three-dimensional 123i-meta-iodobenzylguanidine...

DOI: 10.1161/CIRCEP.114.002105

1

Three-Dimensional 123I-Meta-Iodobenzylguanidine Cardiac Innervation Maps

to Assess Substrate and Successful Ablation Sites for Ventricular Tachycardia:

A Feasibility Study for a Novel Paradigm of Innervation Imaging

Running title: Klein et al.; 123I-MIBG to Guide VT Ablation

Thomas Klein, MD1,2; Mohammed Abdulghani, MD1,2; Mark Smith, PhD1,3; Rui Huang, MD1,2;

Ramazan Asoglu, MD1,2; Benjamin F. Remo, MD1,2; Aharon Turgeman, MSc, MBA5; Olurotimi

Mesubi, MD1,2; Sunjeet Sidhu, MD1,2, Stephen Synowski, PhD1,2; Anastasios Saliaris, MD1,2;

Vincent See, MD1,2; Stephen Shorofsky, MD, PhD1,2; Wengen Chen, MD, PhD1,3;

Vasken Dilsizian, MD1,3; Timm Dickfeld, MD, PhD1,2

1Maryland Arrhythmia and Cardiology Imaging Group (MACIG), 2Division of Cardiology, 3Department of Radiology, University of Maryland, Baltimore, MD; 4Biosense Webster, Haifa, Israel

Correspondence:

Timm Dickfeld, MD, PhD

Division of Cardiology

University of Maryland School of Medicine

22 S Greene St.

Baltimore, MD 21201

Tel: 410 328 6056

Fax: 410 328 2062

E-mail: [email protected]

Journal Subject Codes: [22] Ablation/ICD/surgery, [106] Electrophysiology, [124] Cardiovascular imaging agents/techniques, [32] Nuclear cardiology and PET

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DOI: 10.1161/CIRCEP.114.002105

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Abstract:

Background - Innervation is a critical component of arrhythmogenesis and may present an

important trigger/substrate modifier not employed in current VT ablation strategies.

Methods and Results - Fifteen patients referred for ischemic VT ablation underwent pre-

procedural cardiac 123I-meta-iodobenzylguanidine (123I-mIBG) imaging, which was used to create

3D innervation models and registered to high-density voltage maps. 3D 123I-mIBG innervation

maps demonstrated areas of complete denervation and 123I-mIBG transition zone in all patients,

which corresponded to 0-31% and 32-52% uptake. 123I-mIBG denervated areas were ~2.5-fold

larger than bipolar voltage-defined scar (median 24.6% (Q1-Q3:18.3-34.4%) vs. 10.6% (Q1-

Q3:3.9-16.4%), p<0.001) and included the inferior wall in all patients, with no difference in the

transition/border zone (11.4% (Q1-Q3:9.5-13.2%) vs. 16.6% (Q1-Q3:12.0-18.8%), p=0.07).

Bipolar/unipolar voltages varied widely within areas of denervation; 0.8mV (Q1-Q3:0.3-1.7mV)

and 4.0mV (Q1-Q3:2.9-5.6mV) and 123I-mIBG transition zones (0.8mV (Q1-Q3:0.4-1.8mV) and

4.6mV (Q1-Q3:3.2-6.3mV). Bipolar voltages in denervated areas and 123I-mIBG transition zones

were <0.5mV, 0.5-1.5mV and >1.5mV in 35%, 36%, 29%, and 35%, 35%, 30%, respectively

(p>0.05). Successful ablation sites were within bipolar voltage-defined scar (7%), border zone

(57%), and areas of normal voltage (36%), but all ablation sites were abnormally innervated

(denervation/123I-mIBG transition zone in 50% each).

Conclusions - 123I-mIBG innervation defects are larger than bipolar voltage-defined scar and

cannot be detected with standard voltage criteria. 36% of successful VT ablation sites

demonstrated normal voltages (>1.5mV), but all ablation sites were within areas of abnormal

innervation. 123I-mIBG innervation maps may provide critical information about triggers/substrate

modifiers and could improve understanding of VT substrate and facilitate VT ablation.

Clinical Trial Registration – https://clinicaltrials.gov; Unique Identifier: NCT01250912

Key words: ventricular tachycardia, image-guided intervention, cardiac neurotransmission, mapping, innervation, cardiac imaging, ventricular tachycardia ablation, image integration

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Introduction

The current concept of reentrant ventricular tachycardia (VT) in the setting of structural heart

disease postulates a complex interplay of triggering mechanisms initiating VT as well as fixed

anatomic substrate capable of maintaining the arrhythmia.1 Modern ablation approaches

primarily target anatomic substrate, which consists of scar with embedded bands of surviving

myocardium that represent necessary areas of slow conduction.2 With this approach, the success

rate of VT ablation remains limited, with a VT recurrence rate of 47% over 6 months in a large

series despite experienced operators and use of state-of-the-art ablation technology.3

