Rationale and design of the IRON-AF study: a double-blind, randomised, placebo-controlled study to assess the effect of intravenous ferric carboxymaltose in patients with atrial fibrillation and iron deficiency.

INTRODUCTION: Atrial fibrillation (AF) is associated with significantly impaired quality-of-life. Iron deficiency (ID) is prevalent in patients with AF. Correction of ID in other patient populations with intravenous iron supplementation has been shown to be a safe, convenient and effective way of improving exercise tolerance, fatigue and quality-of-life. The IRON-AF (Effect of Iron Repletion in Atrial Fibrillation) study is designed to assess the effect of iron repletion with intravenous ferric carboxymaltose in patients with AF and ID. METHODS AND ANALYSIS: The IRON-AF study is a double-blind, randomised controlled trial that will recruit at least 84 patients with AF and ID. Patients will be randomised to receive infusions of either ferric carboxymaltose or placebo, given in repletion and then maintenance doses. The study will have follow-up visits at weeks 4, 8 and 12. The primary endpoint is change in peak oxygen uptake from baseline to week 12, as measured by cardiopulmonary exercise testing (CPET) on a cycle ergometer. Secondary endpoints include changes in quality-of-life and AF disease burden scores, blood parameters, other CPET parameters, transthoracic echocardiogram parameters, 6-minute walk test distance, 7-day Holter/Event monitor burden of AF, health resource utilisation and mortality. ETHICS AND DISSEMINATION: The study protocol has been approved by the Central Adelaide Local Health Network Human Research Ethics Committee, Australia. The results of this study will be disseminated through publications in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620000285954).

Risk factor management and atrial fibrillation.

The management of atrial fibrillation (AF) is multifaceted and treatment paradigms have changed significantly in the last century. The treatment of AF requires a comprehensive approach which goes beyond the treatment of the arrhythmia alone. Risk factor management has been introduced as a crucial pillar of AF management. As a result, the landscape of care delivery is changing as well, and novel models of comprehensive care delivery for AF have been introduced. This article reviews the evidence for the role of risk factor management in AF, how this can be integrated and implemented in clinical practice by applying novel models of care delivery, and finally identifies areas for ongoing research and potential healthcare reform to comprehensively manage the burgeoning AF population.

Clinical evidence of autonomic dysfunction due to atrial fibrillation: implications for rhythm control strategy.

PURPOSE: The role of the autonomic nervous system in the genesis of atrial fibrillation (AF) has been well studied; however, the converse remains poorly understood. Pulmonary veins (PV) contain receptors important in cardiac reflexes. Here, we evaluated reflex responses in patients with paroxysmal AF (PAF) to lower body negative pressure (LBNP). METHODS: Thirty-four PAF patients (including 14 PAF patients post successful PV Isolation; PVI) were compared to 14 age and sex-matched controls. Mean arterial pressure (MAP), heart rate (HR), systemic vascular resistance index (SVRI), cardiac index (CI), and stroke volume index (SVI) were measured continuously during - 0, - 20, and - 40 mmHg LBNP. LBNP reduces venous return, deactivating atrial receptors, thereby eliciting a reflex increase in SVRI to maintain MAP. RESULTS: AF patients have higher BMI than the controls (p = 0.02). In control subjects, LBNP did not alter MAP as SVRI increased. In PAF patients, LBNP resulted in a reduction in MAP (- 4.8%) with attenuated SVRI response (+ 4.2%) compared to controls (p < 0.05). However, in the post-PVI group, SVRI increase was similar to controls (p = 0.12) although that was insufficient to maintain MAP. In all patients, both reduction in SVI and CI and increase in HR were similar in response to LBNP. CONCLUSIONS: This study provides novel clinical evidence of autonomic dysfunction in PAF patients. Successful PVI results in partial recovery of the cardiac reflex. Therefore, not only does autonomic disturbance predispose to AF but it is also a consequence of AF; potentially contributing to disease progression. This could help explain the dictum "AF begets AF."

Integrated care in atrial fibrillation: a systematic review and meta-analysis.

OBJECTIVE: Atrial fibrillation (AF) is an emerging global epidemic associated with significant morbidity and mortality. Whilst other chronic cardiovascular conditions have demonstrated enhanced patient outcomes from coordinated systems of care, the use of this approach in AF is a comparatively new concept. Recent evidence has suggested that the integrated care approach may be of benefit in the AF population, yet has not been widely implemented in routine clinical practice. We sought to undertake a systematic review and meta-analysis to evaluate the impact of integrated care approaches to care delivery in the AF population on outcomes including mortality, hospitalisations, emergency department visits, cerebrovascular events and patient-reported outcomes. METHODS: PubMed, Embase and CINAHL databases were searched until February 2016 to identify papers addressing the impact of integrated care in the AF population. Three studies, with a total study population of 1383, were identified that compared integrated care approaches with usual care in AF populations. RESULTS: Use of this approach was associated with a reduction in all-cause mortality (OR 0.51, 95% CI 0.32 to 0.80, p=0.003) and cardiovascular hospitalisations (OR 0.58, 95% CI 0.44 to 0.77, p=0.0002) but did not significantly impact on AF-related hospitalisations (OR 0.82, 95% CI 0.56 to 1.19, p=0.29) or cerebrovascular events (OR 1.00, 95% CI 0.48 to 2.09, p=1.00). CONCLUSIONS: The use of the integrated care approach in AF is associated with reduced cardiovascular hospitalisations and all-cause mortality. Further research is needed to identify optimal settings, methods and components of delivering integrated care to the burgeoning AF population.

Identification of Rotors during Human Atrial Fibrillation Using Contact Mapping and Phase Singularity Detection: Technical Considerations.

