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Research

Study Summaries

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Atrial Fibrillation (AF) occurs in a wide spectrum of patients. Some patients have no structural heart disease while others have all varieties of heart disease with associated atrial pathology. It is therefore no surprise that the pathophysiology of AF is diverse.

One important factor in understanding how to treat AF, especially with catheter ablation, is locating the triggers for AF in the left atrium. Dr. Rishi Arora et al. reported the following work from his laboratory in the American Journal of Physiology—Heart and Circulation Physiology, 2008. He demonstrated in the normal canine heart model that parasympathetic nerve trunks and fibers in the left atrium are preferentially located in the posterior left atrium. Also, other receptors as well are significantly more pronounced in the posterior left atrium compared to the rest of the left atrium. So, when these areas are targeted and can be successfully isolated from conduction with catheter ablation and selective parasympathetic blockade is achieved, it significantly alters responsiveness in the entire left atrium. This achieves a near-complete elimination of vagal-induced AF. These results suggest that a targeted disruption of parasympathetic elements in the posterior left atrium may help successfully modify the basis of AF in the left atrium.

A limitation of this study is that the work was performed in a normal canine heart which cannot be directly compared to the human left atrium. Further studies would need to be done in more diseased hearts, as the extent to which nerve remodeling occurs in the setting of AF is not known.

In 2009, Drs. Gary Aistrup and Arora et al. reported results from a study performed in their laboratory in the Journal of Cardiovascular Research showing the capability of using specific cell membrane protein inhibition to achieve selective parasympathetic denervation in the posterior left atrium, with a resulting change in vagal responsiveness across the entire left atrium. When these proteins couple with certain receptors it mediates an intracellular event, causing the slowing or speeding of cellular activity present in cardiac conduction cells.

Drs. Jason Ng and Arora et al. reported in Circulation, 2011 the demonstration of autonomic (involuntary) remodeling of the left atria due to congestive heart failure (CHF). These findings have important implications on the treatment of AF in the setting of CHF. Catheter ablation in and around the pulmonary veins and posterior left atrium has recently emerged as a viable therapy for focal AF. However, in patients with structural heart disease, like occurs in CHF with enlargement of the chambers of the heart, significantly more extensive ablation has to be performed in order to increase ‘cure’ rates for AF. Yet, success rates in the setting of structural heart disease do not appear to exceed 50-60%. This study indicates that the autonomic nervous system contributes to the creation of the basis for AF. The parasympathetic (“rest & digest”) nervous system is involved in the maintenance of AF, and the sympathetic (“fight or flight”) nervous system affects the frequency of AF. Targeted approaches to selectively interrupt autonomic signaling in the posterior left atrium may therefore help increase the success rates of current ablative or surgical therapies for AF.

Dr. Rod Passman et al. published the Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL AF) study in the American Heart Journal, 2010, which is currently being conducted as a multi-center (50 sites in Europe, Canada & the United States) outpatient study enrolling 450 patients who have experienced cryptogenic stroke, meaning the stroke mechanism cannot be determined. Patients will be randomized in a 1:1 fashion to standard arrhythmia monitoring (control arm) or implantation of the subcutaneous cardiac monitor (Reveal XT; Medtronic, Inc., Minneapolis, MN) (continuous monitoring arm). Patients with AF are at increased risk for ischemic stroke caused by a blood clot in the brain. In patients who have suffered a stroke, screening for AF is routinely performed only for a short period after the stroke to evaluate for possible causes. If AF is detected after an ischemic stroke, oral anticoagulation therapy is recommended for secondary stroke prevention. In 25% to 30% of stroke patients the strokes are cryptogenic. The incidence of paroxysmal (intermittent) AF undetected by short-term monitoring in patients with cryptogenic stroke is unknown, but has important therapeutic implications on patient care. The optimum monitoring duration and method of AF detection after stroke are unknown. The purpose of this study is to evaluate the incidence of AF and time to AF detection in patients after cryptogenic stroke using the Reveal XT insertable cardiac monitor.

The primary end point of the Crystal AF study is time to detection of AF within 6 months after stroke. The clinical follow-up period will be at least 12 months. Study completion is expected at the end of 2012. The results will be reported on this website for your review.

