Accepted Manuscript The Past, the Present and the Future of Cardiac Arrhythmia Ablation Jason G. Andrade, MD Léna Rivard, MD Laurent Macle, MD PII:

S0828-282X(14)01209-4

DOI:

10.1016/j.cjca.2014.07.731

Reference:

CJCA 1358

To appear in:

Canadian Journal of Cardiology

Received Date: 27 May 2014 Revised Date:

20 July 2014

Accepted Date: 21 July 2014

Please cite this article as: Andrade JG, Rivard L, Macle L, The Past, the Present and the Future of Cardiac Arrhythmia Ablation, Canadian Journal of Cardiology (2014), doi: 10.1016/j.cjca.2014.07.731. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The Past, the Present and the Future of Cardiac Arrhythmia Ablation

Jason G. Andrade MD1,2; Léna Rivard MD1; Laurent Macle MD1

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From 1the Electrophysiology Service at the Montreal Heart Institute and the Department of Medicine, Université de Montréal, Montreal, Canada; and 2The Department of Medicine, The University of British Columbia, British Columbia, Canada

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Please address all correspondence to: Dr. Laurent Macle Electrophysiology Service Montreal Heart Institute 5000 Belanger St. E. Montreal, QC, Canada, H1T 1C8 E-mail: [email protected]

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Short Title:

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Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs [22] Ablation/ICD/surgery [106] Electrophysiology

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ACCEPTED MANUSCRIPT SUMMARY The development and evolution of catheter ablation for the treatment of cardiac arrhythmias has progressed significantly since the 1980’s, with the techniques and technologies becoming increasingly complex, and advancing in parallel with an increasing understanding about

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arrhythmia mechanisms. The purpose of this review is to discuss the contemporary and future practice of invasive arrhythmia management within its historical context. ABSTRACT

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The development and evolution of percutaneous catheter ablation for the treatment of cardiac arrhythmias has advanced significantly since the early days of direct current shock ablation, and in parallel with an increasing understanding about arrhythmia mechanisms. Given the ever-

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changing landscape that is cardiac electrophysiology, the purpose of this review is discuss the future of invasive arrhythmia management within the context of the history and contemporary practice of this cardiac subspecialty. Topics of discussion include: 1) the evolution of ablation technologies from DC shock and radiofrequency to alternative energy sources such as cryothermal ablation; 2) the use and development of non-fluoroscopic navigation systems; 3) the

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progression of ablation toolsets and modalities; and 4) the advancement of ablation strategies and techniques, including ablation of complex atrial and ventricular dysrhythmias tailored to the

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individual patient.

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ACCEPTED MANUSCRIPT INTRODUCTION The development and evolution of catheter ablation for the treatment of cardiac arrhythmias represents a major accomplishment. Rarely have such significant advances in both technology and technique been seen so rapidly and over such a short period of time. Catheter ablation

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procedures have been utilised worldwide in hundreds of thousands of patients. Since it’s clinical introduction in the early 1980’s the techniques and technologies surrounding cardiac catheter ablation have become increasingly complex, evolving significantly in parallel with an increasing understanding about arrhythmia mechanisms (Figure 1). Given the ever-changing landscape that

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is cardiac electrophysiology, the purpose of this review is discuss the future of invasive

arrhythmia management within the context of the history and contemporary practice of this

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cardiac subspecialty. WHERE WE HAVE BEEN

The beginnings of invasive electrophysiology and catheter ablation Invasive electrophysiology owes its early existence to a combination of critical developments in the late 1960s and early 1970s.(1-4) The combination of intracardiac catheter recordings of

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cardiac electrical activation (such as the His bundle activity described by Scherlag and colleagues in the late 1960’s – Figure 2), and programmed stimulation techniques (as described by Henrick Joan Joost Wellens in the early 1970s) led to significant advances in the understanding of tachycardia mechanisms (particularly Wolff-Parkinson-White syndrome, but also

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atrioventricular node re-entry and atrial flutter). As a result of this greater understanding, open surgical techniques were developed for the treatment of various arrhythmia substrates including

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atrioventricular or accessory pathway mediated tachycardia,(5) ventricular tachycardia,(6) and atrial fibrillation.(7,8)