A possible explanation for this limited success is that the current anatomic scar -based

ablation strategy does not incorporate VT triggers and substrate-modulators, such as abnormal

innervation, which is known to play an important role in arrhythmogenesis. Abnormal cardiac

innervation has long been associated with an increased risk of sudden cardiac death and

ventricular arrhythmias.4 Decreased reuptake by impaired myocardial presynaptic nerve

terminals in patients with ischemic cardiomyopathy results in a buildup of these catecholamines

in the synaptic cleft.5-7 This leads to a downregulation of postsynaptic beta-adrenergic receptors,

with resultant worsening cardiomyopathy and increased arrhythmogenesis.8, 9

Cardiac sympathetic innervation can be directly imaged with commonly used nuclear

radioisotope, 123I-meta-iodobenzylguanidine (123I-mIBG). As a norepinephrine analogue, 123I-

mIBG is similarly released into the synaptic cleft in response to sympathetic input by presynaptic

nerve terminals. Recently, global cardiac denervation, as assessed with 123I-mIBG, was

demonstrated to correlate with the occurrence of implantable cardioverter-defibrillator (ICD)

therapies in both ischemic and non-ischemic subjects.10, 11

To incorporate this new dimension of ventricular arrhythmogenesis (VT

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triggers/substrate modulators) into ablation of drug-refractory VT, this study sought to integrate

regional sympathetic innervation information in the form of 3D innervation maps with standard

voltage maps. Additionally, it aimed to achieve pathophysiological insights by comparing and

integrating three-dimensional (3D) 123I-mIBG innervation maps with standard electroanatomic

maps.

Methods

Study protocol

The study was designed as a prospective, single-center feasibility study of patients with ischemic

heart disease scheduled for radiofrequency ablation for pharmacologically refractory VT at

University of Maryland Medical Center (Baltimore, MD, USA) from January 2010 through

January 2014. All study protocols were approved by the University of Maryland Institutional

Review Board.

123I-mIBG Scintigraphy

Pre-procedural 123I-mIBG planar and SPECT imaging was obtained in 15 patients with ischemic

heart disease and drug-refractory VT prior to VT ablation. Patients were pretreated with either

perchlorate (potassium or sodium) or an iodine solution at least 60 minutes prior to injection to

block uptake of free iodine by the thyroid gland. Patients were then administered 370 MBq (10

mCi) of 123I-mIBG (GE Healthcare, Buckinghamshire, UK) intravenously. Planar imaging of the

anterior thorax (128 x 128 matrix) was performed 15 minutes later, as was SPECT imaging using

a dual--head gamma camera (minimum 30 projections/head, 20 to 30 seconds/projection, 64 x 64

matrix, Philips SKYLight SPECT Camera, Philips Medical Systems, Milpitas, CA, USA).

Repeat planar and SPECT imaging was performed 4 hours after injection. All camera heads were

equipped with low-energy, high-resolution collimators, and all acquisitions were performed

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with a 20% energy window centered at the 159 keV photopeak of 123I.

Analysis of Planar 123I-mIBG Images

Heart to mediastinal ratio (H/M) was determined on 4 hour planar images from the mean

counts/pixel in a visually drawn region of interest (ROI) over the cardiac silhouette divided by the

mean counts/pixel in a 7x7 pixel ROI placed in the mediastinum (Figure 1).12

Three-Dimensional Regional 123I-mIBG Innervation Map Reconstruction and Integration

with Voltage Maps

3D reconstructions of the left ventricular myocardium and denervation defects were created using

the Amira Visual Imaging software (Visage Imaging, San Diego, USA) (Figure 2). On each two-

dimensional 123I-mIBG SPECT slice, areas of normally innervated myocardium, denervation and

transition zone (TZ) were traced manually by two experienced cardiac nuclear medicine

physicians (VD, WC), who were blinded to the patient’s characteristics. Disagreements were

resolved by mutual discussion. To develop quantitative criteria of the innervation categories, the

voxel-based signal intensities of the visually determined denervated, transition and normal zones

were normalized to a remote segment distant from the voltage-defined scar and determined for

each of the patients (“denervation” and “transition zone” will be used to describe innervation

properties, while “scar” and “border zone” will refer to voltage criteria based information).

Using the complete sequential 2D datasets, individual 3D innervation maps displaying

each of the three tissue categories (normal, denervated, transition zone) were created for each of

the patients in the Amira environment. The axial 123I-mIBG dataset underwent DICOM3

formatting to allow recognition by the proprietary CartoMERGE software (Biosense Webster,

Diamond Bar, USA) and converted to CARTO-3 or CARTO-XP (CARTO, Biosense Webster,

Diamond Bar, USA) readable mesh files. These 123I-mIBG SPECT datasets were subsequently

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transferred to the clinical CARTO workstation by using the clinical CartoMERGE Image

Processing tool. At least partial reconstruction of the right ventricle (RV) was performed to

minimize rotational errors during the registration process. Registration was performed by

obtaining 3 matching landmark pairs (at the RV septal insertion, mitral valve and apex). Area and

distance measurements on the voltage and 123I-mIBG innervation maps were performed using the

internal CartoMERGE software.

