- Email: [email protected]
Electrophysiology at a crossroads: A revisit
Author’s Accepted Manuscript “Electrophysiology at a crossroads – A revisit” Mark E. Josephson
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(16)30554-9S1547-5271(06)02355-1 http://dx.doi.org/10.1016/j.hrthm.2016.07.024 HRTHM6797
To appear in: Heart Rhythm Cite this article as: Mark E. Josephson, “Electrophysiology at a crossroads – A revisit”, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2016.07.024 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 galley proof before it is published in its final citable 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.
“Electrophysiology at a Crossroads – A Revisit”
Mark E. Josephson, MD Beth Israel Deaconess Medical Center, Boston, MA
Corresponding Author Contact Information: Dr. Mark E. Josephson, MD Beth Israel Deaconess Medical Center Division of Cardiology 185 Pilgrim Road Baker 4 Boston, MA 02215 [email protected]
Nearly a decade ago I wrote an article for the Heart Rhythm Journal expressing concerns about the evolution of the field of clinical cardiac electrophysiology(1). In that article I had concerns about the practice of clinical electrophysiology at that time and how it had changed from the initial 25 years of electrophysiology. I decided to review this past decade to see what changes have occurred in response to my concerns.
As I stated in that article, during the early decades of clinical cardiac electrophysiology all new findings and therapeutic options were subject to continuous debate both on a local and national level in the hopes that the product of the research would be improved. At the time of my 2007 article I expressed concern about the current lack of willingness of practicing electrophysiologists and electrophysiology training programs to spend time to critically determine the mechanisms of arrhythmias or arrhythmia syndromes and perform research based on hypotheses. My conclusion at the time was that there was a lack of critical thinking among electrophysiologists following the development of the ICD and catheter ablation. It seemed that the goal of electrophysiology training and practice was to perform therapeutic interventions without assessing the underlying mechanism of disorders or carefully testing the underlying rationale for the therapeutic interventions. I used as a primary example atrial fibrillation (AF) which at the time had seemed to take 1
over the imagination of most electrophysiologists regardless of the fact that there was little understanding of the mechanisms underlying AF other than the probable role of pulmonary vein firing in paroxysmal AF. Numerous types of ablation strategies were employed including forming lines across the posterior wall of the left atrium, across the mitral isthmus between the left inferior pulmonary vein and the mitral valve, ablating all sorts of fractionated electrograms, and ganglionated plexi. I warned at that time that these were all being done without any understanding of their real role in the fibrillatory process and predicted that they would fail, or in fact, lead to proarrhythmia. Part of the reason that the growth in atrial fibrillation ablations has been logarithmic is the tendency of current electrophysiologists to believe all reported results and to adapt suggestions without skepticism or critical analysis. Because of publication bias favoring positive results, none of which have borne out, more and more atrial fibrillation ablations are being performed in the hopes of “curing” this chronic disease.
Fellows, practicing
electrophysiologists, and hospitals are all pushing to do more ablations for a variety of different reasons and incentives. Academic centers say that all these techniques were used in attempts to learn about atrial fibrillation; so called “learning while burning”. This is in stark contrast to the early days of electrophysiology where one had to learn before we
either
burned
or
performed
a
therapeutic
intervention.
When
clinical
electrophysiology was in its infancy, therapeutic interventions demanded scientific rationale.
Another area of concern expressed in the earlier manuscript was the enthusiastic use of ICDs for primary prevention. I noted that dual chamber and even bi-ventricular pacing ICDs were being implanted in elderly patients for primary prevention even though there were no data to support this practice. I also noted that there did not seem to be any further interest in risk stratifying patients for ICD implantation for primary prevention except for isolated groups of investigators in this country and Australia. The analysis of the cost effectiveness of implanting ICDs for primary prevention began in the last decade in order to develop information to demonstrate that sometimes the cost of devices and their complications, both immediate and long term, would temper the widespread application of device therapy. While the number of ICDs implanted has 2
levelled off over the past 5 years, there continues to be widespread blind adherence to guidelines without thoughtful individualization of risks and benefits.
I also suggested at that time that a number of disease entities which were starting to be ablated, such as idiopathic ventricular fibrillation, idiopathic LV outflow tract tachycardias, papillary muscle VTs as well as verapamil sensitive idiopathic left ventricular tachycardias, were not well understood. For example, electrophysiologists consider the verapamil sensitive idiopathic left ventricular tachycardias as a fascicular tachycardia despite the lack of evidence. New syndromes of polymorphic tachycardia associated with long QT and short QT, Brugada syndrome, catecholaminergic ventricular tachycardia, idiopathic fibrillation have been described and ablations have been used to treat these without a clear understanding of where and how they originate. I expressed great concern that today’s training programs are training ablationists and defibrillationists, and not electrophysiologists.
In fact, many electrophysiology
applicants prioritize their choices by the number of ablations done at a given program primarily as a reflection as to how many cases they will do. The same is true for ICD implantation. My concern was a lack of intellectual curiosity in the applicant pool that chose the high ablation/defibrillation implantation programs.
Too many programs
provided an inadequate understanding of the role of the electrocardiogram for localizing the origin of arrhythmias or the underlying substrate. There was limited education about basic mechanisms of arrhythmias and cellular electrophysiology, and how that knowledge might influence therapy. In fact, I was concerned that the physicians going into and completing training had abdicated their role as physicians in order to apply wasteful, potentially harmful, and cost ineffective therapy and that the training programs didn’t provide any insight into that behavior.
