Tjong et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7
Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8
1488
T ransvenous pacemakers and im-plantable cardioverter-defibrillators(ICDs) are effective treatment modal-
ities for cardiac bradyarrhythmias and tachyar-rhythmias (1–4). However, these systems areassociated with device-related complications,mostly related to the transvenous leads, whichresult in morbidity and mortality. Transvenouspace and shock leads have shown high failurerates during long-term clinical follow-up (5–7).Device infections (sometimes involving thepocket but more so when systemic) are associ-ated with a high risk of mortality (8).
To reduce complications related to trans-venous leads, both the leadless pacemaker(LP) and the subcutaneous implantable
cardioverter-defibrillators (S-ICDs) were introducedand have shown clinical efficacy and safety (9–13). Todate, these systems are only available for patientseither requiring single-chamber right ventricular(RV) pacing or shock-only defibrillation therapy. Com-bined use of both devices could bring the benefits ofleadless therapy to a larger patient population byproviding both bradycardia pacing and defibrillationtherapy. Limited evidence on the combined use of bothdevices has been reported in case studies (14,15). Forpatients in need of antitachycardia pacing (ATP) ther-apy, there are no leadless solutions available to date.
We recently reported the first proof-of-conceptstudy of a unidirectional LP and S-ICD that candeliver bradycardia pacing, ATP, and defibrillationtherapy (16). These combined device systems requiresafe and reliable device–device communication andenable a novel treatment concept of modular cardiacrhythm management (CRM) therapy. The presentpreclinical study describes the acute and chronicperformance of this modular CRM system. The ob-jectives of this study were to assess the acute andchronic feasibility and performance of this novelmodular CRM therapy, with regard to the following:1) the performance of an ATP-enabled LP; 2) unidi-rectional device–device communication from anS-ICD to an LP; 3) S-ICD–triggered ATP delivery byan LP; and 4) S-ICD and LP rhythm discriminationduring device–device communication, LP pacing, andventricular fibrillation.
METHODS
These data were collected prospectively involvingboth acute and chronic experiments in 3 animalmodels (ovine, n ¼ 8; porcine, n ¼ 5; and canine,n ¼ 27). The protocols were pre-reviewed andacceptable to animal use and utilization ethics boards
at both Academic Medical Center, University ofAmsterdam (Amsterdam, the Netherlands) and Bos-ton Scientific Corporation (St. Paul, Minnesota). Theywere to be conducted in compliance with the appli-cable government guidelines.
MODULAR CRM THERAPY SYSTEM. The modularATP-enabled LP and S-ICD system (both, Boston Sci-entific Corporation, Marlborough, Massachusetts)are shown in Figure 1. The prototype modular CRMsystem comprises an S-ICD and a standard S-ICD elec-trode, an LP, a catheter-based delivery and retrievalsystem, and programmers with software dedicated foreach device (Online Figure 1). The S-ICD pulse gener-ator is a device based on the EMBLEMplatform (BostonScientific Corporation) with updated firmware toenable conducted communication to the LP. The LP is arate-responsive, single-chamber pacemaker that has aself-contained battery and active-fixation nitinoltines. The S-ICD uses unidirectional conductivecommunication to command the LP and radio-frequency signals to communicate with its program-mer. The LP uses conductive communication tocommunicate with its programmer.
During the course of the study, development of theLP was ongoing, and improvements in the micropro-cessor and software were introduced; no changeswere made to the design or shape of the LP, thedelivery catheter, or the S-ICD.
IMPLANTATION PROTOCOLS. An ATP-enabled LPprototype was implanted in the RV apex, using apercutaneous, transfemoral approach through a 21-Fintroducer sheath using a designated delivery cath-eter with “telescope feature” for catheter extension(Figure 2). The LP was deployed by engaging 4 nitinoltines into the myocardium. After evaluating adequatefixation with gentle traction and obtaining satisfac-tory electrical measurements, the LP was releasedby removing the tether. The LP was interrogated, andbaseline performance measures were obtained.
The S-ICD prototype was implanted under fluoro-scopic guidance with the pulse generator placementin the left lateral side of the thorax and the coil onthe contralateral side of the thorax (position rangingfrom right parasternal to right lateral side) to ensurean adequate shock and communication vector be-tween coil and pulse generator, which would berepresentative of what is expected in chronic humanuse. During the course of the study, an externalbandaging technique was introduced to stabilize theS-ICD in the pocket because of excessive motion ofthe S-ICD pulse generator in the canine skin pockets.A bandage was wrapped around the abdomen andback of the animal and on top of the S-ICD pocket to
(A) Overview of modular cardiac rhythm management (CRM) system prototypes with detailed image of the novel antitachycardia pacing-(ATP)-enabled leadless
pacemaker (LP) (dimensions 31.9 mm length � 6.0 mm diameter, 0.8 cc volume). (B) Schematic depiction of human modular CRM system implant. (C) Fluoroscopy
imaging of the implanted modular CRM system and left ventricular pacing catheter in canine subject in the anterior posterior view. ª 2017 Boston Scientific Corporation
or its affiliates. All rights reserved. Used with permission of Boston Scientific Corporation.