Voltage Map and VT Ablation

All VT ablation procedures were performed under general anesthesia. Once vascular access was

obtained, recording and pacing catheters were positioned in the RV, along the His bundle and in

the coronary sinus. An 8 Fr, 3.5 mm irrigated-tip catheter (Navistar Thermocool; Biosense

Webster; Diamond Bar, USA) was positioned in the left ventricle (LV) through a retrograde aortic

approach (n=11) or transseptal approach (n=4). Intravenous heparin was used during the

procedure to maintain an activated clotting time of 300 to 350 seconds.

Voltage maps were created with a 3.5-mm open irrigation-tip catheter (Thermo-Cool;

Biosense Webster) or a multi-electrode mapping catheter (PentaRay; Biosense Webster) using a

filling threshold of 10mm. 301±245 mapping points were taken per patient. Unipolar signals

were filtered at 2 to 240 Hz, and bipolar signals were filtered at 30 to 500 Hz, and were acquired

during sinus rhythm or ventricular pacing in patients with pacemaker dependency or

resynchronization therapy. Standard clinical voltage criteria were used to define scar (bipolar

voltage <0.5 mV), border zones (0.5 to 1.5 mV), and normal (>1.5 mV) myocardium. For

unipolar voltage, a cut-off value of 5.8 mV was used to differentiate scar from non-scarred

myocardium.13

Near-field bipolar electrograms (EGM) were analyzed at a speed of 400 mm/sec.

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Fractionated EGMs were defined as having a voltage 0.5mV,

amplitude/duration ratio < 0.005. Isolated potentials were separated from ventricular EGMs by an

isoelectric segment and a segment with low-voltage noise (<0.05 mV) greater than 20ms duration

at a gain of 40-80 mm/mV.14

Fluoroscopy, local EGM characteristics, and real-time intracardiac echocardiography were

used to confirm stable catheter contact during electroanatomic mapping. Programmed electrical

stimulation (PES) was performed from the RV apex and RV outflow tract as well as from up to 2

LV sites with additional isoproterenol infusion when VT was not inducible from the RV. This

protocol included the use of up to 3-drive train cycle lengths (350, 400, and 600 milliseconds) and

up to 3 extra-stimuli with minimal coupling interval of 200 milliseconds.

Ventricular Tachycardia Ablation

The ablation procedures targeted clinical VT as documented by 12-lead electrocardiograms or

presumed clinical VT defined by cycle lengths, local RV timing to far-field EGM and far-field

morphology from ICD recordings.

For hemodynamically unstable or non-

longest Stim-QRS (if multiple sites with identical match found) defining the site closest to central

isthmus were used to approximate the VT channel/exit sites and limited activation mapping was

performed if possible. Limited activation mapping of these sites in VT was performed in four of

the fifteen subjects to confirm the site of earliest activation. Radiofrequency ablation lesions (40-

50 W, 60 seconds) were applied at these locations. Additional VT substrate modification was

performed as clinically indicated by creating tangential ablation lesions along scar borders or

radial lesions transecting the scar towards the scar center or anatomic boundary such as mitral

valve ring. At the end of ablation, PES was repeated and successful ablation was defined as the

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inability to induce the clinical or presumed clinical VT.15-19

Comparison between 3D Innervation Maps and Voltage Maps

Voltage-defined scar and border zone (BZ) size and percent of total LV mass was quantified for

bipolar and unipolar voltage and compared with area of denervation and transition zone from 123I-

mIBG innervation map using the CartoMERGE surface measurement tool. Additionally, each 3D

reconstructed 123I-mIBG innervation map and voltage maps was analyzed using the standard 17-

segment AHA model.12 Individual segments were categorized as myocardium with abnormal

voltage or innervation if any such myocardium was present in that segment. Successful ablation

points were examined on 123I-mIBG innervation and voltage maps.

Statistics

SPSS (IBM) for Windows 16.0 was used for statistical analyses. Continuous variables are

expressed as median and quartiles (Q1-Q3) unless otherwise noted. Comparisons between paired

measurements were conducted with a non-parametric t test (Wilcoxon Signed-Rank) 2-tailed t

test. Differences were considered significant at a level of p<0.05.

Results

Patient Characteristics

Fifteen patients with ischemic, drug-refractory VT were enrolled in the study (Table 1). All

patients had evidence of prior myocardial infarction by cardiac imaging. All had prior

revascularization, with prior coronary artery bypass grafting (n=6), prior coronary stenting (n=8)

or both (n=1). No revascularization was performed within 6 months of VT ablation.

Planar and Regional 123I-mIBG Analysis

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in areas of denervation was 25% (Q1-Q3 15.3-31.7%; 24±10% mean±SD)) [min-max 4-50%] and

increased to 40% (Q1-Q3 30.2-43.6%; 38±10% mean±SD) [14-72%] in the TZ (p <0.001).

