UNIVERSITY OF PISA
Postgraduate School of Cardiovascular Medicine
Director Prof. M.Marzilli
Integration of radionuclide imaging of
cardiac intrinsic nervous system
with 3D electro-anatomical mapping
for atrial fibrillation ablation
“A novel, multidisciplinary tool to locate ganglionated plexi”
CANDIDATE
Dr. Francesca Menichetti
TUTOR
Prof. Mario Marzilli
SUPERVISORS
Prof. Maria Grazia Bongiorni
Dr. Sabine Ernst
“Hearts will never be practical until they can be made unbreakable”
(L. Frank Baum,The Wonderful Wizard of Oz)
11 LIST OF CONTENTS
ABSTRACT ... 14
1 - INTRODUCTION ... 16
1.1- General overview on atrial fibrillation ... 16
1.2- Image integration for atrial fibrillation ablation ... 16
1.3- Contact force measurement for atrial fibrillation ablation ... 19
1.4- New targets for atrial fibrillation ablation ... 20
1.5- Potential role of renal sympathetic denervation for the treatment of atrial fibrillation. ... 22
1.6- Autonomic Nervous System and Atrial Fibrillation ... 22
1.7- Ganglionated plexi, anatomy and physiopathology ... 24
1.8- Contribution of the autonomic nervous system to formation of CFAEs ... 26
1.9- Ganglionated plexi ablation as a target for antiarrhythmic therapy ... 27
1.10- Recent developments in imaging of the autonomic innervation of the atria ... 29
2- OBJECTIVE OF THE RESEARCH ... 30
3- METHODS ... 30
3.1- Patients... 30
3.2- Cardiac image acquisition ... 31
3.3- Invasive validation of GP localisation ... 32
3.4- High-frequency stimulation (HFS) ... 33
3.4- Additional lesions and protocol ... 35
3.5- Post-procedural follow-up ... 36
3.6- Endpoint ... 37
3.7- Statistical analysis ... 37
4- RESULTS ... 37
4.1- Functional hybrid image acquisition and radiation exposure ... 38
4.2- Confirmation of GP locations ... 40
4.3- Effect of GP ablation ... 40
4.4- Effect of subsequent AF ablation ... 41
4.5- Follow-up results ... 41
4.6- Complications ... 42
5- DISCUSSION ... 43
5.1- Characterisation of functional information ... 43
5.2- Localisation and distribution of GPs ... 44
12 5.4- Limitations ... 45 6- CONCLUSION ... 46 7- REFERENCES ... 47
LIST OF ABBREVIATIONS AND ACRONYMS AF= atrial fibrillation
RA= right atrium CS= coronary sinus LA= left atrium
EAM=electo-anatomical-mapping ANS= autonomic nervous system GP= ganglionated plexi
PVI= pulmonary vein isolation cCT= contrast enhanced CT
CFAEs= complex fractionated atrial electrogram CMR= cardiac magnetic imaging
RF=radiofrequency IVC= inferior vena cava
LIPV=left inferior pulmonary vein LSPV = left superior pulmonary vein RIPV =right inferior pulmonary vein RSPV = right superior pulmonary vein. ST= smart touch
RAD= renal artery denervation HRV=heart rate variability FAM=fast anatomical map LAA= left atrial appendage
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LIST OF FIGURES
Figure 1: Three-dimensional reconstructions of cCT to assess LA and PVs anatomy.. ... 17
Figure 2: Segmentation of a cCT dataset for image integration. ... 18
Figure 3: Example of a smart touch catheter. ... 20
Figure 4: Current approaches to atrial fibrillation ablation. ... 21
Figure 5: Sympathetic activation and AF loop ... 24
Figure 6: Example of histologic examination of the fat pad containing GP ... 24
Figure 7: Schematic anatomic Location of the 4 GPs in a posterior view of the left atria ... 26
Figura 8: Kaplan Mayer of AF recurrence across the different Ablation Strategies ... 28
Figura 9: An example of image fusion ... 32
Figura 10: Hybrid image of high-uptake mIBG sites with cCT. ... 33
Figura 11: Examples of high frequency stimulation (HFS)... 34
Figura 12: Example of GP localisation with tagged effect of the HFS stimulation.. ... 35
Figura 13: Median activity and location GPs normalized to mediastinum. ... 40
Figura 14: Follow up flow chart.. ... 42
LIST OF TABLES Table 1: patient demographics………38
Table 2: ablated patient demographics……….38
Table 3: ablated patient ecocardiographic characteristics………..38
14
ABSTRACT
BACKGROUNG and OBJECTIVES: The intrinsic cardiac autonomic nervous system has been proposed to play an important role in atrial fibrillation (AF). Several studies have reported favorable outcomes by adding ganglionated plexi (GP) ablation to pulmonary vein isolation (PVI). I-123 mIBG SPECT imaging with a dedicated cardiac camera with solid state detectors (D-SPECT) detects sites with high tracer uptake corresponding to norepinephrine activity and can be merged with 3D reconstructions from either contrast enhanced CT (cCT) or cardiac magnetic imaging (CMR). We have assessed whether I-123 mIBG SPECT (MIBG) can facilitate localization of these GP's to guide AF ablation procedures.
METHODS: The patients (pts) underwent I-123 mIBG nuclear imaging (D-SPECT, Spectrum-Dynamics) and co-registration of cCT or CMR. The focal uptake sites in the epicardial fat pads around the atria were documented and their activity was normalized to mediastinal activity. Subsequently, the merged data was imported into the 3D electro-anatomical mapping system (CARTO 3, Biosense Webster).
A subset of pts underwent an AF ablation allowing an invasive confirmation of mIBG uptake sites using high frequency stimulation (HFS) to identify GP sites. Irrigated tip radiofrequency (RF) ablation for 30 sec (30 Watts, 17 ml/sec flow) with a contact force of > 10 g was performed on confirmed GPs until HFS was no longer positive. Finally standard antral pulmonary vein isolation was performed. All patients underwent close follow up with clinic examinations and sequential Holter recordings.
RESULTS: 13 pts (mean age 57.5 years) underwent I-123 mIBG SPECT. They were injected with 372±6 MBq MBq of I-123 mIBG (radiation exposure of 2.4 mSv). The assessment of the location of the GPs revealed a very individual distribution with uncommon anatomical sites present in the majority of patients. Mean number of GPs was 5.
Eight patients underwent an AF catheter ablation procedure. In this subgroup, HFS stimulation allowed identification of confined locations corresponding to GPs. No correlation was observed with CFAE areas. The mIBG guided mapping and ablation amounted to a median of 43 minutes. The median of EP fluoroscopy time was 8.18 minutes (equivalent dosage of 860 cGycm2). On a median follow up of 10.7 months 4/8 pts are still on antiarrhythmic medication and 7/8 pts are in SR.
15
CONCLUSIONS: Registration of mIBG with cCT or CMR and electroanatomical mapping is feasible and facilitates localization of GP's. The so localized GPs are amenable to catheter ablation in patients with AF in addition to PVI. Further studies in large patient cohorts are necessary for confirm the effect of mIBG-guided GP ablation for different subtypes of AF.
