Listen to this manuscript’s

audio summary by

JACC Editor-in-Chief

Dr. Valentin Fuster.

J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 0 , N O . 5 , 2 0 1 7

ª 2 0 1 7 B Y T H E A M E R I C A N CO L L E G E O F C A R D I O L O G Y F O U N DA T I O N

P U B L I S H E D B Y E L S E V I E R

I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0 0

h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 7 . 0 6 . 0 0 8

Temperature-Controlled RadiofrequencyAblation for Pulmonary Vein Isolation inPatients With Atrial Fibrillation

Jin Iwasawa, MD,a Jacob S. Koruth, MD,a Jan Petru, MD,b Libor Dujka, MD,b Stepan Kralovec,b Katerina Mzourkova,b

Srinivas R. Dukkipati, MD,a Petr Neuzil, MD, PHD,b Vivek Y. Reddy, MDa,b

ABSTRACT

Fro

Pra

Dr

oth

ser

Ma

BACKGROUND Saline irrigation improved the safety of radiofrequency (RF) ablation, but the thermal feedback for

energy titration is absent.

OBJECTIVES To allow temperature-controlled irrigated ablation, a novel irrigated RF catheter was designed with a

diamond-embedded tip (for rapid cooling) and 6 surface thermocouples to reflect tissue temperature. High-resolution

electrograms (EGMs) from the split-tip electrode allowed rapid lesion assessment. The authors evaluated the preclinical

and clinical performance of this catheter for pulmonary vein (PV) isolation.

METHODS Using the DiamondTemp (DT) catheter, pigs (n ¼ 6) underwent discrete atrial ablation in a temperature

control mode (60�C/50 W) until there was w80% EGM amplitude reduction. In a single-center clinical feasibility study,

35 patients underwent PV isolation with the DT catheter (study group); patients were planned for PV remapping after

3 months, regardless of symptomatology. A control group included 35 patients who underwent PV isolation with a

standard force-sensing catheter.

RESULTS Porcine lesion histology revealed transmurality in 51 of 55 lesions (92.7%). In patients, all PVs were suc-

cessfully isolated; no char or thrombus formation was observed. Compared with the control group, the study cohort had

shorter mean RF application duration (26.3 � 5.2 min vs. 89.2 � 27.2 min; p < 0.001), shorter mean fluoroscopic time

(11.2 � 8.5 min vs. 19.5 � 6.8 min; p < 0.001), and lower acute dormant PV reconduction (0 of 35 vs. 5 of 35; p ¼ 0.024).

At 3 months, 23 patients underwent remapping: 39 of 46 PV pairs (84.8%) remained durably isolated in 17 of these

patients (73.9%).

CONCLUSIONS This first-in-human series demonstrated that temperature-controlled irrigated ablation produced

rapid, efficient, and durable PV isolation. (ACT DiamondTemp Temperature-Controlled and Contact Sensing RF

Ablation Clinical Trial for Atrial Fibrillation [TRAC-AF]; NCT02821351) (J Am Coll Cardiol 2017;70:542–53)

© 2017 by the American College of Cardiology Foundation.

P ulmonary vein (PV) isolation is the mainstayof catheter ablation for patients with atrialfibrillation (AF) (1). Technological advances,

such as balloon catheters to facilitate PV isolation,are increasingly being used (2,3). However, point-by-point radiofrequency (RF) ablation catheters remainthe most frequently used technology, largely because

m the aHelmsley Electrophysiology Center, Mount Sinai Medical Center, N

gue, Czech Republic. Drs. Koruth and Neuzil have received research gran

. Reddy has served as a consultant to and has received research grant su

er authors have reported that they have no relationships relevant to the c

ved as Guest Editor for this paper.

nuscript received March 13, 2017; revised manuscript received May 2, 20

of the greater flexibility of the lesion set that can bedeployed. Although conceptually straightforward,placing contiguous and transmural point-by-point RFlesions around the PVs is technically challenging.This is supported by the reported near-universal pres-ence of PV reconnections in redo-AF ablation cases andthe low rate of durable PV isolation observed in the

ew York, New York; and the bNa Homolce Hospital,

t support from Advanced Cardiac Therapeutics, Inc.

pport from Advanced Cardiac Therapeutics, Inc. All

ontents of this paper to disclose. Andrea Natale, MD,

17, accepted June 1, 2017.

AB BR E V I A T I O N S

AND ACRONYM S

AF = atrial fibrillation

CF = contact force

DT = DiamondTemp

EGM = electrogram

J A C C V O L . 7 0 , N O . 5 , 2 0 1 7 Iwasawa et al.A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3 Temperature-Controlled Irrigated RF Ablation

543

GAP-AF study (4–7). From a safety perspective, theadvent of saline irrigation has decreased the incidenceof thrombus and char formation on the ablation tip.However, saline irrigation on current ablation cathe-ters also precludes temperature feedback, so thesecatheters are typically operated in a power controlmode.