Owing to limitations associated with the open surgical treatment of cardiac arrhythmias, percutaneous catheter ablation was developed in the early 1980s and has since revolutionized the field of electrophysiology (Figure 3).(9-11) Employing the use of high- and low-energy direct current shocks, the initial studies concentrated the use of this technique on reasonably wellunderstood focal arrhythmia substrates such as the atrioventricular (AV) junction or His-Bundle (i.e. complete AV node ablation), AV re-entrant tachycardias (i.e. accessory AV pathways), and ischemic ventricular tachycardia (i.e. diastolic pathway or VT exit site).(9-14) Unfortunately, 3

ACCEPTED MANUSCRIPT these early ablation procedures were long (>4–8 h), and of limited utility. Specifically, the risk of barotrauma as well as other significant complications (myocardial depression, proarrhythmia, unintended AV block, myocardial perforation, venous thrombosis, and sudden death), limited these procedures to patients with more malignant dysrhythmias or severe co-morbidities.

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Radiofrequency ablation

Technological advancements in the late 1980s led to the development of catheters capable of delivering continuous-wave unmodulated radiofrequency (RF) energy. This shift from direct current to RF ablation represented a major advance in the field of invasive cardiac

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electrophysiology. Compared to direct current shocks RF ablation offered the advantages of: 1) Minimal discomfort during energy delivery (allowing the procedure to be performed in conscious

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patients), 2) Absent skeletal- and cardiac-muscle stimulation, 3) Relatively discrete ablation lesions with absent barotrauma, and 4) The potential for the premature termination of ablation in an effort to avoid impending complications.(15) As such, RF energy provided a reasonably low risk treatment option, quickly supplanting open-heart surgery as the preferred invasive modality for the treatment of supraventricular and ventricular arrhythmias.

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However, despite the rapid and widespread adoption of percutaneous catheter ablation the early use of RF energy was not without its limitations. While the standard RF ablation is appropriate for focal ablation in thin myocardium (e.g. focal atrial tachycardia, accessory pathways, and AV nodal substrates) its use is limited by complications related to the use of high-power settings

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and/or high target temperatures when performing more extensive ablation in thicker tissues (i.e. the ventricle), or ablation in the systemic circulation. Specifically, irreversible tissue destruction

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requires a temperature of ≥50°C. However, the attainment of high temperatures at the electrodetissue interface may result in carbonization, tissue desiccation, and/or plasma coagulation (charring and thrombus formation). These factors may increase the risk of perforation and/or thromboembolism.

In response, temperature and/or energy limited ablation was developed. Under temperature control, RF power delivery is regulated to maintain a constant electrode temperature (commonly 55°C or 60°C), which is thought to prevent electrode-tissue interface temperature from increasing to the point of creating an impedance rise, soft thrombus formation, and/or steam “pop.” However, the ablation electrode temperature is dependent on the opposing effects of 4

ACCEPTED MANUSCRIPT heating from the tissue and cooling by the blood flowing around the electrode at any given electrode temperature. As such, the reduced electrode cooling associated with the presence of low blood flow causes the ablation electrode to reach the target temperature at a lower power level, which limits the RF power delivered and subsequent lesion size. Unfortunately, in these

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circumstances increasing the electrode temperature to 65°C or 70°C only minimally increases RF power at the expense of a significant increase in the risk of thrombus formation and impedance rise.

As such, RF ablation catheters underwent further evolutions to increase electrode cooling in

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order to allow RF power to be maintained in a desirable range in the presence of low blood flow. The first approach was the development of larger-tip ablation catheters, on the rationale that for

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the same degree of blood flow their greater surface area (i.e. increased electrode circumference and length) would increase convective cooling. The second approach was the development of continuous electrode irrigation by circulating fluid either within the electrode (closed loop) or by flushing saline through small openings in the distal ablation electrode (open irrigation). The use of “active electrode cooling” by continuous irrigation facilitates the creation of deeper lesions by sustaining adequate RF power even at sites with low blood flow. Indeed the use of irrigated RF

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ablation catheters has become the standard of care for ablation in the systemic circulation (such as atrial fibrillation)(16) or in thicker myocardial substrates (such as the ventricle).(17) Cryothermal Ablation

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While RF ablation remains the standard of care for the treatment of the majority of arrhythmic substrates novel ablation energy modalities have been sought in an effort to address the

