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View metadata, citation and similar papers at core.ac.ukJournal of the American College of Cardiology 2012 by the American College of Cardiology FoundationPublished by Elsevier Inc.brought to you byVol. 60, No. 23, 2012ISSN 0735-1097/ Heart Rhythm DisordersA Novel Low-Energy Electrotherapy That TerminatesVentricular Tachycardia With Lower Energy Than aBiphasic Shock When Antitachycardia Pacing FailsAjit H. Janardhan, MD, PHD,* Wenwen Li, PHD,† Vadim V. Fedorov, PHD,† Michael Yeung, MD,*Michael J. Wallendorf, PHD,‡ Richard B. Schuessler, PHD,†§ Igor R. Efimov, PHD*†St. Louis, MissouriObjectivesThe authors sought to develop a low-energy electrotherapy that terminates ventricular tachycardia (VT) whenantitachycardia pacing (ATP) fails.BackgroundHigh-energy implantable cardioverter-defibrillator (ICD) shocks are associated with device failure, significant morbidity, and increased mortality. A low-energy alternative to ICD shocks is desirable.MethodsMyocardial infarction was created in 25 dogs. Sustained, monomorphic VT was induced by programmed stimulation. Defibrillation electrodes were placed in the right ventricular apex, and coronary sinus and left ventricularepicardium. If ATP failed to terminate sustained VT, the defibrillation thresholds (DFTs) of standard versus experimental electrotherapies were measured.ResultsSustained VT ranged from 276 to 438 beats/min (mean 339 beats/min). The right ventricular–coronary sinusshock vector had lower impedance than the right ventricular–left ventricular patch (54.4 18.1 versus 109.8 16.9 ; p 0.001). A single shock required between 0.3 0.2 J to 5.9 2.5 J (mean 2.64 3.22 J; p 0.008) to terminate VT, and varied depending upon the phase of the VT cycle in which it was delivered. By contrast, multiple shocks delivered within 1 VT cycle length were not phase dependent and achieved lower DFTcompared with a single shock (0.13 0.09 J for 3 shocks, 0.08 0.04 J for 5 shocks, and 0.09 0.07 J for 7shocks; p 0.001). Finally, a multistage electrotherapy (MSE) achieved significantly lower DFT compared with asingle biphasic shock (0.03 0.05 J versus 2.37 1.20 J; respectively, p 0.001). At a peak shock amplitudeof 20 V, MSE achieved 91.3% of terminations versus 10.5% for a biphasic shock (p 0.001).ConclusionsMSE achieved a major reduction in DFT compared with a single biphasic shock for ATP-refractory monomorphicVT, and represents a novel electrotherapy to reduce high-energy ICD shocks. (J Am Coll Cardiol 2012;60:2393–8) 2012 by the American College of Cardiology FoundationRandomized, prospective clinical trials have demonstratedthat implantable cardioverter-defibrillators (ICDs) decreasemortality in patients with coronary artery disease or priormyocardial infarction (MI) who are at increased risk ofventricular tachycardia (VT) or ventricular fibrillation (1,2).From the *Department of Medicine, Cardiovascular Division, Washington UniversitySchool of Medicine, St. Louis, Missouri; †Department of Biomedical Engineering,Washington University, St. Louis, Missouri; ‡Division of Biostatistics, WashingtonUniversity, Saint Louis, Missouri; and the §Department of Surgery, CardiothoracicDivision, Washington University School of Medicine, St. Louis, Missouri. This studywas supported by National Institutes of Health grants R01 HL-067322, R01HL-082729, and T32 HL-007081. Dr. Li is an employee of Cardialen, Inc. Dr.Schuessler has received a research grant from Cardialen. Dr. Efimov is a cofounder,shareholder, member of the board of directors, and chairman of the scientific advisoryboard of Cardialen, Inc. All other authors have reported that they have