Monday, July 16, 2012

Integrated Model Speeds Understanding of Atrial Fibrillation and Stroke

Advances, Summer 2012

A new circular ablation catheter is placed at the entrance of the right superior vein.This catheter allows ablation from 10 electrodes simultaneously compared to the conventional single electrode ablation catheter. This technology has the potential of not only shortening the time of the procedure, but also improving the efficacy by reducing the chance of gaps forming between ablation points.

While historically treated as separate diseases, stroke and atrial fibrillation (AF) are now understood by the medical community to be related conditions. Growing knowledge of the interactions between the cardiovascular system and the brain provides fertile ground for more effective risk assessment and improved management of these patients—an opportunity that is particularly compelling in light of the new anticoagulation agents and mechanical devices recently added to the clinical armamentarium. To take full advantage of this opportunity, Massachusetts General Hospital is launching an innovative care model that fully integrates clinical, research, and educational efforts in stroke, vascular, and heart services into the Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care. This approach will accelerate the pace of discovery and speed safer, more effective, and more efficient care strategies for stroke and AF patients to the clinical setting. 

In recent years, Mass General heart, vascular, and stroke specialists have worked together informally on studies to prevent stroke and manage arrhythmias in patients with AF. The success of these collaborations, detailed on the following pages, indicates the power of a unified approach to improving AF-associated stroke care. The new Institute will expand on this success to fully integrate cardiologic, vascular, and stroke research, as well as multidisciplinary care and educational opportunities, with an infrastructure for collecting and assessing quality measures. The Mass General Institute for Heart, Vascular, and Stroke Care is currently the only facility in the country that incorporates neurology and stroke services with vascular medicine.
New Approaches to Risk Stratification
Risk stratification schemes in clinical use today lack the ability to predict with precision which AF patients are most highly prone to stroke. Identifying independent risk factors for these patients would help elucidate stroke pathogenesis associated with AF as well as allow stratification of risk for individual patients. Understanding in both areas could help clinicians prevent stroke in their patients and ensure services and medications are provided to those most likely to benefit from them. Improvement of these schemes, however, has been hampered by the complex interaction of contributing factors.

Inset: Rost NS, et al. (2012). Brain natriuretic peptide predicts functional outcome in ischemic stroke. Stroke, 43(2): 441-5.

Recent studies have indicated an association between genetic variants on chromosome 4q25 and AF. While variants on other chromosomes are under investigation at Mass General and elsewhere, says Karen Furie, MD, MPH, director of Mass General’s Stroke Service and Stroke Prevention Clinic, chromosome 4q25 variants hold the most promise for accurate early identification of AF-prone patients. As a result, researchers at Mass General are conducting more in-depth studies on the role of this region in AF. Recently, Patrick T. Ellinor, MD, PhD, director of Mass General’s Arrhythmia/Step Down Unit, and co-investigators looked for additional AF susceptibility signals at the 4q25 locus in individuals of European descent. In addition to confirming the importance of the previously identified variant, the researchers found two novel AF susceptibility signals on chromosome 4q25. A subset of individuals with the highest-risk genetic variants has a sixfold increased risk for developing AF. Further studies are ongoing to determine whether these genetic variants are also associated with an increased risk of stroke, heart failure, or death in patients with AF.

Also, Mass General clinical researchers are searching for a validated serum marker that improves prediction of mortality and informs risk stratification. According to Dr. Furie, a widely available biomarker of this sort could help guide decisions regarding rehabilitative efforts, management strategies, and post-discharge monitoring. In addition, a serum biomarker could help identify the etiology of a stroke event—information critical to selecting the right course to prevent secondary stroke.

Earlier research has established a connection between cardioembolic (CE) stroke and increased post-stroke mortality with elevated serum levels of brain natriuretic peptide (BNP). BNP has also been identified as a predictor for development of AF. To determine whether serum BNP levels can be used independently as predictors of functional outcome, Dr. Furie and co-investigators compared BNP levels at hospital admission with patient outcomes after six months in a group of patients with ischemic stroke treated at Mass General.

The study showed that patients with elevated serum BNP levels on hospital admission had an increased risk for long-term mortality and poorer functional outcomes, regardless of other risk factors such as gender, age, and premorbid stroke-related disability. This association was significant in CE stroke patients but not in other stroke subtypes, indicating BNP levels may not be useful for assessing outcomes after non-CE strokes (see the table above). The study also showed that elevated BNP is associated with lower left ventricular ejection fraction and a greater increase in left atrium diameter in patients with ischemic stroke. These findings may be helpful in determining prevention strategies.