SEE PAGE 554PV = pulmonary vein

radiofrequency

It is in this context that we investigated theDiamondTemp (DT) ablation catheter (AdvancedCardiac Therapeutics, Inc., Santa Clara, California), acomposite-tip, diamond-embedded, temperature-sensing, saline-irrigated RF ablation catheter. Thecatheter has 6 insulated thermocouples on the abla-tion tip surface to directly measure the tissue surfacetemperature, thereby potentiating temperature-guided irrigated ablation. To provide rapid diffusionof heat, the ablation tip is embedded with industrial-grade diamond, a material with a thermal diffusivitythat is 2 orders of magnitude higher than platinum.Finally, instead of the standard 3.5- or 4-mm distalablation electrode, the DT catheter distal electrode isa composite tip to provide higher resolution electro-grams (EGMs). During RF delivery, the composite tipbehaves as a single RF electrode. Herein, we reportour pre-clinical and first-in-human clinical experi-ence using this novel temperature-controlledirrigated RF ablation catheter.

METHODS

This catheter was evaluated in 2 phases. Thepre-clinical phase involved electrophysiological andhistological assessment of ablation lesions created bythis catheter in a series of porcine experiments. Theclinical phase involved a single-center evaluation inthe TRAC-AF (ACT DiamondTemp Temperature-Controlled and Contact Sensing RF Ablation ClinicalTrial for Atrial Fibrillation) trial. In this prospectivefirst-in-human study, patients underwent PV isolationwith theDT catheter to treat paroxysmal AF, alongwitha pre-specified PV remapping procedure atw3 monthsregardless of intervening symptomatology. Thus, inaddition to the acute procedural performance of thecatheter, we also assessed the 3-month durability ofelectrical PV isolation. With regard to the proceduralperformance, the TRAC-AF outcomes were comparedwith another retrospective cohort of patients withparoxysmal AF who underwent PV isolation using astandard force-sensing irrigated catheter at MountSinai Hospital (New York, New York).

The preclinical experiments were approved by theInstitutional Animal Care and Use Committees at

Mount Sinai Hospital, and the clinical phasewas approved by the human ethics commit-tee at Homolka Hospital, Prague, Czech Re-public, and by the Czech Republic CompetentAuthority, SUKL (State Institute for DrugControl). Written informed consent was ob-tained from all patients. The authors had fullaccess to and take full responsibility for theintegrity of the data, and agree to this paper

as written.

CATHETER DESIGN. The diamond-tip irrigated DTcatheter is a 7.5-F externally irrigated catheterdesigned to deliver RF energy via a 4.1-mm cathetertip electrode (Figure 1). The tip segment consists of acomposite tip electrode and 2 ring electrodes, allmade of platinum-iridium. Unique to the catheter’sdesign, the 2-part composite ablation electrode tip isembedded with 2 industrial-grade diamonds, inter-connected at the distal tip electrode, which allowrapid heat shunting by virtue of their high thermaldiffusivity. This permits accurate temperature esti-mation along the entire length of the electrode. Thedistal aspect of the composite electrode is 0.6 mmand has 6 irrigation ports. By allowing effectivecooling, the diamonds reduce the irrigation rate to8 ml/min during ablation. Although the dual com-posite ablation tip acts as a single electrode duringablation, the 2 aspects of this tip are electricallyinsulated to allow for high-resolution EGM sensingseparately.

Finally, there are 3 surface thermocouples at thedistal end and 3 thermocouples at the proximal end tomonitor the tip�tissue interface temperature duringirrigated ablation (Figure 1). A custom RF generator(Advanced Cardiac Therapeutics) delivers RF energyin a temperature-control mode. The temperaturerecording capability was validated in a bench-topmodel consisting of irrigated ablation on freshporcine hearts. Temperature sensors were insertedinto the target tissue adjacent to the ablation cath-eter. The catheter temperature was set to 55�C and60�C (i.e., maximum surface thermocouple tempera-ture) with contact force (CF) between 12 and 15g, andablation performed in temperature-control mode. In aseries of 20 ablation runs, the average study catheterset temperature of 58.5�C corresponded to a meantissue temperature of 64.2�C at 1-mm depth. Thisdifference between the surface recording andrecording at 1-mm depth was consistent with thenature of irrigated ablation that drives the hot spot ofRF ablation deeper into the tissue.

PRECLINICAL STUDY. After an overnight fast,percutaneous venous access was obtained in 6 pigs;

RF =

FIGURE 1 Ablation Catheter Tip and Functionality

(A) The distal ablation tip electrode is 4.1 mm long, with 3-mm spacing between the tip and first ring electrode. Embedded near the tip electrode are 3 distal and

3 proximal thermocouples (TCs) that monitor tip�tissue surface temperature, which is influenced in part by the thermal diffusivity of the (B) diamonds embedded in (C)

the w1 cm tip. (D) The highest temperature recorded from all thermocouples, power (increases over time), and change in impedance. (E) Temperatures recorded

from all 6 TCs over the course of a single ablation. RF ¼ radiofrequency.