norelationships relevant to the contents of this paper to disclose. Drs. Janardhan and Licontributed equally to this work.Manuscript received April 27, 2012; revised manuscript received July 31, 2012,accepted August 6, 2012.COREprovided by Elsevier - Publisher ConnectorMore than 80% of victims of sudden cardiac death havecoronary artery disease (3), with the most common arrhythmia being sustained monomorphic VT (4). A high-energybiphasic shock is the only existing electrotherapy whenantitachycardia pacing (ATP) fails to terminate VT. However, ICD shocks have been shown to damage the myocardium and reduce the quality of life (5,6). Moreover, patientsSee page 2399receiving high-energy shocks have a 2- to 3-fold increase inmortality (7,8) compared with those who do not receiveshocks. Although it is unclear whether it is the shocksthemselves or a change in underlying cardiac status thatactually causes higher mortality, even inappropriate shocks(9) are associated with a higher mortality, for example,inappropriate shocks often occur during atrial fibrillation,

2394Janardhan et al.Low-Energy Multistage Electrotherapy for VTAbbreviationsand AcronymsATP ⴝ antitachycardiapacingCL ⴝ cycle lengthCS ⴝ coronary sinusDFT ⴝ defibrillationthresholdICD ⴝ implantablecardioverter-defibrillatorLV ⴝ leftventricle/ventricularLVP ⴝ left ventricularpatchMI ⴝ myocardial infarctionwhich itself can result in a highermortality in patients with poorleft ventricular (LV) function.Despite these disadvantages, alternative low-energy electrotherapies have not been introducedinto ICD technology since theincorporation of ATP. The purpose of this study was to developa novel electrotherapy that terminates VT with lower energy thana biphasic shock for ATPrefractory monomorphic VT.MethodsSurgical procedures. All animalprocedures were performed inRV ⴝ rightaccordance with the Position ofventricle/ventricularthe American Heart AssociationVT ⴝ ventricularon the use of research animalstachycardia(updated in 1985) and were approved by the Animal StudiesCommittee at Washington University. MI was created afteranesthetization of mongrel dogs (n 25) of either sexweighing 20 to 25 kg, by surgical ligation of the leftanterior descending coronary artery for 2 h, as describedpreviously (10). Four days after MI, animals were reanesthetized, a median sternotomy was performed, and cardiopulmonary bypass was initiated after the administration of heparin.Electrode configuration. In the 24 dogs that survived MI(1 dog died suddenly 1 day after left anterior descendingcoronary artery ligation), a 15-cm2 custom epicardial LVpatch (LVP) was placed over the posterolateral LV, and an8-F standard defibrillation/bipolar pacing lead (6935,Medtronic, Minneapolis, Minnesota) was implanted in theright ventricular (RV) apex (Fig. 1). In 5 animals, anadditional 8-F standard defibrillation lead (6937A,Medtronic) was placed into the coronary sinus (CS) (Fig. 1).Pacing was delivered from the RV bipole. Shock therapieswere delivered across the RV-LVP or RV-CS vectors; allshocks were RV anodal. A bipolar button electrode wassewn to the RV epicardium for ventricular sensing.Defibrillation protocol. Four days after MI, loading (2mg/kg) and maintenance (0.05 mg/kg/min) infusions offlecainide acetate (Sigma-Aldrich, St. Louis, Missouri)were administered intravenously. VT was induced byrapid RV pacing protocols (programmed electrical stimulation). Sustained, monomorphic VT was defined as afast but organized ventricular rhythm 500 beats/min,lasting 30 s. Ventricular fibrillation was defined as anarrhythmia 500 beats/min, and if induced, terminatedusing an external defibrillator. The heart was allowed