J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7 Tjong et al.D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8 Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD
1489
hold the S-ICD stable for postural changes of theanimal during communication testing.
The S-ICD uses 1 of 3 electrocardiographicrecording “vectors” for heart rhythm discrimination.The most optimal sensing vector for each implant waschosen and programmed. S-ICD to LP communicationwas assessed and checked for interference, and heartrhythm discrimination was evaluated. A decapolarelectrophysiology catheter (Polaris X Steerable Diag-nostic Catheter, Boston Scientific Corporation, Marl-borough, Massachusetts) was inserted into the leftventricle via left femoral artery access and used topace the left ventricle to simulate monomorphicventricular tachycardia (VT) morphology at rates inthe therapy zone settings of the S-ICD.
ACUTE AND 3-MONTH MODULAR CRM SYSTEM
PERFORMANCE. The purpose of the acute experi-ments was to assess the safety and feasibility of theATP-enabled LP and S-ICD implantation to test uni-directional device–device communication, S-ICD–initiated ATP delivery, and S-ICD and LP rhythmdiscrimination during intrinsic rhythm, LP pacing,and ventricular fibrillation (VF). Healthy domesticovine (mean weight 78 � 12 kg), porcine (mean weight65 � 11 kg), and canine (mean weight 29 � 3 kg)models were used. All but 23 canines were killedimmediately after the experiments.
In the chronic experiments, the 3-month safetyand performance of the combined LP and S-ICD im-plants were assessed. The objectives of the acute
experiments were assessed in this chronic modelwith a follow-up duration of 90 days using theremaining 23 healthy canines (mean weight 30 � 3 kg).After successful implantation, the animals wererecovered and followed up at serial time points. At 3,7, 14, 28, 45, 60, and 75 days post-implant, the animalsunderwent follow-up evaluations that included clin-ical assessment, assessment of LP and S-ICD perfor-mance, and device–device communication. At 90 �14 days after implantation, ATP and shock, S-ICDrhythm discrimination, and post-shock LP perfor-mance testing was performed in 13 of 23 animals,which were hereafter immediately killed. Theremaining 10 animals will be followed up for long-termsafety and performance of the modular CRM system.
All chronic animals underwent standard trans-thoracic two-dimensional echocardiography at base-line pre-implant, immediately post-implant, and atday 90 by using a commercially available ultrasoundsystem (Vivid 9, General Electric, Fairfield, Con-necticut) with a 2.5-MHz transducer. Valvular regur-gitation was estimated visually by using Dopplercolor flow. The following parameters were evaluated:valvular regurgitation severity (none, 0; mild, 1þ;moderate, 2þ; moderate to severe, 3þ; and severe,4þ); RV long- and short-axis dimensions; left ven-tricular ejection fraction by biplane method of discs;heart function and wall motion by visual estimation;pericardial effusion by visual estimation; distancefrom tricuspid valve to device; and tricuspid valveinteraction by visual estimation.
FIGURE 2 Implantation of the LP
(A) The leadless pacemaker (LP) delivery catheter is advanced through 21-F introducer sheath in the inferior vena cava. (B) The delivery catheter is advanced and
deflected in the right ventricle by using the telescope feature to extend the LP into the right ventricular apicoseptal region. (C) The LP is fixated with 4 nitinol tines that
engage in the myocardial tissue. (D) Close-up of the LP fixation mechanism. (E) Implanted LP released from delivery catheter but still connected with tether to test
electrical measurements and adequate fixation by gentle traction on the tether.
Tjong et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7
Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8
1490
DEVICE–DEVICE COMMUNICATION. Communicationbetween the S-ICD and the LP is unidirectional,from S-ICD to LP, via electrically conducted signals.A series of short electrical pulses (the “ATPrequest”) is transmitted by the S-ICD using a vector(the “communication vector”) from the shockingcoil to the can. The orientation of the LP relative tothe communication vector of the S-ICD can affectits ability to sense the communication signals.Theoretically, optimal communication is achievedwhen the long-axis of the LP is positioned parallelto the communication vector; given anatomicalconstraints, this approach is also generally approx-imately perpendicular (90�) to the S-ICD coil(Online Figure 2). The LP is designed to recognizethe communication signals as being sent from theS-ICD and to distinguish communication signalsfrom noise or other sources of electromagneticinterference.