Iwasawa et al. J A C C V O L . 7 0 , N O . 5 , 2 0 1 7

Temperature-Controlled Irrigated RF Ablation A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3

544

transseptal puncture was performed after heparin-ization. A deflectable sheath was advanced into theatria, and a total of 70 ablation applications weredelivered at randomly selected, disparate sites inboth atria in temperature control mode to 60�C(maximum power: 50 W) until an w80% reductionwas seen in the amplitude of the composite-tip EGM.Individual ablation lesions were anatomically definedbased on electroanatomic maps, intracardiacechocardiography, and fluoroscopic guidance. Theanimals recovered for 7 days and then were killed.The explanted heart and surrounding tissue weresubjected to gross examination, with individuallesions identified based on their anatomical positionso that they could be correlated to the correspondingstored RF parameters. The explanted hearts were

immersion-stained with triphenyl tetrazolium chlo-ride. After identification, all lesions were submittedfor histological analysis with hematoxylin and eosinand Masson’s trichrome staining. Lesion depth andoverall myocardial thicknesses were assessed onhistology.CLINICAL COHORTS. TRAC-AF was designed as aprospective, open-label, nonrandomized, single-center study of patients with symptomatic parox-ysmal AF. Patients age 18 to 75 years were enteredinto the study if they had paroxysmal AF refractoryto at least 1 antiarrhythmic drug. Key exclusioncriteria included previous PV isolation procedure,cardiac surgery in the previous 3 months, moderate-to-severe valvular disease, left ventricular ejectionfraction <30%, left atrium diameter >6 cm,

FIGURE 2 PV Isolation Lesion Set

Ipsilateral pulmonary vein (PV) pairs were isolated with a single wide area circumferential

antral ablation lesion set guided by electroanatomic mapping.

TABLE 1 Porcine Atrial Ablation Parameters (N ¼ 64)

Ablation time, s 13.3 � 6.0

Mean power, W 34.1 � 7.2

Max power, W 39.4 � 8.5

Voltage change, % 74.9 � 12.0

Impedance change, U 10.6 � 11.5

Temp distal average, �C 45.2 � 6.1

Temp proximal average, �C 46.5 � 4.3

Lesion length, mm 5.9 � 2.9

Lesion width, mm 4.9 � 2.1

Lesion area, mm2 23.4 � 14.1

Values are mean � SD.

J A C C V O L . 7 0 , N O . 5 , 2 0 1 7 Iwasawa et al.A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3 Temperature-Controlled Irrigated RF Ablation

545

contraindications to long-term antithrombotic ther-apy, and severe pulmonary disease. Consecutive pa-tients (the study group) underwent ablation with theDT irrigated catheter at Homolka Hospital (Prague,Czech Republic) between January 2016 and March2016. These ablation procedures were performed by 2operators (V.R., P.N.).

Patients were discharged the day after ablation ifclinical status was stable and anticoagulation wasuninterrupted. Post-procedure antiarrhythmic medi-cations were either discontinued or reduced indosage for 1 month, after which they were completelydiscontinued. There was a 1-month blanking periodafter ablation. The follow-up at 7 days was conductedover the phone to assess if any adverse events hadoccurred. Post-procedure clinic visits were performedat 3 and 6 months, including 12-lead electrocardio-grams. All patients were required to wear a Holtermonitor for 24 h before their first visit, followed by anevent monitor for 2 weeks at 3 and 6 months.

At w3 months after the index procedure, patientsunderwent a repeat procedure to assess for PVreconnection, regardless of the intervening symp-tomatology. During this procedure, the durability ofPV isolation was assessed with a circular mappingcatheter. If PV reconnection was identified, the DTcatheter was used to ablate the site(s) of break-through to achieve re-isolation.

As a comparator for procedural performance, weexamined an additional cohort of 35 consecutiveparoxysmal AF patients (the control group) whounderwent ablation with a CF-sensing irrigated tipcatheter (Thermocool SmartTouch, Biosense WebsterInc., Irvine, California) at Mount Sinai Hospital by asingle operator (V.R.) between July 2015 andApril 2016.

ABLATION PROCEDURE. The study procedures wereperformed under either conscious sedation (n ¼ 34) orgeneral anesthesia (n ¼ 3). Double transseptal punc-tures were performed, and the ablation catheter wasplaced within a deflectable sheath (Agilis, St. JudeMedical, Minneapolis, Minnesota). Intracardiacechocardiography and esophageal temperaturemonitoring were performed in all cases; ablation wasterminated if temperatures reached 38.5�C. IpsilateralPVs were isolated with wide-area circumferentialantral ablation lesion sets guided by electroanatomicmapping (NavX, St. Jude Medical) (Figure 2). PVisolation was achieved with interrupted point-by-point ablation (dragging was not permitted in thisstudy). As per our usual practice, a double ablationline was placed along the anterior aspect of the lesionset of the right PVs.

The contact level was assessed by the operatorusing traditional criteria (e.g., EGMs, cathetermotion, proximity to the electroanatomical map sur-face, intracardiac ultrasound imaging) because CFmonitoring was not available. Each lesion was deliv-ered in a temperature control mode set to 60�C(maximum: 50 W) until a 75% to 80% reduction in thesplit-tip EGM amplitude occurred, followed by abla-tion for an additional 3 to 5 s. The goal temperaturewas reduced to 50�C when ablating posteriorly inproximity to the esophagus. The saline irrigation ratewas 2 ml/min during mapping and 8 ml/min duringablation. Additional ablation for atrial flutter waspermitted if it occurred spontaneously or wasinduced during the procedure.

FIGURE 3 Preclinical Electrograms and Histology

(A) Preclinical study pre- and post-ablation split-tip electrograms show reduction from 1.77 to 0.25 mV. (B) In this histological segment (Masson’s trichrome) of an

atrial ablation demonstrating a transmural lesion, fibrotic replacement was incomplete because the animals were killed after 1 week, thereby accounting for the

necrotic core. D1-D2 ¼ distal tip1-distal tip2; D2-R1 ¼ distal tip2-ring1; DCS ¼ distal coronary sinus; ECG ¼ electrocardiogram; MCS ¼ middle coronary sinus;

PCS ¼ proximal coronary sinus; R1-R2 ¼ ring1-ring2.