to recoverfor 5 to 10 min after any external defibrillation before reinduction of VT.MSE ⴝ multistageelectrotherapyJACC Vol. 60, No. 23, 2012December 11, 2012:2393–8After monomorphic VT was induced, ATP was attempted. ATP consisted of 8 pacing stimuli, each of 2-msduration delivered at a rate of 88% of the VT cycle length(CL), delivered from the RV bipole at an amplitude 4 timesthe ventricular pacing capture threshold current. If ATP failedto terminate VT, defibrillation thresholds (DFTs) of variouselectrotherapies (defined later in the text) were measured.DFT, in volts, was defined as the peak shock amplitude thatterminated VT. DFT, in joules, was calculated by multiplyingthe energy of a single shock by the number of shocks applied (formultiple-shock and multistage electrotherapies).Experimental and standard electrotherapies were deliveredusing a randomized protocol with respect to sequence to avoidtime bias, using a voltage-regulated, step-up protocol. Theamplitude of the peak shock voltage was increased after eachunsuccessful termination, beginning at twice the minimumvoltage required to capture the ventricle with a 10-ms monophasic shock, until VT was terminated. Reinduction of VT wasattempted after a 5-min recovery period, according to theprotocol. Electrotherapies were delivered from computercontrolled regulated power supplies (BOP 100-4M, Kepco,Flushing, New York). Impedances were calculated using a currentprobe (A622, Tektronix, Beaverton, Oregon).Electrotherapies tested. The electrotherapies tested areshown in Figure 2. One (1MP), 3 (3MP), 5 (5MP), or 7(7MP) monophasic shocks were delivered within 1 VT CL(Fig. 2A); each individual shock was 10 ms in duration. Asingle biphasic shock (1BP, 6-ms and 4-ms duration of thefirst and second phases, respectively; 2:1 ratio of the leadingedge voltages of the 2 phases is shown in Fig. 2B).Multistage electrotherapy (MSE), shown in Figure 2C,Figure 1Anatomic Position of Defibrillation ElectrodesSchematic of a canine heart with the locations of the electrodes used for application of electrotherapies. Anteroposterior (left) and posteroanterior (right)views showing locations of the defibrillation leads and shock vectors (blackarrows). Shocks were delivered from the RV defibrillation coil (RV) to the CSdefibrillation coil (CS), or from the RV coil to epicardial LV defibrillation patch(LVP). CS coronary sinus; LVP left ventricular patch; RA right atrium;RV right ventricle.

Janardhan et al.Low-Energy Multistage Electrotherapy for VTJACC Vol. 60, No. 23, 2012December 11, 2012:2393–82395ResultsFigure 2Defibrillation Wave Formsand Low-Energy ElectrotherapiesSchematic diagrams of the electrotherapies applied. Pulse widths of individualshocks were 10 ms. (A) One (1MP), 3 (3MP), 5 (5MP), or 7 (7MP) monophasicshocks delivered within 1 VT cycle length (CL). (B) A single biphasic shock(1BP) with pulse widths of 6 ms for the first (positive) phase and 4 ms for thesecond (negative) phase. (C) Multistage electrotherapy (MSE). Stage 1 consisted of 3 monophasic shocks delivered in 1 VT CL, followed by a 100-msdelay. Stage 2 consisted of 6 lower-voltage monophasic shocks delivered at arate of 88% of the VT CL, followed by a 100-ms delay. Stage 3 consisted of 8pacing stimuli, each of 2-ms duration delivered from the endocardial RV lead(tip to ring) at a rate of 88% of the VT CL. BP biphasic; MP monophasic;VT ventricular tachycardia; other abbreviations as in Figure 1.consisted of 3 monophasic shocks delivered within 1 VTCL (Stage 1), followed by 6 MP shocks delivered with aninterval of 88% of the VT CL at twice the ventricular shockcapture voltage (Stage 2), followed by ATP (Stage 