In other words, electrophysiology had
become a surgical practice, rather than a field aimed at understanding mechanisms and applying mechanistic knowledge to therapy.
As I review what has happened over the last decade in hopes that there would be a reawakening of earlier behavior, I am sadly disappointed. I have now been personally 3
performing electrophysiologic procedures for 45 years and have watched the field apparently mature rapidly from an inquisitive area of exploration of the mechanisms of arrhythmias and their therapy to one in which therapeutic interventions, without further consideration of understanding underlying mechanisms or risks, have been widely employed. For example, atrial fibrillation ablations have not decreased or become more thoughtful, but have in fact, increased logarithmically. This is due in part by financial pressure of institutions in order to gain patients.
It is also a consequence of new
technologies that have evolved specifically for the purpose of AF ablation including cryoablation with balloon catheters, and with new mapping systems and modifications of older mapping systems. The cryoablation system has a limited electrophysiologic basis and can be performed by any interventional cardiologist. There was rapid acceptance of these new technologies for ablating AF in the hopes of greater success without any further understanding of the underlying mechanisms of both paroxysmal and, in particular, persistent and permanent atrial fibrillation. The results have not improved, but have remained static for nearly two decades for AF ablation. As predicted in my original article, widespread application of lesions other than isolation of the pulmonary veins has not lead to any enhancement of outcomes as proven now by clinical trials (2,3). It is well documented that extra lesions in the left atrium produce macroreentrant atrial tachycardias which are often more persistent and symptomatic than atrial fibrillation itself. There has become the widespread acceptance of the philosophy that no patients should remain on an antiarrhythmic agent and that all arrhythmias should be “cured” by the ablation. The fact that the physician’s role is to make the patient feel better, not worse, is not taken into consideration. The use of pulmonary vein isolation and an antiarrhythmic agent which prevents clinical atrial fibrillation should be considered a therapeutic success, not a failure. The enthusiastic use of ablation in the atrium is now recognized to produce a stiff atrium which can lead to heart failure and worsening of clinical symptoms.
The ICD situation has improved somewhat. There seems to be a slowing down of implantation of devices in all patients with low ejection fractions, but the reasons for that are unclear. It is certainly not a reflection of enhanced interest in risk stratification, but 4
more recognition of the harm that ICDs can render, in terms of heart failure and perhaps even mortality.
Nevertheless, we are still implanting too many ICDs for primary
prevention and only a small fraction of them have appropriate shocks, let alone the relatively high incidence of inappropriate shocks and lead recalls. There still seems to be limited interest in risk stratification. The current modality of looking at an ejection fraction remains the major guideline that has never been shown to be specific nor sensitive for sudden death. Electrophysiology testing has been the only reproducible modality demonstrated to have benefit in a randomized clinical trial.
Absence of
inducible ventricular tachycardia/fibrillation early following infarction has been repeatedly shown, in a series of studies from Australia to have prognostic utility: patients who have no inducible VT/VF have the same prognosis as those who have ICDs implanted (4, 5, 6).
This information was previously suggested by results of the
MUSTT trial completed nearly two decades ago (7).
In the hopes of developing new therapeutic approaches to ventricular tachycardia, ventricular tachycardia ablation has become used increasingly, and has become a focus for several centers in the United States. Similar to the atrial fibrillation story, the hopes of “cure” of ventricular arrhythmias has been the goal without any reason to suspect that would even be possible.
While early studies using entrainment mapping for well
tolerated tachycardia showed a reasonable acute success, when analyzed in toto there is close to a 50 percent recurrence rate in such patients and a continued mortality due to the underlying structural heart disease. It is clear we understand very little about the underlying substrate for ventricular arrhythmias in non-coronary artery patients.
In
those patients with prior infarction in whom we think we understand the substrate best, we still need to learn more. “Bombarding” the entire area of ventricular “scar”, both on the endo-, as well as the epicardium is surely not the optimal procedure (8).
Since most ventricular tachycardias currently are not hemodynamically tolerated, entrainment mapping, which can be very useful in tolerated tachycardias cannot be accomplished in these patients because of hemodynamic instability. As such, substrate mapping was developed as a method of dealing with such patients. The problem is that 5
we do not understand the substrate as well as we think we do, and the technology used to define the substrate is inadequate to do so.
Moreover, there are a number of
assumptions and misconceptions inherent in the basis of substrate mapping, as practiced by most electrophysiologists. Thus, it is not surprising to have a similar lack of success in VT ablation as ablation using entrainment mapping of tolerated tachycardias. While I personally have suggested limitations in substrate mapping in the last several additions of Clinical Cardiac Electrophysiology, they have not been heeded. These limitations include, among others, the influence of catheter tip electrode size on the field of view. The standard electrode catheter which is now 3.5 or 4.0 mm, is bigger than the initial mapping catheter we used thirty-five years ago which was 2.0 mm, and it certainly is larger than the < l.0 mm electrode seen in the Pentaray (CARTO) and in the Orion (Rhythmia) catheters.
This difference is critical, since the major measurement that
people use in substrate mapping is the bipolar voltage. It is critical to understand that the voltage can be markedly influenced by a number of factors.