Iwasawa et al. J A C C V O L . 7 0 , N O . 5 , 2 0 1 7

Temperature-Controlled Irrigated RF Ablation A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3

546

All control group procedures were also performedunder general anesthesia, using a different electro-anatomical mapping system (CARTO, BiosenseWebster Inc.) and a CF-sensing catheter (ThermocoolSmartTouch, Biosense Webster Inc.). Automaticlesion annotation software (Visitag, BiosenseWebster Inc.) was set to stability, with a minimum

time of 8 s and maximum range of 2 mm, and aminimum force of 6g >50% of the time. RF energywas delivered by an interrupted point-by-pointablation technique in power-control mode (powertypically at 35 W and irrigation at 30 ml/min). Thegoal CF during ablation was >10g. Contralateralesophageal deviation was used during these

FIGURE 4 Study Flow and PV Reconnection Distribution

Enrolled (n = 37)

PV Isolation (n = 35)

3-Month Re-Map (n = 23)

A B

Right Pulmonary veins Left Pulmonary veins

Ante

rior

Ante

rior

Post

erio

r

Post

erio

r

(A) The number of patients whowere enrolled, who underwent completion of pulmonary vein (PV) isolation, andwho presented for the 3-month

remap procedure in this study. (B) This distribution of PV reconnection sites was noted in 6 of 9 patients during the repeat study.

J A C C V O L . 7 0 , N O . 5 , 2 0 1 7 Iwasawa et al.A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3 Temperature-Controlled Irrigated RF Ablation

547

procedures (8). In instances when the esophagus wasin closer proximity to the point of ablation, ablationwas stopped if esophageal temperatures reached38.5�C. As per our usual practice, a cavo-tricuspidablation line was routinely placed.

For both the study and control groups, afterconfirmation of PV isolation using multipolar circularmapping catheters, 18 mg intravenous adenosine wasadministered. The occurrence of 1 blocked P-wave ora sinus pause confirmed an effective adenosine dose.Sites of dormant electrical conduction were recorded,and supplementary RF energy was delivered toeliminate dormant conduction.

TABLE 2 Baseline Clinical Characteristics

Study Group(n ¼ 35)

Control Group(n ¼ 35) p Value

Age, yrs 60 � 10 63 � 11 0.312

Male 24 (69) 28 (80) 0.274

LVEF, % 64 � 4 63 � 12 0.371

LA diameter, mm 44 � 4 40 � 5 0.052

AF duration, months 42 � 34 46 � 44 0.682

Hypertension 27 (77) 17 (49) 0.019

Heart failure 0 (0) 1 (3) 0.307

Diabetes mellitus 6 (17) 3 (9) 0.253

Stroke 1 (3) 3 (9) 0.296

CAD 5 (14) 7 (20) 0.490

Antiarrhythmic therapy

Class I 16 (46) 8 (22) 0.044

Class II 16 (46) 25 (71) 0.029

Class III 9 (26) 14 (40) 0.203

Class IV 3 (9) 2 (6) 0.500

Values are mean � SD or n (%).

AF ¼ atrial fibrillation; CAD ¼ coronary artery disease; LA ¼ left atrial;LVEF ¼ left ventricular ejection fraction.

STATISTICAL ANALYSIS. Continuous variables areexpressed as mean � SD, and categorical variables asfrequency (percentage). We used chi-square tests tocompare the categorical variables, and the 2-sampleStudent t test was used to compare normally distrib-uted continuous variables. The Mann-Whitney U testwas used to compare the continuous variables thatwere not normally distributed. A p value <0.05 wasconsidered statistically significant. Statistical analysiswas performed using SPSS Statistics 23 (IBM, Armonk,New York).

RESULTS

PRECLINICAL. A total of 70 discrete RF energyapplications were delivered to the atria. When

TABLE 3 Procedural Details

Study Group(n ¼ 35)

Control Group(n ¼ 35) p Value

No. of ablation lesionsper patient

83.6 � 13.2 151.6 � 38.2 <0.001

Left PV lesion set 37.9 � 8.8 60.2 � 18.2 <0.001

Right PV lesion set 46.1 � 9.5 91.3 � 26.0 <0.001

RF application time perpoint, s

18.8 � 1.9 35.1 � 4.1 <0.001

Left PV lesion set 17.6 � 1.9 33.8 � 5.4 <0.001

Right PV lesion set 19.7 � 2.4 35.8 � 4.2 <0.001

Total RF application timeper patient, min

26.3 � 5.2 89.2 � 27.2 <0.001

Left PV lesion set 11.2 � 3.3 34.4 � 13.1 <0.001

Right PV lesion set 15.1 � 3.7 54.8 � 17.9 <0.001

Fluoroscopy time, min 11.2 � 8.5 19.5 � 6.8 <0.001

Average impedance drop, U 13.1 � 3.5 8.1 � 2.1 <0.001

Average power, W 36.3 � 2.6 31.2 � 2.5 <0.001

Values are mean � SD.