3);individual stages were separated by 100-ms delays.Statistical analysis. The defibrillation protocol randomized the sequence of electrotherapies to prevent theconfounding effects of treatments with respect to time.Recovery periods were observed after each termination toprevent carryover effects. DFTs for comparisons of electrotherapies tested were analyzed using a linear mixedeffects model with animal ID as a random effect andtreatment as a fixed effect. Energy and voltage DFTvalues were log transformed to stabilize the variance.Estimates were calculated with the MIXED procedure inSAS (version 9.3, SAS Institute, Cary, North Carolina).Paired Student’s t test was used to compare impedances ofthe 2 shock vectors tested, and performed in Prism 5.0c(GraphPad Software, La Jolla, California). Results arereported as mean SD. A p value of ⱕ0.05 was consideredsignificant.Characteristics of monomorphic VT in canine heartswith 4-day-old infarct. One hundred and ninety episodesof monomorphic, sustained VT (lasting 30 s) were induced in 16 of the 24 dogs (66.7%) that survived MI; in 8dogs, only ventricular fibrillation or polymorphic VT couldbe induced. VT ranged from 276 to 438 beats/min (mean339 beats/min). ATP successfully terminated VT in 17 of170 trials, a success rate of 10.0%.Phase dependence of a single shock. The energy requiredfor a single shock to terminate VT varied significantlydepending upon the phase of the VT cycle in which it wasdelivered (DFT phase dependence) in this in vivo model.The DFT of a single 10-ms monophasic shock variedsignificantly when delivered at 0%, 20%, 40%, 60%, or 80%of the VT CL. Shocks were delivered between the RV coiland the LVP. Application of a single shock revealed that theDFT dramatically changed based upon the phase of application. Phase-dependent DFT for a single shock was seen inall dogs tested (n 5). Across all dogs, the mean DFT ofthe optimal phase in each animal compared with the meanDFT of the least effective phase was 0.3 0.2 J versus 5.9 2.5 J, respectively (p 0.008). Notably, the optimal phasevaried between animals and could not be determined apriori.DFTs of single versus multiple shocks. We hypothesizedthat multiple low-energy shocks applied evenly within 1 VTCL would not have phase dependence, thus enabling areduction in the DFT compared with a single shock. Afterinduction of sustained VT, ATP was attempted. If ATPfailed, 1, 3, 5, or 7 MP shocks (1MP, 3MP, 5MP, or 7MP,respectively) were applied within 1 VT CL (Fig. 3A). Asingle (1MP) 1.1-J MP shock failed to terminate VT (uppertracing), whereas 3MP, 5MP, and 7MP shocks (of 0.24 J,0.16 J, and 0.2 J, respectively) terminated VT. Mean DFTsacross all dogs tested (n 6) are summarized in Figure 3B.In all animals tested, multiple shocks significantly loweredthe DFT compared with a single shock and did not exhibitphase dependence.Multistage electrotherapy. Previous electrotherapies wereapplied from endocardium to epicardium (RV-LVP vector)(Fig. 1). To move toward the goal of developing a leadsystem that is practical in humans yet enables low DFT, wetested whether shocks applied entirely within the heart(RV-CS vector) (Fig. 1) would achieve low impedance. Themean impedance of shocks delivered between the RV-CSvector was significantly lower than the RV-LVP vector(54.4 18.1 versus 109.8 16.9 , respectively, p 0.001). These results showed that low impedance can beachieved using transvenous electrodes rather than an epicardial patch electrode.To further reduce the DFT, we expanded multiple shocksto a MSE (Fig. 2C). Using the RV-CS vector, MSE wascompared to the existing clinical standard, a single biphasicshock. After induction of sustained monomorphic VT,

