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Arrhythmia Management

ATRIAL FIBRILLATION

Looking to the Future in Managing Atrial Fibrillation

a report by

D a v i d N K e n i g s b e r g , M D and K e n n e t h A E l l e n b o g e n , M D

Department of Medicine, Virginia Commonwealth Univeristy Medical Center

David N Kenigsberg, MD, is a Clinical Cardiac Electrophysiology Fellow at the Virginia Commonwealth University Medical Center in Richmond, Virginia. Previously he was the Chief Cardiology Fellow at Henry Ford Hospital where he was awarded the Division of Cardiology Frances Fernandez Fellowship Award. Dr Kenigsberg trained in Internal Medicine at Jackson Memorial Hospital in Miami, Florida. Dr Kenigsberg was a semifinalist in the 51st Annual Westinghouse Science Talent Search. He serves as the fellow in training representative for the Virginia Chapter of the American College of Cardiology.

Atrial fibrillation (AF) is a common and recurrent arrhythmia resulting in significant morbidity and mortality. Our approach to the patient with AF has changed dramatically over the past decade. We have gone from palliating patients with rate controlling medications or administering antiarrhythmic medications with potential systemic side effects and proarrhythmia, to now curing many of them with a catheter-based ablative approach. In the next 10 years, looking to the future of AF therapy, even more dramatic progress in this field is predicted. This advancement will come with improvements to the catheter-based ablative approaches; establishment of an efficacious stand-alone surgical approach; emergence of suitable atrial antiarrhythmic medications; institution of superior methods to avoid thromboembolic events; and novel pharmacologic and genetic methods to prevent AF. A catheter-based ablative approach was pioneered by Haissaguerre and colleagues when they discovered pulmonary vein (PV) potentials and their role in the initiation of AF. Later, Jalife's group reported on the importance of the posterior left atrium in the maintenance of this arrhythmia by microreentrant circuits or `rotors' exhibiting high-frequency activity from which spiral wavefronts of activation invade the left atrial tissue in an animal model of AF. Currently, the catheter-based ablative approaches to AF include: · segmental ostial ablation of the PV guided by a multipolar circumferential mapping catheter and fluoroscopy with an end-point of PV isolation described by Haissaguerre et al.; · a circumferential extra-ostial left atrial ablation with an end-point of ablation of left atrial signals within the circumferential areas around the right and left pulmonary veins described by Pappone et al.; and · more recently, an approach that targets complex fractionated electrograms recorded from both the right and left atria described by Nadamanee. There are a variety of variants to these approaches

pioneered by a number of investigators worldwide. These include ablation of the left atrium guided by intracardiac echocardiography (ICE) and antral isolation guided by multiple lasso catheters. Improvements to the strategy, design, and technique of these original approaches have been made and continue to be spawned in order to improve efficacy. For instance, the addition of ablation in the coronary sinus, along the mitral annulus, the intra-atrial septum, and along the roof of the left atrium have all been incorporated into the ablative approach, especially in patients with persistent forms of AF, to improve effectiveness of the procedure. Other important improvements that should soon become widely available include the use of electroanatomic mapping systems like CARTOTM (Biosense Webster, Diamond Bar, CA) to identify complex fractionated electrograms based on electrogram characteristics or spectral analysis of the local recordings. This too will improve efficacy and allow more general application of the approach described by Nadamanee. Image integration of computed tomography (CT) or magnetic resonance imaging (MRI) with the electroanatomic mapping systems has allowed for preprocedural knowledge of the location of the esophagus and pulmonary veins, enabling improved safety. In the future, the use of realtime MRI imaging may allow for accurate assessment of the catheter position in relation to the pulmonary veins, other key left atrial structures, and the esophagus. Furthermore, histology-like imaging of lesion size, location, and the identification of the presence of anatomic gaps between lesions will likely improve the formation of contiguous lines and thus improve efficacy. Newer ablative energy sources, including laser, ultrasound, and cryo, will become available for clinical use in the coming years. Cryoballoon (CryoCath Technologies, Montreal, Canada) is an alternative to radiofrequency energy that uses freezing instead of burning to create ablative lesions. Animal data has

Kenneth A Ellenbogen, MD, is the Kontos Professor of Medicine, ViceChair of the Division of Cardiology and Director of the Electrophysiology Laboratory at Virginia Commonwealth University Medical Center in Richmond. Dr Ellenbogen undertook his cardiology training at Duke University Medical Center in Durham, NC and his internal medicine training at The Johns Hopkins Medical Center in Baltimore, MD. He serves on the editorial board of numerous peerreviewed journals including Circulation and Heart Rhythm and serves as the senior editor of Pacing and Clinical Electrophysiology.