Device–device communication testing consisted of:1) evaluation of successful communication betweenthe S-ICD and LP during sinus rhythm and simulatedVT; 2) evaluation of the communication threshold,defined as the minimum transmit amplitude for suc-cessful receipt of the ATP request by the LP; and3) evaluation of the device orientation of the LPwithin the communication vector (measured by theangle between the long-axis of the LP and the S-ICDcoil) (Online Methods for extended description).
ATP THERAPY DELIVERY BY THE LP. ATP therapydelivery success was defined as successful ATP de-livery by the LP following an ATP request signal. Inthe acute experiments, this outcome was tested bothon the manual ATP request and after an automatedATP request initiated by the modular CRM systemduring a simulated VT. In the chronic experiments,the full automated therapy sequence of the modularCRM system (ATP followed by S-ICD shock) wasevaluated at 90 days post-implant. The S-ICD wasprogrammed with a conditional shock zone of 170to 220 beats/min (with 3 ATP requests, then shock),and a shock zone of >220 beats/min, and the leftventricular catheter was used to pace into the con-ditional shock zone and evaluate the S-ICD’s therapyresponse. Other scenarios were also evaluated, suchas a single shock zone of >170 beats/min to evaluate asingle ATP request and parallel charging for shockdelivery. The number of successful ATP communica-tions and ATP deliveries was recorded. If the heartrate was above the programmed LP tachycardialower limit (e.g., 155 beats/min) when the series ofpulses is received, the LP will deliver ATP in accor-dance with its programmed parameters (i.e., scheme,coupling/burst interval).
GROSS PATHOLOGY EXAMINATION. In all chronicanimals (n ¼ 13) killed after 90 days of follow-up, agross pathological examination was performed to
J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7 Tjong et al.D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8 Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD
1491
assess the following: 1) LP fixation/position in theright ventricle; 2) the existence of tissue encapsula-tion of the LP; and 3) the existence of pericardialeffusion/tine protrusion.
STATISTICAL ANALYSIS. Descriptive statistics arepresented as mean � SD or median (interquartilerange) for continuous variables and as frequenciesand percentages for categorical variables. In thechronic experiments, the paired Student t test wasused to compare means of continuous variables atspecific time points; to test R-wave differences overtime, a linear regression model was used. All analyseswere conducted with SPSS version 20.0 (IBM SPSSStatistics, IBM Corporation, Armonk, New York).
RESULTS
IMPLANTATION OF THE MODULAR CRM SYSTEM. In38 animals, the LP was successfully implanted via theright femoral vein. In 1 animal, the catheter could notbe introduced on the right side due to incompatiblevessel diameter but was successfully implanted viathe left side. One animal was replaced due to anaborted procedure because of a prototype cathetermalfunction without an LP implant attempt. The LPwas implanted in 24 (62%) in the RV apex, 14 (36%) ina low septal position, and 1 (2%) in the RV outflowtract. The duration of the implant procedure of theLP ranged between 59 and 119 min. Echocardio-graphic evaluation post-implant (n ¼ 23) showed nopericardial effusion, no changes in tricuspid regurgi-tation, and no interaction of the LP with the tricuspidvalve compared with baseline (Online Table 1, OnlineVideo 1). The mean distance of the LP to the tricuspidvalve leaflets was 2.2 � 0.6 cm.
The S-ICD was successfully implanted in all 39animals with the pulse generator on the left lateralside and the coil of the lead on the contralateral side(ranging from right parasternal to right lateral chest).
ACUTE MODULAR CRM PERFORMANCE. Duringacute testing, the LP bradycardia pacing functionalitywas assessed in all 39 animals. The mean pacingthreshold, R-wave amplitude, and impedance atimplant were 0.53 � 0.42 V at 0.5 ms, 19.9 � 9.9 mV,and 727 � 193 U, respectively. Pacing thresholdtesting was performed at 0.4 ms (n ¼ 11) or 0.5 ms(n ¼ 28) pulse width; for this analysis, these valuesare pooled, and the R-wave amplitude measurementsin the canine (n ¼ 26) models were right-censored at25 mV.
S-ICD heart rhythm discrimination was correctduring intrinsic and LP pacing above the intrinsic
rate and did not result in oversensing (Figure 3).Induction of VF in the presence of ventricularasynchronous pacing at 60 ppm was performed in7 animals to verify proper discrimination and therapydelivery by the S-ICD (Online Figure 3).
