1714Chin Medj201l;1241):1714-79Original articleEpicardial isolation of pulmonary veins with ethanol inopen chest dogsYIN Xian-dong, NING Man, SANG Cai-hua, MIAO Cheng-long, LIANG Cui, TANG Ri-bo, LONG De-yongYU Rong-hui, LIU Xing-peng, DONG Jian-zeng and MA Chang-shengKeywords: ethanol; pulmonary vein isolation; epicardial; atrial fibrillationBackground Radiofrequency(RF) ablation has become a widely accepted treatment for atrial fibrillation(AF). Thisstudy aimed to identify the efficacy and safety of pulmonary vein (Pv)ablation with ethanol and to explore an alternativeenergy source for catheter ablation of AF.Methods Twelve open-chest mongrel dogs were randomized into ethanol ablation group and control group Both theinjections and electrophysiological mapping procedures were performed epicardial In ethanol ablation group(n=6).injections were performed to circumferentially ablate the root of each PV(0. 2 ml each site, 3 mm apart) with 95%ethanolusing an 1 ml injector In control group(n=6), saline was injected other than ethanol. Pv isolation was confirmed with acircular catheter immediately after the procedure and at follow up of 30 days. Pv isolation was defined as the absence ofPV potentials at each electrode of the circular catheter positioned at the Pv side of the lesions, as well as completeconduction block into left atrium( LA)during PV pacingResults Pv electrical isolation with complete bidirectional conduction block was achieved with ethanol immediately andat 30 days in 95% of PVs, while saline injection caused only transient conduction changes between LA and PVs. Inethanol group, histologic analysis showed transmural lesions at 30 days. And there was no evidence of Pv stenosis orthrombus formation Mean LA diameter was not significantly different between baseline and 30 daysEthanol is a safe energy source to effectively isolate Pv in canine model and mayedure of aChin Med J2011;124(10:17141719Radiofrequency(RF) ablation has become a widely and control group(n=6). Experiments were approved byaccepted treatment for atrial fibrillation (AF). the local ethics committee for the use of experimentalStudies have demonstrated that RF current is effective animals. Anesthesia was induced intravenously with 22and relatively safe in producing precise and effective mg/kg katamine hydrochloride. Then the dogs werelesions. Despite achieving acute pulmonary vein(Pv) intubated and ventilated with an inspired isofluraneisolation, conduction recurrence is very frequent, (concentration was 1.5%-2.0% in an oxygen/nitroussuggesting that RF lesions around PV are either oxide mixture). A tidal volume of 15 mlkg and 15frequently nontransmural or frequently incompletebreaths/min were supplied by a mechanical ventilatorThalso experience-dependent, (Siemens Corp, Germany). A left thoracotomy wastime-consuming and associated with increased risk of performed in the fourth intercostal space at the leftcomplications, such as stenosis, embolism, pericardial middle axillary line. The pericardium was opened toforation and tamponade, and damage to neighboring expose the left atria (LA). The surrounding tissue wasstructurescarefully dissected to expose the left PVs and theirorifices into the LA. The surface electrocardiogram(ECG)Because of these limitations, altemative energy sources was continuously monitored and stored in a recordingcontinue to be evaluated for aF ablation. Ethanol hasbeen found to be safe and effective in chemical ablation DOL: 10.3760/cma. j. issn. 0366-6999.201 1 11. 020of cardiac and noncardiac tissue for the past 20 years. It Department of Cardiology, Beijing Anzhen Hospital,Capitalhas been proved that transcoronary ethanol ablation can Medical University, Beijing 100029, China (Yin XD, Ning M,ause coagulative necrosis of both the myocardium and Sang CH, Miao CL, Liang C, Tang RB, Long DY Yu RH, Liu XPthe arteries. This study was aimed at evaluating the Dong JZ and Ma cs)efficacy and safety of PV isolation using ethanol in dogsDr. DONG Jian-zeng,中國煤化工 pital Medical UniversityMETHODSCNMHGOyahoo. cn, jz_dong@Animal preparationThis study was supported by the grants from National NaturalScience Foundation of China(No. 30971239 and No. 81070147)Twelve adult mongrel dogs of either sex weighing(26**4) and the Natural Science Foundation of Beijing(No 7101004)g were randomized into ethanol ablation group(n=b) Disclosure of conflicts of interest:NoneChinese Medical Joumal 2011: 