2396Janardhan et al.Low-Energy Multistage Electrotherapy for VTJACC Vol. 60, No. 23, 2012December 11, 2012:2393–8Expanding upon this concept, MSE dramatically reducedthe DFT compared with a single biphasic shock for ATPrefractory monomorphic VT. Importantly, we showed thatMSE (and a single biphasic shock) could be deliveredendocardially using commercially available transvenous defibrillation leads placed in the RV and CS.In this model, the success rate of ATP was 10%. Thiscontrasts with human trials in which ATP terminated 78%to 94% of monomorphic VT 200 beats/min (11–13). Inhumans, the efficacy of ATP has been shown to be lowerwith increasing rate of VT, terminating 84% of VT episodesranging from 188 to 214 beats/min, and only 69% ofepisodes ranging from 214 to 250 beats/min (14). Otherstudies have shown the success rate for fast VT to rangefrom 47% to 79% (15–18). The average rate of VT in ourmodel was 339 beats/min, significantly faster than thosereported in human ATP trials, and likely explains whyATP was relatively unsuccessful in this model. Importantly, the low-energy MSE described in this report isnot envisioned as an alternative to ATP. Rather, it isintended to complement ATP and provide an alternativeFigure 3DFTs of Single and MultipleMonophasic Shock Electrotherapies(A) Surface electrocardiogram tracings during applications of single and multiple monophasic shock electrotherapies. An 80-V (1.1 J) single monophasicshock (1MP) failed to terminate VT (top panel). In the same animal, 3 monophasic shocks (3MP; second panel), 5 monophasic shocks (5MP; third panel),and 7 monophasic shocks (7MP; lower panel) delivered within 1 VT cycle terminated VT successfully with 22 V (0.24 J), 14 V (0.16 J), and 13 V (0.2 J),respectively. (B) Mean DFTs (logarithmic scale) of 1MP, 3MP, 5MP, and 7MPwith respect to peak voltage (left panel) and total energy (right panel) overn 6 dogs tested is shown. NS not significant; other abbreviations as inFigures 1 and 2.ATP was attempted, and if it failed, electrotherapies weredelivered according to a randomized protocol. Sampleterminations using a single biphasic shock and MSE areshown in Figure 4A, where the DFT of a single BP shockwas 200 V (4.56 J) compared with 20 V (0.22 J) for MSE.Pooled results (n 5 dogs) are shown in Figure 4B. Themean DFT of MSE was significantly lower than that of asingle biphasic shock in terms of total energy (0.03 0.05J versus 2.37 1.20 J, respectively; p 0.001) and peakshock voltage (7.2 6.9 V versus 137.7 43.8 V,respectively; p 0.001). At a peak shock amplitude of 20 V,MSE achieved 91.3% of terminations versus 10.5% for abiphasic shock (p 0.001). Importantly, these resultsdemonstrate that low DFT can be achieved using transvenously implanted leads, and does not require an epicardialelectrode.DiscussionOur study showed that the DFT of a single shock toterminate post-MI monomorphic VT in vivo was phasedependent, and that multiple low-energy shocks deliveredwithin a single VT CL eliminated phase dependence.Figure 4Sample Terminations and Mean DFTsof a Single Biphasic Shock Versus MSE(A) Surface electrocardiogram (ECG) and ventricular electrogram (VEG) of a termination of monomorphic VT by a single biphasic shock (1BP) with peak leading edge voltage of 200 V (4.56 J). Arrows indicate the time of electrotherapyapplication. (B) Surface ECG and VEG of a termination of monomorphic VT byMSE with peak voltage of 20 V (0.22 J). (C) Mean DFTs of a single biphasicshock (Single Biphasic) and MSE (Multi-Stage) are shown with respect to peakvoltage (left panel) and total energy (right panel). SR sinus rhythm; otherabbreviations as in Figures 2 and 3.

