapeutic strategies and outcomes from an international mu ulticenter registry. egistry. Circ Arrhythm Electrophysiol. 2015 Feb 24. doi: 10.1161/CIRCEP.114.002217. 10.1161/CIRCEP.114.0002 022217. 217. [Epub [Ep Epub u ahead of print]. 10. Rosso R, Kalman JM, Rogowski O, Diamant S, Birger A, Biner S, Belhassen B, Viskin S. Calcium channel versus Calc ciu ium m ch chan annell bl an bblockers ockers and beta-blockers ver rsus beta-blockers alonee ffor o preventing exerciseor induced tachycardia. Rhythm. ndu ducced arrhythmias arrh rh hythmias in catecholaminergic polymorphic polymo orp phic ventricular ventricula larr tachyc la y ardia. Heart Rhyt y hm. 22007;4:1149-1154. 0007;4:1149-11 154 54. 11. Werf C,, K Kannankeril Sacher F,, Kr Krahn Viskin S,, Le Leenhardt Shimizu W,, 11 1. va van der We W rff C annnan nke keri r l PJ ri PJ, S accherr F rah hn AD AD,, Vi Visk kin nS een nhaard rdtt A, S him mizzu W Sumitomo Sumi mito mi tomo to mo N, N, Fish Fish FA, FA, A Bhuiyan Bhu h iyan an ZA, ZA, Willems Wil ille lems le ms AR, AR, R van va der der Veen Ve MJ, MJ, Watanabe Wata attanab be H, H Laborderie Lab bor orde deri de riee J, ri J, Haissaguerre M,, Knollmann Hais Ha issa is sagu sa guer erre er re M Knol Kn ollm ol lman lm annn BC, an BC Wilde Wild Wi ldee AA. ld AA Flecainide Flec Fl ecai ec aini ai nide ni de ttherapy hera he rapy ra py rreduces educ ed uces ces eexercise-induced xeerc xerc rcis isee-in is indu in duce cedd ce ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57:2244-2254. 12. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10:1932-1963. 13. Palanca V, Quesada A, Trigo A, Jimenez J. [Arrhythmic storm induced by AICD discharge in a patient with catecholaminergic polymorphic ventricular tachycardia]. Rev Esp Cardiol. 2006;59:1079-1080. 14. Sherrid MV, Daubert JP. Risks and challenges of implantable cardioverter-defibrillators in young adults. Prog Cardiovasc Dis. 2008;51:237-263.
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DOI: 10.1161/CIRCULATIONAHA.115.017174
15. Bos JM, Bos KM, Johnson JN, Moir C, Ackerman MJ. Left cardiac sympathetic denervation in long QT syndrome: Analysis of therapeutic nonresponders. Circ Arrhythm Electrophysiol. 2013;6:705-711. 16. Schneider HE, Steinmetz M, Krause U, Kriebel T, Ruschewski W, Paul T. Left cardiac sympathetic denervation for the management of life-threatening ventricular tachyarrhythmias in young patients with catecholaminergic polymorphic ventricular tachycardia and long QT syndrome. Clin Res Cardiol. 2013;102:33-42. 17. Collura CA, Johnson JN, Moir C, Ackerman MJ. 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. 18. De Ferrari GM, Dusi V, Spazzolini C, Bos JM, Abrams DJ, Berul CI, Crotti L, Davis AM, Eldar M, Kharlap M, Khoury A, Krahn AD, Leenhardt A, Moir CR, Odero A, Nordkamp LO, Paul T, Rosés i Noguer F, Shkolnikova M, Till J, Wilde AAM, Ackerman M, Schwartz PJ. Clinical Management of Catecholaminergic Polymorphic Ventricular Tachycardia: the Role of Left Cardiac Sympathetic Denervation. Circulation. 2015;131:XX 2015;131:XX-XXX. XXX. 19. Hofferberth SC, Cecchin F, Loberman D, Fynn-Thompson F. Left thoracoscop thoracoscopic op pic sympathectomy ympathectomy for cardiac denervation in patients with life-threatening ventricular arrhythmias. J Thorac Cardiovasc Surg g 2014;147:404-409. 20. Watanabe Davies Roach 200. W atanabe be H, Chopra N, Laver D, Hwang HS, D avies SS, Roa oacch DE, Duff HJ, Roden DM, oa Wilde catecholaminergic Willde AA, Knollmann Knol ollm man an nn BC. BC. Flecainide Fleecai Fl ecai aini nide ni de prevents preve veents nt ca ateecho hola ho lami la minnerg mi rgicc ppolymorphic rg olym ol y orph ym phic ph ic vventricular entr en tric icul ic ular ul ar tachycardia and humans. ach hycardia in mice micce an nd huma mans. Nat Med. ma Med. 2009;15:380-383. Me 2009 20 0 ;1 15:38800-38 383.. 