Recent Mass General studies have also investigated the role of imaging to help identify AF patients at increased risk for stroke. Researchers have focused on imaging of the left atrial appendage (LAA), a small pouch in the heart’s left upper chamber. Clot formation within the LAA, resulting from a tendency of blood to pool there in individuals with AF, accounts for the majority of strokes in patients with nonvalvular AF. Traditionally, clinicians rely on transesophageal echo (TEE) imaging of the LAA to help define risk. While TEE can identify CE risk factors, including the presence of clots and low blood velocities within the LAA, its value as a screening tool is limited by the fact that it is invasive and allows for only two-dimensional visualization of the LAA.

Moussa Mansour, MD, director of the Electrophyisology Laboratory and of the Atrial Fibrillation Program; Jeremy Ruskin, MD, director of the Cardiac Arrhythmia Service; and co-investigators at Mass General used magnetic resonance imaging and angiography (MRI/MRA) to provide three-dimensional images that allowed for detection of LAA characteristics that may link AF to stroke. The study showed that dimensions of the LAA, particularly of the LAA neck, were independent predictors of risk for stroke or TIA (transient ischemic attack) in a small group of patients. Larger LAAs, explains Dr. Ruskin, may be associated with more strokes or TIAs because they have lower emptying velocities than those in small necks and thus are more conducive to clot formation. According to Dr. Ruskin, this is the first risk classification scheme to use an anatomic parameter. Findings will be validated in a larger patient population.

Research and Experience Yield Drug Therapy Alternatives
Although warfarin (Coumadin) is currently the most common treatment for stroke prevention in people with AF, the new thrombin inhibitors and factor 10-A inhibitors provide promising alternatives for patients with histories of major bleeding who have already experienced a TIA or stroke, despite adequate anticoagulation with a pharmacologic agent, or who are at high risk for falls. These new agents alleviate the need for regular monitoring of therapeutic levels and carry fewer drug-to-drug and drug-to-food interactions. These drugs have challenges, however, including cost, twice-daily dosing, and lack of an antidote or readily available clinical monitoring. Additionally, some patients may prefer a nonpharmacologic solution to allow them to eliminate the need for taking medication. Nonpharmacologic options are needed to protect this subset of patients with AF from stroke.

Left atrial appendage clot.

Among the alternatives available at Mass General are catheter ablation, LAA occlusion devices, and the Cox-Maze procedure. Mass General physicians have had promising success with cardiac ablation procedures in clinical trials involving patients with persistent AF (continuing for months to years) as well as in patients with the paroxysmal (intermittent) disease. According to Dr. Ruskin, catheter ablation in patients with persistent AF is far less common and more challenging than in patients with paroxysmal disease. At Mass General, however, the procedure is done in roughly equal numbers for both types of arrhythmias with excellent results.

Good outcomes in both paroxysmal and persistent AF, explains Dr. Ruskin, are dependent on the experience and skill of the cardiac electrophysiologist. Dr. Mansour has published widely on the development of techniques for catheter ablation of AF and is experienced with a variety of approaches, including the newly approved cryoballoon ablation procedure. This minimally invasive operation involves insertion of a balloon catheter into the heart via the femoral vein. Once in place, the balloon is inflated and cooled using nitrous oxide. Cryoblation is associated with less pain during energy delivery. Furthermore, it has a safety and effectiveness profile that is comparable to that of radiofrequency ablation.

Improved outcomes also rely on extensive and skilled mapping of the left atrium and, occasionally, the right atrium. Mass General clinical researchers are collaborating across departments and with experts from other institutions to advance the development of new devices that will aid in both the atrial mapping and the performing of the AF ablation surgery. Current projects in this area include the development of a unique platform for very closely spaced electrodes for mapping of AF.

Mass General, with Dr. Mansour as principal investigator, was among the first sites in the U.S. to offer the Watchman® Left Atrial Appendage Closure device and was the only hospital in New England to participate in the PROTECT AF trial, which compared the device with long-term warfarin therapy in patients with nonvalvular AF. The Watchman device permanently covers the LAA opening, capturing clots before they can leave the heart. Results of the trial, published in The Lancet in August 2009, indicated that the Watchman device was at least as effective as warfarin at preventing stroke. The FDA has requested an additional study to provide further safety and effectiveness data.

