Future of Catheter Ablation

Mark Fellman, MS

Uri Yaron, PhD

Although tremendous advances in catheter ablation for treatment of cardiac arrhythmias has occurred in the past 3 decades, and ablation of some arrhythmias has become routine and highly effective (e.g. >95% success rates in ablation and cure of atrioventricular nodal reentrant tachycardia [AVNRT], atrioventricular reentrant tachycardia [AVRT] due to accessory pathways, and atrial flutter), significant advances are still needed to treat the increasingly common arrhythmias atrial fibrillation (AF) and ventricular tachycardia (VT), where success rates still hover in the 50% to 70% range after initial ablation attempts. To achieve better acute and long-term success rates in treatment of these arrhythmias with catheter ablation, with fewer procedures, and to reduce morbidity and mortality associated with these arrhythmias, a multifaceted approach to research and development of new technologies and methodologies will be required.

This will entail both basic and translational research

• to better understand the mechanisms underlying these arrhythmias (i.e., focal or macro-reentry, focal drivers, etc.), research to better map and identify the sources initiating and maintaining these arrhythmias (i.e., high-density contact mapping, noncontact mapping, etc.);
• to better understand how to ablate the cardiac tissue causing these arrhythmias (that is, improvement of existing energy sources and energy delivery, development of newer energy sources that may be more effective, etc.);
• into how to monitor the efficacy of ablation of the cardiac tissues initiating or maintaining these arrhythmias; and
• into new approaches to ablate AF or VT (i.e., utilizing existing or new mapping and ablation technologies).

Three decades of work and progress in ablation of cardiac arrhythmias, while very dramatic overall, has not translated into significant improvement in outcomes with regards to treatment of AF and VT, however. This suggests that research producing significant advances in all these areas simultaneously will be required to move the needle on treatment and prevention of recurrences of AF and VT. The following sections will describe some of the research and development currently ongoing in these areas.

Currently, high-density contact mapping systems are being increasingly utilized clinically, and as part of clinical research studies, in order to rapidly obtain and record much higher electrogram densities (i.e., hundreds to thousands of points) and display their location on the endocardial and epicardial surfaces of the heart. The endocardial and epicardial locations on the surface of the heart are recorded simultaneously with the electrograms, which are annotated either manually or automatically with respect to activation time relative to a reference electrogram recorded on an anatomically fixed electrode catheter within the heart. The timing of each electrogram is then converted into an activation time map, which is then displayed as part of the three-dimensional (3D) geometry on the mapping system monitor. This activation sequence map, representing the sequence of electrical activation of the heart during an arrhythmia, can then also be displayed as a video (i.e., propagated) on the mapping system monitor. Viewing this information in real time allows the ablating electrophysiologist to visualize the reentrant or focal nature of the arrhythmia being mapped, and thus guide ablation to specific areas of interest in hopes of terminating the arrhythmia and preventing its recurrence. In addition, utilization of these high-density mapping systems to map during sinus rhythm or pacing, in patients with hemodynamically unstable arrhythmias, may provide insight into areas in the heart that may need to be ablated to eliminate the arrhythmia as well (e.g., areas with late potentials or abnormal low-voltage fractionated electrograms). As electrode size diminishes and the density of electrodes available on newer mapping catheters increases, in addition to the capacity of the mapping systems to record and automatically analyze thousands of electrograms simultaneously without input or validation from the operator (examples inclide Rhythmia™ with Orion Basket catheter™, Ensite Precision™ with HD Grid™,  or Carto™ with Pentaray), high-density point-mapping of repetitive arrhythmias becomes possible, allowing the operator to identify smaller critical areas in the arrhythmia circuit or focal areas that should be targeted for ablation (1-3). This may improve efficacy of ablation, but also significantly reduce the amount of ablation necessary to treat specific arrhythmias, such as atypical atrial flutter or atrial tachycardia (AT), and VT (i.e, where currently tissue homogenization with extensive ablation is often done when such critical areas cannot be identified).

The use of a contact mapping system has one major limitation, however, in that it can only map sustained, stable, repetitive arrhythmias (e.g., supraventricular tachycardia, AT, typical or atypical atrial flutter, and hemodynamically tolerated VT). In those cases where the arrhythmia is not sustained or is not hemodynamically tolerated, the use of contact voltage mapping (i.e., measuring tissue voltage amplitude) during sinus rhythm or pacing has been done, with extensive substrate ablation in order to cure the arrhythmia. Additionally, pace-mapping (i.e., pacing at multiple sites to mimic the arrhythmia morphology on surface electrocardiogram) has been done to localize the site of origin of the arrhythmia in order to cure it with ablation. These approaches are better tolerated by the patient, without resorting to hemodynamic support (e.g., with extra-corporeal membrane oxygenation or ECMO or the Impella™), but are less accurate and may require more extensive ablation to be as effective.