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1 - INTRODUCTION
1.1- General overview on atrial fibrillation
Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality. 1
In view of an aging population, the prevalence and incidence of AF are on the rise and are expected to double in the coming decades, posing a huge burden. Catheter ablation is now a well-established treatment option for patients and the role of the pulmonary veins (PVs) in initiating23and maintaining45paroxysms of atrial fibrillation (AF) has been well documented.
The cornerstone for AF ablation is achievement of complete isolation of the pulmonary veins (PVs). Since the development of this procedure, much progress has been made, with improvement in long-term success and decreases in complication rates in experienced centers. Nowadays paroxysmal AF can be eliminated in an amount of patients undergoing antral PV isolation6. However, these outcomes are attained at the expense of repeat procedures, most often for PV reconnection.
In a recent meta-analysis rates of single-procedure success for non-paroxysmal AF ablation were 50.8% at 1 year and 41.6% at 3 years. The pooled 12-month success rate after a single procedure was 51.9%; it increased to 77.8% when multiple procedures were used (average number of procedures: 1.67).7 Although these results are encouraging and can be realized with a low risk of complications at experienced centers, the potential for late recurrence years after the ablation procedure is sobering.8
1.2- Image integration for atrial fibrillation ablation
From anatomical studies it has become apparent that LA and PV anatomy is highly variable.9 Typically, four separate PVs are present: two right-sided and two left-sided PVs. Large in vivo studies using cCT and CMR scanning have demonstrated that a single PV ostium on the left side or an additional right-sided PV are the most common variations (Figure 1). 10 11 These anatomical variants may be present in up to 30% of patients, and may affect the planned ablation strategy. In general, three-dimensional imaging techniques such as cCT and CMR are used for assessment of PV anatomy.
17 Using threedimensional reconstructions and cross-sectional images, these techniques provide the most detailed information on PV anatomy.
Figure 1: Three-dimensional reconstructions of cCT to assess LA and PVs anatomy. Normal pulmonary vein anatomy includes four pulmonary veins draining separately into the left atrium (upper panel). Variations of pulmonary vein anatomy include a single (or ‘common’) ostium of the left-sided pulmonary veins (lower left panel, black double-arrow), and an additional right-sided pulmonary vein (lower right panel, black arrow). LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein.
Electro-anatomic mapping systems provide on-line electrophysiological data, and allow tracking of mapping/ablation catheters and annotation of ablation points.12 A limitation of electro-anatomical mapping systems (EAM), however, is the use of reconstructed anatomy. In recent years, multimodality image integration into an EAM system was successfully performed in patients undergoing catheter ablation for AF. With a greater appreciation of the complex and variable nature of the PV and LA anatomy this technology may improve the efficacy,13 and safety of the procedure,
reducing radiation dose14, albeit at the price of longer procedure durations.15 Moreover this integration of pre-procedural images of the LA anatomy into catheter localization systems has facilitated identification of the antral region of the PVs in the posterior LA, reducing PVs stenoses associated with ablation deep within the PVs.16
18 Dedicated software has been developed to integrate EAM and pre-procedural acquired cCT or CMR images17 with the use of calibration, translation, and rotation processes. With new dedicated software, cCT or CMR images can be imported and used during the actual procedure. The image integration process consists of several steps, including ‘segmentation of the reconstructed geometry (Figure 2), fusion of the structures using fiducial markers (landmarks), and optimization of the integration by adjusting the reconstructed geometry.
Several studies have demonstrated the feasibility of this new technique and its value during AF ablation. 1718Finally, some studies 1920 compared the conventional mapping with the image integration and the second one may also improve the outcome of catheter ablation procedures. However, larger randomized studies are needed to confirm these findings.
Figure 2: Segmentation of a cCT dataset for image integration. The segmentation process consists of several steps. After the raw CT data are loaded into the electroanatomic mapping system, a transverse slice at the level of the chamber of interest is selected (A). By setting the intensity threshold, the borders of the LA and PVs can be delineated (B). Subsequently, specific labels (green dots) are placed in the middle of the left atrium and other cardiac chambers for ‘region identification’ (C). Finally, an automatic algorithm creates a three-dimensional volume segmented into the different structures, based on the specific labels and the delineated borders (D). The segmented CT image can then be used during the actual ablation procedure.
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1.3- Contact force measurement for atrial fibrillation ablation
Over the past decade, a large body of clinical research has been dedicated to the development of a more efficacious tool. It is well known that durable and transmural lesions are needed to achieve long-term success. Catheter stability and good tissue contact as well as power delivered by radiofrequency catheters are the variables needed to achieve that goal. Optimization of electrode-tissue contact can produce better lesions (with greater transmurality) while preventing complications secondary to excessive force.21 Up until recently, electrophysiologists were left with surrogate measures of contact, such as intracardiac electrograms and impedance changes during ablation.22
Nowadays there are catheters that directly measures contact force (CF) continuously, providing the data in real time and allowing electrophysiologists to have an objective measure of tissue contact. This technology has allowed us to focus on electrode-tissue contact, keeping CF at a safe yet effective level (Figure3). This increases the chances that transmural and durable lesions will be created, and in turn that we will achieve better outcomes.
The safety and effectiveness of the ST Catheter has been evaluated both in prospective multicenter and smaller single-center studies. The catheter has been available clinically since 2012 in Europe, where a growing body of evidence has demonstrated a link between contact force and better outcomes.2324
Many other studies have shown that AF ablation guided by CF is more effective both acutely and long term.25 When contact forces were kept at 10-20g, there was a significantly lower chance of acute vein reconnection,26 while better long-term success rates were seen. Interestingly, use of the ST Catheter while diligently keeping CF between 10-20 was also associated with lower procedural, ablation and fluoroscopy times because more efficacious lesions were delivered.
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Figure 3: Example of a smart touch catheter. Ablation of the right-sides PVs while using a ST Catheter before (A) and after slight catheter manipulation (B). After the catheter is manipulated, a greater force is measured, while the direction is pointing upwards, more perpendicular to the tissue (arrow in front of ablation catheter).