Unidirectional device–device communication fromthe S-ICD to the LP via conductive communicationwas attempted in all implanted animals and wassuccessful in 306 (99%) of 309 communicationattempts in the dorsal position of the animals.
All ATP requests that were triggered by the S-ICDand received by the LP (306 of 306) resulted in ATPtherapy delivery. Figure 4 displays an example ofsuccessful ATP delivery by the LP. ATP therapy con-sisted of 10 beats of pacing at the maximum pacingoutput of 5 V at 1 ms timed at 81% of the previouscoupling interval. An example of the complete ther-apy sequence (3 times ATP therapy bursts followed byan S-ICD shock) can be appreciated in Online Video 2.
In all animals with anteroposterior fluoroscopyimages (n ¼ 23) obtained at implantation, the deviceorientation of the LP was assessed. The median angleof the LP to the S-ICD coil was 28� (range 4 to 39�). Thedevice–device communication was successful in all ofthese animals, with a mean communication thresholdof 2.5 � 0.8 V.
3-MONTH MODULAR CRM PERFORMANCE. All but1 animal (22 of 23 [96%]) completed the 90-dayfollow-up of the modular CRM system. In the 1 ani-mal, only chronic LP performance was obtaineddue to removal of the S-ICD at day 9 post-implantbecause of a pocket infection. In 9 other animals, alocal S-ICD pocket infection was suspected but didnot lead to device removal or systemic infection inthese animals. Potential causes of these infectionswere suboptimal sterile conditions of the animaloperating room, no use of pre-operative antibiotics,and bandage technique. Several precautions wereintroduced to minimize the risk for infection in sub-sequent animal implants.
The chronic electrical performance of the LPshowed a small increase in pacing threshold(p < 0.001) and a decrease in R-wave amplitude(p ¼ 0.001) and impedance (p ¼ 0.04) between base-line and 90 days of follow-up (Table 1). The electricalmeasurements at 7, 28, and 90 days, respectively,were as follows: mean pacing threshold (at 0.5 ms),0.56 � 0.37 V (n ¼ 20), 0.54 � 0.30 V (n ¼ 20), and0.72 � 0.45 V (n ¼ 19); mean R-wave amplitude, 26.3 �6.8 mV (n ¼ 14), 25.0 � 9.4 mV (n ¼ 15), and 23.3 �9.4 mV (n ¼ 23); and mean impedance, 785 � 129 U
(n ¼ 14), 827 � 105 U (n ¼ 20), and 728 � 141 U (n ¼ 22)
FIGURE 3 S-ICD Rhythm Discrimination During High-Rate LP Pacing
Subcutaneous implantable cardioverter-defibrillator (S-ICD) rhythm discrimination during normal sinus rhythm (NSR) and during high-rate
leadless pacemaker (LP) pacing showing adequate rhythm discrimination in all 3 S-ICD–sensing vectors.
Tjong et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7
Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8
1492
(Online Figure 4). R-wave measurements were clip-ped at 25 mV. Several data points at different timepoints were excluded from the analysis based onthe following reasons: LP prototypes without steroid-eluting drug on electrode (n ¼ 3), suspected prototypeLP malfunction (n ¼ 1), and inaccurate measurementsof R wave and impedance due to prototype pro-grammer software coding errors (n ¼ 9).
Echocardiographic evaluation at 90 days (n ¼ 17)revealed no pericardial effusion or mean change intricuspid regurgitation; interaction between thetricuspid valve was noted in 2 animals (12%), leadingto an increase in tricuspid regurgitation in 1 animal(Online Table 1, Online Video 1).
The chronic device–device communication successwas 100% (92 of 92 attempts) (Figure 5). In addition,100% of the communication signals were successfullytranslated into ATP delivery by the LP. The meancommunication thresholds decreased from baselineto 90-day follow-up in all 3 postures: 2.5 � 0.8 V to1.6 � 0.6 V for the dorsal (supine) position, 1.9 � 0.4 Vto 1.6 � 0.5 V for the left lateral position, and 1.8 �
0.4 V to 1.4 � 0.5 V for the right lateral position.All communication thresholds at 90 days were belowthe nominal threshold of 4 V.
Post-shock LP performance was assessed in 7 of39 animals and showed no alterations in electricalperformance: mean change in pacing threshold of0.0 � 0.3 V at 0.5 ms and a mean change in impedanceof �4 � 57 U, respectively. Furthermore, no disloca-tions or device resets were noted.