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perceived limitations associated with RF ablation. Of the novel ablation energy sources cryothermal ablation is the most promising. Cryotherapy, or the use of freezing temperatures to elicit a specific tissue response, has a long history of safe and effective use in medicine. In contrast to RF energy, which effectuates an ablation lesion through the resistive tissue heating associated with the delivery of alternating current (cycle lengths of 300-750 kHz), cryothermal ablation results in cold-induced tissue injury through a combination of direct cellular damage (ice crystal formation during hypothermia) and ischemic cell death (microcirculatory failure and subsequent vascular stasis during thawing). When compared to RF-energy cryothermal energy offers the advantages of: 1) improved catheter stability, 2) the creation of an ablation lesion that is less arrhythmogenic, 3) reversible tissue suppression (which allows for active 5

ACCEPTED MANUSCRIPT electrophysiologic evaluation of potential ablation sites during mapping and/or ablation), 4) a lower risk of damage to collateral structures, and 5) a lower risk of periprocedural thromboembolism (i.e. cryo results in a lesser degree of endothelial disruption and platelet activation).(18,19)

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While cryoenergy has been employed in modern surgical procedures for over 50 years, the development of steerable percutaneous cryocatheters represents a more recent landmark in the history of clinical cardiac electrophysiology. The first transcatheter cryoablation procedure in humans was performed at the Montreal Heart Institute in August 1998, whereby a patient

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underwent AV node ablation for recalcitrant rapid atrial fibrillation.(20) Since the publication of the initial feasibility case series, the indications for cryoablation have expanded. As a result of the

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favourable safety profile cryoablation has been increasingly utilised for focal ablation close to the AV node (AVNRT, and right-sided paraseptal and para-Hisian pathways), and more recently for pulmonary vein isolation utilising a dedicated balloon ablation catheter (discussed later).(21) Expanded Indications

Concurrent to the development of alternative energy sources was the realisation of a greater

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understanding of supraventricular arrhythmia mechanisms, which resulted in an evolution of catheter ablation to novel arrhythmia substrates and patient populations. For example, the concept of dual AV-node physiology (ie the presence of separate fast and slow AV nodal inputs) led to a change from complete AV-node ablation to selective AV node modification (i.e.

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elimination of the anterograde limb, or slow pathway) for patients afflicted with AV node reentrant tachycardia.(22) Likewise, the understanding that some arrhythmias can originate from a

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single focus of abnormal automaticity (such as atrial tachycardia or idiopathic right ventricular outflow tract VT), or by re-entry around fixed or functional barriers (such as typical atrial flutter or ischemic VT) allowed these arrhythmias to be cured by targeting ablation to critical zones (eg. the cavotricuspid isthmus in typical atrial flutter - FIGURE 4). More recently the invasive management of arrhythmias has extended from discrete organised dysrhythmias to complex chaotic arrhythmias such as atrial fibrillation. In the late 1990’s Haïssaguerre and colleagues demonstrated that AF was a triggered arrhythmia initiated by rapidly repetitive discharges originating predominantly from the pulmonary veins (PVs).(23) The identification of sites of AF initiation and/or maintenance within the PVs has led to the 6

ACCEPTED MANUSCRIPT development of percutaneous procedures designed to electrically isolate the PV from the vulnerable substrate in the left atrium (LA), with the intention of arrhythmia cure. Indeed catheter ablation has moved from an “experimental therapy” to the standard of care for the treatment of drug-refractory symptomatic AF over the past 15 years.

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As a result of these developments, the efficacy of catheter ablation has improved significantly. This in turn has led to expanding indications beyond simple ablation, such as the ablation of AF, ventricular tachycardia including idiopathic polymorphic VT, idiopathic ventricular fibrillation

IMPROVED ARRHYTHMIA MAPPING AND NAVIGATION

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Electroanatomic mapping

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(VF), and arrhythmias in congenital heart disease.

A major innovation in the practice of cardiac electrophysiology has to do with the development of advanced intraprocedural imaging. In the early days of invasive electrophysiology point-by-point mapping of local electrical signals was necessary to define the activation patterns, with serial replacement of the mapping and ablation catheters required for therapeutic treatment. This tedium was supplanted in the early to mid-1990s with the development of multipolar diagnostic

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catheters that enabled the simultaneous recording (and stimulation) of wider areas of activation, and in doing so facilitated a rapid comprehension and localisation of arrhythmia circuits. However, it was the development of electroanatomical mapping (EAM), non-contact mapping,

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and the fusion of these additional tools with cardiac imaging that have spurred the greatest advances. Electroanatomical mapping (EAM) systems, which aid navigation by allowing catheter