1.4- New targets for atrial fibrillation ablation
PV isolation is still mandatory for the treatment of persistent and long-standing AF. However, recurrent and chronic AF induces progressive electrical and tissue structural remodeling, thus making AF a self-perpetuating disease. 27In order to interrupt this looping process, the ablation procedure in non-paroxysmal AF patients usually requires some kind of substrate modification. Three approaches were developed: linear lesions, complex fractionated atrial electrograms (CFAEs) ablation, and electrical rotor elimination
Linear lesions have been applied on the left atria roof and on the mitral isthmus with the aim of preventing macro-re-entry-dependent arrhythmias; several studies reported that additional lines improve the efficacy of the procedure. 28 29 30 The downside of this approach becomes evident when the lines are not electrically continuous; in those cases, atrial tachycardia can develop 31 and frequently requires repeat procedures.32 In order to reduce macro-re-entry arrhythmias recurrences, the operator should validate the presence of a bidirectional conduction block across all ablation lines.33
In an effort to improve outcomes, complex fractionated atrial electrograms (CFAEs)34 ablation was proposed. Manifest controversies still exist concerning the usefulness of
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this approach because it frequently requires wide left atrial ablation, and it is hampered by a high post-procedural atrial tachycardia rate.3536
Recent evidence demonstrated that electrical rotors have a key role in sustaining AF in humans. Using a 64-pole basket catheter to record monophasic action potentials in human left atria the electrical rotors and focal impulse sources can be identified. 37 A computational approach was used to analyze the repolarization and conduction dynamics with the aim of reconstructing spatio-temporal AF maps; ablation guided by identification of focal impulses and rotors improved the overall procedure success.3839 Figure 4 summarized the current approaches to AF ablation. Despite all these innovations, results of catheter ablation in patients with AF are still not satisfactory.
Figure 4: Current approaches to atrial fibrillation (AF) ablation. A, Wide-area circumferential ablation—antral pulmonary vein (PV) isolation. Variations on this ablation include isolation of each PV antrum separately as opposed to combination isolation of ipsilateral veins. End points for ablation are bidirectional conduction block into and out of PVs and intact circumferential lesions. B, PV segmental ostial ablation. Ablation of each PV ostium is done to achieve the same end points as in A but without complete empirical ablation around the vein and includes less of the antrum. C, Linear ablation. In some instances (typically in persistent AF or as part of a step-wise approach in subsequent ablations after recurrence), linear lesions are added to PV isolation. D, Complex fractionated electrograms (CFEs) ablation. Common sites of CFEs are shown in the figure and an example of a CFE. E, Ganglionic plexi (GP) ablation. The left atrial autonomic GP and axons are shown.. Ablation of GPs is performed either by empirical ablation over these areas or by mapping using high-frequency stimulation to identify areas that result in a vagal effect. F, Rotor ablation. Rotors are depicted by large and small gray rotating lines. Stable, driving rotors are targeted by novel mapping approaches for ablation.40
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1.5- Potential role of renal sympathetic denervation for the treatment of atrial fibrillation.
Renal artery denervation (RDN) has been introduced as an ablation procedure that can effectively treat drug-resistant forms of hypertension. The ablative lesions reduce the afferent and efferent sympathetic nerve traffic to and from the kidneys, thus improving blood pressure control. Because of better control of blood pressure, and because the procedure reduces central sympathetic output to sensitive structures within the cardiovascular system, it has been hypothesized that RDN may be a valuable antiarrhythmic intervention.
Recent studies have shown that changes in ANS activity may have an impact on the remodelling process due to AF.41 42 Another study described the effect of RDN on permanent AF.43 In 1-year follow-up, a reduction of ventricular heart rate and blood pressure was observed. Further studies conducted on pig models for AF revealed a reduction in the heart rate during sinus rhythm, increased atrio-ventricular node conduction duration and a reduction in ventricular rate during AF episodes by 24%.44 Modulation of the atrial effective refractory period or AF-induced atrial electrical remodelling was not observed. It should however be emphasized that studies on pig models provide only assessment of short-term results of the procedure.
Other studies investigated the impact of RDN on patients with refractory symptomatic AF, referred for pulmonary vein isolation (PVI). The research showed that RDN resulted in a reduction of blood pressure, both systolic and diastolic in 1-year follow-up and reduced AF recurrences when performed with PVI.45
Modulation of autonomic nervous system activity obtained by the RDN procedure may provide better control of ventricular heart rhythm in patients with AF and also decrease susceptibility for AF but further investigation is required. All those data suggest that block of both afferent and efferent sympathetic nerves is more effective than elimination of efferent cardiac nerves only.
1.6- Autonomic Nervous System and Atrial Fibrillation
Besides several other mechanisms, such as atrial stretch and atrial structural alterations,46 47 48 49 50, the autonomic nervous system (ANS) has been considered to contribute to the creation of AF substrates. 51 The autonomic nervous system of the
23
heart consists of extrinsic and intrinsic ganglia. 52 The parasympathetic components of the extrinsic cardiac nervous system originate in the vagus nerve. The sympathetic components originate primarily in the cervical spinal cord and in the vagus nerve, which contains both sympathetic and parasympathetic fibers. 53 Mechanical stress receptors, baroreceptors, and chemoreceptors located in the heart and great vessels modulate autonomic tone. The intrinsic cardiac ANS includes clusters of ganglia, known as autonomic ganglionated plexi (GP), located in specific epicardial fat pads and within the ligament of Marshall. The GP receive input from the central (extrinsic) ANS and contain afferent neurons, post-ganglionic efferent parasympathetic and sympathetic neurons, and numerous interconnecting neurons that provide communication within and between the GP. Additionally, the GPs, can modulate the interactions between the extrinsic and intrinsic nervous systems. 54
Several observations suggest that the ANS plays an important role in the initiation and the maintenance of AF. 55 Studies in lone AF patients and in animal models of intermittent rapid atrial pacing and congestive heart failure have indicated that AF onset is associated with simultaneous sympathovagal activation rather than with an increase in vagal or sympathetic drive alone.5657585960 In animal models and humans, beta-adrenergic agonists (isoproterenol and epinephrine) can induce AF.6162 Increased AF susceptibility in rats with chronic endurance exercise is caused by vagal promotion and occurs via augmented baroreflex responsiveness and increased cardiomyocyte sensitivity to cholinergic stimulation.63 Interestingly, it has been shown that postoperative AF is more common in patients after lung transplantation than in heart transplant recipients, who have functional pulmonary vein isolation (PVI). Cardiac autonomic denervation, which just occurs in heart transplant patients, might explain reduced post-operative AF.64
Figure 5 shows the circular positive-feedback enhancement of the pathophysiological changes of the cardiac ANS .
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Figure 5: Sympathetic activation increases calcium entry and the spontaneous release of calcium from the sarcoplasmic reticulum leading to atrial ectopies (trigger loop). Increased vagal activation together with atrial fibrillation (AF)–induced atrial electrical remodeling shortens action potential duration, facilitating re-entry and thereby promoting AF (electrical loop). In the structural loop, atrial stretch during different conditions including congestive heart failure, hypertension, or obstructive sleep apnea (OSA) activates numerous profibrotic pathways resulting in atrial structural alterations and conduction disturbances, also facilitating re-entrant mechanisms. The circular positive-feedback enhancement of these pathophysiological changes explains the general tendency of AF to become more stable with time. Figure by Linz D et al65
1.7- Ganglionated plexi, anatomy and physiopathology
Histology studies in human cadavers revealed the fine structures of the interconnecting nerves which reach the heart via the paravertebral ganglia and along the vagus nerves. In fat pads on the atrial epicardium, larger “nest” of nervous cell bodies form so called ganglionated plexus (GP) that contain both sympathetic and parasympathetic nerves which vary in size between 20–2000 micrometers (Figure 6).