GROSS PATHOLOGY EXAMINATION. At necropsy,the LP was observed to be implanted in the RV api-coseptal region in 46% (6 of 13) of the animals and inthe RV free wall in the remaining 54%. Deviceencapsulation of the LP ranged from 0% to 100%,with a median of 70% (Figure 6). Three of the 13 LPsdid not have any encapsulation, 5 were partiallycovered (10% to 90%), and 5 LPs were completelyencapsulated. In none of the animals was substantialpericardial effusion (>10 ml) observed. In 3 animals(3 of 13 [23%]), a single tine was observed on theepicardial surface, with no pericardial effusion.
FIGURE 4 ATP Delivery by the LP Commanded by the S-ICD
A modular CRM therapy sequence is displayed: a simulated monomorphic ventricular tachycardia triggers an ATP request from the S-ICD, which
results in 10 beats of ATP delivered by the LP. VT ¼ ventricular tachycardia; other abbreviations as in Figure 1.
J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7 Tjong et al.D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8 Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD
1493
DISCUSSION
MAIN FINDINGS. There were 4 important findings inthis preclinical study on a modular CRM system,consisting of an S-ICD that can unidirectionallycommand a novel LP. First, an LP was successfullyimplanted in 98% of the animals (39 of 40). Second,unidirectional conductive communication betweenthe S-ICD and LP was successful in all implanted an-imals. Third, ATP was successfully delivered bothwhen commanded manually via the S-ICD and auto-matically when the S-ICD detected a simulated VT at arate within the programmed therapy zone. Finally, LPpacing did not have a negative impact on S-ICDsensing of the cardiac rhythm, either at rest or during(simulated) ventricular arrhythmias.
MODULAR CRM IMPLANTATION, SAFETY, AND
PERFORMANCE. LP implantation was feasible viathe femoral vein, despite the relatively large-sized
catheters compared with the smaller sized venousanatomy of these animals. These outcomes aresimilar to the high implantation success rates (95.8%to 99.2%) of the currently available LP systems inhuman with varying body habitus (11,12) using simi-larly sized introducer sheaths (18-F to 23-F). The de-livery catheter has a unique telescoping extensionfeature that enables advancement of its distal portionwhile maintaining a stable position of its proximalportion deflected in the right atrium. This limits for-ward pressure on the RV apex during implantationand allows flexibility to accommodate various cardiacanatomies.
There were no cardiac adverse events related tothe implant procedure; specifically, no occurrence ofpericardial effusion or device dislodgements,confirmed by echocardiography and necropsy. In thechronic animal model, tine protrusion from theepicardium was observed at necropsy in 3 animalswithout pericardial effusion. This outcome suggests
Pre- to post-shock change in pacing threshold, V at 0.5 ms 0.0 � 0.5 0.1 � 0.1 0 – – 0.0 � 0.1
Pre- to post-shock change in impedance, U 18 � 49 26 � 40 5 – – –48 � 58
Values are n (%) or mean � SD. *p value between baseline and 90 days, for pacing threshold and impedance tested with the Student t test, for R wave calculated with a linear regression analysis. †Pacingthreshold data from 3 animals were excluded because the leadless pacemaker (LP) prototypes did not have steroid-eluting electrode. ‡Impedance and pacing threshold data from 1 animal were excluded dueto suspected device malfunction at day 90. §R-wave and impedance data from 7 animals at baseline, 9 animals at day 7, and 7 animals at day 28 were excluded due to programmer software malfunction.
Tjong et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7
Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8
1494
that with the tine fixation mechanism, protrusionthrough the myocardium can occur. The human Micrastudy reported a pericardial effusion rate of 1.6%without tamponade using a similar fixation mecha-nism (nitinol tines) and suggests an increased risk forcardiac perforation compared with transvenouspacemaker leads; data on tine protrusion were notreported (12). A more septal or apicoseptal implantlocation may mitigate this risk.
The S-ICD pocket infections were likely due tosuboptimal sterile conditions, and none of the in-fections was systemic. We expect the infection rate ofthe individual components of this modular systemwill be similar to the currently reported S-ICD and LPinfection rates (10,17,18).
The electrical performance of the LP was adequateand showed a slight increase in pacing threshold anda decrease in impedance and R wave during 90 daysof follow-up. The results and trends were similar toother LP systems tested in animals (19). The long-term electrical performance of this system will beevaluated in ongoing chronic animal experiments.Human data with LP and conventional transvenouspacemakers with active-fixation pacemaker leadsshow similar stable electrical performance (11,12,20).S-ICD sensing was adequate in all animals in at least1 sensing vector. No inappropriate sensing or therapywas observed during LP pacing at rest, duringcommunication, or during ventricular arrhythmias.A previous case series reporting outcomes in S-ICDwith concomitant transvenous pacemakers demon-strated similar results (21), but these findings must
be confirmed in large clinical cohorts with longfollow-up.