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localization in three dimensions in near real-time, are based on the simultaneous recording of spatial information and electrical activity from electrodes placed on a roving catheter. The maps generated with these systems are highly accurate, and facilitate arrhythmia localization while reducing fluoroscopic exposure and radiation dose. However, with the conventional forms of these mapping systems, the spatial and electrical activation data are gathered using a single or a small number of electrodes on a roving catheter. As a result the acquisition of the electroanatomic maps can be labour intensive and time consuming. The use of specialised multielectrode mapping catheters can facilitate the creation of high-density electroanatomic maps through the simultaneous collection of multiple data points from several closely spaced electrodes. The extra detail provided by high-density maps is thought to be particularly useful in 7

ACCEPTED MANUSCRIPT the creation of activation maps of intermittent phenomena (such as extrasystoles), and for the ablation of complex arrhythmias, such as atypical atrial tachycardia. A potential limitation of the current generation of EAM systems is the static nature of the geometry. A potential development is the integration of intracardiac echocardiography with EAM.

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In effect, complex geometries can be rapidly created through the use of images obtained from a flexible ultrasound probe, with the benefit of being able to alter the images quickly in the event of changes in intraprocedural anatomy (i.e. tissue edema, or changes in volume status). Taking this a step further, it is possible that the use of three-dimensional intracardiac echo may facilitate the

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real-time catheter navigation. Remote Magnetic and Robotic Navigation

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Remote catheter navigation has been developed in an effort to enhance the accuracy of catheter positioning, manipulation, stability, and control during complex cardiac arrhythmia procedures. Conceptually there are two types of navigation systems commercially available. The first utilizes large magnets placed externally to the patient to deflect and navigate the catheter within the patient based on alterations of the magnetic fields. The second utilizes a remote catheter

Non-Fluoroscopic Navigation

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manipulator fixed on fluoroscopy table to direct a steerable dual lumen catheter.

Lastly, a novel non-fluoroscopic Navigation System (MediGuide, St. Jude Medical) has recently

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been developed. This system consists of three components: a transmitter generating a 3-D electromagnetic field, an electromagnetic field reference sensor attached to the patient, and a

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miniaturized coil sensor within the catheter. The transmitter produces a set of magnetic fields in a range of frequencies between 10-15 KHz, with a magnitude of less than 200 micro Tesla, and is mounted on the fluoroscopy detector, aligning the 3-D electromagnetic field with the fluoroscopy field. The reference sensor provides information about the spatial relationship between the chest wall and the fluoroscopy detector and allows accurate compensation for respiratory and patient movement. The sensor tip catheter is tracked non-fluoroscopically within the 3-D electromagnetic field and projected onto the pre-recorded cine loops gated to a real time ECG. Single-centers studies have demonstrated beneficial effects of the MediGuide technology on reduction of fluoroscopy time and radiation exposure for catheter ablation of atrial and ventricular arrhythmias. 8

ACCEPTED MANUSCRIPT IMPROVING LESION DURABILITY While focal point-by-point radiofrequency catheter ablation (RFCA) has shown considerable success in the treatment of multiple arrhythmia substrates, there are well-documented limitations. Typically these revolve around the complementary issues of: 1) the inherent

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difficulty in creating contiguous curvilinear lesions using techniques originally developed for discrete (point-by-point) ablation, and 2) a relatively suboptimal ability to effectuate a lasting transmural lesion. In response, a considerable effort has been directed towards developing novel techniques and technologies in order to achieve safer and more effective ablation procedures

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that are (potentially) less reliant on operator dexterity and skillset. Pharmacologic Challenges

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While a positive effect may be observed acutely, the combination of inadequate electrode–tissue contact, insufficient power delivery, and/or tissue edema may prevent the creation of irreversible ablation lesions. Subsequently, as the acute inflammatory effects of RF-ablation resolves, the transient injury induced at the time of index ablation recovers allowing the cells to resume excitability. Several pharmacologic agents have been proposed as a means to evaluate the

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effectiveness of the ablation lesion, i.e. differentiate permanent conduction block from dormant conduction (i.e. viable but latently non-conducting tissue), of which adenosine shows the most promise. For patients with SVT, adenosine administration immediately after apparent successful accessory pathway ablation can reveal recurrent conduction over a bypass tract, a finding that is

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highly predictive of early recurrence (PPV 100%, NPV 95%).(24) Likewise, the administration of adenosine has been shown to result in an acute resumption of conduction across the