PV ¼ pulmonary vein; RF ¼ radiofrequency.

CENTRAL ILLUSTRATION Catheter Tip�Tissue Interactions

Iwasawa, J. et al. J Am Coll Cardiol. 2017;70(5):542–53.

(A) A standard irrigated radiofrequency (RF) catheter typically uses constant power output. When there is poor or tenuous tip�tissue contact (left), the

attenuated transfer of RF energy into the tissue produces less tissue heating, thereby resulting in a smaller than intended lesion or a nontransmural

ablation lesion. Conversely, with forceful tip�tissue contact (right), the excessive amount of RF energy transferred into the tissue can overheat the tissue

to >100�C, which results in a steam pop that can disrupt the tissue, potentially even leading to cardiac perforation. (B) The DiamondTemp-irrigated RF

ablation catheter, however, modulates the power output based on feedback from the thermocouples situated on the catheter surface. Accordingly,

regardless of the nature of tip�tissue contact, the proper amount of energy is delivered to result in a uniformly transmural lesion. Thus, in instances of

tenuous tip�tissue contact (left), power automatically increases to achieve the target tip temperature (65�C); with forceful tip�tissue contact (right),

there is a compensatory decrease in the power output to maintain the target temperature.

Iwasawa et al. J A C C V O L . 7 0 , N O . 5 , 2 0 1 7

Temperature-Controlled Irrigated RF Ablation A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3

548

J A C C V O L . 7 0 , N O . 5 , 2 0 1 7 Iwasawa et al.A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3 Temperature-Controlled Irrigated RF Ablation

549

the animals were killed 7 days later, 6 lesionswere not found on examination; the biophysicalparameters and lesion dimensions of the remaining64 lesions are shown in Table 1. The average lesionarea, as measured on the endocardial surface, was23.4 � 14.1 mm2. These dimensions and transmuralityrates were achieved in 13.3 � 6.0 s of RF time (range:5 to 32 s). The split-tip EGM amplitude reduction frombaseline at the end of the lesion (Figure 3A) was notedto be 74.9 � 12.0%. Of the 64 lesions, histologicalspecimens were of sufficient quality for analysis in 55lesions (30 left atria, 25 right atria). The mean tissuethickness (measured on histology) was 1.9 � 0.9 mm(range: 0.5 to 4.2 mm), and transmural necrosisoccurred in 92.7% (51 of 55 lesions) (Figure 3B). Nosteam pops, char formation, or increases in imped-ance occurred during ablation.

CLINICAL. In the study cohort, a total of 37 patientswere enrolled (Figure 4A). However, 2 patients did notundergo ablation with the DT catheter; in 1 patient,because the atrium was so extensively scarred thatablation would have been futile, and for the other,because of a technical fault with the mapping system(not the DT catheter), which resulted in the use of aballoon catheter for ablation. Thus, the analyzedpatients in the study cohort included 35 patients; acorresponding group of 35 patients were included inthe control cohort.

Per baseline clinical characteristics (Table 2), themean ages of the study and control cohorts were60 � 10 and 63 � 11 years, respectively; most weremen. Left ventricular function was preserved, and themain comorbidity was hypertension.

In the study cohort, 13 of 35 subjects (37.1%) werein AF at the beginning of the procedure; all otherswere in sinus rhythm. Acute PV isolation was ach-ieved in all patients in both groups. The shorter meanduration for each RF lesion in the study group(p < 0.001) suggested that EGM diminution occurredfaster with the DT catheter (Table 3). Similarly, the RFapplication time for PV isolation was significantlylower for the study group than for the control group(p < 0.001). This translated to a 70% reduction in totalRF time. In the study group, dormant conductionwith adenosine provocation was not present in any(0%) of the 35 patients (70 PV pairs). However, in thecontrol group, dormant conduction was unmasked in5 of 35 patients (14%; 5 of 70 PV pairs; p ¼ 0.024 vs.study group).

With regard to other procedural characteristics, ofall the individual lesions made in the study group,76% of lesions had an impedance drop of >10 U

(Table 3). The mean CF per ablation lesion in thecontrol group was 24.8 � 4.0g. In the study group, 3patients underwent additional ablation for atrialflutter (2 atypical left atrial flutters and 1 typicalcavotricuspid flutter). In the control group, 33 pa-tients underwent cavotricuspid isthmus ablation aspart of a routine strategy (i.e., empiric cavotricuspidisthmus ablation). The overall mean fluoroscopy timein the study group was also significantly lower thanthe control group (p < 0.001). The overall amountof saline infused through the DT catheter was only384 � 71 ml; the saline infused for the control groupcases was not recorded.

There were no occurrences of char formation orsteam pop occurrence in the study group. In thisgroup, a mean of 5.8 RF applications per patientdemonstrated a luminal esophageal temperature riseof >38.5�C. One study group patient developed adelayed pericardial effusion 8 h after the procedure;this was drained, and the patient was discharged. Afew weeks later, the same patient returned withrecurrent pericardial effusion that was again drained.No further accumulation occurred, and the patientdid well in follow-up. The exact etiology of thiseffusion was unclear; during the procedure, therewere no instances of audible pops, and at the end ofthe procedure, the intracardiac echocardiographycatheter was used to document the absence of anypericardial effusion.