Myocardium with preserved sympathetic innervation demonstrated a significantly higher uptake

of 67% (Q1-Q3 52.2-71.4%; 63± 11% mean±SD) [39-100%], respectively (p<0.001). Resulting

midpoints were 0-31%, 31-52% and >52% for denervated area, transition zone and normally

innervated myocardium, respectively (Figure 3).

Comparison Between 3D Reconstructed 123I-mIBG Images and Electroanatomic Maps

3D reconstructions of 123I-mIBG SPECT images were successfully performed in all patients. All

patients had areas of denervation, transition zone and normal innervation on MIBG innervation

maps, and areas of voltage defined scar, border zone and normal myocardium on bipolar and

unipolar electroanatomic maps.

The region of bipolar voltage-defined scar was inferior in 11 patients (73%), anterior in 6

patients (40%), lateral in 10 patients (67%), and septal in 9 patients (60%) while denervated areas

were found in the inferior wall in 15 patients (100%), anterior wall in 3 patients (20%), the lateral

wall in 14 patients (93%), and the septum in 12 patients (80%). The segmental 17-segment

analysis showed that the denervated area commonly extended more inferiorly and inferoapically

than the bipolar electroanatomic scar, affecting at least parts of the inferior wall in all patients

(Figure 4).

123I-mIBG denervated areas were about 2.5 times larger than bipolar voltage-defined scar

(24.6% (Q1-Q3 18.3-34.4%) vs. 10.6% (Q1-Q3 3.9-16.4%), p<0.001), while the size of 123I-

mIBG transition zone was statistically similar to bipolar-defined border zone with a trend to a

larger voltage-defined border zone (11.4% (Q1-Q3 9.5-13.2%) vs. 16.6% (Q1-Q3 12.0-18.8%),

p=0.07). Similarly, in the segmental analysis, denervation was seen in 9 (Q1-Q3 8-10) segments

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of the left ventricle, while 7 (Q1-Q3 4-9) segments demonstrated bipolar scar (p=0.09). 123I-

mIBG transition zone was seen in 10 (Q1-Q3 9-12) segments and bipolar border zone in 10 (Q1-

Q3 9-16) segments (p=0.16). 7 (Q1-Q3 3-8) segments only contained bipolar voltage

measurements >1.5mV, while 5 (Q1-Q3 4-6) segments did not contain any areas of either

denervation or transition zone (A single segment commonly contained areas of both, denervation

and transition zone).

Unipolar scar was significantly larger than bipolar scar (29.2%, (Q1-Q3 17.7-58%) vs.

10.6% (Q1-Q3 3.9-16.4%), p=0.003), which was largely due to three patients with diffuse

unipolar scar affecting >75% of the LV myocardium. Unipolar scar co-localized with bipolar scar

in all patients. No significant differences were found between the 123I-mIBG denervated area and

the unipolar scar area (p=0.55).

Regional analysis revealed that 76% of segments with bipolar scar had severe innervation

defects, while 84% of bipolar scar had any abnormal innervation (either denervation or transition

zone).

Bipolar and unipolar voltages varied widely within areas of complete denervation (0.8mV

(Q1-Q3 0.3-1.7mV; 1.3±1.5mV mean±SD) and (4.0mV (Q1-Q3 2.9-5.6mV; 4.4±2.3mV

mean±SD) and 123I-mIBG transition zone (0.8mV (Q1-Q3 0.4-1.8mV; 1.5±1.8mV mean±SD) and

(4.6mV (Q1-Q3 3.2-6.3mV, 5.0±2.6mV mean±SD). Bipolar voltage measurements of mapping

points in the denervated area and 123I-mIBG transition zone were in scar (<0.5mV), border zone

(0.5-1.5mV) and normal category (>1.5mV) in 35%, 36% and 29% as well as 35%, 35% and

30%, respectively. The number of mapping points corresponding to scar, border zone and normal

voltage were not statistically different within denervated area or transition zone (p>0.05 each),

suggesting that voltage was a poor discriminator to predict myocardial innervation state.

pap tients with diffususususeeee

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11

Out of a total of 1487 points within 123I-mIBG denervated areas, 3.1% (Q1-Q3 1.1-5.2%;

5.1±8.7% mean±SD) demonstrated isolated potentials, with 7.1% (Q1-Q3 4.6-15.2%;

11.7±12.1% mean±SD),) demonstrating fractionation. In the MIBG defined transition zone, out of

a total of 611 mapping points 0% (Q1-Q3 0-0%; 0.7±1.7% (mean±SD) showed isolated

potentials, with 7.4% (Q1-Q3 1.9-18.6%; 10.8±10.9% mean±SD) showing fractionation.

VT Ablation

VT ablation was performed in all patients. No inducible VT was present in two patients. In the

remaining 13 patients, 57 VTs were induced, including both clinical and nonclinical VTs.