In fact, most
electrophysiologists assume low voltage equals scar. This is not the case. In physics and in electrophysiology V = IR; there is no S for scar. The measured voltage reflects the sum of current flow recorded by the electrodes. When using a rather large tip electrode in an area exhibiting abnormal conduction, the recorded bipolar voltage will be low because of cancellation of forces. A small electrode placed in the same area can show a near normal electrogram.(Fig 1),(9).
Furthermore, both voltage and
configuration of bipolar electrograms is markedly influenced by electrode contact, the angle of the catheter tip recording the signal, the wave front of activation engaging that tissue, and conduction velocity, which can be markedly influenced by sodium channel, blocking agents, non-uniform anisotropic conduction, wave curvature, and impedance mismatch. electrograms,
These factors, which influence the voltage and configuration of are
poorly
understood
by
most
clinical
electrophysiologists,
demonstrating a major lack of understanding of basic electrophysiology(10).
New
technology has allowed the potential to simultaneously record multiple small electrodes, but it is frequently applied with a similar lack of understanding of the factors affecting voltage and electrode configuration. The effect of wavefront of activation is, in fact,
6
simple to understand; e.g. one can see isolated late potentials or no late potentials based on the direction of the activation wavefront (Fig 2).
Unfortunately, the new technology which should be used to better understand the VT circuit and substrate, has been used primarily to ablate instead of to learn more about the circuit. We have spent significant time trying to do that and demonstrated recently (11), that the standard catheter overestimates the size of the reentrant circuit and the assumed isthmus, perhaps explaining why, in part, many ablations are not successful. We have also demonstrated that propagation occurs through areas of what may appear to be fixed barriers defining an isthmus, suggesting that such lines of “block” are usually not fixed and permanent due to the infarct but, in fact, are functional. No one has attempted to find other mechanisms for these so called barriers, and some of the data suggests that the mechanism of the tachycardia may be a very small rotor-like activity due to non-uniform anisotropy with potential for other sites to develop similar activity once the initial site is ablated (Fig 3). Instead of using this information to define the arrhythmia mechanism itself more precisely, which could then allow one to integrate it with the underlying anatomic substrate, most practitioners and investigators just continue to ablate away with linear lesions. In fact, “homogenization” by destroying all abnormal electrograms has been suggested as a means to improve ablation success(8). In my mind this represents a failure because it expresses the underlying ignorance and disinterest in the tachycardia mechanism or substrate.
Unfortunately similar strategies are being used to treat ventricular arrhythmias in noninfarct-related cardiomyopathies, which have all been met with resounding failure. We desperately need to better understand the arrhythmia substrate in patients with nonischemic cardiomyopathies. It is almost impossible to know what a substrate is unless you know what the circuit is. Only after you identify the circuit precisely can you see what underlies that in sinus rhythm and in response to pacing from multiple sites. There has also been a lack of interest in using programmed stimulation to determine the role refractoriness and excitability play in producing unidirectional block permitting initiation and perpetuation of ventricular tachyarrhythmias. 7
We have similar thoughts about ablation of Purkinje like potentials in patients with idiopathic ventricular fibrillation and polymorphic tachycardias, though they arise from different mechanisms. The idea that you can target one Purkinje fiber at a moment in time without knowing what else is going on shows a lack of understanding of what ablation can do. This is important because if you don’t eradicate the focus per se and ablate distal or proximal to it, then propagation of the focus in either direction will lead to continuation of the arrhythmia. In order to successfully ablate such arrhythmias you must have a reproducible single site of origin and you must isolate or destroy it to prevent propagation in both directions. I am not satisfied that that is typically what is done. In my opinion there just seems to be widespread ablation of Purkinje potentials, which may in some way help prevent ventricular fibrillation, since it is apparent that Purkinje activity is important in maintaining fibrillation, but shows no insight into our understanding of what we are ablating and why we are ablating it. It also damages normal tissue.
We obviously rely too much on technology without recognizing the limitations of that technology.
The limitations of the technology are not routinely taught in training
programs.
In fact, I consider pressure put by the ACGME and HRS to provide
guidelines for training programs a culprit in fostering the bad behavior of electrophysiologists. All of the clinical guidelines suggest that programs should perform a certain number of procedures, and fellows should perform a certain number of procedures with no emphasis on understanding why the procedures are done or what the basic mechanistic foundation for the procedures is. Rather, the guidelines focus on procedural numbers. This obviously is the reason that fellowship applicants want to get the most exposure to procedures. That obviously doesn’t ensure they will understand why they are doing them, or what is the mechanism of what they are doing. I personally believe that there is probably an inverse relationship between the number of procedures done and the understanding of the underlying pathophysiology for which procedure is performed. Training programs, while recognizing the importance of cost effectiveness as a field of intellectual pursuit, have not in practice developed ways to develop cost 8
effective use of all of our therapies. New guidelines for fellowship training stress the need for more training so that fellows can be exposed to more technologies because technologies continue to grow. This is in hopes that they will become experts in all of these technologies - an unrealistic goal. There is nothing in the new guidelines that stresses developing understanding of the pathophysiologic basis of arrhythmias. This should perhaps be the primary thing being taught along with electrocardiography, cellular electrophysiology, and the fundamentals of clinical electrophysiology.
There are other roadblocks facing electrophysiology training programs.