124(11): 1714-1719l715system(Bard Electrophysiology, MA. USA). An 8-mmrecovery room and monitored for 24 hours. Then the dogsdiameter circular decapolar catheter(Lasso, Biosense were housed in a kennel for 30 days later to evaluate theWebster, Inc, Diamond Bar, CA. USA)was positioned late effects of ethanol ablation. All animals receivedcircumferentially at the left PV wall to obtain baseline antibiotic prophylaxis with penicillin 160 mega IUelectrical information(Figure 1). No anticoagulant or intramuscularly three times a day for 3 days post surgeryntiplatelet treatment was used preoperatively and No anticoagulant or antiplatelet treatment was usedintraoperatively in all the animals. Standard surgical postoperatively in this modelinstrumentation and sterile precautions were used in allexperimentsFollow-up studies and pathological preparationRepeated electrophysiological testing was performed 30days after initial ablation. General anesthesia wasinitiated and maintained as described earlier. The left Pvswere redissected followed by follow-up mapping andL MPpacing. Then the animals were euthanized with anintravenous injection of l0% potassium chloride underdeep general anesthesia. After euthanization, hearts andlungs were resected. the LA was opened, the Pv ostiawere identified, and the specimen was inspected grosslyfor any evidence of intraatrial thrombus formation, PVstenosis or endothelial disruption. Then the hearts wereimmersed in 10% formalin for 24 hours. The circularFigure 1. Schematic representation of the pulmonary vein(PVethanol lesions of cach pv were carefullylesion and the mapping catheter. The circular catheter wasy cross-sectionedpositioned circumferentially at the left PV wall and was about I at 3-mm intervals from the veno- atrial junction to the firstcm distal to the lesion. LA: left atrial: LSPV: left superior PVPV branching. Serial sections about 4 um in thicknessLMPV: left middle PV: LSPV: left inferior Pvwere embedded in paraffin and stained withhematoxylin-eosin(HE) techniquePV isolation and lesion assessmentIn ethanol ablation group, epicardial injections were Statistical analysisperformed manually with an I ml insulin syringe in order Results are described as mean* standard deviation(SD)to circumferentially ablate the root of each PV(0.2 ml Comparison of preoperative and postoperative variableseach site and 3 mm apart). Anatomic localization of was performed using paired t test. A value of P < 0.05lesions was less than 0.5 cm, at PV side, away from the was considered statistically significant. SPSS 11.0(SPSSintersecton of PV and LA. At each ablation site. the Inc. USA)was used for data analysisneedle was advanced about 0.5 mm into the pv wallcpicardially. If no blood was aspirated. 95% ethanol wasRESULTSslowly injected. After completion of the circumferentiallesion set, the circular catheter(about I cm away distal to All dogs had 3 or 4 left PVs. Eleven dogs had 3 left PVsthe lesion) was used to determine if PV isolation had been and one had 4 left PVs( Figure 2A and B). Except for theachieved. If not, additional injections of ethanol were one in saline group, PV potentials can be recorded in allapplied to the earliest electrical spikes along the PVs. There were a total of 36 left PVs which showedcircumferential lesions guided by the circular catheter intact electrical conduction between LA and PVs duringwith the endpoint of achieving complete PV isolation. In baseline electrophysiological studies(Figure 3 A).Therecontrol group, normal saline was injected other than were 5.25=0.87(range 4-7)injections around each PVethanol. Usually, the left superior Pv was treated first, before isolation was completed with (1. 17+0. 16)mlfollowed by the left middle PV and the left inferior PV. (range 1.0-1. 