Figure 6: Example of histologic examination of the fat pad containing GP. A) Collagen fibers under the epicardium B) Ganglioinic cells forming the GP. Original magnification is x20 in (A) and x 40 in (B) to (I).
The GPs contain local circuit neurons of several types and chemo- and mechanosensory neurons, which are distributed throughout the heart.49 GP are particularly well innervated with both adrenergic and vagal nerve endings and are
25
housed in so-called fat pads, which are mainly located around the pulmonary vein ostia. GP may modulate the interactions and balance between extrinsic and intrinsic cardiac autonomic nervous systems 54and contain efferent cholinergic and adrenergic neurons influencing the atrial myocardium. Different neuromodulations (e.g., by spinal cord stimulation) can stabilize local circuit neurons of the intrinsic cardiac system attenuating neuronally mediated atrial arrhythmias.66 Stochastic interactions in intrinsic cardiac local circuit neurons control regional cardiac function and excessive activation of these neurons precedes and persists throughout episodes of atrial fibrillation in dog models.67 Additionally, high-frequency electrical stimulation of autonomic ganglia in the pulmonary vein area led to episodes of AF and atrial tachycardia that could be inhibited by both sympathetic and vagal pharmacological blockade in dogs.68
In animal models, stimulating the vagosympathetic trunk (“vagus nerve”) allows AF to sustain but requires pacing or other stimuli to initiate AF. 69 70In contrast, stimulating the GP produces repetitive short bursts of rapid, irregular firing in the adjacent PV, initiating sustained AF.71 The focal firing in the PVs has a pause-dependent initiation pattern and produces EGMs that are very similar to the pattern of firing recorded in the PVs of patients with paroxysmal AF. 72 Focal firing in the PVs by GP stimulation requires both sympathetic and parasympathetic activity.61 73 Parasympathetic stimulation shortens the action potential duration (and effective refractory period) in atrial and PV myocytes, and sympathetic stimulation increases calcium loading and automaticity. Combined, they cause pause-induced early after depolarizations (EADs) and triggered activity in PV and atrial myocytes. The mechanism of triggered firing may relate to the combination of a very short action potential duration and increased calcium release during systole, leading to high intracellular calcium during and after repolarization. These observations suggest that the high calcium concentration may activate the sodium/calcium exchanger, leading to a net inward current, EADs, and triggered firing.74 Compared to atrial myocytes, PV myocytes have a shorter action potential duration and greater sensitivity to autonomic stimulation, which may explain the predominance of focal firing in PVs in patients with paroxysmal AF and the interruption of focal firing by ablation of the autonomic GP.75Interruption of nerves from the GP to the PVs may explain, at least in part, the frequent elimination of focal
26 firing within the PVs produced by PVI procedures.76 These findings suggest that interruption of nerves from the GP may have a role in the success of PVI procedures and may explain the success of early ablation studies targeting only the GP in patients with paroxysmal AF.77Regeneration of those axons may contribute to late recurrence of AF after PVI. 8 78
In human hearts, there are at least 7 GP and the 4 major left atrial GP are located around the antrum of the PVs (Figure 7). High-frequency stimulation (HFS; 20 Hz, 10 mV voltage amplitude and 5 ms pulse duration) can localize GPs during an invasive EP study. Each GP contains both parasympathetic and sympathetic neural elements; stimulation of the former typically elicits an immediate response (within 2–4 seconds), while stimulation of the latter induces a delayed response (8–10 seconds).79 Ablation of the nerve cell bodies, by targeting the GP, may permanently denervate the PVs. The addition of GP ablation to PVI appears to be synergistic, because each of these procedures is currently incomplete: all GP tissue cannot be localized for ablation by the current endocardial stimulation techniques; and PVI procedures are frequently associated with late reconnection to the atrium.8081
Figure 7: Schematic anatomic Location of the 4 GPs in a posterior view of the left atria. The 5 major left atrial autonomic GP and axons (superior left GP, inferior left GP, anterior right GP, inferior right GP, and ligament of Marshall) are shown in yellow, whereas the coronary sinus and the vein and ligament of Marshall are shown in blue, which travels from the coronary sinus to the region between the left superior PV and the left atrial appendage. Figure by Calkins et al82
1.8- Contribution of the autonomic nervous system to formation of CFAEs
Over the last few years, electrophysiologically guided ablation techniques have been developed, in order to modify the arrhythmogenic substrate underlying AF. Clinical
27
studies performed in the last decade suggests that areas in the atrium demonstrating complex fractionated atrial electrograms (CFAE) may represent a suitable target site for ablation; ablation at these sites appears to increase the efficacy of PV isolation procedures.83 84 One possible explanation for this improvement in ablation success is that several CFAE sites may be located in the anatomic vicinity of autonomic ganglionated plexi (GPs).85 Indeed, Katritsis et al showed that not only did CFAEs occur over presumed GP sites in over two thirds of patients with paroxysmal AF, but in patients that did not have CFAEs at the GP sites, CFAEs were rarely recorded elsewhere in the left atrial wall.86 A recent study by Pokushalov et al87 suggests that additional identification of CFAEs around the atrial regions with a positive reaction to high-frequency stimulation (HFS) might improve the accuracy of GP's boundaries location, and even enhance the success rate of AF ablation. Nonetheless, the precise relationship of CFAEs to vagal inputs is not entirely clear, especially as vagal responses are not evoked at all presumed GP sites or sites where CFAEs are recorded.88 Other data indicates that heightened vagal activity may contribute to the formation of CFAE-like EGMs.89 More recently, Habel et al showed that CFAEs organize and DF decreases in the atrium in response to autonomic blockade.90 Knecht et al also showed that CFAEs organize in response to double autonomic blockade and this modification was accompanied by an increase in AF cycle length, suggesting that the latter was a possible mechanism mediating autonomic responsiveness of CFAEs.91 Chaldoupi et al showed that CFAEs in the right atrial free wall and the superior/posterior wall of the left atrium are autonomically sensitive, with CFAEs in both atria organizing in the presence of double autonomic blockade.92
Taken together, the findings of these studies support a role for the autonomic nervous system in contributing to AF electrograms, both in the absence and presence of structural heart disease.
1.9- Ganglionated plexi ablation as a target for antiarrhythmic therapy
GP may modulate the interactions between the systemic and intrinsic cardiac autonomic nervous systems and contain efferent cholinergic and adrenergic neurons. In large-animal studies, ablation of the autonomic ganglia at the base of the pulmonary veins has been shown to contribute to the effectiveness of PVI in vagally induced AF
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and has also been shown to eliminate rapid pulmonary vein firing in response to GP high frequency stimulation.93 In a dog model for central sleep apnea, GP ablation inhibited AF inducibility.94 GP ablation, alone or with PVI, has been used in patients with both paroxysmal and persistent AF with variable success, although success rates appear to be better in patients with paroxysmal than persistent AF.9596
Because conventional PVI transects 3 of the 4 major atrial GP as well as the ligament of Marshall, it is possible that autonomic denervation by GP ablation plays a central role in the efficacy of PVI.