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suggested that cryoablation can provide a homogeneous change in the juxtaposed tissue, eliminating muscular cellular elements without destruction of tissue architecture and preservation of the endocardial surface. Furthermore, positioning of the balloon at the level of the pulmonary vein antrum, with intracardiac echocardiographic guidance, will allow for the delivery of circumferential lesions without the need to manipulate an ablation catheter into difficult to reach positions around the vein. This technology may prove useful in improving procedural efficacy and reducing fluoroscopy times. The use of remote navigational systems where either a variable magnetic field or a robotic sheath help the operator manipulate the ablation catheter will continue to become more widespread in the years to come. These tools will become more affordable and less cumbersome, two factors that have limited their ubiquity to this point. Furthermore, integration of remote navigation with electroanatomic mapping, like CARTO, has recently become available. It is likely that these tools in combination will result in a marked improvement in safety and efficacy of the procedure. The ability to perform remote catheter manipulation will allow quicker and easier mastery of this procedure, as well as provide enhanced safety for the physician operator who need not be near the X-ray tube or wearing a lead apron during these procedures. Use of remote catheter navigation systems may have a major impact on the penetration of atrial fibrillation ablation techniques. Another advance undergoing investigation is the use of alternative energy sources delivered via balloon technology. Cryoenergy is the nearest to clinical application; however, laser and ultrasound are also being studied. It is likely that balloon ablation will also simplify the technique and will increase efficacy. As catheter-based ablation has evolved and continues to improve, patient eligibility criteria have changed. This procedure is now offered to patients with paroxysmal AF, including older patients with structural heart disease and permanent or chronic forms of AF. In fact, Oral et al. recently published a 12-month success rate of 74% for maintaining normal sinus rhythm in 146 patients with medically refractory chronic AF undergoing circumferential ablation. Aside from offering this procedure to more challenging patient populations, like those with chronic AF, AF ablation with a catheter-based approach, currently a secondline treatment option, may eventually find itself as firstline therapy for AF as long as the efficacy and safety continue to improve. For patients in whom the benefits of a catheter-based approach to potentially cure AF may be outweighed by the risks, there now exists a surgical alternative. A surgical approach to AF, first described by Cox, has in recent years become a common adjunctive procedure in patients undergoing mitral valve or other cardiothoracic surgeries. Interest in making surgery a potentially stand-alone operative procedure to cure AF has increased. Recently, a minimally invasive Maze procedure (mini-Maze) has been developed and is undergoing multicenter clinical trial. This procedure involves the use of a video-assisted mini-thoracotomy to expose the pulmonary veins, after which a bipolar ablation clamp system, the AtriCure device (AtriCure, Cincinnati, OH), is applied to create a continuous transmural line of block. Also involved in this procedure is the Isolator Transpolar Pen, used to locate and ablate the cardiac ganglia for added efficacy. This surgical ablative approach, the authors predict, will prove valuable as a first-line therapy to combat AF in certain patient populations not deemed good candidates for a catheter-based approach. Newer options for antiarrhythmic drugs that prevent the occurrence of AF without proarrhythmia are needed. Drugs like dronedarone (Sanofi-Aventis, Paris, France), a drug with similar structure to that of amiodarone but without the potential lifethreatening side effects including toxicity to the lung, liver, and thyroid, is currently being evaluated in large multicenter clinical trials. Preliminary data suggest that this agent may prove to be a promising alternative for the treatment and prevention of AF recurrences. Other drugs reported to delay atrial depolarization and increase the refractory period of the atrium, sparing the ventricle and hence decreasing proarrhythmia risk, are being developed and studied. One of these agents, ADZ7009, has been studied in animals in vivo. Other similar atrial selective agents, like the IKur/Ito blocker AVE0118, have been found to work synergistically to increase atrial refractoriness with the IKr blocker ibutilide in animal models. The advent of a pure atrial antiarrhymic agent without ventricular proarrhythmic side effects looks promising and one should be available for clinical use in the next ten years. It is well known that AF is associated with a six-fold increased risk of stroke. Multiple clinical trials have documented the benefits of chronic anticoagulation with warfarin in reducing the risk of cerebrovascular events by 62% in patients with AF. The difficulties of using warfarin, including the need for frequent blood tests, interactions with food and other medications,