PV REMAPPING AND FOLLOW-UP. Of the 35 studygroup patients, 23 (66%) agreed to undergo PVremapping, at a mean of 128 � 57 days (range: 57 to229 days) after the index ablation procedure. Threepatients had left common veins, whereas all othersubjects had 4 PVs each, resulting in a total of 89 PVsanalyzed. Durable PV isolation was noted in 39 of 46PV pairs and 80 of 89 PVs; this translated to durableisolation rates of 84.8% on a per PV pair basis and89.9% on a per PV basis. The distribution of PVreconnections were 2 in the left superior PV, 1 leftinferior PV, 2 right inferior PVs, and 4 right superiorPVs. The focal areas of PV reconnection were identi-fied in 6 of 9 PVs (Figure 4B); the precise areas of PVreconnections were not accurately determined for theother 3 PVs. On a per-patient basis, 17 of 23 patients(73.9%) demonstrated durable PV isolation duringthis remapping procedure.

At 6-month follow-up, AF was recorded on theevent recorder in 7 of 35 patients (20%). Five of thesepatients with clinical recurrence were remapped;however, 19 of 20 PVs in these 5 patients had beendurably isolated, suggesting a non-PV trigger for the

FIGURE 5 Continuous Drag Lesion With Accompanying RF Parameters

(A) This shows the epicardial aspect of a continuous endocardial drag lesion placed

between the superior vena cava (SVC) and inferior vena cava (IVC) in swine atria; the

lesion is both contiguous and transmural. (B) In the biophysical data associated with this

entire drag lesion (w150 s), a gradual reduction and then an increase in RF power are

seen as it reacts to changes in tissue temperature with each successive movement.

Iwasawa et al. J A C C V O L . 7 0 , N O . 5 , 2 0 1 7

Temperature-Controlled Irrigated RF Ablation A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3

550

AF. Two months following the ablation procedure, 1patient died; a post-mortem examination indicatedthat the cause of death was systolic heart failurerelated to coronary artery disease. This was adjudi-cated to be unrelated to either the procedure or studycatheter. No other complications were noted in anyother subjects.

DISCUSSION

Irrigated RF ablation was introduced to minimize thefrequency of thrombus or char formation, and thesubsequent risk of embolic stroke during left-sidedablation. However, saline irrigation rendered theuse of temperature as a feedback to control thetitration of power during thermal RF ablationimpossible. We reported the initial preclinical and

first-in-human experiences with a novel catheterdesigned with an array of thermocouples situateddirectly at the tip�tissue interface to permit reintro-duction of temperature-controlled, saline-irrigatedRF ablation.

In the preclinical experiments, 75% reduction involtage was achieved with 13.3 � 6.0 s of RF, and wedemonstrated a transmurality rate of 92.7%. Thisapproach to rapid lesion creation was then testedclinically in 35 patients who underwent PV isolation;100% acute isolation was achieved efficiently with26.3 � 5.2 min of RF application time per patient.There were no instances of dormant reconductionwith adenosine, and the 3-month durable isolationrates on a per-vein pair and per-patient basis were85% and 74%, respectively.

RF-BASED PV ISOLATION. Currently availableapproaches to PV isolation using RF can be broadlyseparated into 2 categories: 1) point-by-point RFablation to create peri-venous circumferential lesionssets (9); and 2) “1-shot” PV isolation approachesusing either balloons or multipolar catheters (9–12).Although 1-shot ablation approaches are less depen-dent on operator expertise, they are largely limited bytheir ostial level of PV isolation and their inability totarget discrete non-PV sites (13). Conversely, point-by-point irrigated RF ablation has the flexibility toprovide both a wide antral isolation and the ability toperform extra PV ablation. However, this approach isalmost universally delivered in a power-controlmode, which is widely acknowledged to be labo-rious. Despite advances, such as force sensing and useof indirect lesion assessment tools (e.g., force�timeintegral and ablation index), PV isolation requiressignificant time and skill. Furthermore, an unaccept-ably high incidence of chronic PV reconnections re-mains: w70% of patients had PV reconnections atw3 months post-ablation in the GAP-AF study (7).Inadequate rates of durable PV isolation in the post-force sensing era can be explained by either discon-tinuous lesion placement and/or inadequate lesionformation. The latter, in particular, is sensitive tocreating consistently wide and deep enough lesions. Itis reasonable to speculate that improvements in lesionformation would translate into improvements in thedurability of PV isolation. In addition, if such lesionscan be formed quickly, the currently laborious point-by-point ablation technique may change to a moreefficient approach.

In this study, we evaluated a unique catheterdesign that allowed for reliable measurement ofcatheter�tissue interface temperatures despite the

FIGURE 6 Comparison of RF Times Among Studies

***

**

***

***

p < 0.001p < 0.001120

100

RF A

pplic

atio

n Ti

me

for P

VI (m

in)

80

60

40

20

0

p < 0.001

50±24 min47±26 min

89±27 min

26±5 min

TRAC-AFStudy Group

TRAC-AFControl Group

TOCCASTAR-TactiCath

Heartlight-Thermocool

*

RF times in the TRAC-AF (ACT DiamondTemp Temperature-Controlled and Contact

Sensing RF Ablation Clinical Trial for Atrial Fibrillation) study arm are shown in

comparison to that of the control arm, the TactiCath arm of the TOCCASTAR (TactiCath

Contact Force Ablation Catheter Study for Atrial Fibrillation), and the Thermocool arm of

the Heartlight clinical trial. PVI ¼ pulmonary vein isolation; RF ¼ radiofrequency.