The comparison of GP ablation plus PVI versus PVI alone was investigated by Katritsis et al.80 97 in a randomized controlled trial. They demonstrated that GP ablation significantly improved success rates after PVI compared to PVI alone (Figure 8).
Figure 8: Atrial Fibrillation or Other Sustained Atrial Arrhythmia Recurrence Across the 3 Different Ablation Strategies. Kaplan-Meier estimates were used to calculate the 2-year event rates and comparison was performed using the log-rank test stratified by study site. A 3-month blanking period after the ablation procedure was adopted. Figure by Katritsis et al97
In conclusion, the initial clinical studies incorporating the GPs into conventional LA ablation showed very good outcomes. However, studies using a GP-only approach were met with disappointment. In part, this was attributed to the suboptimal sensitivity of both HFS and anatomical approach in identifying the extent of GPs.
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1.10- Recent developments in imaging of the autonomic innervation of the atria The fact that norepinephrine (NE) is the neurotransmitter of the sympathetic neurons, whereas acetylcholine encodes the parasympathetic ones, serves to a great advantage since molecular imaging can selectively image the sympathetic system with I-123 metaiodobenzylguanidine (mIBG), an analogue of NE. Planar and Single Photon Computed Tomography mIBG imaging, assessing the heart to mediastinum ratio (H/M) and mIBG washout from the heart, has an established role for the assessment of the ANS involvement. 98 99 100 In particular the Heart-to-Mediastinum (H/M) ratio is a measure of 123-I-MIBG uptake derived by drawing regions of interest (ROI) over the heart and over the upper mediastinum in an anterior planar image, and taking the ratio of mean counts per pixel in the heart to the mean counts per pixel in the mediastinum.
Akutsu et al101 showed in a study of 98 patients with paroxysmal AF that a reduced 123-I-MIBG uptake was a powerful independent predictor of the development of permanent AF alone and heart failure plus permanent AF. On the other hand, Arimoto et al102 have demonstrated that a high washout rate on 123-I-MIBG imaging was an independent predictor of AF recurrence in patients with paroxysmal and persistent AF that had undergone AF ablation.
In a related surgical study, there was evidence of re-innervation of sympathetic nerves in patients that have undergone the MAZE procedure for AF.103 These findings are consistent with animal studies that have demonstrated autonomic re-innervation, with restoration of vagal responsiveness a few weeks after epicardial, GP denervation had been performed.104
Recently, novel dedicated cardiac cameras with solid state detectors were introduced, enabling significantly improved sensitivity as well as improved spatial and energy resolution and allowing high quality 3D molecular imaging.105 This high quality D-SPECT can provide novel imaging information on so far “invisible” structures like the GPs.105 The combination of the mIBG images superimposed on the 3D scan is novel in itself whilst all components themselves are established medical procedures including the contrast CT or CMR scan and catheter ablation catheters/mapping system.
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2- OBJECTIVE OF THE RESEARCH
The role of the autonomic nervous system (ANS) for the initiation and maintenance of cardiac arrhythmia has been studied for many decades, but due to the discrete anatomical structures involved imaging and direct interaction with the ANS has been challenging. Moreover the GP functional mapping by high-frequency stimulation is time-consuming and prolongs the invasive procedure substantially.
We report on our initial experience of fusing molecular imaging information with 3D DICOM information from computer tomography or magnetic resonance imaging to locate GPs in patients with atrial fibrillation. Using this 3D image information to guide GP ablation could significantly facilitate AF ablation and result in improved ablation outcomes.
The present study was designed to answer the following questions: 1) Is this fusing molecular imaging method reliable?
2) Which is the real GP location in each patient? Is it possible customize the GP ablation on the bases of these anatomical and functional information?
3) Does the addition of GP ablation to PVI increase the success rate of AF ablation in patients with AF without an increase in the procedural risks and complication rates?
3- METHODS
3.1- Patients
Patients with paroxysmal or persistent AF and an indication for catheter ablation of AF have been prospectively recruited. The screening visit involved detailed past medical history including first diagnosis of AF and related symptoms and details of any previous catheter ablation for AF or atrial flutter. The flowchart was composed by a physical examination, a 12 leads ECG recording, an evaluation of AF related symptoms, a standard laboratory tests and a complete echocardiography. A 48 hours Holter recording was performed to assess the baseline heart rate variability (HRV). During the analysis, only normal beats were measured, and all AF, extrasystolic beats, and artefacts were eliminated. Pregnant patients were excluded from the study.
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3.2- Cardiac image acquisition
The 123I-mIBG D-SPECT was performed on a dedicated cardiac SPECT camera with solid state (Cadmium Zinc Telluride, CZT) and a 9 head detector system (D-SPECT, Spectrum Dynamics Ltd, Caesarea, Israel). Patients were injected with 5 to 10 mCi (185-370 MBq) mIBG. Images were acquired with the region of interest set such that the entire heart was included and the centre of the region of interest was located around the base of the ventricles. Scan time ranging between 10 and 14 minutes was performed at 10 minutes after mIBG administration and was repeated at 4 hours after the injection.
In order to obtain the 3D images of the individual anatomy, the patients underwent either contrast CT scan or a non-contrast CMR scan. The software package provides values of CT dose index. These include weighted CT dose index (CTDIvol, expressed in
mGy), which was introduced in multislice CT to allow for variations in exposure in the z direction when the pitch was not equal to one. Another radiation dose measurement is the Dose Length Product (DLP), which is the dose in one rotation x exposure length (CTDIvol × scan length). DLP is expressed in mGycm and is a convenient index for total
dose.
Using standard 3D segmentation software of either CT or CMR information and manual correction if necessary, all 4 cardiac chambers, as well as the pulmonary veins, the superior vena cava (SVC), inferior vena cava (IVC), pulmonary artery (PA) and the aorta were reconstructed. Segmented 3D preliminary analysis was processed on the DSPECT to develop a mathematical representation of the cardiac chambers. A registration step (DSPECT LRS, Spectrum Dynamics, Israel) was run on the DSPECT workstation and is based on translational requirements of the CT and DSPECT models of the same heart. The DSPECT image is further modelled to describe the ventricles as the primary radiating source and the rest of the myocardial tissue to be modelled as the secondary radiating source. The raw data is analysed using the differentiation between primary and secondary radiating sources such that the analysis can reconstruct the secondary radiating sources using the prior knowledge of the primary radiating sources. The thereby reconstructed Hybrid DSPECT image is of high resolution and is being processed using an image processing technique that defines the contours of the 4 chambers using an edge detection algorithm and an approximated minimal error linear
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model to define endocardial contours of the atria. After a normalization step with the mediastinum as the reference, we assessed the activity level of I-123 mIBG uptake of the identified sites. (Figure 9) Then high uptake sites were marked in accordance to their location and intensity of uptake, using ellipsoid representations and finally they were merged to the 3D contours of the cardiac chambers.