DEVICE–DEVICE COMMUNICATION. The modularCRM system uses a novel concept of intrabodydevice–device communication to enable coordinatedleadless pacing and defibrillation therapy. Conductedcommunication has been proven to be a successfultechnology in intrabody communication, using thebody tissue as a conductor (11,13,22). Currently,similar conducted signals are used for S-ICD leadimpedance measurements and have little impact onbattery longevity, and they do not cause undesiredtissue stimulation. The unidirectional communica-tion signals are sent from the S-ICD coil to the S-ICDpulse generator, creating a communication vectorbetween the S-ICD coil and can. The RV position ofthe LP is within this communication vector, assumingnormal human anatomy. The optimal position of thelong-axis of the LP is parallel to the communicationvector, resulting in the largest voltage differencebetween anode and cathode.
In this study, we showed that unidirectionaldevice–device communication was successful in allanimals, with a high success rate of 99% of allcommunication attempts. The unsuccessful commu-nication attempts (3 of 309) all occurred in 1 ovinesubject during the first experiment performed. In thisanimal, the S-ICD lead was placed in a suboptimalposition (high lateral in the right axillary midline andslightly curved) and not representative of the humansituation, which is believed to be the reason for the
FIGURE 5 Device–Device Communication Between S-ICD and LP
(A) Acute and chronic device–device communication success from the S-ICD to the LP. (B) Communication thresholds are displayed during
90 days of follow-up in 3 postures: dorsal, left lateral, and right lateral. The communication signal amplitude can range from 0 to 7 V, and the
nominal setting is 4 V. Abbreviations as in Figure 3.
J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7 Tjong et al.D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8 Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD
1495
failed attempts. The mean communication thresholdwas below the nominal setting of 4 V, which iscurrently used in the S-ICD lead impedance mea-surements and causes no muscle stimulation. Theunfavorable device orientation in these animals(vertical position) did not seem to adversely affectcommunication success. This finding is reassuring,considering the expected device orientation inhumans, which will be more horizontal and parallel tothe communication vector, and thus more favorable.Electromagnetic interference could hypotheticallydisturb the conducted device–device communication.This situation was not observed in our chronic animalstudy; however, no electromagnetic interferencetests were performed. Two safety features were
developed to minimize the risk of communicationinterference: first, a specific communication protocol(signal sequence) is used by the S-ICD and recognizedby the receiving LP. Second, the LP has a built-insafety feature that inhibits ATP if the intrinsic heartrhythm is below a predefined threshold (e.g., 155beats/min).
ATP THERAPY. This study reported a high successrate (100%) of ATP delivery by the LP when com-manded by the S-ICD. The ATP settings of the LP areprogrammable, similarly to conventional transvenouspacemakers. In this first iteration of the modular CRMsystem, ATP can be programmed with up to 3 burstsof ATP in the conditional shock zone (10 beats at 5 V
FIGURE 6 Gross Pathology Examination of LP Implantation After 90 Days
(A) Gross pathological examination of an incised right ventricle exposing a leadless pacemaker (LP) implanted for 90 days with no evidence of
device encapsulation. (B) The LP is fully encapsulated 90 days post-implant.
Tjong et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7
Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8
1496
at 1 ms at varying coupling intervals ranging from50% to 94%) followed by a S-ICD shock. When pro-grammed in the conditional shock zone (fast VTzone), time to first therapy (ATP) will be shorter inthis modular CRM system compared with S-ICDtherapy alone because ATP delivery does not requirecharging of the high-voltage capacitor. In the shockzone (VF zone), 1 burst of ATP will be delivered dur-ing charging similar to transvenous ICDs. A delayedtherapy response is therefore not expected in thismodular CRM system. The impact of both conductivecommunication and ATP bursts on S-ICD and LPbattery longevity is expected to be negligible. Forinstance, 1,000 bursts of ATP per year would result inan approximately 1.5-week LP longevity decrease,whereas 1 h of conductive telemetry per year wouldresult in about 2 months of LP longevity decreasewith conservative assumptions. Post-shock pacing bythe LP is available when programmed to a demandpacing mode (e.g., VVI) and will occur according toprogrammed settings.
