Reversal Agents in the Era of NOACs.

The incidence and prevalence of atrial fibrillation (AF) is expected to more than double between 2010 and 2030. Accordingly, the use of non-vitamin K oral anticoagulant (NOAC) agents for thromboembolic stroke prevention is anticipated to increase. The development of effective and safe antidotes is needed to address the unmet need for rapid anticoagulation reversal. The immediate role for these novel antidotes is for reversal of NOAC activity in life threatening bleeding and urgent surgical intervention. In addition, reversal agents may play an important role in simplifying bridging protocols in the peri-procedural period for catheter ablation of AF and elective surgery. Currently, novel reversal agents are either decoy drug receptors or small molecule non-specific anticoagulant activity inhibitors. These agents are at various stages of FDA investigation and approval, with emerging prospective data for safety and efficacy. The purpose of this review is to outline the currently developed NOAC molecular antagonists, their potential clinical roles and future directions.

Periprocedural Management of Novel Oral Anticoagulants During Atrial Fibrillation Ablation: Controversies and Review of the Current Evidence.

Oral anticoagulation (OAC) has been the cornerstone for the prevention of thromboembolic complications in patients with atrial fibrillation (AF) at significant risk of stroke. Catheter ablation is an established efficacious technique for the treatment of AF. Ameliorating the risk of stroke or transient ischaemic attack (TIA) in patients with AF undergoing ablation requires meticulous planning of pharmacotherapy. The advent of non-vitamin K oral anticoagulants (NOACs) has broadened the therapeutic scope, representing a viable alternative to traditional vitamin K antagonists (VKA) in non-valvular AF. Potential advantages of NOACs include greater pharmacokinetic predictability, at least comparable efficacy as compared to VKA and a superior haemorrhagic complication profile. However, robust evidence for the safety and efficacy of periprocedural NOAC use for AF ablation remains uncertain with a non-uniform clinical approach between and within institutions. The following review will summarise the current and emerging evidence on periprocedural management of NOACs in patients undergoing catheter ablation of AF. An overview of NOAC pharmacology will provide a foundation for the review of reversal agents in the context of catheter ablation of AF. The purpose of the review is to outline key studies and identify key areas for further critical research with the ultimate aim of developing evidence-based guidelines for optimal care.

Impact of weight reduction on pericardial adipose tissue and cardiac structure in patients with atrial fibrillation.

BACKGROUND: Obesity and pericardial adipose tissue are independent risk factors for atrial fibrillation (AF) and adverse cardiac structural remodeling. The effect of weight reduction on pericardial adipose tissue and cardiac structure remains unknown. METHODS: We prospectively performed cardiac magnetic resonance imaging on 87 participants with AF undergoing either structured weight management (intervention) or general lifestyle advice (control). We measured pericardial adipose tissue, atrial and ventricular volumes, and myocardial mass at baseline and 12 months. RESULTS: In total, 69 participants underwent baseline and 12-month follow-up cardiac magnetic resonance imaging (intervention n = 36 and controls n = 33). From baseline to 12 months, weight loss (kg, mean [95% CI]) was greater in the intervention group from 101.5 kg (97.2-105.8 kg) to 86.5 kg (81.2-91.9 kg) as compared with controls from 102.6 kg (97.2-108.1 kg) to 98.7 kg (91.0-106.3 kg) (time-group interaction P < .001). The intervention group showed a reduction in left atrial volumes (mL) from 105.0 mL (98.9-111.1 mL) to 96.4 mL (91.6-101.1 mL), whereas the change in the control group was from 108.8 mL (99.6-117.9 mL) to 108.9 mL (99.8-118.0 mL) (time-group interaction P < .001). There was a decline in pericardial adipose tissue (cm(3)) from 140.9 cm(3) (129.3-152.4 cm(3)) to 118.8 cm(3) (108.1-129.6 cm(3)) and myocardial mass (g) from 137.6 g (128.1-147.2 g) to 123.1 g (114.5-131.7 g) in the intervention group, whereas the change in the control group was from 143.2 cm(3) (124.6-161.7 cm(3)) to 147.2 cm(3) (128.9-165.4 cm(3)) for pericardial adipose tissue and 138.3 g (124.8-151.8 g) to 140.7 g (127.4-154.1 g) for myocardial mass (both variables, time-group interaction P < .001). CONCLUSIONS: Weight reduction results in favorable structural remodeling and a reduction in pericardial adipose tissue burden.

Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial.

IMPORTANCE: Obesity is a risk factor for atrial fibrillation. Whether weight reduction and cardiometabolic risk factor management can reduce the burden of atrial fibrillation is not known. OBJECTIVE: To determine the effect of weight reduction and management of cardiometabolic risk factors on atrial fibrillation burden and cardiac structure. DESIGN, SETTING, AND PATIENTS: Single-center, partially blinded, randomized controlled study conducted between June 2010 and December 2011 in Adelaide, Australia, among overweight and obese ambulatory patients (N = 150) with symptomatic atrial fibrillation. Patients underwent a median of 15 months of follow-up. INTERVENTIONS: Patients were randomized to weight management (intervention) or general lifestyle advice (control). Both groups underwent intensive management of cardiometabolic risk factors. MAIN OUTCOMES AND MEASURES: The primary outcomes were Atrial Fibrillation Severity Scale scores: symptom burden and symptom severity. Scores were measured every 3 months from baseline to 15 months. Secondary outcomes performed at baseline and 12 months were total atrial fibrillation episodes and cumulative duration measured by 7-day Holter, echocardiographic left atrial area, and interventricular septal thickness. RESULTS: Of 248 patients screened, 150 were randomized (75 per group) and underwent follow-up. The intervention group showed a significantly greater reduction, compared with the control group, in weight (14.3 and 3.6 kg, respectively; P < .001) and in atrial fibrillation symptom burden scores (11.8 and 2.6 points, P < .001), symptom severity scores (8.4 and 1.7 points, P < .001), number of episodes (2.5 and no change, P = .01), and cumulative duration (692-minute decline and 419-minute increase, P = .002). Additionally, there was a reduction in interventricular septal thickness in the intervention and control groups (1.1 and 0.6 mm, P = .02) and left atrial area (3.5 and 1.9 cm2, P = .02). CONCLUSIONS AND RELEVANCE: In this study, weight reduction with intensive risk factor management resulted in a reduction in atrial fibrillation symptom burden and severity and in beneficial cardiac remodeling. These findings support therapy directed at weight and risk factors in the management of atrial fibrillation. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000497000.

Aortic stiffness in lone atrial fibrillation: a novel risk factor for arrhythmia recurrence.

BACKGROUND: Recent community-based research has linked aortic stiffness to the development of atrial fibrillation. We posit that aortic stiffness contributes to adverse atrial remodeling leading to the persistence of atrial fibrillation following catheter ablation in lone atrial fibrillation patients, despite the absence of apparent structural heart disease. Here, we aim to evaluate aortic stiffness in lone atrial fibrillation patients and determine its association with arrhythmia recurrence following radio-frequency catheter ablation. METHODS: We studied 68 consecutive lone atrial fibrillation patients who underwent catheter ablation procedure for atrial fibrillation and 50 healthy age- and sex-matched community controls. We performed radial artery applanation tonometry to obtain central measures of aortic stiffness: pulse pressure, augmentation pressure and augmentation index. Following ablation, arrhythmia recurrence was monitored at months 3, 6, 9, 12 and 6 monthly thereafter. RESULTS: Compared to healthy controls, lone atrial fibrillation patients had significantly elevated peripheral pulse pressure, central pulse pressure, augmentation pressure and larger left atrial dimensions (all P<0.05). During a mean follow-up of 2.9±1.4 years, 38 of the 68 lone atrial fibrillation patients had atrial fibrillation recurrence after initial catheter ablation procedure. Neither blood pressure nor aortic stiffness indices differed between patients with and without atrial fibrillation recurrence. However, patients with highest levels (≥75(th) percentile) of peripheral pulse pressure, central pulse pressure and augmentation pressure had higher atrial fibrillation recurrence rates (all P<0.05). Only central aortic stiffness indices were associated with lower survival free from atrial fibrillation using Kaplan-Meier analysis. CONCLUSION: Aortic stiffness is an important risk factor in patients with lone atrial fibrillation and contributes to higher atrial fibrillation recurrence following catheter ablation procedure.

Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation.

BACKGROUND: Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown. OBJECTIVE: To examine the effect of progressive weight gain on the substrate for AF. METHODS: Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor ß1, and connective tissue growth factor. RESULTS: Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor ß1 (P = .02) and platelet-derived growth factor (P = .02) levels. CONCLUSIONS: Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.

Mapping and ablation of the pulmonary veins and cavo-tricuspid isthmus with a magnetic resonance imaging-compatible externally irrigated ablation catheter and integrated electrophysiology system.

BACKGROUND: Magnetic resonance imaging (MRI)-guided interventional electrophysiology (EP) has rapidly emerged as a promising alternative to x-ray-guided ablation. We aimed to evaluate an externally irrigated MRI-compatible ablation catheter and integrated EP pacing and recording system, testing the feasibility of pulmonary vein and cavo-tricuspid isthmus ablation. METHODS AND RESULTS: Externally irrigated MRI-compatible ablation and diagnostic EP catheters and an integrated EP recording system (Imricor Medical Systems, Burnsville, MN) were tested in n=11 sheep in a 1.5-T MRI scanner. Power-controlled (40 W, 120-second duration) lesions were formed at the pulmonary vein and cavo-tricuspid isthmus. Real-time intracardiac electrograms were recorded during MRI. Steady-state free precession non-breath-hold images were repeatedly acquired to guide catheter navigation. Lesion visualization was performed using noncontrast (T2-weighted turbo spin echo pulse sequence) and gadolinium-diethylene triamine pentaacetic acid-enhanced T1-weighted imaging (inversion-recovery gradient echo pulse sequence). Catheters were able to be visualized and navigated under cardiovascular magnetic resonance guidance. In total, 8±2.5 lesions (radiofrequency time, 16±4.2 minutes) were formed at the pulmonary vein ostia, and 6.5±1.3 lesions (radiofrequency time, 13±2.2 minutes) were formed at the cavo-tricuspid isthmus, with the end point of bidirectional block. The mean procedure time was 150±55 minutes. Lesion visualization with both T2W imaging and contrast-enhanced imaging correlated with sites of injury at autopsy. CONCLUSIONS: These data demonstrate the feasibility of using multiple catheters, an integrated EP pacing and recording system, and externally irrigated ablation with cardiovascular magnetic resonance guidance to undertake clinically relevant biatrial mapping and ablation.

Importance of the underlying substrate in determining thrombus location in atrial fibrillation: implications for left atrial appendage closure.

CONTEXT: The left atrial appendage (LAA) has been suggested to be the dominant location of thrombus in atrial fibrillation (AF) and has led to the development of LAA occlusion as a therapeutic modality to reduce stroke risk. However, the patient populations that would benefit most from this therapy are not well defined. OBJECTIVE: A systematic review was performed to better define subgroups amenable to appendage closure. DATA SOURCES: The English scientific literature was searched using Pubmed through to March 1, 2011. Reference lists of relevant and review articles were screened to retrieve additional articles. STUDY SELECTION: Studies were only included if they described the location of thrombus in left atrium. Case reports and case series describing less than 10 thrombi were excluded. DATA EXTRACTION: Two reviewers independently extracted data and assessed quality of each study. RESULTS: A total of 34 studies reporting on the location of atrial thrombus in patients with AF were included: 17 in valvular AF, 10 non-valvular AF and 8 in mixed valvular and non-valvular AF. Atrial thrombi were located outside the LAA in 56% (95% CI 53, 60) of valvular AF, 22% (95% CI 19, 25) in mixed cohorts and 11% (95% CI 6, 15) non-valvular AF. In non valvular AF, the studies with higher proportion of thrombi in the left atrial cavity had non-anticoagulated patients and a greater proportion of ventricular dysfunction and history of stroke. CONCLUSION: The location of atrial thrombus in patients with AF is dependent on the underlying substrate. In valvular AF, more than half the thrombi are located in the left atrial cavity. In the non-valvular AF group, a smaller proportion of thrombi were located outside the appendage. However, in certain subgroups (ie. non anti-coagulated, left ventricular dysfunction or prior stroke) the chances of left atrial cavity thrombus are higher.