Figure 9: an example of image fusion for cCT (A) and image fusion for CMR (B) for the superior left GP.
3.3- Invasive validation of GP localisation
In a subgroup of patients, a catheter ablation for atrial fibrillation was performed which also included functional confirmation of the pre-imaged GP sites by HFS as previously reported106 Patients were studied in a fasted state and under general anaesthesia (iv. Propofol and Fentanyl infusion) after exclusion of an intracardiac thrombus by trans- oesophageal echocardiography as per institutional standard. The AF ablation was performed under ongoing oral anticoagulation; during the procedure bolus heparin were applied IV to achieve an activated clotting time of 250–350 sec. If possible, trans-septal access was gained using a modified Brockenbrough approach . The fused 3D image was imported in the 3D electro-anatomical mapping (EAM) system (CARTO 3 or CARTO 3 RMT, all Biosense Webster, Haifa, Israel) and merged with the 3D fast anatomical map (FAM) of the left atrium (LA) and PV ostia using an irrigated tip mapping catheter (either CARTO Navistar Smart-Touch bidirectional or CARTO Navistar ThermoCool RMT). If atrial fibrillation (AF) was not already present, atrial burst pacing
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was performed to induce sustained arrhythmia. As a first step, detailed 3D maps were acquired using FAM in combination with user-defined annotation of CFAEs for all pulmonary veins (PVs), left atrium (LA) and left atrial appendage (LAA). Merging of the two 3D surfaces was done manually to achieve the best visual “fit” around the LA contour (Figure 10).
Figure 10: Hybrid image of high-uptake mIBG sites with cCT in a patient with persistent AF with previous ablation attempts.
3.4- High-frequency stimulation (HFS)
At the GP sites indicated by the fusion 3D images, HFS was carried in a systematic fashion with a minimum of 10g of contact force. Stimulation parameters were set to 20 Hz, 5 ms pulse duration and a voltage amplitude of 10 mV (EPS320, MicroPace EP Inc, Santa Ana, CA). Recordings were made on the electrophysiologic (EP) recording system (AXIOM Sensis, Siemens, Forchheim, Germany) and included recordings from diagnostic EP catheters (decapolar, BARD) inside the coronary sinus and His recording region (octapolar, custom-made, IBI, St. Jude Medical), as well as from a circumferential mapping catheter (fixed-curved Lasso, decapolar, Biosense Webster, Israel) and the mapping catheter. In order to see the hemodynamic consequence of the AV node conduction, arterial pressure was simultaneously displayed during HFS (Figure 11).
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Figure 11: Examples of positive (left) and negative (right panel) effect of high frequency stimulation (HFS) at the anterior right ganglionated plexus (ARGP) of a patient with paroxysmal AF (de novo ablation).
After identification of all GPs and the immediate surrounding area by HFS, selective irrigated tip radiofrequency (RF) ablation for 30 sec (30 Watts, 17 ml/sec flow) with a contact force of > 10 g was performed on the functionally identified sites (with ablation in the inferior right GP area being last). Subsequently, HFS stimulation was repeated at all ablated sites to demonstrate that AV nodal conduction could no longer be impaired. If the AV nodal slowing effect persisted, more RF applications were performed. All sites were marked with coloured tags on the CARTO system to mark the respective effect (Figure 12).
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Figure 12: Example of the localisation of the superior left GP (SLGP) with tagged effect of the HFS stimulation attempts shown in posterior-anterior (PA) (left panel) and right lateral (RL) projection. Please note that on the exact site of the GP (yellow arrow), the HFS effect is negative (orange tag). However, adjacent sites are positive for HFS (purple tags) and are subsequently ablated.
3.4- Additional lesions and protocol
In addition to the GP ablation, PV conduction was evaluated in all patients. In case of (re-) connection, antral PVI was achieved with a long linear lesion around the superior and inferior PVs of the same side using a single circumferential PV mapping catheter to delineate the endpoint of complete isolation. This endpoint was evaluated during ongoing AF and later during SR or constant atrial pacing with a minimum waiting time of 20 min from isolation. In case of complete isolation of all PVs, CFAEs were targeted in the LA, RA and coronary sinus (CS), where RF settings were lowered to max 20 Watts. In the absence of significant AF cycle length prolongation after CFAE ablation, DCCV was performed to restore SR at the end of the procedure using a 200 J biphasic shock (anterior–posterior patch positions).
In case of conversion to atrial tachycardia (AT), a 3D map of the respective atrial chamber was performed in combination with conventional entrainment manoeuvres from the various diagnostic catheters. Catheter ablation was carried out in order to terminate the AT with up to 30 Watts and a minimal contact force of 10 g.
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During the invasive EP studies was performed an intra-procedural assessment which included exclusion of intracardiac thrombi by TOE, ongoing oral anticoagulation and vigilant assessment of activated clotting times (ACT) every 30 min.
3.5- Post-procedural follow-up
All patients underwent close monitoring immediately and on the post–ablation day with continuous telemetry. All the patients underwent a transthoracic echocardiogram to exclude any relevant pericardial effusion. The pre-procedural anticoagulation was continued and the antiarrhythmic medication maintained that was previously used for a minimum of 6 more weeks. Moreover all ablated patients were recommended to take a proton pump inhibitors (30 mg of Lanzoprazole) for 6 weeks. Follow-up was scheduled at 6 weeks and after 3, 6 and 12 months and included 48 hours Holter recordings. In a stepwise fashion, anti-arrhythmic medication was stopped if the patient had been demonstrated to be in SR and had no further palpitations. Anticoagulation was continued in accordance to the CHADS2-VASC score.
A blanking period of 3 months was applied for AF recurrence. If AF or AT was discovered after 3 months, the patient was scheduled either for DC cardioversion or repeat ablation (according to patient and physician preference). A repeat ablation of sustained AF would require a repeat of the mIBG scan.
A standard assessment of potential complications related to procedures of ablation of atrial fibrillation was performed immediately pre-discharge and during follow-up visits, such as immediate or remote pericardial collection (assessed via transthoracic echocardiogram), pulmonary vein stenosis (if clinically suspected, a CT chest with contrast should be performed), phrenic nerve palsy (chest X ray), valve damage (TTE), atrio-oesophageal fistula (CT chest with contrast injection), vascular complications (vascular Doppler ultrasound or CT with contrast injection). Any other untoward adverse events was recorded.
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3.6- Endpoint
Primary endpoints
• AF termination during mIBG guided ablation
• Freedom from AF/flutter/tachycardia (> 30 sec) off antiarrhythmic medication at the follow up
Secondary endpoints
• Freedom of AF on previously failed antiarrhythmic medication
3.7- Statistical analysis
This is a prospective, single-arm, feasibility study which has tested a new technology of GP ablation in patients with AF. Therefore no power calculation has been done.