One significant challenge with installing the Watchman is determining the dimensions and anatomic variances of the LAA so that the proper-sized device can be implanted. To ameliorate this challenge, Dr. Mansour and colleagues at Mass General are comparing different types of imaging to determine relative accuracy in assessing relevant LAA dimensions, as well as investigating imaging approaches that will eliminate the need for general anesthesia or heavy sedation. Ultimately, this line of inquiry will improve the efficiency and safety of the Watchman. Studies such as these highlight Mass General’s commitment to playing a leadership role in improving quality measures consistent with health care reform.
Advanced Surgical Procedures Minimize Invasiveness

Patients who have failed catheter-based and medical treatment approaches for AF may be candidates for a surgical procedure that offers an 85 to 90 percent cure rate, with cure defined as no symptomatic episodes of AF with the patient off medication. While some medical centers suggest pulmonary vein isolation to treat AF, Thoralf M. Sundt III, MD, chief of cardiac surgery at Mass General, believes that the most effective procedure is the Cox-Maze, or Maze. Pulmonary vein isolation, stresses Dr. Sundt, is a different procedure from a full Cox-Maze.

Left: Cox-Maze procedure for atrial fibrillation. Right: Schematic of the Cox-Maze. SAN, sinoatrial node; LAA, left atrial appendage; PV, pulmonary veins; AVN, atrioventricular node; RAA, right atrial appendage. Illustrations: Eric T. Olson

The Cox-Maze approach, named for developer James Cox, MD, uses a specific set of lesions within the atria to control electrical impulses and return the heart to sinus rhythm. Surgeons historically formed the lesions using a scalpel. Modifications to the lesion sets since the procedure was first performed in 1987 have improved both safety and efficacy, and surgeons at Mass General may now use cryotherapy or radiofrequency ablation in lieu of or in addition to a scalpel. The current iteration of the procedure using these newer technologies is referred to as the Cox 4. The surgical Maze procedure may not be the first-line therapy, but it may offer hope to those who fail less invasive approaches in the treatment of refractory atrial fibrillation.

At the Mass General Institute for Heart, Vascular, and Stroke Care, Cox procedures are most commonly performed concomitantly with mitral valve repair. Dr. Sundt trained with Dr. Cox during the development of the procedure and has been performing the Cox for more than 20 years. Dr. Sundt explains that a leaky mitral valve allows blood to flow back into the atrium. The chamber stretches, eventually causing fibrillation. Repairing the valve and performing a Cox procedure returns most patients to sinus rhythm and eliminates the need for both mechanical valve replacement and anticoagulation therapy. A select group of patients who have failed both catheter-based and medical AF therapies may be candidates for a Cox-Maze as a single surgery.

The efficacy of the Cox procedure has been proven, says Dr. Sundt. Efforts are continuing to make it even less invasive. For example, some patients may be eligible for robotic-assisted mitral valve repairs, which have been available at Mass General since 2009. Robotic-assisted heart surgery is less invasive than traditional heart surgery, resulting in increased safety and shorter hospital stays, as well as allowing patients to avoid valve replacement.

International Symposium Provides Updates in Research and Care
Fully comprehending the relationships between stroke, heart, and the vascular system requires multidisciplinary educational opportunities as well as multidisciplinary translational research and care. As part of the Mass General Institute for Heart, Vascular, and Stroke Care, Mass General cardiologists, neurologists, and related specialists are developing continuing medical education (CME) opportunities to update and educate community physicians on important findings related to stroke risk identification in AF patients and on new management options.

One example of Mass General’s commitment to playing a leadership role in education is the annual Boston AF Symposium. Since its inception in 1995, this symposium, hosted by Mass General, has evolved into a major scientific forum that provides health care professionals with the opportunity to learn about AF research and treatment from a distinguished international faculty. The 2012 Boston AF Symposium witnessed the launch of the latest Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation, in which Drs. Ruskin and Mansour participated. The statement, originally published in 2007, provides the definition for a successful AF ablation as well as recommendations about procedural indications and anticoagulation strategies. These guidelines will help primary care physicians and cardiac specialists in the community determine which patients are appropriate for referral for catheter ablation and LAA exclusion procedures.
Leaders in Health Care Policy