Thus, in certain arrhythmias such as non-sustained AT, AF or hemodynamically unstable VT, or ventricular fibrillation (VF), the use of a noncontact mapping system may be required in order to map activation wavefronts during the tachycardia. Specifically, in the case of AF or VF, the activation patterns of these arrhythmias are not stable or consistently repetitive, but often chaotic and unstable, and they can only be mapped by a system that can record at least several seconds of the arrhythmia and display the wandering activation wavefronts on the endocardial or epicardial geometry. One such mapping system (4,5) currently in clinical use and being utilized in clinical research is the high-resolution noncontact charge-density AcQMap System™. The use of a noncontact mapping system that can demonstrate continuous propagation of electrical wavefronts during arrhythmias such as AF may allow development of new approaches to ablation (e.g., new lesion sets), or the identification of new focal or reentrant sources that initiate or maintain the arrhythmia (e.g., focal drivers and localized rotational or irregular activity), which, if ablated, may improve long-term outcomes and reduce recurrence rates (6). In a recently published study of the use of this mapping system in patients with persistent AF, there was an increase in long-term success measured as freedom from AF recurrence (on or off antiarrhythmic drugs) at 12-month follow-up of 72.5% after one procedure and 93.2% after one or two procedures (6). An additional advantage of this noncontact mapping system is that the basket catheter used to record electrograms from the entire surface of the atrium simultaneously also is embedded with ultrasound crystals that allow it to simultaneously generate an internal 3D geometry of the cardiac chamber in which it is mapping, thus avoiding one pitfall of the existing contact mapping systems that can import a 3D computed tomography geometry that is obtained prior to the ablation procedure (i.e., usually 1 or more days before, resulting in possible variations in cardiac chamber volume that will affect accuracy of mapping). Another new mapping system that can generate a 3D live image of the cardiac chamber being mapped, without point-by-point mapping using a novel approach of measuring tissue di-electric field, is currently undergoing investigation as well (7). This system is catheter vendor agnostic (i.e., any steerable mapping catheter can be used), and can continuously track the position of the mapping and reference catheters within the cardiac chamber of interest and any changes in geometry that may occur during the procedure (7). Activation sequence mapping is not yet available with this system but importing this data onto the 3D geometry is feasible and under investigation.

New ablation technologies are being continually studied, and some brought into clinical use and/or clinical research. In the past, this has included the research and development, and clinical utilization after U.S. Food and Drug Administration approval of new catheter designs (e.g., externally irrigated ablation catheters, contact force-sensing ablation catheters) and new energy sources as alternatives to radiofrequency (RF) ablation (e.g., cryoablation, microwave, laser, and ultrasound ablation). While all these alternative energy sources have largely been demonstrated to be equivalent to RF catheter ablation, and some have become more widely utilized than others, such as cryoablation versus microwave ablation, they all have some limitations (e.g., technical issues such as tissue visualization in a blood pool, catheter shapes to deliver energy to tissue, cost, etc.) that prevent them from entirely overtaking the standard of RF ablation used in most electrophysiology laboratories today. Some laboratories may use a combination of energy sources for different arrhythmias as well, and thus their percent utilization may depend in part on the clinical characteristics of the population of patients with specific arrhythmias seen in their practice (e.g., cryoballoon ablation for paroxysmal AF or irrigated RF ablation for epicardial VT). Thus, while research to refine catheter delivery systems to take advantage of the properties of available energy sources is ongoing (i.e., RF, cryo, microwave, heat, laser, etc.), it is unclear at this time which energy sources, if any, will become the predominate ablation energy source utilized by most electrophysiology laboratories to treat cardiac arrhythmias in the future.

Because RF ablation requires point-by-point ablation at many sites for cure of arrhythmias such as AF and VT, the procedure and ablation time is relatively long, compared to some of the newer “one-shot” approaches (e.g., cryoballoon ablation for pulmonary vein isolation [PVI] for paroxysmal AF). Thus, research and development of rapid delivery systems for RF ablation has been extensive, resulting in development of several RF balloon ablation delivery devices, none of which however have received widespread use clinically to date, however (8,9). Research and testing of catheter delivery systems using alternative energy sources such as microwave and cryoablation energy is also ongoing at various academic centers around the world, including linear ablation catheters utilizing microwave or cryoablation energy (10,11) to achieve PVI with wide area circumferential ablation (WACA) as a treatment for AF (both persistent and paroxysmal).