Descriptive statistic data with regard to baseline and procedural variables will be reported; continuous variables will be expressed by mean ± standard deviation or median and interquartile range (25th, 75th percentile), depending on the normality of distribution; categorical variables will be summarized by frequencies and percentages. The outcome of radiofrequency ablation on the entire cohort of patients will be presented in the form of percentage of patients free from symptomatic or documented arrhythmia or with only mild symptoms related to arrhythmia recurrence. Depending on the severity of symptoms and documentation of tachycardia during follow-up, patients will be divided into sub-groups of success/recurrence Baseline and procedural parameters will be compared between groups in order to identify predictors.
Unfortunately we are presenting here the preliminary results for some of the first patients enrolled so the power of this statistic is too low in order to perform a complete analysis.
4- RESULTS
A total of 13 patients (4 female, median age 57,5yrs) underwent functional combined imaging consisting of 3D cardiac scan (CT or CMR) and mIBG. Table 1 gives an overview about the patient demographics and past medical history.
38 All patients imaged 11 CT, 2 CMR
Age (yrs) 57,5 ± 8.9 Sex (m/f) 11/4 Paroxysmal AF 5 Persistent AF 5 Longstanding persistent AF 1 Previous ablation 5
Table 1: all patient demographics
Eight patients (2 female, median age 58,9 yrs) underwent AF catheter ablation procedure. Table 2 shows the ablated patient demographics and past medical history and Table 3 their echocardiographyc characteristics . Values are presented as median with interquartile range and confirm quite a normal heart in the setting of AF substrate regarding LA measurement and LV function. Atrial fibrillation was paroxysmal in 4/8 pts (50%) the and persistent in 3/8 pts (37%). Hypertension was highly represented (7/8, 87%) and in 2/8 pts (25%) an ASD treated by occluder device was present as congenital substrate. The ablation was a redo procedure for 2/8 (25%) pts.
Median age 58,9
Sex (m/f) 6/2
Hypertension 7
Coronary artery disease 3 Congenital heart disease 2
Paroxysmal AF 4
Persistent AF 3
Longstanding persistent AF 1 Previous ablation 2
Table 2: ablated patient demographics
LA area (cmq) 21,6 LA volume (ml) 72 LA volume index (ml/m2) 37 RA area (cmq) 19 LV EDD (cm) 5,1 LV EDV (ml) 98 LV EDV index (ml/m2) 44 LV-EF 58,5 TAPSE (mm) 22 IM (0-3+) 1
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4.1- Functional hybrid image acquisition and radiation exposure
All patients underwent the D-SPECT studies without complications. The median injected dose of mIBG was 372±6 MBq (median radiation exposure of 2,4 mSv). Results of the mIBG scan included heart to mediastinum (H/M) ratio (3,5±1,9) and the GP activity (1015±337,3 Photons/Sec/ml).
Three-dimensional cardiac image acquisition was performed using contrast enhanced computed tomography (cCT) in all but 2 patients who underwent cardiac magnetic resonance (CMR) imaging using a non-contrast free breathing sequence.
Transseptal access was gained using a modified Brockenbrough approach in all patient but in one; in this case the case a large atrial septal occluder device was present, so a retrograde access was chosen in combination with magnetic navigation.107108109
Table 4 shows the total radiation exposure from the various imaging steps. The CT scan radiation dose measurement include weighted CT dose index (CTDIvol, expressed in
mGy) and the dose length product (DLP, expressed in mGycm).
Nuclear Imaging CT scan Radiation Dosage Ablation procedure D-SPECT mSv CTDIvol (mGy) DLP (mGy/cm) Duration (min) Fluoro time (min) Dosage (cGycm2) All patients 2,6 37,3 508,6 245 8,2 689 AF ablation patients 2,4 41,3 615,0 242,5 8,1 641
Table 4: total radiation exposure.
Figure 13 illustrates the median activity levels at the respective GP sites. Assessment of the activity of the epicardial high uptake sites revealed a very individual distribution with non-anatomical GP sites present in the majority of patients. Some uncommon anatomical sites like in right atrium or in the distal septal PVs were discovered in the majority of patients. Mean number of GPs was 5.
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Figure 13: Median activity and location GPs normalized to mediastinum (median of 5).
4.2- Confirmation of GP locations
Invasive HFS stimulation allowed confirmation of the GP sites in all patients that underwent a catheter ablation procedure for atrial fibrillation. Aiming at the area indicated by the ellipsoids on the 3D hybrid image, HFS was applied at sites with good catheter stability and minimal CF of 10 g. Once a positive site was identified, surrounding tissue was tested for HFS to delineate the area of positive response (marked with purple tags) until negative sites were surrounding the area (orange tags). In cases, were GP ellipsoids were depicted at some distance to the reconstructed surface of a given cardiac chamber, care was taken to position the stimulation catheter as close as possible, but without risking perforation. Similarly, sites that were in very close proximity to ventricular myocardium were assessed with great care, such that no in-adverted dislodgement across the AV annulus occurred risking accelerated ventricular stimulation. No adverse event was observed in relation to the HFS, specifically we did not observe any ventricular pro-arrhythmia.
4.3- Effect of GP ablation
We performed irrigated tip RF ablation only on the sites that tested positively during the HFS and not necessarily on the location of the 3D sphere itself. This did not lead
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any acute effect of GP ablation and specifically we only once observed transient AV nodal slowing during ablation in the area of the right superior GP. AF cycle lengths measurements, before and after all targeted GPs were ablated, on all available diagnostic catheter recordings did not change. There was no termination to SR in the immediate period after GP ablation. Overall time for the GP confirmation and subsequent ablation and validation amounted to 43±14 min in median (as measured from the first HFS tag to the last one taken on the 3D map).
4.4- Effect of subsequent AF ablation
A total of 8 patients underwent (re)-PV isolation which resulted in AF termination during or immediately after complete antral PV isolation in 3 patients (all paroxysmal). In 4 patients, additional CFAE ablation was carried out which resulted in termination into SR in 1 case Conversion to right AT was observed in 1 patient which was subsequently ablated. Finally, 3 patients required DCCV at the end of the procedure.
4.5- Follow-up results
All invasively studied patients were discharged on the post-procedural day and had no evidence of significant pericardial effusion. Sequential Holter recordings re-assessed the rhythm outcome, which demonstrated 7 of 8 (87%) ablated patients in SR. Regarding anti-arrhythmic therapy, at a median follow up of 10, 7 months 4/8 pts (50%) are still on medication and 4/8 pts (50%) are freedom from AF/flutter/tachycardia (> 30 sec) off antiarrhythmic medication. Finally, regarding the secondary endpoints 3/8 pts (37%) are free of AF on previously failed antiarrhythmic medication.
Figure 14 shows the study flow chart and the outcome with respect of type of AF and the need for anti-arrhythmic therapy.
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Figure 14: follow up flow chart
One patient with recurrent atrial tachycardia underwent a second ablation procedure (which also included HFS at the RA-GP sites) and was found to be in a peri-mitral re-entrant tachycardia which was subsequently ablated. As this patient had undergone previous ablations overseas which included linear lesion deployment, this was judged as most likely a gap-related arrhythmia due to the previous non-GP ablations. One pt with long standing persistent AF, previous multiple ablations and only 1 GP (too far from LA and not ablated) is back in AF.