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cavotricuspid isthmus in up to 9% of patients undergoing a typical atrial flutter ablation, and across circumferential left atrial ablation lines in up to 60% of patients undergoing a pulmonary vein isolation procedure.(25-30) Preliminary results indicate that the elimination of adenosineprovoked dormant PV conduction post-PVI reduces atrial tachyarrhythmia recurrence by >50%. Electrode-tissue contact force Ablation electrode-tissue contact is an important determinant of lesion quality (size, depth, and ultimately durability). Conventionally, this has been assessed using a combination of fluoroscopic imaging (“catheter tip motion”), tactile feedback, as well as examining the effect of energy delivery on local electrograms and impedance. While broadly utilized, these surrogate measures 9

ACCEPTED MANUSCRIPT are at best inexact. Contact force sensing is a newly developed technology that allows for the realtime quantitative estimation of the degree of contact between the tip of the catheter and the target myocardium. To date three independent systems have been developed, two of which rely on the defection of a sensor within the catheter tip to estimate the grams of axial and lateral

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contact force. The third estimates contact force through the use of complex local impedance measurements at the catheter tip. Irrespective of the system used it is hoped that the real-time assessment of catheter electrode-tissue contact force will improve procedural efficacy (by minimizing the creation of suboptimal lesions) as well as decrease the risk of complications. Recent data suggests that incorporating contact force data into the ablation strategy results in a

Novel Ablation Toolsets And Modalities

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profile to that observed with standard irrigated RF.(31,32)

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reduction in procedure time, ablation time and total energy delivery, with a comparable safety

Multi-Electrode Radiofrequency Ablation catheters are a purpose-built AF ablation toolset that was developed to address the technical difficulties associated with created continuous radiofrequency lesions (Figure 5). The first system consists of: 1) The pulmonary vein ablation catheter (PVAC, Medtronic Ablation Frontiers, Carlsbad, CA), which is a 9-F deflectable circular

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multi-electrode catheter that enables mapping and circumferential PV ablation, and 2) The multiarray septal catheter (MASC) and multi-array ablation catheter (MAAC), which facilitate LA mapping and substrate modification for patients with more persistent forms of AF. The

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accompanying multichannel RF generator enables the delivery of energy in a unipolar (between electrode and indifferent electrode on the body) or bipolar (between any two adjacent electrodes) configuration to all electrodes simultaneously or individually. During an RF

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application, energy delivery to individual electrodes is temperature controlled by a software algorithm that modulates power in order to reach the user-defined target temperature (Usually 60°C with maximum 8 W per electrode with the PVAC in a 4:1 power setting or 10 W in all other settings). Based on contemporary studies the 1-year freedom from recurrent AF after PVACbased ablation compares favorably to conventional irrigated RF, with shorter procedure and fluoroscopy time.(33-35) However, while the rate of acute procedural complications reported with PVAC is relatively low (2.0%) and compares favorably with irrigated RF, an excessively high rate (37.5-45.1%) of silent cerebral ischemic lesions has been reported.(33,35) With modification from the first to second generation catheter (PVAC Gold) there has been a 10

ACCEPTED MANUSCRIPT significant decrease in cerebral ischemic events. Recently an irrigated multi-electrode ablation system has been developed (nMARQ; Biosense Webster). Safety and efficacy data are pending for this promising technology, which is not approved in North America. The Cryoballoon Ablation system (Arctic Front; Medtronic, Minneapolis, MN) is designed

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specifically for circumferential PV ablation. It consists of a steerable 10.5-Fr catheter with distally mounted polyurethane and polyester balloons. Cryorefrigerant (nitrous oxide; N2O), which is housed in the external cryoconsole, is delivered to the distal aspect of the inner balloon via an ultrafine injection tube. The cryorefrigerant then absorbs heat from the tissue before returning to

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the console through a central lumen maintained under vacuum. In a recent meta-analysis, we reported that cryoballoon ablation results in a high procedural success rate and 1-year freedom

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from recurrent AF (1 year single procedure success of 60% off AAD; 73% if a 3-month blanking period was included), which is comparable to conventional irrigated RF and multielectrode ablation.(35)

The HeartLight Visually-Guided Laser Ablation balloon (CardioFocus, Marlborough, MA) is an endoscopic laser ablation catheter that allows direct visualization of the left atrial endocardial surface. The ablation system has three components: a variable diameter compliant balloon (25 to