4 ml)injection of ethanol into the wall ofEpicardial pacing was performed from the Pv to each PV And time required for complete ablation of eachdetermine LA capture before and after the procedure PV was(52+9)seconds(40-70 seconds)in this groupusing an epicardial bipolar electrode. Bipolar pacing wasperformed at each PV distal to the ablation site at a rate Electrophysiological assessment20s above the heart rate of the individual animal. All targeted PVs appeared healthy at baseline with PVSuccessful Py isolation was defined as eradication of all potential amplitudes of at least I mV in all the animals. InPV potentials at each electrode of the circular catheter ethanol group, successful electrical isolation waspositioned at the PV aspect of the lesions during sinus achie)roscH areata veins immediately afterrhythm or dissociation of PV potential from LA potentials ethan中國煤化工 could not be isolated(entry block) as well as complete conduction block into the becaCNMHGnol into the posteriorLA during Pv pacing at an output of 20 mA(exit block)caiuiiMIIection, PV potentialsrecorded by the circular catheter diminished during SRPostoperative management after the procedure(Figure 3 B)and bidirectional block was verified duringAfter the procedure, all animals were transferred to a SR and pacing from PV. In saline group, transient (<301716Chin med j20l12411):17141719⊙igure 2. Gross anatomy of the left PV and histological examination of thsites. A: The 3 left Pvs(arrows) before ablationprocedure. B: The PV lesions were shown after the ethanol animal wasat 30-day follow-up. C: In ethanol group, atrialmyocardium was replaced by granulation tissue and collagen fibrils(arrows)was transmural and well demarcated from normalmyocardium(left). The internal elastic lamina was normal and endothelialwas preserved. D: The tissue appeared normal insaline group (C, D: HE, Original magnification x 200)seconds) decrease of bipolar Pv potential amplitude was PV stenosis. Histologic analysis showed transmuralobserved in 4 of the 6 dogs and transient(<30 seconds) lesions with no endothelial discontinuity after ethanolchange in the PV potential activation sequence in 2 of the ablation. All lesions consisted of fibrous connective tissue6 dogs. Bipolar pacing performed at distal PV showed with a distinct transition to the surrounding area. Andnormal conduct connection between Pv and LA. At thenormal tissues were shown in saline animals( Figure 2C,30-day follow-up, pacing and mapping were performed in D)all the animals. Bidirectional conduction block wasA Before ethanol injectionAfer ethoobserved across all of Pvs the lesions in ethanol groupxcept in one PV, possibly because it was incompletelydissected from the surrounding tissues. While in salinegroup, bidirectional conduction was present in all PVs.Safety of ethanol injecAll animals tolerated the procedure well without acuteomplications attributable to ethanol injection. Occasionalatrial extrasystoles were observed during injection in all100mmthe animals, and transient(<10 seconds) episode of AF orFigure 3. Surface ECG leads and electrograms recorded withAT was present during injection in 4 dogs in ethanol group.he circular decapolar catheter positioned circumferentially atThere was no sustained arrhythmia or significant changes the left PV before and after ethanol injection.A:Beforeon surface ECG No signs of systemic thromboembo. pv was normal. PV spikes, following the atrialCA) andlization were detected during the follow-up periodpotential, are clearly seen in the sinus rhythm. B: After ethanolTransthoracic echocardiographyCardiac hemodynamic information was obtained byDISCUSSIONtransthoracic echocardiography, which was completed atbaseline and before repeated electrophysiological studies. About the procedureFrom a standard apical 4-chamber view, La diameters In the present study, the dogs chest needs to be opened towere measured. LA function was assessed by the perform ethanol injection. After suitable endocardiadetermination of LA ejection fraction(Table).ablation tools are developed in the future, ethanolablation can be performed endocardial and there is noTable. Transthoracic echocardiography dataneed to open chest. If ethanol is feasible in isolating PVepicardially, it may cause similar effect endocardial. AndLA Ethis study may be the first step of endocardial ablation ofEthanol0.51±0050.53±0.489PV using ethanol. In this study, only the left PVs wereSaline0.52±0020.53±Inte/s were not exposedLA diameter(mm)20.7:2621.3=1.20478中國煤化工 that if ethanol is22.0±1.90.353CNMH Ge same thingnHistologyGross inspection of the ablation sites at 30 days did not PV stenosisshow any evidence of intraatrial thrombus formation or Applications of RF current within the PVs may result inChinese Medical Journal 2011 124(11): 1714-17191717PV stenosis or complete occlusion. The reported lesions had less endothelial disruption and thromboticincidence rate of apparent Pv stenosis after RF Pv material than RF current lesion. The overall incidence ofmechanism is predominantly due to intimal thickening, cryoablation in an experimental