38 21. Po C,, D Dechering Reinke Muszynski A,, Ze Zellerhoff Bittner Kobe Wasmer K,, Pott tt C ech cher ch erin ingg DG, in DG G Rein inke in ke F, Mu Musz szyn sz ynsk ski ki A Zell ller ll erho er hoff ho ff S, Bi Bit ttne nerr A, A K obee JJ,, W ob asme as merr K me Schulze-Bahr E,, Mo Monnig G,, Ko Kotthoff S,, Ec Eckardt L.. S Successful treatment Schu Sc hulz lzee-Ba Bahr Ba hr E Monn nnig nn ig G Kott ttho tt hoff ho ff S Ecka kard ka rdtt L rd uccce ucce cess ssfu ss full tr trea eatm ea tmen tm entt of ccatecholaminergic en atec at echo ec hola ho lami la mine mi nerg ne rgic rg ic polymorphic ventricular tachycardia with flecainide: A case report and review of the current literature. Europace. 2011;13:897-901
7 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
Sympathectomy for CPVT Patients: Should We Have the Nerve? Kumar Narayanan and Sumeet S. Chugh Circulation. published online May 27, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2015/05/27/CIRCULATIONAHA.115.017174
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Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
Sympathectomy for CPVT Patients: Should We Have the Nerve?
Running title: Narayanan et al.; Sympathectomy for CPVT
Kumar Narayanan, MD; Sumeet S. Chugh, MD
The Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA A
A dd dress for Correspondence: Corrres Co rr spond pond nden nce ce:: Address Sum Su meet S. Ch hughh MD D Sumeet Chugh Thee He Hear artt In ar Instit ittut utee Heart Institute Advanced Health Sciences Pavilion Suite A3100 Cedars-Sinai Medical Center 127 S. San Vicente Blvd Los Angeles, CA 90048 Tel: 310-423-1206 Fax: 310-423-3522 E-mail: [email protected]
Journal Subject Code: Treatment:[27] Other treatment
Key words: sympathectomy, Editorial, catecholaminergic polymorphic ventricular tachycardia
1 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
Since the early descriptions almost four decades ago1, 2, there has been considerable expansion in the knowledge base for catecholaminergic polymorphic ventricular tachycardia (CPVT), with identification of underlying genetic mutations3, 4 and a better understanding of mechanisms leading to ventricular arrhythmias5, 6. However, as a malignant entity predisposing mostly young, apparently healthy individuals to sudden cardiac arrest (SCA), CPVT continues to pose a management challenge to the clinical cardiologist, often compounded by emotionally fraught situations. Risk stratification for CPVT remains problematic, particularly since long-term followup data in adequate numbers of patients is hard to obtain in this rare entity; yet clinical experience suggests fairly high event rates in diagnosed subjects7. The therapeutic approach to CPVT relies mainly on countering sympathetic stimulation as the key trigger of aarrhythmia rrhy rr hyth hy thmi th miaa in mi this his syndrome. Beta blockers have conventionally been the cornerstone of management with sizeable izeeab able le reductions red educ u tioons uc ons in arrhythmia burden; unfortunately unforttun unat a ely breakthrough eevents veents despite beta blocker therapy herrapy are nott uncommon unccomm mmon on8. Side Sidde Si de effects eff ffec ff ecctss suc such ucch as lethargy lettharg rgyy related rg rela re lateed to bbeta-blockade la eta--bloc et occka kade de aalso l o re ls resu result sult su lt iin n non-compliance no onn-co c mplian ance inn thi an this is yyoung oung ng ppopulation oppul ulatiionn9. Calcium Calciu Ca um ch channel han nneel bl bloc blockers occkers kerss su such uch aass vverapamil erapa pam pa mill hhave ave imi mite tedd ef te effi fica fi cacy ca cy10 aand nd