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32 mm), the lesion generator (a 980-nm laser diode source which produces a 30-degree arc of light energy), and a 2-F fiberoptic endoscope (115-degree field of view). The ablation energy is projected perpendicular to the catheter shaft. After delivering contiguous lesions around a

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pulmonary vein, the balloon is withdrawn and a circular mapping catheter can be used to judge PV isolation. If the PV remains connected, additional lesions can be delivered until isolation is achieved. A recently published multicenter clinical study demonstrated a favorable safety profile

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with 1 year outcomes comparable to conventional irrigated RF (60.2% 1 year freedom from recurrent AF after 1-2 procedures).(36) IMPROVING ABLATION TARGETS Atrial fibrillation

Initial attempts at catheter ablation for atrial fibrillation attempted to recreate the surgical maze procedure, which followed the “multiple wavelet hypothesis” of AF.(7,8) This theory postulated that compartmentalizing the LA into smaller regions incapable of sustaining the critical number of circulating wavelets would result in improved arrhythmia free survival. Unfortunately these 11

ACCEPTED MANUSCRIPT approaches were only marginally successful and carried relatively high complication rates. The discovery in the late 1990’s by Haïssaguerre and colleagues that AF was a triggered arrhythmia initiated by rapidly repetitive discharges originating predominantly from the pulmonary veins (PVs) represented a monumental shift in thinking around AF.(37) As a result percutaneous

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procedures designed to isolate these PV triggers were developed. While isolation of the pulmonary veins remains the cornerstone of the invasive management of paroxysmal AF the invasive ablation strategy itself has undergone significant evolution over the past 15 years. Initially, the procedure targeted elimination of the focal triggers within the PV musculature however this approach was associated with modest clinical efficacy, and a significant risk of

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complication. Thereafter the procedure evolved to target the more proximal extensions of the myocardial sleeves, whereby the earliest PV potentials were targeted at the tubular ostium of

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each vein. Although this “segmental, ostial” isolation resulted in improved outcomes, the recognition that sites of AF initiation and/or maintenance were frequently located within the PV antrum resulted in a shift in ablation strategies to target the more proximal perivenous LA tissue. The early circumferential PV ablation (CPVA) strategies aimed to “compartmentalize” a significant portion of the LA via the creation of wide encircling lines of ablation outside and around the PV antra. As this approach did not necessarily document electrical isolation of the PVs

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it was limited by the induction of a high rate of macro re-entrant arrhythmias because of residual PV connections. The contemporary AF ablation procedure has evolved to a hybrid of the above approaches whereby circumferential ablative lesions are placed within the LA myocardium

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outside of the tubular veins with a goal of electrical pulmonary vein isolation (i.e. bidirectional conduction block). This contemporary approach, as recommended by major heart rhythm societies, therefore targets not only the initiating triggers of AF (the PVs) but also the mass of

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electrically active LA tissue capable of sustaining the AF perpetuating fibrillatory wavelets.(37) Within the past year randomised trials of procedural refinements aiming to increase the effectiveness of the lesion set in order to obtain more durable pulmonary vein isolation have been published. Specifically, post-isolation adenosine testing (to unmask reconnection), and contact force sensing catheters have demonstrated improved clinical outcomes. Likewise, novel technological innovations such as cryoballoon ablation, laser ablation, and multi-electrode ablation designed specifically for pulmonary vein isolation will continue to evolve in the hopes that alternative energies or delivery mechanisms will lead to improved outcomes (Figure 5). In the case of persistent AF, ablation beyond the pulmonary veins is often necessary due to a 12

ACCEPTED MANUSCRIPT predominance of non-PV triggers as well as a shift in the sites of AF perpetuation to regions outside the LA-PV junction. Proposed adjunctive ablation strategies include: 1) Linear ablation, which is derived from the surgical Cox maze procedure; 2) Complex fractionated atrial electrograms ablation, which are local signals during AF that are either at a very short cycle

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length, or are fractionated with two or more components. It is postulated that they represent areas of slow conduction, conduction block, or “pivot” points for a local AF perpetuating re-entry; 3) “Rotor ablation,” which is based on the “localized source hypothesis” that proposes that AF is perpetuated by rapid, organized discrete micro re-entrant circuits (rotors) or focal impulses that disorganize into fibrillatory waves at their periphery (i.e. central highly organized activation with

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surrounding variable propagation and fractionation). Several techniques have been proposed to identify these potential pathophysiologic sites including, a) Shannon entropy analysis of invasive