Another limiting characteristic of current ablation systems and energy sources is their inability to produce deep lesions in ventricular myocardium under some circumstances. This is particularly problematic in ablation of VT, the sources of which (i.e., focal source or reentrant circuit) may be deep in ventricular myocardium. At present, the maximum depth of ablation lesions in myocardium is typically 6 to 8 mm, whatever the energy delivery system or energy source used, size of ablation electrode, or variations in duration of energy delivery or maximum power used. In order to achieve deeper lesion formation during RF catheter ablation, which may be necessary to cure some cases of VT, studies have evaluated the use of different irrigant solutions (12) and shown that external irrigation of the ablation catheter with dextrose in water (D5W) and half-normal saline produced deeper lesions than normal saline (i.e., the standard irrigant), and the use of bipolar ablation (13) and novel catheter designs, such as a retractable needle ablation catheter (14) or an expandable spherical ablation catheter (15), which also produce deeper more effective ablation lesions, all of which will be important when attempting to ablate VT in certain locations in the heart.

And potentially the most radical novel technology currently being studied is that of pulsed electric fields (PEF) for cardiac ablation (16). PEF ablation causes myocardial cell death by irreversible electroporation of tissue, which leads to increased cell membrane permeability and cell death. Preliminary studies have also suggested the PEF ablation may be able to produce more extensive contiguous and transmural ablation lesions than can be achieved with other, existing ablation technology (17). Electroporation as a method of ablation is also unlikely to cause collateral damage to surrounding tissues (e.g., nerves or esophagus) since it does not produce thermal injury as its mechanism of ablation (18). Pulse electrical fields can be delivered through needle electrodes, but not through the wide variety of ablation or mapping electrode catheters currently in use today for mapping and ablation of cardiac arrhythmias (16). Thus, extensive research is ongoing to develop catheter delivery systems for PEF ablation (16).

Existing approaches for ablation of most reentrant or focal tachycardias in the atria or ventricles involves a combination of electrogram analysis, 3D activation mapping, and entrainment to identify the mechanism of an arrhythmia and to localize its site of origin or a critical zone in the reentry circuit where ablation will terminate it and render it noninducible in the electrophysiology laboratory, and then prevent its recurrence during long-term follow-up. Whereas these approaches are relatively standard for most supraventricular tachycardias (e.g., AVNRT, AVRT, atrial flutter, AT, and paroxysmal AF), and various forms of ventricular tachycardia (e.g., ischemic and nonischemic reentrant VT, focal idiopathic VT), for some arrhythmias such as persistent AF and refractory VT or VF, novel ablation strategies, such as lesions sets beyond the standard approach, have been developed and studied or are undergoing study currently to assess their efficacy in acute and long-term outcomes.

In the case of persistent AF ablation, it has recently been shown that neither linear ablation (e.g., left atrial [LA] roof and mitral lines) or ablation of areas in the LA demonstrating complex fractionated electrograms during atrial remodeling, in addition to standard PVI with WACA, provides any advantage over standard WACA alone with PVI, with respect to long-term outcomes and recurrence rates of AF (19). Consequently, the optimal approach to ablation of persistent AF is unknown, and the subject of substantial research. One such approach is the ablation of the entire posterior LA wall in addition to WACA, since the embryological origin of the PVs and the LA posterior wall are similar, and thus the posterior wall is considered to possibly be a source of AF triggers as well, and thus arrhythmogenic. This concept has been recently validated in a meta-analysis of five studies with 594 patients comparing AF ablation with and without posterior LA wall isolation, showing statistically significant improvement in long-term outcome with less AF recurrence in those undergoing LA posterior wall ablation (20). However, a more recent meta-analysis of the benefit of posterior wall isolation showed no benefit of this approach in reducing recurrence rates of AF (21), suggesting that this approach needs further study, likely in a large randomized clinical trial to validate its utility. In addition, ablation of potential triggers and sources of atrial activity that maintain AF have been recently proposed as a means of increasing long-term efficacy of AF ablation using the novel AcQMap System noncontact mapping system (mentioned earlier) to identify such areas (6). Recent data from a study of AF ablation using this mapping system suggest improved long-term outcomes, but again this will need to be validated in a large randomized clinical trial (6). Finally, while the results of stand-alone surgical ablation of AF have consistently exceeded those of catheter ablation in the past, including the stand-alone Cox MAZE IV operation with success rates upwards of 85% over 12 months in patients on and 74% in patients off antiarrhythmic drugs (22), the open MAZE procedure is highly invasive, requiring a thoracotomy, and consequently requires longer recovery times than with most catheter ablation procedures for AF. Thus, while the full, stand-alone Cox MAZE operation may be more effective than other surgical approaches, research has nonetheless been ongoing and will continue with various hybrid procedures and robotically performed variations of the Cox MAZE operation (23,24).