Key Points

  • New Institute integrates stroke, vascular, and heart services to accelerate advances in stroke-related atrial fibrillation (AF) research and patient care
  • Emerging risk stratification strategies include identification of novel genetic variants, elevated serum levels of brain natriuretic peptide, and dimensions of the left atrial appendage
  • Technological improvements and physician experience yield comparable outcomes in patients with paroxysmal and persistent AF following catheter ablation
  • Alternative imaging approaches show promise for improving safety and efficiency of LAA occlusion device implants
  • Surgical options to eliminate AF include minimally invasive and complex combination procedures
  • Updated AF consensus document modifies definition of paroxysmal and persistent AF

As a leader in cardiovascular and neurologic research and patient care and an early adopter of the accountable care organization (ACO) model, Mass General specialists participate in policy debates regarding meaningful quality metrics. The goal, says Michael R. Jaff, DO, chair of the Mass General Institute for Heart, Vascular, and Stroke Care, is not simply to satisfy regulatory demands for measurements relating to health care but to develop quality indicators that will transform clinical practice by producing better outcomes, increased efficiencies, improved patient experiences, and safer environments for patients at reduced per capita costs.

Citing the risk stratification research, new approaches to imaging during LAA device implantation, contributions to the expert consensus statement, and other studies under way in basic and clinical research programs, Dr. Jaff points out that Mass General heart, vascular, and stroke specialists focus on improving care quality and safety while functioning as separate departments. Within the new integrated care model, multi- and interdisciplinary committees will review and prioritize initiatives across the full spectrum of care and within the financial and data collection infrastructure. These efforts simultaneously ensure that care quality for all patients will be judged based on meaningful measures, speeding the most promising treatment modifications into clinical use.  •

Selected References

Beinart R, et al. (2011). Left atrial appendage dimensions predict the risk of stroke/TIA in patients with atrial fibrillation. J Cardiovasc Electrophysiol, 22(1): 10-15.

Lubitz S, et al. (2010). Independent susceptibility markers for atrial fibrillation on chromosome 4q25. Circulation, 122: 976-84.

Ozcan C, Mansour M. (2011). Cyroballoon catheter ablation in atrial fibrillation. Cardiol Res Pract, 2011: 256347. Epub June 20, 2011.

Rost NS, et al. (2012). Brain natriuretic peptide predicts functional outcome in ischemic stroke. Stroke, 43(2): 441-45. Epub Nov. 23, 2011.


Patrick Ellinor, MD, PhD

  • Director, Arrhythmia/Step Down Unit, Massachusetts General Hospital
  • Associate Professor of Medicine, Harvard Medical School

Karen L. Furie, MD, MPH

  • Director, Stroke Service, Massachusetts General Hospital
  • Director, Stroke Prevention Clinic, Massachusetts General

Moussa C. Mansour, MD

  • Director, Atrial Fibrillation Program, Massachusetts General Hospital
  • Director, Cardiac Electrophysiology Laboratory, Massachusetts General Hospital
  • Associate Professor of Medicine, Harvard Medical School

Jeremy N. Ruskin, MD

  • Director, Cardiac Arrhythmia Service, Massachusetts General Hospital
  • Associate Professor of Medicine, Harvard Medical School

Thoralf M. Sundt III, MD

  • Chief, Cardiac Surgery, Massachusetts General Hospital
  • Co-Director, Institute for Heart, Vascular, and Stroke Care, Massachusetts General Hospital
  • Co-Director, Heart Center, Massachusetts General Hospital
  • Edward D. Churchill Professor of Surgery, Harvard Medical School

Massachusetts General Hospital Institute for Heart, Vascular and Stroke Care
The goal of the Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care is to advance the diagnosis and treatment of heart, vascular, and cerebrovascular conditions by providing comprehensive patient care while shaping the medicine of tomorrow. Under unified leadership from Mass General’s Corrigan Minehan Heart Center, the Vascular Center, and the Stroke Service, the Institute is pioneering a new model that involves complete integration of clinical care and research across disciplines. This patient- and disease-focused model combines basic, translational, and clinical research with the expertise of a multi-specialty panel of expert scientists and clinicians. By bridging multiple disciplines, the leadership of the Mass General Institute for Heart, Vascular, and Stroke Care is developing educational programs that reinforce the opportunities offered through integrated care, while also working to address critical issues of health policy and reform.

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