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bipolar signal amplitude distribution to differentiate the pivot from surrounding peripheral regions;(38) and b) simultaneous multielectrode activation analysis using a proprietary 64electrode catheter and a software algorithm (Focal Impulse and Rotor Modulation – FIRM, RhythmView, Topera, Inc.). With respect to the latter, a spatiotemporal activation analysis of simultaneously recorded electrograms using this panoramic mapping catheter is performed. Using this proprietary technology a digital electroanatomic map is created revealing focal

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impulses (defined by centrifugal activation isochrones from a point origin) or electrical rotors (defined as sequential isochrones around a center of rotation with waves emanating outwardly).(38,39) While the incremental benefit of each of these approaches requires extensive

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study, it is most likely that the major innovations in the interventional management of more advanced AF will be centered on refining the overall ablation strategy, as well as tailoring the

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specific approach to the individual patient. Ventricular tachycardia

Similar to atrial fibrillation, catheter ablation for ventricular tachycardia and fibrillation has undergone a significant evolution over the past 25 years from its origins with open surgical aneurysm resection for VT after myocardial infarction. Initially, catheter ablation focused only on the mapping of inducible hemodynamically stable ventricular tachycardias, either idiopathic outflow tract arrhythmias or re-entrant ischemic VTs. Unfortunately hemodynamically unstable VT is observed in more than 60% of patients with structural heart disease who undergo ablative therapy, a population in whom the overall survival has improved significantly in the ICD 13

ACCEPTED MANUSCRIPT era. Within the last decade, substrate-based ablation strategies, which aim to identify surrogates for arrhythmia circuits within myocardial scar during sinus rhythm, have been described for both ischemic and non-ischemic cardiomyopathies. For patients with ischemic heart disease, localized RF lesions can be applied to the tissue bordering the scar or areas of delayed activation within a

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scar. Furthermore, the majority of patients with structural cardiac disease will have multiple inducible VTs due to numerous arrhythmia circuits (and isthmuses), which necessitate precise yet time-consuming mapping and more extensive ablation. In the case of non-ischemic

cardiomyopathies a common link in the pathogenesis seems to be the perivalvular anatomic distribution of scars. However, unique characteristics associated with the different arrhythmia

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syndromes have been described. As such, these substrate-based ablation strategies aim to minimize the need to induce and map during VT, in an effort to enhance the safety and efficacy of

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the procedure.

Additional areas where the practice of VT ablation has evolved include: 1) the ablation of premature ventricular contractions, which has become common practice in the treatment of symptoms, to improve left ventricular function, and to improve the percentage of biventricular pacing in patients with CRT. 2) The importance of epicardial substrate has become increasingly

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understood in recent years (Figure 6). Specifically, up to 50% of patients with non-ischemic cardiomyopathies (especially arrhythmogenic right ventricular cardiomyopathy) will require epicardial mapping and ablation. 3) From a strategy standpoint the timing of ablation has moved from being limited to medically refractory dysrhythmias to a first line or preventative procedure.

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Superiority of the ablation procedure over medication has been shown in highly specialized centers and a large multicenter randomized trial comparing ablation vs. antiarrythmic drugs in

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patients with VT and ischemic cardiomyopathy is ongoing. Lastly, similar to the ablation of AF alternative energy sources and technologies have been explored including cryoablation, highintensity focused ultrasound, as well as intramyocardial RF ablation using a needle electrode. CONCLUSION

In the past 25 years the practice of clinical cardiac electrophysiology has evolved tremendously. While still a relatively young field, it can be expected that technological and strategic innovations will continue to improve efficacy and safety outcomes in this rapidly expanding field.

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Figure 2: Seminal Events in the history of invasive arrhythmia management. Top panels – reproduced with permission from Scherlag et al.(1) demonstrate the intracardiac recording of the His bundle electrogram through the use of a multipolar electrode catheter (top left anteroposterior fluoroscopic view demonstrating the location and position of the catheter during His bundle recordings; top right – simultaneous atrial [P], His bundle [H], and ventricular [QRS] electrograms recorded at different amplifier frequencies). Bottom panels – reproduced with permission from Wellens et al.(40) demonstrate the initiation (bottom left) and termination (bottom right) of ventricular tachycardia through the delivery of a single premature ventricular beat (ie the use of programmed stimulation).