Janardhan et al.Low-Energy Multistage Electrotherapy for VTJACC Vol. 60, No. 23, 2012December 11, 2012:2393–8to potentially damaging, high-energy biphasic shockswhen ATP fails.Our study agrees with in vitro studies in post-MI rabbithearts showing the phase dependence of single monophasicand biphasic shocks (19,20). We found a 20-fold energydifference between single optimally and poorly timedshocks, similar to those reported in in vitro studies. Notably,in both the current in vivo canine study and previouslyin vitro rabbit studies, and the optimal phase for singleshock application could not be predicted a priori.Lowering the DFT by repetitive shocks was first shownby Gurvich in 1945 (21). More recently, repetitive subthreshold (below the ventricular capture threshold) pacingwas shown to terminate VT in guinea pig hearts whenapplied to the endocardium (22). Previous studies in in vitrorabbit heart preparations showed that multiple shocks extinguished the re-entrant circuit by maintaining an area ofmyocardium refractory to activation, into which the reentrant wave front collides (19). It is likely that themechanism of defibrillation in the canine MI model of VTis similar.The current standard ICD electrotherapy for ATPrefractory monomorphic VT is a high-energy biphasicshock. A low-energy electrotherapy would be desirable toreplace the shock if it were effective. The mean DFT of theMSE in this report was nearly 80-fold lower in energy thanthat of a biphasic shock. Moreover, at low voltage (20 V),MSE achieved significantly more terminations than a biphasic shock, making it a suitable low-energy electrotherapyto reduce the need for full output ICD shocks.Nearly all ICD shocks are delivered from the RV coil toan “active can”/superior vena cava coil configuration, delivering current, not only through the heart itself, but alsothrough the chest wall musculature and sensory nerves,thereby dissipating energy over structures outside of theheart and causing pain. Implanting commercially availabledefibrillation leads in the CS (already Food and DrugAdministration approved for defibrillation from the CS andazygous vein) and RV enables application of a shock vectorthat largely confines energy to the heart itself, and wasshown to be effective for delivering MSE. Notably, thisconfiguration would still allow ICD shocks to be applied viathe traditional RV to superior vena cava/active can vectorshould MSE fail.Though MSE may require design changes prior to incorporation into ICDs, such therapies require significantly lowervoltage for defibrillation, which requires much less time forcharging the capacitor than a full-output ICD shock. Reducingthe number of full-output ICD shocks would likely prolongbattery life and may reduce the malfunction rate of highvoltage components. Effective low-energy electrotherapy maybe significantly less painful to patients, and importantly, reducethe likelihood of patients receiving a high-energy shock. Also,if high-energy shocks are themselves partially responsible forthe increased mortality observed in patients who receive them,2397effective lower-energy electrotherapy may conceivably reducemortality.ConclusionsIn the present study, we found that the DFT of a singlemonophasic shock to terminate VT in canine hearts withhealing MI is phase dependent. Multiple shocks deliveredwithin a single VT CL achieved lower DFTs than a singlerandomly timed shock without requiring a priori knowledgeof phase dependence. MSE, which incorporated multipleMP shocks within the first stage, further reduced the DFT.MSE is a low-voltage, low-energy electrotherapy thatterminates VT with lower DFT than a single biphasicshock, yet it is significantly more effective than ATP in thismodel. If successful in humans, MSE may reduce the needfor high-energy shocks.AcknowledgmentsThe authors thank Timo Weimar, Yoshiyuki Watanabe,Toshinobu Kazui, Sarah Gutbrod, Diane Toeniskoetter,and Naomi Still for technical assistance.Reprint requests and correspondence: Dr. Igor R. Efimov,Department of Biomedical Engineering, 1 Brookings Drive,Washington University, St. Louis, Missouri 63130. E-mail:[email protected] Moss AJ, Hall WJ, Cannom DS, et al., for the Multicenter AutomaticDefibrillator Implantation Trial Investigators. Improved survival withan implanted defibrillator in patients with coronary disease at high riskfor ventricular arrhythmia. N Engl J Med 1996;335:1933– 40.2. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, HafleyG, for the Multicenter Unsustained Tachycardia Trial Investigators. Arandomized study of the prevention of sudden death in patients withcoronary artery disease. N Engl J Med 1999;341:1882–90.3. Zipes DP, Wellens HJ. Sudden cardiac death. 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Flushing, New York). Impedances were calculated using a current probe (A622, Tektronix, Beaverton, Oregon). Electrotherapies tested. The electrotherapies tested are shown in Figure 2. One (1MP), 3 (3MP), 5 (5MP), or 7 (7MP) monophasic shocks were delivered within 1 VT CL