tthe he cclass lass la ss IIcc ag agen agent entt fl en flec flecainide ecaain ec inid idee has id has shown show sh ownn some some promise pro romi mise mi se11 tthough houg ho ugh gh long-term long lo ng-ter ter erm m limited efficacy data are lacking. At the present time, implantable cardioverter defibrillators (ICDs) are advocated for those with sustained VT/syncope or aborted cardiac arrest despite beta blockers12. However, concerns have been raised about the possibility of VT storm and death due to the sympathetic surge following ICD shocks13 as well as the relatively high rate of inappropriate shocks and device complications in these young patients14. Left cardiac sympathetic denervation (LCSD) has emerged as an alternative approach to sympathetic blockade and has been effectively used in other inherited arrhythmia syndromes such as the long QT syndrome15. While scattered reports of the success of LCSD in abolishing arrhythmia in CPVT exist16, 17, recommendation for its
2 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
adoption as standard therapy has been hampered by lack of data on long-term efficacy. In the current issue of Circulation De Ferrari and colleagues aim their paper18 at this important knowledge gap. Using clinical data gathered from multiple leading centers over several years, they present a retrospective analysis of 63 patients who underwent LCSD for CPVT. Patients were mostly symptomatic, i.e. they had a major cardiac event (MCE) arrhythmic syncope, aborted cardiac arrest or appropriate ICD shocks. All therapy, including LCSD was at the discretion of treating physicians. LCSD was considered complete if the lower half of the stellate ganglion (T1) plus T2-T4 were ablated; if either T1 or T4 was spared, it was considered incomplete. A significant reduction in the percentage of patients with MCEs was seen ymp mpto toma to mati ma ticc prior ti pr post LCSD, from 86% to 21%. It is noteworthy that 9 of the 63 patients were asy asymptomatic too LCSD and continued to be so. Additionally, 16 patients had been symptom-free on medical herrap apyy al alon onee prio on iorr to LCSD. Therefore, the mai io in re esults of this study pe pert r ain to the 38 patients therapy alone prior main results pertain whoo had breakthrough breaktthro hrough gh M CEss de CE desp spit sp ite me it m ediical ca ther rapy w ithh m it axi xima xi mall ma llyy to ll ttolerated leraate tedd be beta ta bblockers lock lo cker ck erss er who MCEs despite medical therapy with maximally an nd/ d/or o fleca ain inidee. E veen in thi his hi hi hhigh gh rrisk issk su ssubgroup, bgro bg oup, tthere herre wa as a si ssizeable zeab ze ab ble l re educ ucctiion o inn the th and/or flecainide. Even this was reduction perc pe rcen rc enta en tage ta ge of of symptomatic symp sy mpto mp toma to mati ma ticc patients ti pati pa tien ti ents en ts (100% (10 100% 0% to to 32%) 32%) as wel elll as iin el n th thee year ye ear arly ly eevent veent rrate vent atee (d at (dec ecre ec reas re ased as ed d percentage well yearly (decreased from 3.4 pre-, to 0.5 post-LCSD). Importantly, the time periods over which MCE data were gathered were similar pre- and post-LCSD. Even after exclusion of patients with very high event rates pre-LCSD, reduction in MCEs remained impressive. Furthermore, as potential proof of a dose-response relationship, subjects with incomplete LCSD were more likely to suffer recurrent events compared to those with complete denervation. What do these results mean for the clinician managing patients with CPVT? Clearly, the work of De Ferrari et al, following on earlier smaller reports16, 19 gives LCSD a much needed shot-in-the-arm. Is it time to include LCSD as standard therapy in the management of CPVT?