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Figure 3: The evolution of invasive arrhythmia management. The top panel demonstrates an open surgical ablation performed in 1989. The bottom panel demonstrates a percutaneous catheter ablation performed in 2011. In the top panel the electrophysiologist is simultaneously utilizing the computerized mapping system (Cardiomap; developed at the Université de Montréal) and while trying to induced the dysrhythmia utilizing the Bloom stimulator. In the bottom panel the same electrophysiologist is performing an atrial fibrillation ablation with the aid of multimodality imaging (fluoroscopy, intracardiac echocardiography, and rotational angiography), and an electroanatomic mapping system.

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Figure 4: Representative arrhythmia activation maps demonstrating a macro-reentrant arrhythmia (top panel) and a focal arrhythmia (bottom panel). In the bottom panel an early area of activation (white spot) is noted within the right superior pulmonary vein (PV tachycardia). The remainder of the left atrium is activated in a centrifugal manner (relative timing coloured red-orange-yellow-green-blue-purple from earlier to later). When compared to the tachycardia cycle less than 50% of the arrhythmia is recorded, with a corresponding electrically silent period during the tachycardia cycle. The top panel demonstrates a macro-reentrant tachycardia around the mitral valve (perimitral flutter). In this arrhythmia the relative area of earliest activation (white) is recorded adjacent to the region with the latest activation, with the totality of the arrhythmia cycle recorded within the adjacent tissue. Figure 5: Contemporary atrial fibrillation ablation technologies (top) and techniques (bottom). Central to all AF ablation strategies is circumferential pulmonary vein isolation (PVI). This can be accomplished with a standard point-by-point radiofrequency ablation catheter, as guided by a multielectrode circular mapping catheter (CMC – Top left), a cryoballoon ablation (CB) with accompanying small diameter circular mapping catheter (top middle), or a multielectrode ablation catheter (MEA). For more advanced AF substrate ablation is often required. This can be accomplished through the use of linear ablation lesions (bottom left), ablation of complex fractionated electrograms (bottom right), and ablation of AF perpetuating “rotors” (bottom middle). In the bottom left image additional linear lesions (blue points) were placed at the left atrial “roof” (between the superior pulmonary veins) and the “mitral isthmus” (between the left inferior pulmonary vein and the mitral valve) in order to compartmentalize the left atrium into smaller regions incapable of sustaining re-entry. In the bottom right image complex 18

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fractionated atrial electrogram (CFAEs - (i.e. those with a very short cycle length, or with multiple component fractionation) were identified using an automated algorithm and targeted for ablation. In the bottom middle image a “FIRM” map was created using a proprietary mapping algorithm demonstrating an AF perpetuating left atrial rotor (clockwise activation with wavebreak and collision; AF cycle of 160 milliseconds), which is subsequently targeted for ablation. Legend - CS: Coronary sinus catheter, RS: Right superior pulmonary vein; LS: Left superior pulmonary vein; RI: Right inferior pulmonary vein; LI: Left inferior pulmonary vein; LAA: Left atrial appendage.

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Figure 6: Ventricular tachycardia mapping and ablation. Panel A demonstrates the endocardial ablation of a monomorphic ventricular tachycardia in a 76 year old with ischemic cardiomyopathy. The electroanatomic voltage map (top left) demonstrates dense scar (coloured grey) surrounded by border zones of abnormal tissue throughout the anterolateral left ventricle and apical septum (intermediate colours; normal tissue represented as purple). In the apical aspect of the anterolateral left ventricle a mid-diastolic potential (arrows) is noted on the distal ablation catheter during ventricular tachycardia. These discrete electrical signals are thought to represent activation a critical zone of slow conduction within the arrhythmia circuit. Ablation in this region resulted in arrhythmia termination and subsequent non-inducibility. Panel B demonstrates the epicardial ablation of a monomorphic ventricular tachycardia in a 38 year old with arrhythmogenic right ventricular cardiomyopathy. The bottom left panels demonstrate the fluoroscopic localization of the diagnostic and ablation catheters, as well as the corresponding surface ECG and cardiac tracings. The ablation catheter (ABL) is positioned within the endocardial right ventricle, and the multielectrode diagnostic catheter is positioned in the pericardial space along the epicardial aspect of the right ventricle. Using this catheter an epicardial voltage map was created (panel C). While mapping the epicardium a PVC matching the clinical VT was observed. Preceding the electrical activation of the PVC by 125 msec is a small potential that is also observed in sinus rhythm in mid-diastole. Ablation in this region resulted in arrhythmia non-inducibility. Legend - CS: Coronary sinus catheter, RV – right ventricle,

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