In the case of VT, several important advances in ablation methodologies have resulted in slightly improved long-term success rates in preventing arrhythmia recurrence, but significant advances and research are still needed to improve outcome of ablation for recurrent VT in patients with both ischemic and nonischemic cardiomyopathy. The standard approach to mapping and ablation of hemodynamically tolerated VT, whether epicardial or endocardial, is to produce a 3D map of the reentry circuit during VT (spontaneous or induced), and then perform pacing entrainment maneuvers at areas suggested by the 3D map to be within the reentry circuit, in order to identify critical locations (e.g., a critical isthmus within an area of scar) where ablation will terminate and render VT noninducible. While this approach works well, and is usually effective in preventing VT recurrence, in patients whose VT causes hemodynamic collapse, alternative methods for ablation are required, unless hemodynamic support is provided in the form of an assist device such as the Impella or ECMO. In such patients, substrate-based ablation may be performed during sinus rhythm or pacing, guided by 3D mapping of low voltage areas presumed to represent scar, using high-density mapping systems (as described earlier) to identify potential sources of the VT (25). These so-called “substrate-based approaches” include a variety of ablation approaches previously described, such as linear ablation, late potential ablation, LAVA (local abnormal ventricular activities) ablation, scar homogenization, and core isolation (25). These substrate-based ablation strategies depend on the ability of the mapping systems employed to properly define areas of low voltage that correlate with scar, dense scar, and transitional border zone based on standard unipolar and bipolar voltage mapping, and the recording of abnormal electrograms (LAVA and/or late potentials), and localization of channels within the scar that may be assumed to represent the substrate for reentrant circuits. In view of the limitations described previously in existing mapping systems, and the limitations of current catheter ablation technologies to produce adequate lesion size (i.e., depth), these approaches, while potentially even better than mapping of hemodynamically tolerated VTs, need further development to improve efficacy of catheter ablation for VT.

In the case VF, recent studies have suggested that in some case it may be triggered by premature ventricular contractions originating from the ventricular outflow tracts or the Purkinje fiber network, and that these triggers may be mapped and targeted for ablation (26,27). Additionally, recent studies in an animal model of VT and in patients have shown that targeting rotational activity mapped during the first few seconds of induced VF, may suppress further recurrence of this arrhythmia in select cases (28,29). Further research in this promising area will be required for its validation as a viable technique in patients with recurrent refractory VF.

To further improve outcomes of ablation, particularly for AF and VT, it will be necessary to confirm that each ablation produces a complete, preferably transmural, lesion, in order to prevent recurrences of arrhythmia, due to either recurrent conduction through myocardial connections to the pulmonary veins in the case of AF ablation or recurrent conduction through isthmuses of surviving myocardial tissue responsible for reentry in areas of scar in VT cases.

To achieve this end, research is ongoing on measurement of ablation lesion creation, including measurement of tissue function at sites of lesion creation, and lesion transmurality, in either acutely or previously created lesions. Measurement of tissue function includes the demonstration of conduction block across lesions (e.g., demonstration of PVI, conduction block across linear lesions, etc.) and measurement of electrical stimulation characteristics of lesions (e.g., demonstration of inability to stimulate tissue via the mapping catheter). Studies assessing long-term outcomes when demonstrating these phenomena have been achieved have been published, and further research is currently ongoing (30,31).

Assessment of tissue viability after ablation has also been studied using optical mapping with autofluorescence spectroscopy for NADH, a metabolic indicator of tissue viability, and ultrasound to distinguish tissue characteristics such as simple hemorrhage versus necrosis. Such approaches of assessment of tissue viability after ablation require further research but could be a useful real-time indicator of ablation lesion completeness (32-34). Assessment of lesion transmurality during ablation is more difficult, but this has also been attempted using intracardiac ultrasound (35), particularly near-field ultrasound, which shows some promise (i.e., up to 87% identification of transmural atrial lesions), magnetic resonance imagining real-time imaging (36), and methods using spectral imaging (37,38) integrated on ablation catheters to identify lesion characteristics and transmurality (e.g., endoscopic multispectral reflectance imaging, which may identify up to 90% of transmural ablation lesions in the atrium), but these approaches require further research into their clinical applicability.