There are
economics which drive cardiovascular medicine divisions to make money and not gain knowledge. The development of accountable care organizations will limit the time one can spend to do clinical investigation of arrhythmias, which cost both time and money. Advances in technology have led to guidelines increasing the amount of clinical training required. This will increase fellows’ time for clinical work and limit time for research. It stimulates industry driven research which in turn limits scientific, hypothesis driven research (clinical or basic) unencumbered by clinical time. This requires more time, which in turn requires more money. The government isn’t going to provide this money. Perhaps institutions can use technical revenues to help, though that amount of money will shrink over time.
I think the ACGME should require a year of unencumbered
research which is fully supported by the government or make it easier for grant support to be obtained, either from industry or the government. Certainly more research training grants should be made available by the NIH. These grants should not only support basic research, but clinical research as well, based on the quality of the proposal and on an academic career path by the awardee. HRS training grants should support research as well as “advanced ablation and device implantation”. We need to close the gap between the basic and clinical scientist. There needs to be real translational research. There also needs to be cooperation between technology and clinical science. New technology should be used to understand the underpinnings of arrhythmogenesis so that more successful therapy can be appropriately applied.
9
Finally, we need good leaders of academic electrophysiology programs who embody the principles of the early pioneers of clinical cardiac electrophysiology and who demand intellectual honesty, scientific curiosity, and intellectual debate. It is only by getting back to the basics that the field of electrophysiology will continue to grow instead of stagnate. References: 1. Josephson ME. Electrophysiology at a Crossroads. Heart Rhythm 2007;4: 658661. PMID: 17467638 2. Verma A, Jiang CY, Betts TR, et al. Approaches to Catheter Ablation for Persistent Atrial Fibrillation. New Engl J Med 2015;372:1812-1822. PMID: 25946280 3. Dixit S, Lin D, Frankel DS, Marchlinski FE. Catheter Ablation for Persistent Atrial Fibrillation: Antral Pulmonary Vein Isolation and Elimination of Nonpulmonary Vein Triggers are Sufficient. Circ Arrhythm Electrophysiol 2012;5:1216-1223. PMID: 23250551 4. Zaman S, Sivagangabalan G, Narayan A, Thiagalingam A, Rosas DL, Kovoor P. Outcomes of Early Risk Stratiafication and Targeted Implantable CardioverterDefibrillator Implantation after ST-Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention. Circulation 2009;120:194-200. PMID: PMID: 19581496 5. Kumar S, Sivagangabalan G, Zaman S, West EF, Narayan A, Thiagalingam A, Kovoor P. Electrophysiology-Guided Defibrillator Implantation early After STElevation Myocardial Infartion. Heart Rhythm 2010;7:1589-1597. PMID: 20650333 6. Josephson ME. Programmed Stimulation for Risk Stratification for Postinfarction Sudden Cardiac Arrest: Why and How? Pacing Clin Electrophysiol 2014;37:791794. PMID 24809436 7. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A Randomized Study of the Prevention of Sudden Death in Patients with Coronary Artery Disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882-1890. PMID: 10601507 8. Di Biase L, Santangeli P, Burkhardt DJ, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012;60:132-141. PMID: 22766340 10
9. Anter E, Tschabrunn CM, Joseph ME. High-Resolution Mapping of Scar-Related Atrial Arrhythmias Using Smaller Electrodes with Closer Interelectrode Spacing. Circ Arrhythm Electrophysiol 2015;8:537-545. PMID: 25792508 10. Josephson ME, Anter E. Substrate Mapping for Ventricular Tachycardia: Assumptions and Misconceptions. JACC: Clinical Electrophysiology 2015;1:342352. 11. Tschabrunn CM, Roujol S, Dorman NC, Nezafat R, Josephson ME, Anter E. High-Resolution Mapping of Ventricular Scar: Comparison Between Single and Multielectrode Catheters. Circ Arrhythm Electrophysiol 2016;9 [Epub ahead of print].
Figure Legends Figure 1. Differences in bipolar electrogram (EGM) voltage and configuration depending on electrode size. Recordings from a standard 3.5 mm tip electrode catheter(Standard) and 0.8 mm electrode (Small electrode). Recordings from healthy normal tissue and within scar are shown. In healthy tissue the amplitude and configuration of EGMs is similar. The only difference I a small increase in width using the Standard catheter. In scar the Standard catheter records a very low amplitude, broad multiphasic EGM while the Small electrode catheter records a normal EGM. Modified from Figure 2 in reference 2. Figure 2 Effect of wavefront of activation on the presence and timing of late potentials (LP). A 12 lead electrocardiogram and recordings from a standard ablation catheter are shown during sinus rhythm and right ventricular pacing. In sinus rhythm no discrete late potential is seen (circle). During right ventricular pacing an obvious, discrete late potential is seen (arrow) with a slight reduction in amplitude of large electrogram.
Figure 3. Variable interpretation of ventricular tachycardia circuit during mapping with very small electrodes (0.4 mm; Orion Catheter). The assumed tachycardia circuit is shown on left with a discrete central isthmus, entrance and exit, and 2 barriers. On closer inspection the entire 11
cardiac cycle is see in a pinwheel activation sequence which is shown with the blue arrows. A large arc of very slow conduction produces pseudoblock giving rise to tne apparent left barrier. The right barrier exhibits true block with the outer activation perpendicular to the line of block. Misinterpretation of activation data even with very small electrodes may be an important cause of ablation failure which is even more likely to occur with standard catheters.