study. /and 30.1%withablation was up to 42% in early studies. The thrombus formation was 75.8% with RFproliferation of elastic laminae. Inhomogeneous, dense Weismuller et al injected ethanol directly intofibrosis and shrinking of the tissue induced by rF energy myocardium through a catheter system in thecan lead to PV stenosis. The thermal effect of RF ventricular cavity. Pathology analysis performed 34current can destroy cytoskeleton which is sensitive to weeks after the procedure showed myocardial necrosiswithout intraluminal thrombosisNew energy sources are being studied to avoid the risk of Pathological examination after intracoronary ethanolPV stenosis. Cryothermal energy creates minimal ablpatients with hypertrophic obstructiveendotheliallendocardial disruption and preserves the cardiomyopathy showed coagulative necrosis of theunderlying tissue architecture, which suggest that affected arteries without platelet-fibrin thrombistenosis.But the safety and efficacy are still limited rLcryoenergy may have a low potential risk ofIn the present study, we did not observe thrombusStudies showed that ethanol fixed the tissue in its natural formation, and our histologic analysis showed integrity ofstructure and did not destroy cytoskeleton. In this study, the endocardial layer at 30-day follow-up after thehistological analysis did not show any evidence of Pv ethanol ablation procedure. The lesion proceeds from thestenosis at 30-day follow-up. Thus, it is likely that epicardial to the endocardial layer with minimalepicardial isolation of PV using 95% ethanol is not endocardial disruption, which could be the reason forassociated with stenosisabsence of thrombus formation during epicardial PVisolation using ethanolRecovery of LA-PV conductionRecovered Pv conduction after the initial RF PV Time-consuming and popisolation is still a major concern and is a primary factor of One limitation of Pv isolation using RF energy isecurrent atrial tachycardia in AF patients. Nilsson et al time-consuming. It requires precise catheter manipulationreported that LA-PV conduction was recurrent in more in areas of difficult access and multiple RF applicationsthan 95% of the patients undergoing a second ablation. Deeper tissue lesions are achieved over a longer timeTransmural lesions are important to ensure conduction period of RF current application, An experimental studyblock and maintain long-term efficacy of Pv ablation showed that RF current should be applied for at least 60procedures. In PV isolation procedure with RF energy, seconds to produce an effective lesion, because a steadlimited power and temperature settings used to avoid PV state is not achieved until 40-50 seconds of RFstenosis may be unable to create transmural lesionsapplication. Long procedure time and multiple lesionscan lead to charring and thrombus formation. whileIt has been reported that ethanol can cause transmural each ethanol application only takes a few seconds tolesions of both vessel and myocardium. In rats, injection create effective lesion in previous and present studiesof 70% ethanol into the carotid artery causedfull-thickness necrosis of the vessel wall. In the present Audible steam pops can occur under high RF power andstudy with the use of a canine model, we demonstrated high catheter tip temperatures which may decrease thethat the LA-PV conductions were still blocked at 30-day risk of recurrence. Pops may cause superficial craters orfollow-up, histologic analysis confirmed transmural deep tissue tears with the potential consequences oflesions. Thus ethanol is effective in obtaining permanent cardiac perforation and tamponade. a possible reasontransmural lesions and might be reliably used for for no pop reported in this and previous studies might belong-term PV isolationthat ethanol does not destroy cytoskeletonThrombogenicityLimitationEndothelial cell injury induced by RF ablation can initiate Firstly, the technique was not directly compared withthrombus formation. When continuity of the epicardial RF ablation. Secondly, it has been reported thatendothelium is interrupted, anticoagulant properties are PV stenosis might develop beyond 90 days after ablationlost. And the subendothelial components(collagen, tissue This study describes only 30-day result of ethanolfactor, and von Willebrand,'s factor) become exposed to abl中國煤化工of animals. Long-termcirculating blood. Consequently, platelet adhesion and follorFinally, the lesionactivation occur, and thrombin production ensuer <2CNMH Gaudy助mmicrowave and laser energy achieves endocardial In conclusion, PV isolation using ethanol is reliable.through heating and is therefore subject to the and simple. Durable transmural lesions with commeleteherent risks of thrombus formation. Cryothermal electrical conduction block at the level of Pv can be1718Chin Med j 2011: 124(11): 1714-1719created with ethanol. The creation of circular lines doesErdogan A, et al. 