Insufficient pace map matches were found in two patients leading to substrate modification alone

in those cases. In the remaining 11 patients, the 14 clinical VT sites were successfully mapped

and localized to the interventricular septum (total n=7; RV side n=3; LV side n=4), inferior (n=5),

lateral (n=1), and anterior wall (n=1). Clinical VTs had a cycle lengths of 352ms (Q1-Q3 290-

410ms; 372±96ms mean±SD) with either RBBB (80%) or LBBB (20%). After ablation, 93% of

clinical VTs could no longer be induced.

Electroanatomic and 123I-mIBG Characteristics of Ablation Sites

Successful ablation sites were within bipolar voltage defined scar in 7% (n=1: 0.4mV) and border

zone in 57% (0.8mV (Q1-Q3 0.7-1.3mV; 1.0±0.3mV mean±SD) [0.7-1.4mV] (Figure 5, 6; Table

2), but were within areas of normal bipolar voltage in the remaining 36% of cases 4.0mV (Q1-Q3

1.9-5.0mV; 3.4±1.7mV mean±SD) [1.8-5.5mV] (Figure 7, 8). The distance of successful ablation

sites within normal myocardium to the nearest border zone was 10.2mm (Q1-Q3 3.6-3.7mm;

11.0±10.0mm mean±SD). Successful ablation sites with normal bipolar voltage demonstrated

unipolar voltage of 5.9mV (Q1-Q3 5.3-7.6mV; 7.0±3.0mV mean±SD) [4.0-11.4mV]. The

unipolar voltage of all successful ablation sites was 5.2mV (Q1-Q3 4.2-6.5mV; 5.6±2.5mV

nd nonclinical VTTTTs.s.s.s.

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12

mean±SD).

All successful ablation sites demonstrated an abnormal innervation pattern, with 50%

within denervated myocardium and 50% within 123I-mIBG transition zone. Successful ablation

sites with normal bipolar voltage demonstrated denervation or transition zone in 40 and 60%,

respectively (Table 2).

Successful ablation sites within 123I-mIBG denervation demonstrated a distance to the

closest denervation/transition zone interface of 3.6mm (Q1-Q3 3.3-9.0mm; 6.3±4.5mm

mean±SD). Ablation sites in the transition zone had a minimum distance to the transition

zone/normal myocardium interface and the transition zone/denervation border of 9mm (Q1-Q3

4.5-13.2mm; 9.3±6.3mm mean±SD) and 8mm (Q1-Q3 5-8.8mm; 7.0±3.9mm mean±SD),

respectively.

Follow up

At six months follow-up, 1 patient had died of unrelated, non-cardiac causes (no ICD

interrogation results were available). Six of the remaining 14 patients had recurrent ventricular

arrhythmias; either non-sustained VT not requiring any ICD therapy (n=2) or VT treated with

anti-tachycardia pacing (n=3) or ICD shocks (n=1, died prior to 6 months follow up visit of heart

failure).

Discussion

The main findings of the study are: a) using molecular imaging 3D 123I-mIBG innervation maps

could be successfully reconstructed and integrated into clinical mapping systems; b) denervated

areas were about 2.5 times larger than bipolar scar areas defined by the current gold standard of

voltage mapping and commonly extend into the inferior wall; c) neither bipolar or unipolar

voltage could reliably predict the innervation status of LV myocardium; d) cut-offs of 0-30%, 30-

nce to the transitioonn n n

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13

50% and >50% well-approximate denervation, transition zone and normal myocardium; and e) all

successful VT ablation sites were located in areas of abnormal innervation even if those sites

demonstrated normal bipolar voltage.

Current Approaches to VT Ablation

Current VT ablation strategies primarily target the anatomic VT substrate; i.e., surviving

electrically conducting fibers within a myocardial scar.17 As entrainment mapping is rarely

possibly due to hemodynamic instability, anatomically based, substrate-guided ablation

procedures are frequently performed. These use pace mapping, late/diastolic potentials, or LAVA

as electrical surrogates for anatomic information of surviving myocardial bundles within the

scar.15, 20, 21

To further improve the understanding of the scar substrate, cardiac imaging with

gadolinium-enhanced MRI, PET/CT, and contrast-enhanced multidetector CT has been used to

improve the anatomic understanding of scar substrate, border zone, and detailed cardiac anatomy

when integrated into 3D mapping systems.22-25

Despite the use of these approaches, the success rate of these anatomically based VT

ablation approaches remain suboptimal. In the Thermocool VT Ablation Trial, only slightly more

than half of patients with ischemic cardiomyopathy who underwent VT ablation for recurrent

monomorphic VT were free of VT after 6 months of follow-up.3 Therefore, novel approaches

incorporating other aspects of arrhythmogenesis, such as VT triggers and substrate-modulators

may be beneficial to improve our understanding of VT substrate and improve the success rate of

VT ablation.

Innervation and Arrhythmogenesis

Abnormal innervation has long been associated with an increased risk of sudden cardiac death

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14

and ventricular arrhythmias4; however, this important dimension of proarrhythmia has thus far not

been incorporated clinically to improve substrate characterization and guide ablation therapy of

ventricular arrhythmias.