12
13
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(16)30554-9S1547-5271(06)02355-1 http://dx.doi.org/10.1016/j.hrthm.2016.07.024 HRTHM6797
To appear in: Heart Rhythm Cite this article as: Mark E. Josephson, “Electrophysiology at a crossroads – A revisit”, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2016.07.024 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 galley proof before it is published in its final citable 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.
“Electrophysiology at a Crossroads – A Revisit”
Mark E. Josephson, MD Beth Israel Deaconess Medical Center, Boston, MA
Corresponding Author Contact Information: Dr. Mark E. Josephson, MD Beth Israel Deaconess Medical Center Division of Cardiology 185 Pilgrim Road Baker 4 Boston, MA 02215 [email protected]
Nearly a decade ago I wrote an article for the Heart Rhythm Journal expressing concerns about the evolution of the field of clinical cardiac electrophysiology(1). In that article I had concerns about the practice of clinical electrophysiology at that time and how it had changed from the initial 25 years of electrophysiology. I decided to review this past decade to see what changes have occurred in response to my concerns.
As I stated in that article, during the early decades of clinical cardiac electrophysiology all new findings and therapeutic options were subject to continuous debate both on a local and national level in the hopes that the product of the research would be improved. At the time of my 2007 article I expressed concern about the current lack of willingness of practicing electrophysiologists and electrophysiology training programs to spend time to critically determine the mechanisms of arrhythmias or arrhythmia syndromes and perform research based on hypotheses. My conclusion at the time was that there was a lack of critical thinking among electrophysiologists following the development of the ICD and catheter ablation. It seemed that the goal of electrophysiology training and practice was to perform therapeutic interventions without assessing the underlying mechanism of disorders or carefully testing the underlying rationale for the therapeutic interventions. I used as a primary example atrial fibrillation (AF) which at the time had seemed to take 1
over the imagination of most electrophysiologists regardless of the fact that there was little understanding of the mechanisms underlying AF other than the probable role of pulmonary vein firing in paroxysmal AF. Numerous types of ablation strategies were employed including forming lines across the posterior wall of the left atrium, across the mitral isthmus between the left inferior pulmonary vein and the mitral valve, ablating all sorts of fractionated electrograms, and ganglionated plexi. I warned at that time that these were all being done without any understanding of their real role in the fibrillatory process and predicted that they would fail, or in fact, lead to proarrhythmia. Part of the reason that the growth in atrial fibrillation ablations has been logarithmic is the tendency of current electrophysiologists to believe all reported results and to adapt suggestions without skepticism or critical analysis. Because of publication bias favoring positive results, none of which have borne out, more and more atrial fibrillation ablations are being performed in the hopes of “curing” this chronic disease.
Fellows, practicing
electrophysiologists, and hospitals are all pushing to do more ablations for a variety of different reasons and incentives. Academic centers say that all these techniques were used in attempts to learn about atrial fibrillation; so called “learning while burning”. This is in stark contrast to the early days of electrophysiology where one had to learn before we
either
burned
or
performed
a
therapeutic
intervention.
When
clinical
electrophysiology was in its infancy, therapeutic interventions demanded scientific rationale.
Another area of concern expressed in the earlier manuscript was the enthusiastic use of ICDs for primary prevention. I noted that dual chamber and even bi-ventricular pacing ICDs were being implanted in elderly patients for primary prevention even though there were no data to support this practice. I also noted that there did not seem to be any further interest in risk stratifying patients for ICD implantation for primary prevention except for isolated groups of investigators in this country and Australia. The analysis of the cost effectiveness of implanting ICDs for primary prevention began in the last decade in order to develop information to demonstrate that sometimes the cost of devices and their complications, both immediate and long term, would temper the widespread application of device therapy. While the number of ICDs implanted has 2
levelled off over the past 5 years, there continues to be widespread blind adherence to guidelines without thoughtful individualization of risks and benefits.
I also suggested at that time that a number of disease entities which were starting to be ablated, such as idiopathic ventricular fibrillation, idiopathic LV outflow tract tachycardias, papillary muscle VTs as well as verapamil sensitive idiopathic left ventricular tachycardias, were not well understood. For example, electrophysiologists consider the verapamil sensitive idiopathic left ventricular tachycardias as a fascicular tachycardia despite the lack of evidence. New syndromes of polymorphic tachycardia associated with long QT and short QT, Brugada syndrome, catecholaminergic ventricular tachycardia, idiopathic fibrillation have been described and ablations have been used to treat these without a clear understanding of where and how they originate. I expressed great concern that today’s training programs are training ablationists and defibrillationists, and not electrophysiologists.
In fact, many electrophysiology
applicants prioritize their choices by the number of ablations done at a given program primarily as a reflection as to how many cases they will do. The same is true for ICD implantation. My concern was a lack of intellectual curiosity in the applicant pool that chose the high ablation/defibrillation implantation programs.
Too many programs
provided an inadequate understanding of the role of the electrocardiogram for localizing the origin of arrhythmias or the underlying substrate. There was limited education about basic mechanisms of arrhythmias and cellular electrophysiology, and how that knowledge might influence therapy. In fact, I was concerned that the physicians going into and completing training had abdicated their role as physicians in order to apply wasteful, potentially harmful, and cost ineffective therapy and that the training programs didn’t provide any insight into that behavior.