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Hocini M. Sanders P, Scavee C, Sacher F, et al.(Received April 8, 2011)Incidence and prevention of cardiac tamponade complicatingEdited by WANG Mou-yueLetterA case of multiple system atrophy: onset with the cold hands signTeathhe Editor: The cold hands sign(CHS) presents a distincture in some multiple system atrophy(MSA)patients, but itis receiving little consideration. To our knowledge, there are fewof MSa in a patient with onset of a typical CHls ported here a casereported cases of MSA with onset of CHS. We repA 46-year-old woman saw a doctor becauseld, dusky handswith no pain for I month on May 20, 2008, she was diagnosed aserythromelalgia without any treatment.subsequentlydeveloped urinary incontinence, especially worse hearing a waterflow sound, bradykinesia and clumsiness of left leg, impaireddexterity of left arm. A Parkinson disease( PD) was diagnosed andno treatment was administered because of relatively lightsymptoms in August 2009. She experienced brief episodes ofdizziness while standing from December 2009. On June 28, 2010neurological examination revealed orthostatic hypotension andparkinsonism that was more severe on left side, postural tremor andcold dusky and violaceous hands with delayed capillary refill afterFigure. The cold, dusky and violaceous hands with poor circulatory returnblanching(Figure). There were no cerebellar signs and generalupon application of pressure(left hand)examinat ion did not show any abnormality or contributory clinicalfindings. Routine laboratory investigations including haemogram. CHS is taken as one of"red flags"supporting a MSA diagnosisblood glucose, electrolytes, renal and liver function tests werenormal. ECG was within normal limits. Chest X-ray was normal. DOL: 10.3760/cma. i issn.0366-69992011 11.032Plain brain MRI was normal. The diagnosis of probable MSA-P WANG Zhen-fu. WANG Qiong and wU Wei-pingsubtype was made, Madopar(250 mg, Lid)was administered and Department of Geriatric Neurology. People's Liberation Army General Hospital,her parkinsonism was poorly improvedBeijing 100853, China (Wang ZF, wang Q and Wu WP)Correspondence to: D. WANG Zhen-fu, Department of Geriatric NeurologyKlein et al first described the "cold hands sign(CHS)"of MSA in Peoples Liberation Army General Hospital, Beijing 100853, China(Tel1997whichfeaturescoldduskyandviolaceoushandswithpoor86-10-66876367.Email:zhenfuw@sina.com)circulatory return upon application of pressure. It has been ascribedto impaired peripheral vasomotor system, but the underlyingREFERENCESpathophysiology of CHS is rather poorly understood. Klein et alIvestigated CHS of MSa by assessing skin temperature (S1. Klein C, Brown R, Wenning G Quinn N. The"cold hands sign"inbefore and after cooling the skin, results showed lower basal ST,multiple system atrophy. Mow Disord 1997: 12: 514-518greater reduction in ST after cooling and a prolonged recovery 2. Ziemssen T, Reichmann H Treatment of dysautonomia in extrapyramidalperiod in MSA patients compared to PD patients and healthydisorders. Ther Adv Ncurol Disord 2010: 3: 53-67subjects. Another study in MSA patients assessed skin vasomotor 3. Yamanaka Y, Asahina M, Mathias C]. Akaogi Y. Koyama Y, Hattori Tfunction in response to local heating and revealed reducedSkin vasodilator response to local heating in multiple system atrophy.amplitude of skin blood flow to heating compared to healthy22:2405-2408subjects. It remains a challenge to make a differential diagnosis of 4中國煤化工sD, Mathias C, Trojanowskiatypical parkinsonism from primary PD due to their early similaritydiagnosis of multiple systemThe CHS is helpful for a differential diagnosis of MSA fromCNMHGprimary PD when a patient presents CHS besides parkinsonism,especially for the MSA-P subtype from akinetic-rigid PD in the( Received January 5, 2011)first several ycars. In the updated MSA diagnostic criteria, theEdited by JI Yuan-yuan