Mechanistically, recent studies have suggested that damaged myocardial presynaptic

nerve terminals demonstrate reduced uptake of catecholamines, by the uptake-1 mechanism as has

been shown with radiolabeled catecholamines.5 This leads to accumulation of these

neurotransmitters in the synaptic cleft, with consequential overexposure, and downregulation of

postsynaptic beta-adrenergic receptors and an imbalance between pre- and postsynaptic

signaling.6 It is thought that this disturbance leads to an increased risk of arrhythmias and

contractile dysfunction. This theory is supported by the fact that pharmacologic sympathetic

blockade decreases the risk for ventricular arrhythmias.26 Left and bilateral stellate ganglion

block with resultant cardiac sympathetic denervation has been shown to decrease the rate of ICD

shocks.27 Additionally, nerve sprouting after myocardial injury, which can predispose to

sympathetic hypersensitivity, leading to an increased risk of ventricular arrhythmias, may be

another important concept linking the sympathetic nervous system and the risk for sudden

death.28, 29 This is supported by the finding that the infusion of nerve growth factor resulted in an

upward/leftward shift in the dose-response curves to catecholamines, shortening of refractoriness,

and increased risk for ventricular arrhythmias.28, 30

Using well validated molecular imaging techniques, visualization of these global and

regional sympathetic innervation abnormalities is possible with 123I-mIBG.10, 31 The decreased

reuptake of norepinephrine into presynaptic nerve terminals found in patients with

cardiomyopathy results in lower intensity 123I-mIBG signals. This decreased reuptake of 123I-

mIBG has been demonstrated across a wide spectrum of subgroups known to be at risk for

and pop stsyynaptp icc

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15

ventricular arrhythmias, including ischemic and nonischemic cardiomyopathy, hypertrophic

cardiomyopathy32, arrhythmogenic RV cardiomyopathy, and VT patients with structurally normal

hearts.10, 11

Multiple previous studies demonstrated that the global cardiac innervation (H/M and

washout rate of 123I-mIBG) correlate with increased risk of ICD therapy, worsening heart failure,

and cardiac death.10, 31 However, recent studies have suggested that a regional assessment of

innervation can be performed with 123I-mIBG, which was predictive of VT inducibility and ICD

shocks.10, 33 Given the semi-quantitative regional analysis used in these prior studies, this study

sought to establish quantitative, normalized cut-offs for denervation, transition zone and normal

myocardium. The correlating categories of 0-30%, 30-50% and >50% may facilitate the transition

to a more reproducible use of MIBG for clinical and research applications.

Importantly, this study found that all successful ablation sites demonstrated abnormal

innervation patterns. The fact that 36% of successful ablation sites were in areas with preserved

bipolar myocardial voltage, conventionally thought to indicate lack of LV scar, suggests that

innervation abnormalities could play an important role as a trigger and substrate modulator

responsible for ventricular arrhythmogenesis, As traditional voltage mapping is unable to reliably

detect denervation, molecular innervation tracers such as 123I-mIBG are required. Indeed, the

areas of denervation were more than twice the size of voltage-defined scar. This is consistent with

animal studies in which innervation imaging post-infarct demonstrated a significantly larger

defect than the associated perfusion abnormalities and the extent of innervation/perfusion

mismatch correlated with VT inducibility.5 A likely explanation is that neuronal structures are

more sensitive to hypoxemia than myocytes and that neuronal damage may occur in areas without

significant myocardial fibrosis.

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16

Limitations

The present study has several limitations. This is a first-in-man single-center feasibility study in

patients with ischemic cardiomyopathy. It is unclear if those findings would be applicable in

other patients with VT such as in nonischemic cardiomyopathy. Current 123I-mIBG imaging is

limited by the spatial resolution of SPECT camera technology, which is in the range of 10-12mm.

However 123I-mIBG is the most established innervation tracer and most commonly used for

innervation imaging and studies.

A three-point registration algorithm was used to provide a standardized approach to image

registration, as opposed to visual alignment. Rotational errors were accounted for by including

RV anatomy, as done in prior imaging studies. Despite these measures, registration errors,

similar to in other image integration techniques, may have affected the quantitative analysis.22-24

While technical reasons for the inferior innervation defect cannot be excluded, recent

studies demonstrating inferior denervation in Syndrome X patients but preserved innervation in

the majority of control patients over a 5 ± 3 months follow up support that the inferior imaging

defect is a real phenomenon.34

Finally, the influence of prior VT ablation on innervation is unknown; however, one series

that imaged 5 patients 1-4 months after ablation of VT in the absence of structural heart disease

demonstrated no focal defect in all patients, though one patient had diffusely decreased uptake.35