ATP continues to be an important programmingfeature for patients with transvenous ICDs, and themodular CRM combination presented here allows forATP to be delivered to S-ICD patients when it isclinically necessary. The incidence of recurrentmonomorphic VT in a pooled analysis (10) presented
in a contemporary S-ICD population (young, withmixed substrates) has been estimated at 0.4% perannum. Poole and Gold (23) estimated that the annualneed for ATP (using SCD-HeFT [Sudden Cardiac Deathin Heart Failure Trial] event rates) would be 1.2%per annum. These risk adjustments are small andprogramming dependent but illustrate a use for ATPin selected patients after implantation of an S-ICD ora tricuspid valve–ICD.FUTURE PERSPECTIVE. With the introduction of thismodular CRM system, new opportunities are avail-able to further individualize patient treatment. Themodular CRM system presented here is compatiblewith the EMBLEM S-ICD platform being implantedtoday. Thus, the LP module can be added to patientsin need of ATP who already have an S-ICD, either atinitial implantation or as their cardiac substrate andprescriptive needs evolve. Similarly, a patient whoundergoes implantation with an LP for bradycardiatreatment can receive an S-ICD when an ICD indica-tion arises in the future. A modular CRM system withforward and backward engineering allows for tailoredtherapy with fewer hardware needs and is the futureof device-based arrhythmia therapies.
Furthermore, the development of bidirectionaldevice–device communication can enable futureiterations of this modular CRM system to enhance
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: The novel
modular CRM system provides coordinated leadless bradycardia
along with ATP that uses the subcutaneous defibrillation system,
thereby minimizing intracardiac hardware. Using this modular
approach of therapy has the potential to optimize individualized
patient treatment strategies.
TRANSLATIONAL OUTLOOK I: This preclinical study with
prototype technology demonstrated safety and adequate
performance as an entire modular CRM system. However, before
clinical adoption can be considered, long-term performance
results and human clinical studies, using more developed and
validated modular CRM systems, are required.
TRANSLATIONAL OUTLOOK II: Common pathways of
bidirectional device–device communication as a human body
network have the potential to intelligently enhance chronic
cardiac care in high-risk patients. Basic examples of this potential
include enhanced S-ICD rhythm discrimination, decrease in
oversensing issues and inappropriate therapy, and further
expansion of modular cardiac rhythm artificial intelligence.
J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7 Tjong et al.D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8 Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD
1497
S-ICD rhythm discrimination via LP rhythm confir-mation. This scenario would potential result infurther reduction of oversensing issues (e.g., T-waveoversensing) and inappropriate therapy.
The first-in-man trials with a validated and verifiedmodular CRM system are planned and will be the firstto combine LP therapy and ICD therapy in a coordi-nated fashion. The safety and performance results ofthis modular system are required to consider clinicaladoption.
CONCLUSIONS
We present the preclinical acute and chronic perfor-mance of the combined implantation of an ATP-enabled LP and S-ICD. Appropriate VVI functionality,successful wireless device–device communication,and ATP delivery were demonstrated by the LP. Clin-ical studies on safety and performance are needed.
ADDRESS FOR CORRESPONDENCE: Dr. Fleur V.Y. Tjong,Department of Clinical and Experimental Cardiology,AcademicMedical Center, AMCHeart Center, Meibergdreef9, 1105 AZ, Room F3-240, Amsterdam NH 1105AZ, theNetherlands. E-mail: [email protected].
RE F E RENCE S
1. Tracy CM, Epstein AE, Darbar D, et al. 2012ACCF/AHA/HRS focused update of the 2008guidelines for device-based therapy of cardiacrhythm abnormalities: a report of the AmericanCollege of Cardiology Foundation/American HeartAssociation Task Force on Practice Guidelines.J Am Coll Cardiol 2012;60:1297–313.
2. Moss AJ, Hall WJ, Cannom DS, et al. MulticenterAutomatic Defibrillator Implantation Trial In-vestigators. Improved survival with an implanteddefibrillator in patients with coronary disease athigh risk for ventricular arrhythmia. N Engl J Med1996;335:1933–40.
3. Moss AJ, Zareba W, Hall WJ, et al. MulticenterAutomatic Defibrillator Implantation Trial II.Prophylactic implantation of a defibrillator inpatients with myocardial infarction and reducedejection fraction. N Engl J Med 2002;346:877–83.
4. Bardy GH, Lee KL, Mark DB, et al. Amiodaroneor an implantable cardioverter-defibrillator forcongestive heart failure. N Engl J Med 2005;352:225–37.
5. Kirkfeldt RE, Johansen JB, Nohr EA,Jørgensen OD, Nielsen JC. Complications aftercardiac implantable electronic device implanta-tions: an analysis of a complete, nationwide cohortin Denmark. Eur Heart J 2014;35:1186–94.