J A C C V O L . 7 0 , N O . 5 , 2 0 1 7 Iwasawa et al.A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3 Temperature-Controlled Irrigated RF Ablation

551

presence of an irrigated tip, which is now broadlyaccepted to be essential for any left-sided ablation(Central Illustration). Interface temperatures reflectthe degree of catheter-tissue coupling and cantherefore provide an estimate of the tissue tempera-ture within a lesion. Therefore, by design, tempera-ture could be made part of a feedback loop(temperature control) to allow automated titration ofpower based on catheter�tissue coupling. This haspotential advantages over the current approach ofempiric power-controlled ablation. That is, fixedpower in the setting of varying CF and catheterstability may result in inconsistent lesions. With thedynamic nature of force and stability, automatedtitration of power in conditions of excessive or poorcatheter�tissue contact and stability should result inmore efficient, reliable, and safe lesion formation.

This catheter also has 2 additional features toimprove ablation efficiency: 1) a diamond heat shunttip ablative segment; the high thermal diffusivity ofdiamond allows for both rapid detection of tempera-ture changes to improve temperature feedback, aswell as homogenous and improved cooling of the tip;and 2) a composite tip for EGM recording; thishigh-resolution EGM might be better at monitoringlesion formation. This composite-tip EGM helps theoperator to determine when to terminate ablation andminimize collateral injury. From a safety standpoint,both steam pop or perforation and char formation arerelated to higher tip temperatures; accordingly, it isexpected these will be less frequent with temperaturecontrol.

PRECLINICAL. Although our data were limited bythe relative thinness of porcine atria, we demon-strated a high rate (93% sections) of transmuralitywithout pop or char formation. This was achievedusing a strategy of discontinuing RF once significantEGM reduction was achieved. The ability to achievetransmurality in w13 s indicated that adequatelesion formation could be rapidly achieved withgood safety in thin tissues. The efficiency ofcombining temperature-controlled power titrationwith composite-tip EGM reduction is highlighted inFigure 5—a porcine “drag” lesion in which anendocardial ablation line was placed between thesuperior and inferior vena cavas. Together, thesedata provided the experimental basis for the clinicalphase of evaluation.

CLINICAL. In the TRAC-AF clinical study, despitesignificantly reduced RF times, we demonstratedthat acute PV isolation was achieved in 100% ofcases without any evidence of dormant conduction

upon adenosine challenge, which underscored theoverall efficiency of temperature-controlled RFdelivery (mean duration for each RF lesion was18 s). The RF times in the study arm (26.3 � 5.2min) were 70% lower than our control arm(89.2 � 27.2 min).

The clinical strategy used in the control arminvolved ablation until a pre-determined endpointbased on the automatic lesion annotation software.Furthermore, we typically included redundantlesions along sites of thick atrial tissue (such asanterior to the right PVs), poor stability, and sites offrequent reconnections. This led to our control armdemonstrating significantly longer RF times thanthose observed in other contemporary paroxysmal AFablation studies, such as the TOCCASTAR (TactiCathContact Force Ablation Catheter Study for AtrialFibrillation) and the Heartlight (CardioFocus,Marlborough, Massachusetts) multicenter clinicaltrials (47 and 50 min, respectively) (Figure 6) (3,14).However, even if we were to compare the studyarm with these other studies, the RF time reductions

PERSPECTIVES

COMPETENCY IN PATIENT CARE AND

PROCEDURAL SKILLS: Irrigation facilitates RF

ablation and reduces embolic events by cooling the

catheter tip during thermal energy transfer, but it also

impedes temperature-guided titration of energy

delivery to endocardial tissue. Application of surface

thermocouples at the tip of an irrigated catheter

improved temperature-controlled energy titration,

which enabled safe and effective ablation.

TRANSLATIONAL OUTLOOK: Randomized studies

are needed to compare the outcomes of ablations

procedures performed with temperature-guided

catheters and conventional instruments.

Iwasawa et al. J A C C V O L . 7 0 , N O . 5 , 2 0 1 7

Temperature-Controlled Irrigated RF Ablation A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3

552

(44% and 47%) were still substantial. Furthermore,and most importantly, during the remapping study,39 of 46 PV pairs (84.8%) or 80 of 89 PVs (89.9%)remained electrically isolated, translating to 17 of 23patients (73.9%) with durable PV isolation. These datacompared favorably with other remapping studies,such as the EFFICAS II (TactiCath ProspectiveEffectiveness Pilot Study) study, in which 85% of PVswere durably isolated during a long-term remappingstudy (15).

Importantly, from a safety perspective, therewere no instances of thrombus or char detected onthe ablation catheter tip, nor any observed in-stances of audible pops. However, 1 patient devel-oped delayed tamponade 8 h after the procedure.Although this effusion was, of course, related to theablation procedure, it was curious that there wasno evidence of peri-cardial effusion at the end ofthe procedure by intracardiac echocardiographicimaging.