Conclusions

To our knowledge, this is the first study to integrate detailed 3D innervation maps derived

from123I-mIBG to assess a novel dimension of possible VT triggers and substrate modifiers and to

define possible quantitative cut-offs for abnormal innervation. Our findings of neuronal damage

extending significantly beyond the voltage-defined scar, the inability to predict “neuronal health”

dardized apppproacch h h h totott

countnttt ddeded fffforor bbbby y yy ininclclclcluuudud

m

n s

hile technical reasons for the inferior innervation defect cannot be excluded, recen

monstrating inferior denervation in Syndrome X patients but preserved innervatio

t of control patients o er a 5 ± 3 months follo p s pport that the inferior imag

my, , , asasasas ddddononnneee in pppprirr or imaging studies. Desesespipite these meaaasurereresss, registration errors,

nnnn oooother image inntegggrrationonon tecchhhnh iqiiquues, mmmayy haveveve aaaaffffff ectteted thhe quuuaantitaaaatititivevev aanalylylysi

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17

by current voltage criteria and the finding of abnormal innervation for all successful VT ablation

sites (even with preserved voltage) suggest that 123I-mIBG imaging may provide important

information about VT substrate not available from the current anatomical VT substrate model and

provide supplemental guidance for VT ablations in ischemic VT patients.

Conflict of Interest Disclosures: Timm Dickfeld has research grants from General Electric and

Biosense Webster. In addition, Vasken Dilsizian has research grant from General Electric and

Aharon Turgeman takes salary from Biosense Webster. All other authors have no disclosures.

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e for rrr PrPrPrP acacacttit cecece GGGG, EuEuEuE rororopepepeananan HHHHeaaaartrtrt RRRhyhyhyhyttht m mmm AAA, HeHeHeHearararart t tt RhRhRhRhytytytthmhmhmh SSS.... ACACACA C/C/C/C/AHAHAHHA/A/A/A ESESESESCCCC 2ffororor MManananagagagemememenenenttt ofof PPatatatieientntntsss WiWiiithth VVenenentrtrtricicululararar AArrrrrrhyhyyththmimiasasas aaandnd ttthehe PPrerereveveventntntioionnn oo

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ial infarction ppredidiiictctctcts11112222222244.4.4

CM CaCaCaCamimimimicicicici PPPPGGGGl beta adrenoceptor density in primary and secondary left ventricular hypertroph

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ajjan A, Shivkumaar r r r KK.KKrr rr ararararrhrhrhrhytytytythmhmhmhmiaiaiaias sss orororor eelelelelectctctt360--363636366666.

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Table 1: Patient characteristics (n=15)

Characteristics Values

Gender (Male) 14 (93%)

Age at Time of Ablation (Years) 68.5 ± 8.6

Ejection Fraction 25.0 ± 12.1%

Presence of ICD at Time of Ablation 14 (93%)

Biventricular ICD 4 (27%)

Prior Ablations 2 (13%)

Comorbidities

Diabetes 3 (20%)

Hypertension 14 (93%)

Hyperlipidemia 10 (67%)

Atrial Fibrillation 5 (33%)

Medications

ACEI/ARB 13 (87%)

Beta-Blocker 14 (93%)

Aldosterone Antagonist 4 (27%)

Amiodarone 13 (87%)

Other Antiarrhythmic Drugs 4 (27%)

NYHA Heart Class

Class 1 0 (0%)

Class 2 8 (53%)

Class 3 7 (47%)

Class 4 0 (0%)

Data being presented as Mean ± SD or n (percentage %)

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Table 2: Number of ablation sites categorized by innervation and voltage characteristics

Voltage Map

Scar Border Zone Normal Voltage

Innervation Map

Denervated 1 4 2

Transition zone 1 3 3

Normal Myocardium 0 0 0

Figure Legends:

Figure 1: Heart-to-Mediastinal Ratio (H/M). Planar 123I-mIBG image with a 7x7 pixel region of

interest (ROI) drawn in the mediastinum (yellow square) and an irregular ROI drawn around the

cardiac silhouette defining the epicardial border of the heart (yellow outline). To calculate the

H/M, the mean counts/pixel in the cardiac region are divided by the mean count/pixel in the

mediastinal region.

Figure 2: 3D Reconstruction of the 123I-mIBG SPECT Innervation Maps: A. 123I-mIBG SPECT

short axis series from apex to base (top panel) demonstrating lack of uptake in the inferior wall

consistent with denervation. Example of delineation of denervation (red|), transition zone (yellow)

and normally innervated myocardium (purple) (lower panel). B. 3D reconstruction of a 123I-mIBG

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SPECT-derived innervation map, left lateral view, with denervated myocardium (red), transition

zones (yellow) and normally innervated myocardium (purple). C. 3D reconstruction of 123I-mIBG

SPECT-derived innervation map, apical/left anterior oblique view (tissue categories as in B).

Partial RV reconstruction (orange) displayed to avoid rotational errors during the registration

process.

Figure 3: MIBG Imaging Intensity of Denervation, Transition Zone and Normal Myocardium.

Significant increase of normalized MIBG signal intensity from denervated tissue vs. transition

zone vs. normal myocardium (mean±Standard Deviation bar). Midpoint lines separating the

individual tissue categories shown at 31 and 52% (red, dotted line).