6. Van der Heijden AC, Borleffs CJ, Buiten MS,et al. The clinical course of patients withimplantable cardioverter-defibrillators: extendedexperience on clinical outcome, device
replacements, and device-related complications.Heart Rhythm 2015;12:1169–76.
7. Udo EO, Zuithoff NP, van Hemel NM, et al.Incidence and predictors of short- and long-term complications in pacemaker therapy: theFOLLOWPACE study. Heart Rhythm 2012;9:728–35.
8. Tarakji KJ, Wazni OM, Harb S, Hsu A, Saliba W,Wilkoff BL. Risk factors for 1-year mortality amongpatients with cardiac implantable electronic deviceinfection undergoing transvenous lead extraction:the impact of the infection type and the presenceof vegetation on survival. Europace 2014;16:1490–5.
9. Bardy GH, Smith WM, Hood MA, et al. Anentirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010;363:36–44.
10. Burke MC, Gold MR, Knight BP, et al. Safetyand efficacy of the totally subcutaneousimplantable defibrillator: 2-year results from apooled analysis of the IDE study and EFFORT-LESS registry. J Am Coll Cardiol 2015;65:1605–15.
11. Reddy VY, Exner DV, Cantillon DJ, et al.,LEADLESS II Study Investigators. Percutaneousimplantation of an entirely intracardiac leadlesspacemaker. N Engl J Med 2015;373:1125–35.
12. Reynolds D, Duray GZ, Omar R, et al., MicraTranscatheter Pacing Study Group. A leadlessintracardiac transcatheter pacing system. N Engl JMed 2016;374:533–41.
13. Knops RE, Tjong FV, Neuzil P, et al. Chronicperformance of a leadless cardiac pacemaker:1-year follow-up of the LEADLESS trial. J Am CollCardiol 2015;65:1497–504.
14. Tjong FV, Brouwer TF, Smeding L, et al.Combined leadless pacemaker and subcutaneousimplantable defibrillator therapy: feasibility,safety, and performance. Europace 2016;18:1740–7.
15. Mondésert B, Dubuc M, Khairy P, Guerra PG,Gosselin G, Thibault B. Combination of a leadlesspacemaker and subcutaneous defibrillator: firstin-human report. Heart Rhythm Case Reports2015;1:469–71.
16. Tjong FV, Brouwer TF, Kooiman KM, et al.Communicating antitachycardia pacing-enabledleadless pacemaker and subcutaneous implant-able defibrillator. J Am Coll Cardiol 2016;67:1865–6.
17. Brouwer TF, Yilmaz D, Lindeboom R, et al.Long-term clinical outcomes of subcutaneousversus transvenous implantable defibrillator ther-apy. J Am Coll Cardiol 2016;68:2047–55.
18. Koay A, Khelae S, Kok Wei K, Muhammad Z,Mohd R, Omar R. Treating an infected trans-catheter pacemaker system via percutaneousextraction. Heart Rhythm Case Reports 2016;2:360–2.
19. Koruth JS, Rippy MK, Khairkhahan A, et al.Feasibility and efficacy of percutaneously deliv-ered leadless cardiac pacing in an in vivo ovine
Tjong et al. J A C C : C L I N I C A L E L E C T R O P H Y S I O L O G Y V O L . 3 , N O . 1 3 , 2 0 1 7
Acute and 3-Month Performance of Leadless ATP Pacemaker and S-ICD D E C E M B E R 2 6 , 2 0 1 7 : 1 4 8 7 – 9 8
1498
model. J Cardiovasc Electrophysiol 2015;26:322–8.
20. Kistler PM, Liew G, Mond HG. Long-termperformance of active-fixation pacing leads: aprospective study. PACE 2006;29:226–30.
21. Kuschyk J, Stach K, Tülümen E, et al. Subcu-taneous implantable cardioverter-defibrillator:first single-center experience with other cardiacimplantable electronic devices. Heart Rhythm2015;12:2230–8.
22. Ferguson JE, Redish AD. Wireless communi-cation with implanted medical devices using theconductive properties of the body. Expert RevMed Devices 2011;8:427–33.
23. Poole JE, Gold MR. Who should receive thesubcutaneous implanted defibrillator? The sub-cutaneous implantable cardioverter defibrillator(ICD) should be considered in all ICD patientswho do not require pacing. Circulation 2013;6:1236–45.
KEY WORDS ATP, leadless pacemaker,modular therapy, S-ICD, wirelesscommunication
APPENDIX For an expanded Methodssection as well as a supplemental figures, table,and videos, please see the online version ofthis paper.