STUDY LIMITATIONS. This was a nonrandomizedcomparison, and therefore, it was subject to po-tential bias. Because of its nonrandomized design,it was unknown if fixed power (35 W) and shortduration (w18 s) might have resulted in similaroutcomes. In addition, this was a small study froma single center, and the study patients underwentthe procedure by a single expert operator; there-fore, the generalizability of the results was limited.Further experience with this catheter in multi-center studies is needed to more accuratelydetermine its efficacy and safety. Also, the3-month time point for the remapping study didnot address the possibility of PV reconnection atlater time points.

CONCLUSIONS

Catheter tip�surface thermocouples permitted safeand effective temperature-controlled, saline-irrigatedRF ablation. Using this power titration strategy, thefirst-in-human TRAC-AF clinical series demonstratedthat rapid and durable PV isolation was achievable.These data usher back an era of facile, efficienttemperature-controlled irrigated RF ablation duringPV isolation.

ADDRESS FOR CORRESPONDENCE: Dr. Vivek Y.Reddy, Helmsley Electrophysiology Center, IcahnSchool of Medicine at Mount Sinai, One Gustave L.Levy Place, PO Box 1030, New York, New York 10029.E-mail: vivek.reddy@mountsinai.org.

RE F E RENCE S

1. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on cath-eter and surgical ablation of atrial fibrillation:recommendations for patient selection, proceduraltechniques, patient management and follow-up,definitions, endpoints, and research trial design.Heart Rhythm 2012;9:632–96.

2. Kuch KH, Brugada J, Fümkranz A, et al. Cry-oballoon or radiofrequency ablation for paroxysmalatrial fibrillation. N Engl J Med 2016;374:2235–45.

3. Dukkipati SR, Cuoco P, Kutinsky I, et al. Pul-monary vein isolation using the visually guidedlaser balloon: a prospective, multicenter, andrandomized comparison to standard radio-frequency ablation. J Am Coll Cardiol 2015;66:1350–60.

4. Callans DJ, Gerstenfeld EP, Dixit S, et al.Efficacy of repeat pulmonary vein isolation

procedures in patients with recurrent atrial fibril-lation? J Card Electrophysiol 2004;15:1050–5.

5. Ouyang F, Antz M, Ernst S, et al. Recovered pul-monary vein conduction as a dominant factor forrecurrent atrial tachyarrhythmias after complete cir-cular isolation of the pulmonary veins. Lessons fromdouble Lasso technique. Circulation 2005;111:127–35.

6. Lemola K, Hall B, Cheung P, et al. Mechanismsof recurrent atrial fibrillation after pulmonary veinisolation by segmental ostial ablation. HeartRhythm 2004;1:197–202.

7. Kuck KH, Hoffman BA, Emst S, et al. Impact ofcomplete versus incomplete circumferential linesaround the pulmonary veins during catheterablation of paroxysmal fibrillation: results fromthe Gap-Atrial Fibrillation-German Atrial fibrilla-tion Competence Network 1 Trial. Circ ArrhythmElectrophysiol 2016;9:e003337.

8. Koruth JS, Reddy VY, Miller MA, et al.Mechanical esophageal displacement duringcatheter ablation for atrial fibrillation.J Cardiovasc Electrophysiol 2012;23:147–54.

9. Macle L, Jaïs P, Weerasooriva R, et al. Irrigated-tip catheter ablation of pulmonary veins fortreatment of atrial fibrillation. J Cardiovasc Elec-trophysiol 2002;13:1067–73.

10. Van Belle Y, Janse P, Rivero-Ayerza MJ, et al.Pulmonary vein isolation using an occluding cry-oballoon for circumferential ablation: feasibility,complications, and short-term outcome. Eur HeartJ 2007;28:2231–7.

11. Reddy VY, Neuzil P, Themistoclakis S, et al.Visually-guided balloon catheter ablation of atrialfibrillation: experimental feasibility and first-in-human multicenter clinical outcome. Circulation2009;120:12–20.

J A C C V O L . 7 0 , N O . 5 , 2 0 1 7 Iwasawa et al.A U G U S T 1 , 2 0 1 7 : 5 4 2 – 5 3 Temperature-Controlled Irrigated RF Ablation

553

12. Scaglione M, Caponi D, Anselmino M, et al.Pulmonary vein isolation with a new multipolarirrigated radiofrequency ablation catheter(nMARQTM): feasibility, acute and short-termefficacy, safety, and impact on post ablationsilent vertebral ischemia. J Cardiovasc Electro-physiol 2014;25:1299–305.

13. Reddy VY, Neuzil P, d’Avila A, et al. Ballooncatheter ablation to treat paroxysmal atrial

fibrillation: what is the level of pulmonary venousisolation? Heart Rhyhm 2008;5:353–60.

14. Reddy VY, Dukkipati SR, Neuzil P, et al.Randomized, controlled trial of the safety andeffectiveness of a contact force-sensing irrigatedcatheter for ablation of paroxysmal atrial fibrilla-tion: results of the TactiCath Contact Force AblationCatheter Study for Atrial Fibrillation (TOCCASTAR)study. Circulation 2015;132:907–15.

15. Kautzner J, Neuzil P, Lambert H, et al. EFFICASⅡ:optimization of catheter contact force improvesoutcome of pulmonary vein isolation for paroxysmalatrial fibrillation. Europace 2015;17:1229–35.

KEY WORDS catheter ablation,electrogram, first-in-human, histology,remapping