In other words, electrophysiology had
become a surgical practice, rather than a field aimed at understanding mechanisms and applying mechanistic knowledge to therapy.
As I review what has happened over the last decade in hopes that there would be a reawakening of earlier behavior, I am sadly disappointed. I have now been personally 3
performing electrophysiologic procedures for 45 years and have watched the field apparently mature rapidly from an inquisitive area of exploration of the mechanisms of arrhythmias and their therapy to one in which therapeutic interventions, without further consideration of understanding underlying mechanisms or risks, have been widely employed. For example, atrial fibrillation ablations have not decreased or become more thoughtful, but have in fact, increased logarithmically. This is due in part by financial pressure of institutions in order to gain patients.
It is also a consequence of new
technologies that have evolved specifically for the purpose of AF ablation including cryoablation with balloon catheters, and with new mapping systems and modifications of older mapping systems. The cryoablation system has a limited electrophysiologic basis and can be performed by any interventional cardiologist. There was rapid acceptance of these new technologies for ablating AF in the hopes of greater success without any further understanding of the underlying mechanisms of both paroxysmal and, in particular, persistent and permanent atrial fibrillation. The results have not improved, but have remained static for nearly two decades for AF ablation. As predicted in my original article, widespread application of lesions other than isolation of the pulmonary veins has not lead to any enhancement of outcomes as proven now by clinical trials (2,3). It is well documented that extra lesions in the left atrium produce macroreentrant atrial tachycardias which are often more persistent and symptomatic than atrial fibrillation itself. There has become the widespread acceptance of the philosophy that no patients should remain on an antiarrhythmic agent and that all arrhythmias should be “cured” by the ablation. The fact that the physician’s role is to make the patient feel better, not worse, is not taken into consideration. The use of pulmonary vein isolation and an antiarrhythmic agent which prevents clinical atrial fibrillation should be considered a therapeutic success, not a failure. The enthusiastic use of ablation in the atrium is now recognized to produce a stiff atrium which can lead to heart failure and worsening of clinical symptoms.
The ICD situation has improved somewhat. There seems to be a slowing down of implantation of devices in all patients with low ejection fractions, but the reasons for that are unclear. It is certainly not a reflection of enhanced interest in risk stratification, but 4
more recognition of the harm that ICDs can render, in terms of heart failure and perhaps even mortality.
Nevertheless, we are still implanting too many ICDs for primary
prevention and only a small fraction of them have appropriate shocks, let alone the relatively high incidence of inappropriate shocks and lead recalls. There still seems to be limited interest in risk stratification. The current modality of looking at an ejection fraction remains the major guideline that has never been shown to be specific nor sensitive for sudden death. Electrophysiology testing has been the only reproducible modality demonstrated to have benefit in a randomized clinical trial.
Absence of
inducible ventricular tachycardia/fibrillation early following infarction has been repeatedly shown, in a series of studies from Australia to have prognostic utility: patients who have no inducible VT/VF have the same prognosis as those who have ICDs implanted (4, 5, 6).
This information was previously suggested by results of the
MUSTT trial completed nearly two decades ago (7).
In the hopes of developing new therapeutic approaches to ventricular tachycardia, ventricular tachycardia ablation has become used increasingly, and has become a focus for several centers in the United States. Similar to the atrial fibrillation story, the hopes of “cure” of ventricular arrhythmias has been the goal without any reason to suspect that would even be possible.
While early studies using entrainment mapping for well
tolerated tachycardia showed a reasonable acute success, when analyzed in toto there is close to a 50 percent recurrence rate in such patients and a continued mortality due to the underlying structural heart disease. It is clear we understand very little about the underlying substrate for ventricular arrhythmias in non-coronary artery patients.
In
those patients with prior infarction in whom we think we understand the substrate best, we still need to learn more. “Bombarding” the entire area of ventricular “scar”, both on the endo-, as well as the epicardium is surely not the optimal procedure (8).
Since most ventricular tachycardias currently are not hemodynamically tolerated, entrainment mapping, which can be very useful in tolerated tachycardias cannot be accomplished in these patients because of hemodynamic instability. As such, substrate mapping was developed as a method of dealing with such patients. The problem is that 5
we do not understand the substrate as well as we think we do, and the technology used to define the substrate is inadequate to do so.
Moreover, there are a number of
assumptions and misconceptions inherent in the basis of substrate mapping, as practiced by most electrophysiologists. Thus, it is not surprising to have a similar lack of success in VT ablation as ablation using entrainment mapping of tolerated tachycardias. While I personally have suggested limitations in substrate mapping in the last several additions of Clinical Cardiac Electrophysiology, they have not been heeded. These limitations include, among others, the influence of catheter tip electrode size on the field of view. The standard electrode catheter which is now 3.5 or 4.0 mm, is bigger than the initial mapping catheter we used thirty-five years ago which was 2.0 mm, and it certainly is larger than the < l.0 mm electrode seen in the Pentaray (CARTO) and in the Orion (Rhythmia) catheters.
This difference is critical, since the major measurement that
people use in substrate mapping is the bipolar voltage. It is critical to understand that the voltage can be markedly influenced by a number of factors.