Approach to the difficult transseptal: diathermy facilitated left atrial access.

Percutaneous transseptal left atrial (LA) access is increasingly becoming a routine procedure in the electrophysiology and cardiac catheterisation laboratories. Our aim was to review an unselected large series of this procedure performed over a period of five years. We clinically characterised difficult cases and presented a method of safe and expeditious LA access. Overall, 543 transseptal punctures were performed. Of those, 10 were classified as difficult, with failure to access the LA in three or more attempts. In all 10 cases, surgical electrocautery was successfully used to facilitate needle puncture of the septum. All patients subsequently underwent an uncomplicated procedure. In conclusion, we describe a method to trouble-shoot the difficult transseptal access procedure, outlining the clinical characteristics, echocardiographic features and special precautions that need to be considered when utilising this method.

Pericardial fat is associated with atrial fibrillation severity and ablation outcome.

OBJECTIVES: The aim of this study was to characterize the relationship between pericardial fat and atrial fibrillation (AF). BACKGROUND: Obesity is an important risk factor for AF. Pericardial fat has been hypothesized to exert local pathogenic effects on nearby cardiac structures above and beyond that of systemic adiposity. METHODS: One hundred ten patients undergoing first-time AF ablation and 20 reference patients without AF underwent cardiac magnetic resonance imaging for the quantification of periatrial, periventricular, and total pericardial fat volumes using a previously validated technique. Together with body mass index and body surface area, these were examined in relation to the presence of AF, the severity of AF, left atrial volume, and long-term AF recurrence after ablation. RESULTS: Pericardial fat volumes were significantly associated with the presence of AF, AF chronicity, and AF symptom burden (all p values <0.05). Pericardial fat depots were also predictive of long-term AF recurrence after ablation (p = 0.035). Finally, pericardial fat depots were also associated with left atrial volume (total pericardial fat: r = 0.46, p < 0.001). Importantly, these associations persisted after multivariate adjustment and additional adjustment for body weight. In contrast, however, systemic measures of adiposity, such as body mass index and body surface area, were not associated with these outcomes in multivariate-adjusted models. CONCLUSIONS: Pericardial fat is associated with the presence of AF, the severity of AF, left atrial volumes, and poorer outcomes after AF ablation. These associations are both independent of and stronger than more systemic measures of adiposity. These findings are consistent with the hypothesis of a local pathogenic effect of pericardial fat on the arrhythmogenic substrate supporting AF.

Coronary artery disease affecting the atrial branches is an independent determinant of atrial fibrillation after myocardial infarction.

BACKGROUND: During acute myocardial infarction (MI), the incidence of atrial fibrillation (AF) is 6% to 22%, and its occurrence in this setting is associated with increased short- and long-term morbidity and mortality. OBJECTIVE: The purpose of this case control study was evaluate the characteristics associated with the development of new-onset AF. METHODS: Of 2,460 consecutive patients with acute MI, 149 (6%) were identified as having AF within 7 days of MI. After excluding patients with prior AF, previously documented heart failure, reduced left ventricular (LV) ejection fraction, valvular heart disease, LV hypertrophy, AF after coronary artery bypass grafting, or pericarditis; we identified 42 AF patients in whom coronary anatomy was assessed by invasive angiography and cardiac structure and function was evaluated using transthoracic echocardiography. Another 42 patients from the same cohort with MI but no AF matched for age, gender, and LV ejection fraction were studied as controls. RESULTS: AF patients were more likely to present with an inferior MI (P = .002) but less likely to present with ST-segment elevation MI (P = .02). Univariate associations with AF included indexed left atrial volume (P <.001), LV filling pressure (E/e'; P = .001), right atrial branch disease (P <.001), left atrial branch disease (P = .009), sinoatrial branch disease (P <.001), left main stem disease (P = .02), and time from onset of symptoms to coronary intervention (P = .002). In multivariable analysis, right and left coronary artery atrial branch disease (P = .02) were predictors of AF post-MI. CONCLUSION: Coronary artery disease affecting the atrial branches is an independent predictor for the development of AF after MI.