Figure 4: Comparison of denervated myocardial segments versus electroanatomic scar segments.

Standard 17-segment AHA model with numbers in each myocardial segment representing the

number of patients (out of 15) with 123I-mIBG denervated myocardium in that segment followed

by a backslash and then a second number in each myocardial segment representing the number of

patients (out of 15) with electroanatomic scar in that segment, as defined by bipolar voltage < 0.5

mV.

Figure 5: Comparison of 3D Innervation Map and Electroanatomic Map: Concordant Voltage

Scar-Denervation Location of Successful Ablation Site. A. Bipolar electroanatomic map, inferior

view, demonstrating inferior scar (red) and border zone (yellow-blue) with successful ablation site

(white dot; white arrow) within scar. B. Reconstructed 123I-mIBG scar map, inferior view,

demonstrating regional denervation in the inferior wall (denervated myocardium in red, transition

vated tissue vs. tranannnsisiss t

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25

zone in yellow, and normally innervated myocardium in purple). C. Co-registration of

electroanatomic map and innervation map demonstrates that area of denervation (red transparent

mesh) extends beyond the area of bipolar scar (and border zone). Successful ablation site (white

dot; white arrow) is located in area of voltage-defined scar (as shown in A), but also in area of

myocardial denervation close to the interface of denervation (red mesh) and neuronal transition

zone (non-transparent yellow).

Figure 6: Second comparison of 3D Innervation Map and Electroanatomic Map: Concordant

Voltage Scar-Denervation Location of Successful Ablation Site. Bipolar electroanatomic map,

left lateral view demonstrating a basal lateral scar, with co-registered innervation map overlying

(red mesh – denervation; yellow solid – transition zone; normally innervated tissue not shown for

better visualization). The successful ablation site (green dot, white arrow) is within an area of

inferoapical bipolar border zone as well as denervated myocardium.

Figure 7: Comparison of 3D Innervation Map and Electroanatomic Map: Discordant Preserved

Voltage-Denervation Location of Successful Ablation Site. A. Bipolar electroanatomic map,

inferior view, demonstrating inferior scar with ablation site (yellow dot; white arrow) at inferior

septal location within area of preserved bipolar voltage (>1.5mV). B. Co-registration of

electroanatomic bipolar voltage map and innervation map demonstrating significantly larger area

of denervation than bipolar voltage scar or border zone. Successful ablation point (yellow dot;

white arrow) is located within the area of denervation (red transparent mesh; analogous to Figure

3) close to the denervation/neuronal transition zone interface despite preserved bipolar voltage

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26

(123I-mIBG transition zone in overlying transparent yellow, and normally innervated myocardium

in overlying transparent purple).

Figure 8: Second comparison of 3D Innervation Map and Electroanatomic Map: Discordant

Preserved Voltage-Denervation Location of Successful Septal Ablation Site. A. RV Septum:

Bipolar electroanatomic map of right ventricular side of interventricular septum, left lateral view,

demonstrating inferior scar with distant successful ablation site (white dot; white arrow) at basal

septal location within area of preserved bipolar voltage (>1.5mV). Co-registered innervation map

demonstrates denervated myocardium (red mesh) and transition zone (transparent solid yellow)

overlying with ablation site in denervated myocardium. B. LV Septum: Bipolar electroanatomic

map of left ventricular side of interventricular septum, right anterior oblique view, with co-

registration of innervation map overlying (denervated myocardium in red mesh, transition zone in

transparent yellow). Correspondingly, the location of the successful ablation site shown in A

(white dot; white arrow) is similarly located in an area of denervated myocardium but normal

voltage distant from the inferior scar.

o-reggistered innervvvvatatatatioi

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with ablation site in denervated myocardium. B. LV Septum: Bipolar electroanat

t ventricular side of interventricular septum, r ht anterior oblique view, with co-

n of innervation map overlying (denervated myocardium in red mesh, transition z

t yellow). Correspondingly, the location of the successful ablation site shown in A

hite arro ) is similarl located in an area of dener ated m ocardi m b t norm

withthth aaaablblblb atatattioioioon sisisittett in denervated myocarddddiuiuiuiumm. B. LV Sepepepptum:m:m:m Bipolar electroanat

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Vincent See, Stephen Shorofsky, Wengen Chen, Vasken Dilsizian and Timm DickfeldRemo, Aharon Turgeman, Olurotimi Mesubi, Sunjeet Sidhu, Stephen Synowski, Anastasios Saliaris,

Thomas Klein, Mohammed Abdulghani, Mark Smith, Rui Huang, Ramazan Asoglu, Benjamin F.Novel Paradigm of Innervation Imaging

Substrate and Successful Ablation Sites for Ventricular Tachycardia: A Feasibility Study for a I-Meta-Iodobenzylguanidine Cardiac Innervation Maps to Assess123Three-Dimensional

Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2015 American Heart Association, Inc. All rights reserved.

Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology

published online February 23, 2015;Circ Arrhythm Electrophysiol.

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