In fact, most
electrophysiologists assume low voltage equals scar. This is not the case. In physics and in electrophysiology V = IR; there is no S for scar. The measured voltage reflects the sum of current flow recorded by the electrodes. When using a rather large tip electrode in an area exhibiting abnormal conduction, the recorded bipolar voltage will be low because of cancellation of forces. A small electrode placed in the same area can show a near normal electrogram.(Fig 1),(9).
Furthermore, both voltage and
configuration of bipolar electrograms is markedly influenced by electrode contact, the angle of the catheter tip recording the signal, the wave front of activation engaging that tissue, and conduction velocity, which can be markedly influenced by sodium channel, blocking agents, non-uniform anisotropic conduction, wave curvature, and impedance mismatch. electrograms,
These factors, which influence the voltage and configuration of are
poorly
understood
by
most
clinical
electrophysiologists,
demonstrating a major lack of understanding of basic electrophysiology(10).
New
technology has allowed the potential to simultaneously record multiple small electrodes, but it is frequently applied with a similar lack of understanding of the factors affecting voltage and electrode configuration. The effect of wavefront of activation is, in fact,
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simple to understand; e.g. one can see isolated late potentials or no late potentials based on the direction of the activation wavefront (Fig 2).
Unfortunately, the new technology which should be used to better understand the VT circuit and substrate, has been used primarily to ablate instead of to learn more about the circuit. We have spent significant time trying to do that and demonstrated recently (11), that the standard catheter overestimates the size of the reentrant circuit and the assumed isthmus, perhaps explaining why, in part, many ablations are not successful. We have also demonstrated that propagation occurs through areas of what may appear to be fixed barriers defining an isthmus, suggesting that such lines of “block” are usually not fixed and permanent due to the infarct but, in fact, are functional. No one has attempted to find other mechanisms for these so called barriers, and some of the data suggests that the mechanism of the tachycardia may be a very small rotor-like activity due to non-uniform anisotropy with potential for other sites to develop similar activity once the initial site is ablated (Fig 3). Instead of using this information to define the arrhythmia mechanism itself more precisely, which could then allow one to integrate it with the underlying anatomic substrate, most practitioners and investigators just continue to ablate away with linear lesions. In fact, “homogenization” by destroying all abnormal electrograms has been suggested as a means to improve ablation success(8). In my mind this represents a failure because it expresses the underlying ignorance and disinterest in the tachycardia mechanism or substrate.
Unfortunately similar strategies are being used to treat ventricular arrhythmias in noninfarct-related cardiomyopathies, which have all been met with resounding failure. We desperately need to better understand the arrhythmia substrate in patients with nonischemic cardiomyopathies. It is almost impossible to know what a substrate is unless you know what the circuit is. Only after you identify the circuit precisely can you see what underlies that in sinus rhythm and in response to pacing from multiple sites. There has also been a lack of interest in using programmed stimulation to determine the role refractoriness and excitability play in producing unidirectional block permitting initiation and perpetuation of ventricular tachyarrhythmias. 7
We have similar thoughts about ablation of Purkinje like potentials in patients with idiopathic ventricular fibrillation and polymorphic tachycardias, though they arise from different mechanisms. The idea that you can target one Purkinje fiber at a moment in time without knowing what else is going on shows a lack of understanding of what ablation can do. This is important because if you don’t eradicate the focus per se and ablate distal or proximal to it, then propagation of the focus in either direction will lead to continuation of the arrhythmia. In order to successfully ablate such arrhythmias you must have a reproducible single site of origin and you must isolate or destroy it to prevent propagation in both directions. I am not satisfied that that is typically what is done. In my opinion there just seems to be widespread ablation of Purkinje potentials, which may in some way help prevent ventricular fibrillation, since it is apparent that Purkinje activity is important in maintaining fibrillation, but shows no insight into our understanding of what we are ablating and why we are ablating it. It also damages normal tissue.
We obviously rely too much on technology without recognizing the limitations of that technology.
The limitations of the technology are not routinely taught in training
programs.
In fact, I consider pressure put by the ACGME and HRS to provide
guidelines for training programs a culprit in fostering the bad behavior of electrophysiologists. All of the clinical guidelines suggest that programs should perform a certain number of procedures, and fellows should perform a certain number of procedures with no emphasis on understanding why the procedures are done or what the basic mechanistic foundation for the procedures is. Rather, the guidelines focus on procedural numbers. This obviously is the reason that fellowship applicants want to get the most exposure to procedures. That obviously doesn’t ensure they will understand why they are doing them, or what is the mechanism of what they are doing. I personally believe that there is probably an inverse relationship between the number of procedures done and the understanding of the underlying pathophysiology for which procedure is performed. Training programs, while recognizing the importance of cost effectiveness as a field of intellectual pursuit, have not in practice developed ways to develop cost 8
effective use of all of our therapies. New guidelines for fellowship training stress the need for more training so that fellows can be exposed to more technologies because technologies continue to grow. This is in hopes that they will become experts in all of these technologies - an unrealistic goal. There is nothing in the new guidelines that stresses developing understanding of the pathophysiologic basis of arrhythmias. This should perhaps be the primary thing being taught along with electrocardiography, cellular electrophysiology, and the fundamentals of clinical electrophysiology.
There are other roadblocks facing electrophysiology training programs.