3 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
Impressive as the present results are, certain caveats should be considered. This was an observational, non-randomized study and the lack of a control group is an important limitation. While it is difficult to perform a randomized trial for a condition such as CPVT, perhaps a group of historical controls, albeit imperfect, could have further strengthened the results. LCSD was performed over 26 years in multiple centers, thus variations in standard of care and surgical expertise both region-wise and over time may have influenced results. Additionally, while beta blocker prescription was almost universal, only 24% of the study population was on flecainide. Flecainide, a drug that potentially directly targets the underlying molecular defect in RYR220, has generated considerable interest recently, with early reports of significant reductions in arrhythmia burden in CPVT over that conferred by beta blockers alone11, 21. A multi-center mu ult ltii-ce icent ce nter nt er randomized andomized controlled trial of flecainide in CPVT, currently under way (ClinicalTrials.gov Identifier: den nti tifi fier fi er:: NC er NCT0 NCT01117454), 011 1117454), will hopefully provide de m more ore definitive answ answers wer ers on the efficacy of flec fl flecainide. cainide. The Th he present preesen ent study en stud st udyy cannot ud cann ca nn not answer answer ns r the th he question quuestion on of of whether whet wh ettheer LCSD LCS LC SD is is supe ssuperior upe peri riorr tto ri o flecainide. trials, would important fl lecai ecai ainide. If the thee early eaarly y promise promi miisee of of this thiis drug th drug rug holds ho up up in n llarger a ge ar gerr tr riaalss, it i w ould d bbee im mpo portaantt forr clin cl clinicians inic in icia ic ians ia ns ttoo fa fact factor ctor ct or tthis his iin n th thee ma mana management nage na geme ge ment me nt sscheme chem ch emee as a de em desi desirable sira si rabl ra blee no bl non non-invasive n-in inva in vasi asi sive vee ooption ptio pt ionn co io comp compared mpar mp ared ar ed to LCSD. Surgical expertise to perform LCSD is currently available only in selected centers, representing a possible bottleneck to its widespread adoption. Also, whether LCSD can be “substituted” for an ICD when symptoms are refractory to medical therapy (as the authors suggest), may need further investigation. De Ferrari and colleagues are to be congratulated for their careful work which represents an important advance in the therapeutic options available for the difficult CPVT patient. For rare syndromes such as CPVT, randomized trials can be difficult to conduct and multicenter, longterm observational studies are a key resource in advancing the field. This useful cooperative
4 Downloaded from http://circ.ahajournals.org/ at University of Arizona on May 28, 2015
DOI: 10.1161/CIRCULATIONAHA.115.017174
study also shows the way forward for clinicians to continue evaluating management options in CPVT. Considering the results of this study, we agree with the authors that it is reasonable to proceed with LCSD for the CPVT patient with recurrent ICD shocks, despite maximally tolerated beta blocker and/or flecainide therapy. It is not unreasonable to consider LCSD in the CPVT patient with OMT and recurrent syncope if a particular clinical situation demands it, but some residual risk will need to be factored in (9% major events in this study). Future studies should focus on whether LCSD can be universally moved up the management ladder in front of an ICD, and whether it affords any long-term benefit in the presently asymptomatic, genotypepositive patient.
Disclosures: None.
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Sympathectomy for CPVT Patients: Should We Have the Nerve? Kumar Narayanan and Sumeet S. Chugh Circulation. published online May 27, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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