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ATRIAL FIBRILLATION

and increased risk of bleeding, have prompted interest in other ways to reduce the risk of stroke. Ximelagatran, an oral direct thrombin inhibitor, was found to be as efficacious as vitamin K antagonist medications in the prevention of embolic events. This efficacy, coupled with the ability to dose the medication based on weight, thus obviating the need to assess therapeutic levels of the medication with frequent blood testing, led to ximelagatran being thought of as a promising alternative. The drug, however, was withdrawn from the market due to liver function abnormalities. In the coming years, many new pharmacologic options for anticoagulation will be developed that have a wider therapeutic window, require no chronic monitoring and are easy to use, and they will likely replace warfarin. Non-pharmacologic device approaches to reduce thromboembolic events are currently being investigated too. The left atrial appendage has been identified as a major source of thromboembolic events in patients with AF. Surgical ligation of the left atrial appendage has been performed for many years as an adjuvant to cardiothoracic surgery.

cardiosphere-derived cells that have been shown, in animal models, to partially replace myocardial scar and may impact substrate development needed to maintain AF. In addition, atrial tissue procured from humans with persistent AF shows an increased expression of ventricular and fetal gene programs with upregulation of transcriptome-involved metabolic genes and downregulation of atrial-specific genes appears to be an integral part of the adaptive response. These discoveries, along with identification of other gene targets like those of potassium channels and connexin, make the possibility of genetic therapy to combat AF a potential reality in the years to come. Drug therapies to prevent or reverse the structural milieu needed to maintain AF are also being studied. Angiotensins-converting enzyme (ACE) inhibitors and angiotensin II receptor-blocking drugs hold promise in preventing AF through their cardiac remodeling effects. Also, preliminary studies suggest that HMG CoA reductase inhibitors (e.g. statins) could reduce the risk of recurrence of AF after electrical cardioversion. Additionally, omega-3 polyunsaturated fatty acids have been shown to decrease the risk of AF in longitudinal studies with over 4,000

Interest in making surgery a potentially stand-alone operative procedure to cure AF has increased.

Recently, the development of a transcatheter percutaneous method for the exclusion of the left atrial appendage has been developed. The Watchman (Atritech, Minneapolis, MN) left atrial appendage system is made of nitinol, a self-expanding metal used in coronary stents, and constrained within a catheter delivery system until deployment in the left atrial appendage. Once the device is endothelialized, the left atrial appendage is excluded from the rest of the left atrium, reducing embolic risk. A safety and efficacy trial of this device is currently under way.The authors predict that this device will become a routine addition to catheter-based ablative treatment of AF in patients at increased risk for cardio-embolic events. Genetic testing of families of patients with AF has proved that some forms of AF are heritable. Furthermore, cardiac stem cells self-assembled into cardiospheres and expanded in monolayers yield

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patients and reduce the incidence of AF post coronary artery bypass grafting (CABG). Further investigation into the ability of these agents and others, like antioxidants, will be the focus of future large-scale clinical trials. Ten years ago, catheter-based ablation of AF was in its infancy. Since that time tremendous strides have been made in improving this catheter-based approach and in developing new approaches to deal with this common and potentially fatal clinical problem. The authors predict that in the next 10 years, approaches to treat AF and its untoward consequences will continue to emerge, as will therapies to prevent AF. In looking to the future in managing AF, it can be said that the future looks bright. A version of this article containing references can be found in the Reference Section on the website supporting this briefing (www.touchcardiology.com).

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