There are
economics which drive cardiovascular medicine divisions to make money and not gain knowledge. The development of accountable care organizations will limit the time one can spend to do clinical investigation of arrhythmias, which cost both time and money. Advances in technology have led to guidelines increasing the amount of clinical training required. This will increase fellows’ time for clinical work and limit time for research. It stimulates industry driven research which in turn limits scientific, hypothesis driven research (clinical or basic) unencumbered by clinical time. This requires more time, which in turn requires more money. The government isn’t going to provide this money. Perhaps institutions can use technical revenues to help, though that amount of money will shrink over time.
I think the ACGME should require a year of unencumbered
research which is fully supported by the government or make it easier for grant support to be obtained, either from industry or the government. Certainly more research training grants should be made available by the NIH. These grants should not only support basic research, but clinical research as well, based on the quality of the proposal and on an academic career path by the awardee. HRS training grants should support research as well as “advanced ablation and device implantation”. We need to close the gap between the basic and clinical scientist. There needs to be real translational research. There also needs to be cooperation between technology and clinical science. New technology should be used to understand the underpinnings of arrhythmogenesis so that more successful therapy can be appropriately applied.
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Finally, we need good leaders of academic electrophysiology programs who embody the principles of the early pioneers of clinical cardiac electrophysiology and who demand intellectual honesty, scientific curiosity, and intellectual debate. It is only by getting back to the basics that the field of electrophysiology will continue to grow instead of stagnate. References: 1. Josephson ME. Electrophysiology at a Crossroads. Heart Rhythm 2007;4: 658661. PMID: 17467638 2. Verma A, Jiang CY, Betts TR, et al. Approaches to Catheter Ablation for Persistent Atrial Fibrillation. New Engl J Med 2015;372:1812-1822. PMID: 25946280 3. Dixit S, Lin D, Frankel DS, Marchlinski FE. Catheter Ablation for Persistent Atrial Fibrillation: Antral Pulmonary Vein Isolation and Elimination of Nonpulmonary Vein Triggers are Sufficient. Circ Arrhythm Electrophysiol 2012;5:1216-1223. PMID: 23250551 4. Zaman S, Sivagangabalan G, Narayan A, Thiagalingam A, Rosas DL, Kovoor P. Outcomes of Early Risk Stratiafication and Targeted Implantable CardioverterDefibrillator Implantation after ST-Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention. Circulation 2009;120:194-200. PMID: PMID: 19581496 5. Kumar S, Sivagangabalan G, Zaman S, West EF, Narayan A, Thiagalingam A, Kovoor P. Electrophysiology-Guided Defibrillator Implantation early After STElevation Myocardial Infartion. Heart Rhythm 2010;7:1589-1597. PMID: 20650333 6. Josephson ME. Programmed Stimulation for Risk Stratification for Postinfarction Sudden Cardiac Arrest: Why and How? Pacing Clin Electrophysiol 2014;37:791794. PMID 24809436 7. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A Randomized Study of the Prevention of Sudden Death in Patients with Coronary Artery Disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882-1890. PMID: 10601507 8. Di Biase L, Santangeli P, Burkhardt DJ, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012;60:132-141. PMID: 22766340 10
9. Anter E, Tschabrunn CM, Joseph ME. High-Resolution Mapping of Scar-Related Atrial Arrhythmias Using Smaller Electrodes with Closer Interelectrode Spacing. Circ Arrhythm Electrophysiol 2015;8:537-545. PMID: 25792508 10. Josephson ME, Anter E. Substrate Mapping for Ventricular Tachycardia: Assumptions and Misconceptions. JACC: Clinical Electrophysiology 2015;1:342352. 11. Tschabrunn CM, Roujol S, Dorman NC, Nezafat R, Josephson ME, Anter E. High-Resolution Mapping of Ventricular Scar: Comparison Between Single and Multielectrode Catheters. Circ Arrhythm Electrophysiol 2016;9 [Epub ahead of print].
Figure Legends Figure 1. Differences in bipolar electrogram (EGM) voltage and configuration depending on electrode size. Recordings from a standard 3.5 mm tip electrode catheter(Standard) and 0.8 mm electrode (Small electrode). Recordings from healthy normal tissue and within scar are shown. In healthy tissue the amplitude and configuration of EGMs is similar. The only difference I a small increase in width using the Standard catheter. In scar the Standard catheter records a very low amplitude, broad multiphasic EGM while the Small electrode catheter records a normal EGM. Modified from Figure 2 in reference 2. Figure 2 Effect of wavefront of activation on the presence and timing of late potentials (LP). A 12 lead electrocardiogram and recordings from a standard ablation catheter are shown during sinus rhythm and right ventricular pacing. In sinus rhythm no discrete late potential is seen (circle). During right ventricular pacing an obvious, discrete late potential is seen (arrow) with a slight reduction in amplitude of large electrogram.
Figure 3. Variable interpretation of ventricular tachycardia circuit during mapping with very small electrodes (0.4 mm; Orion Catheter). The assumed tachycardia circuit is shown on left with a discrete central isthmus, entrance and exit, and 2 barriers. On closer inspection the entire 11
cardiac cycle is see in a pinwheel activation sequence which is shown with the blue arrows. A large arc of very slow conduction produces pseudoblock giving rise to tne apparent left barrier. The right barrier exhibits true block with the outer activation perpendicular to the line of block. Misinterpretation of activation data even with very small electrodes may be an important cause of ablation failure which is even more likely to occur with standard catheters.
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