Assessment of the Holter recordings on the patients with SR restoration, we did not observe any significant pauses or sinus tachycardia (as defined as a mean HR > 100 bpm) after mIBG-guided GP ablation in any of our patients.
4.6- Complications
There were no significant complications in any of the patients. Specifically the D-SPECT nuclear imaging studies were well tolerated by the patients and there was no adverse consequence of the 3D imaging studies. There was no evidence of peri-procedural significant complications. None of the patients reported symptoms. We noted
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hematoma at the puncture sites in 1 patient, which did not require any intervention and receded in the follow-up period.
5- DISCUSSION
We report on our preliminary experience on morphological and functional image fusion in order to localize GPs in a group of patients with AF. Combination of high-resolution molecular imaging using an analogon for norepinephren (I-123 mIBG) with 3D anatomical information from CT or CRM allowed 3D reconstruction of hybrid images that were imported into the 3D electroanatomical mapping system CARTO. During invasive EP studies as part of a catheter ablation procedure of atrial fibrillation in a subgroup of the overall patient group, the so identified GP locations could be validated by a positive response to HFS.
5.1- Characterisation of functional information
The mIBG imaging has been reported using conventional gamma camera imaging for assessment of patients with cardiac arrhythmia and various underlying heart disease. It has been demonstrated to predict adverse outcome for patients with heart failure, after ICD implantation and even predict outcome of catheter ablation of atrial fibrillation.110111112113 However, these reports have been largely limited to H/M ratios and/or wash-out rates. Our study reports for the first time localized mIBG uptake and correlate it specifically to the epicardium of the atria. We were also able to demonstrate different activity levels at these uptake sites, although we are unable at this point in time to demonstrate a correlation to the HFS effect achieved or the type of AF presentation.
The median radiation dose from the mIBG tracer is not negligible but it seems to be justified from the need of evaluating the GP location to guide the ablation. On the other hand, the dose from the nuclear medicine appears counterbalanced by a very low fluoroscopy time which makes acceptable the total radiation dose.114Further studies are needed for a better understanding of the risk/benefit of this new methodic. We did not observe significant differences between the different types of AF. However, this could be due to the overall small number of patients investigated rather
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than a true lack in difference. Equally important would be to know if individuals without any history of arrhythmia or palpitations would have a comparable number of GPs and similar activity levels as arrhythmia patients.
5.2- Localisation and distribution of GPs
Unlike the previously published anatomical and histological data suggested, we found high uptake sites of mIBG not only in the so-called GPs sites around the LA, but also at sites around the RA. Whilst due the limitation to LA sites in the initially studied patients, we confirmed the RA sites by HFS in the later patients. Similarly, if GP sites were located very close to ventricular myocardium we did elect not to perform HFS in order to avoid pro-arrhythmia in the event of ventricular capture.
However, our results underline that the distribution of GPs is highly individual and therefore a simply anatomical approach may not achieve complete GP ablation. Having the 3D roadmap, HFS stimulation for GP localization was technically very easy and did not add more than 40 min to the overall ablation procedure. Interestingly, GP sites as confirmed by positive HFS did not correlate to CFAEs sites as previously published. Therefore, CFAE assessment was highly subjective but was assessed in accordance with the EP specialists present during the case (minimum of 3 persons involved). Larger patient cohorts need to be studied to confirm or reject out observation.
Image registration between the hybrid image and the 3D electro-anatomical maps proved to be difficult and we used various iteration to match all mapped cardiac structures (including PVs and LAA) to achieve an adequate match. In all cases, we attempted to use the respiratory monitoring feature of the CARTO system to minimize the effect of the artificial ventilation (as all of our cases were carried out under general anaesthesia). We purposeful refrained from measuring distance from positive HFS sites to the imaged GP sites, as the hybrid image is collated from the nuclear image (collected over ~10 min) with the 3D DICOM which per se results in a possible registration error. However, we were able when testing the HFS effect in the vicinity of a given GP site to locate its real distribution.
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5.3- Effect of mIBG-guided AF ablation
We studied a mixed group of patients with various types of AF and the majority of the patients had structural underlying heart disease as we recruited patients with a clinical indication for molecular imaging. Two patients had undergone previous ablation attempts for AF, which make the outcome of the ablation difficult to attribute to the GP ablation alone. As many previously applied AF ablation strategies might in-advertently deliver RF in a GP region, we might even under-report the number of GPs. However we were able to located GPs even in these patients in all but one patient (with long-standing persistent AF and multiple ablation attempts). Similar to previous reports on GP ablation as an add on to “conventional” AF ablation strategies, we observed a very respectable clinical outcome which resulted in all of the paroxysmal and all of the persistent AF patients to be in SR (one after repeat ablation). Only 1 patient with persistent AT required re-intervention and is currently in follow-up. The only patient with longstanding persistent AF reverted back to AF about 1 week after the procedure. As he is largely asymptomatic and had previously failed 2 “conventional” AF ablation attempts, no further ablation attempt is planned for this patient. Interestingly, he had only 3 GPs identified which could be an effect of our previous ablation attempts.
Interestingly, some of the GP locations that we identified would very likely be “treated” by the linear lesion that encircles the PVs such that GP ablation could in fact be already be some kind of “collateral damage” of conventional AF ablation strategies. Conversely, we believe that a pure anatomical approach of GP ablation as previously proposed by several groups is very likely to “overlook” individual GPs that are not located at the typical “anatomical” GP sites. Likewise, atrial myocardium might be ablated where in the individual patient does not possess any GP activity and thereby risking unnecessary scarring and potential negative consequences (such as pro-arrhythmia, perforation, etc.). Individual GP localisation as demonstrated in our patients allowed to perform GP ablation in a time-efficient and safe procedure.
5.4- Limitations
This is not a prospective trial but a first clinical experience of a small number of patients who underwent radionuclide imaging in order to assess or exclude underlying
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heart failure systems during arrhythmia. Any comparison between subgroups is purely descriptive due to the small number of patients which is why we have refrained from performing any formal statistical analysis.
Due to the small overall number of patients imaged and the variable underlying cardiac conditions, no firm conclusion can be made on the effect of mIBG-guided ablation of GPs in drug-refractory AF. The imaging results and the invasive confirmation of the identified mIBG uptake sites at least in the subset of the imaged patients make this functional image fusion a valuable new tool that warrants further studies in well-defined patient cohorts.
6- CONCLUSION
We report on our preliminary experience of image fusion between conventional 3D cCT or CMR scans and functional imaging by I-123 mIBG high-resolution D-SPECT in patients with documented atrial fibrillation. Invasive validation of the so identified high uptake sites correlated well with sites responding positively to HFS and subsequent ablation of these GP sites resulted in favourable outcomes in 87% of the patient treated. Further studies in larger and well-defined patient cohorts are necessary for elucidate the effect of mIBG-guided GP ablation for different subtypes of AF.