In 2010, Drs. Jarett Berry & Rod Passman et al. reported in The American Journal of Cardiology the association between fish oil intake and AF. This association has been suggested in experimental and clinical trial data. However, previous observational studies have reported conflicting results regarding this association. So, in this study a comparison was sought in 44,720 older, postmenopausal women from the Women’s Health Initiative clinical trials between dietary fish intake and incident AF. These women were not under any dietary changes and had no AF at baseline. The dietary intake of non-fried fish and omega-3 fatty acid intake was estimated from a Food Frequency Questionnaire at study entry. Incident AF was determined by follow-up ECG at year 3 and 6. A total of 378 incident cases of AF occurred during the follow-up period. When the data was adjusted for age, no association was found between dietary non-fried fish intake and incident AF. Therefore, it was concluded from this large group of healthy women, no evidence of an association between fish or omega-3 fatty acid intake and incident AF was found.

Drs. David Amar and Rod Passman et al. published work in the Journal of the American College of Cardiology, 2004, regarding a practical prediction rule for AF after coronary artery bypass grafting (CABG) using easily available clinical and standard ECG criteria. In a retrospective study in 1,851 consecutive patients undergoing CABG with cardiopulmonary bypass for the first time and no history of AF, a standard 12-lead ECG was performed and examined before surgery. AF was seen in 10% to 65% of patients after cardiac operations and was associated with increased complications and costs. The mechanism responsible for post-operative AF is not entirely clear and is likely caused by multiple factors. As in AF unrelated to surgery, age >60 years is the only characteristic that has been consistently linked to an increased risk of post-operative AF. Independent risk factors for AF after cardiac surgery identified in more than one large study with >500 patients include male gender, history of AF, hypertension, chronic obstructive pulmonary disease, the use of digoxin, and longer aortic cross-clamp time. ECG characteristics predictive of post-operative AF in large studies was lacking, therefore, the goal was to design a prediction rule for post-operative AF risk using both clinical and ECG variables.

The ECG criteria for heart rate, PR-interval and P-wave duration (indicative of atrial activity) were measured. Prolonged P-wave duration of >110ms or PR-interval >180ms were used as defined values for prolongation. Additional characteristics studied were cardiopulmonary bypass time, aortic cross-clamp time; post-operative myocardial infarction occurrence and low cardiac output , defined as having a cardiac index <2.0 l/min/m2 for > 8 hours after surgery regardless of treatment. The primary clinical end point of this study was the new onset of sustained (>5 min) post-operative AF requiring drug treatment or cardioversion and detected by continuous ECG until the time of discharge from the hospital. In addition, the following clinical variables were selected: age, gender, history of AF, chronic obstructive pulmonary disease, hypertension, prior MI, peripheral vascular disease, diabetes mellitus, and pre-operative use of beta-blockers. The three ECG variables selected were pre-operative heart rate, P-wave duration (>110ms), and PR interval (>180ms).

The main findings of this study are that in addition to older age, prior history of AF, presence of P-wave duration >110ms on the standard pre-operative ECG, and a low post-operative cardiac output independently contribute to the risk for post-operative AF. Using these four risk factors, a simple prediction rule and scoring system was developed to estimate the likelihood of post-operative AF occurrence. Three out of four risk factors are easily available before surgery, with age (1 point per year) and prior history of AF (12 points) carrying the most weight in the point scoring system. Presence of P-wave duration >110ms before surgery scored the least (3 points) whereas the development of a low cardiac output after surgery conferred with significant risk (10 points).

To date, the only consistent pre-operative risk factor for an increased incidence of AF following surgery has been age > 60 years. It is well known that aging causes degenerative changes in the atrial myocardium that lead to alterations in electrical properties of the atria.

To the best of our knowledge, this is the largest study combining clinical and standard ECG characteristics in designing such a rule. Using this scoring system, the authors were able to establish low-, intermediate- and high-risk categories for post-operative AF. The high-risk group should receive prophylaxis either before or immediately following surgery and the the low-risk group should not; however, for the intermediate-risk group, cost-to-benefit analyses for potential prevention of AF would provide evidence-based data on which approach to pursue to minimize drug related adverse events and costs. This strategy has the potential to optimize care and improve outcomes.