OBJECTIVE: To explore technical challenges of phase singularity (PS) mapping during atrial fibrillation (AF) using direct contact electrograms. METHODS: AF mapping was performed in high-density epicardial recordings of human paroxysmal (PAF) or persistent (PersAF) (N = 20 pts) AF with an array of 16 × 16 electrodes placed on atrial epicardium. PS points were detected using subsets of electrodes forming rings of varying sizes. RESULTS: PS detection using a 2 × 2 electrode ring identified 0.88 ± 1.00 PS/s in PAF group and 3.91 ± 2.51 per s in PersAF group (p < 0.001) in 2.4 × 2.4 cm mapping area. All detected PS had a short lifespan with the longest being 1100 ms (6.8 rotations). Exploration of the PS detection in a numerical model demonstrated that at least eight electrodes are required to avoid frequent false positive PS detection due to chance. Application of a detection grid consisting a double ring of electrodes (2 × 2 and 4 × 4 rings) decreased the number of false positive detections. The double ring was more resilient to electrode swapping (with just three instances of false positives versus 4380 false positives using 2 × 2 ring). CONCLUSIONS: The number of detected rotors critically depends upon the parameters of the detection algorithm, especially the number of electrodes used to detect PS. Based on our results, we recommend double ring comprised of 2 × 2 and 4 × 4 grid of electrodes for robust rotor detection. SIGNIFICANCE: Great methodological care has to be taken before equating detected PS with rotating waves and using PS detection algorithms to guide catheter ablation of AF.

Feasibility and safety of Reveal LINQ insertion in a sterile procedure room versus electrophysiology laboratory.

BACKGROUND: Insertable cardiac monitors (ICMs) are increasingly utilized for diagnosis of unexplained syncope and arrhythmia monitoring. The Reveal LINQ is a novel miniaturized ICM with improved algorithms. The feasibility and safety of insertion outside the traditional electrophysiology laboratory is unknown. Here we compare outcomes of Reveal LINQ insertion in different environments. METHODS: We report on a prospective, single-centre, non-randomized, observational experience of consecutive Reveal LINQ implantation in the electrophysiology laboratory or a procedure room between October 2013 and October 2015. RESULTS: Of 178 consecutive patients who underwent LINQ device insertion, 80 were implanted in the electrophysiology laboratory and 98 in a procedure room. There were no significant differences in baseline patient characteristics. All implants were performed in the recommended manufacturer method with the exception of 1 which required suture closure. Only a minority received peri-procedural antibiotics with a greater number in the electrophysiology laboratory group (11 [14%] versus 1 [1%], p=0.007). Overall, there were 3 (1.7%) complications with no significant difference between the electrophysiology laboratory and the procedure room groups (2 [3%] versus 1 [1%], p=0.45). There was 1 superficial infection in the procedure room group and 1 superficial infection with device extrusion and 1 traumatic extrusion in the electrophysiology laboratory group. Procedure room implantation subjectively improved laboratory efficiency and patient flow. CONCLUSION: Reveal LINQ insertion can be safely performed outside of the cardiac laboratory provided a sterile technique is followed by the operator using manufacturer recommendations for insertion. These findings have significant resource implications for hospitals undertaking such procedures.

Simultaneous conduction mapping and intracellular membrane potential recording in isolated atria.

We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 × 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MΩ) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease.

Electrophysiological, Electroanatomical, and Structural Remodeling of the Atria as Consequences of Sustained Obesity.

BACKGROUND: Obesity and atrial fibrillation (AF) are public health issues with significant consequences. OBJECTIVES: This study sought to delineate the development of global electrophysiological and structural substrate for AF in sustained obesity. METHODS: Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks; 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping; hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry); and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-ß1 expression. RESULTS: Compared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p < 0.001); LA volume (p < 0.001); LA pressure (p < 0.001), and PA pressures (p < 0.001); reduced atrial CV (LA p < 0.001) with increased conduction heterogeneity (p < 0.001); increased fractionated electrograms (p < 0.001); decreased posterior LA voltage (p < 0.001) and increased voltage heterogeneity (p < 0.001); no change in the effective refractory period (ERP) (p > 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p < 0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-ß1 protein (p = 0.002) were increased in the obese group. CONCLUSIONS: Sustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-ß1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.

Indices of bipolar complex fractionated atrial electrograms correlate poorly with each other and atrial fibrillation substrate complexity.

BACKGROUND: The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood. OBJECTIVE: The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF. METHODS: Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined. RESULTS: All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block. CONCLUSION: The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the divergent and limited success rates of catheter ablation strategies targeting CFAE.

Myocardial infarction and atrial fibrillation: importance of atrial ischemia.

BACKGROUND: Myocardial infarction (MI) is associated with the development of atrial fibrillation (AF). We aimed to characterize the atrial abnormalities because of MI and determine the role of ischemia to the AF substrate. METHODS AND RESULTS: Forty-four sheep were studied. MI was induced by occlusion of the left circumflex artery (LCX) or left anterior descending artery (LAD). Excluding 11 with fatal arrhythmias, equal groups of animals (LCX; LAD; and sham-operated) underwent sequential electrophysiology study for 45 minutes to determine atrial effective refractory periods, conduction velocity, conduction heterogeneity index, and AF inducibility. Postmortem evaluation was performed with 2,3,5 triphenyl tetrazolium chloride staining. MI resulted in greater left ventricular dysfunction (P<0.05), LA pressure (P<0.0003), and reduction in atrial effective refractory periods (P<0.0001) compared with control. 2,3,5 triphenyl tetrazolium chloride staining demonstrated that the left circumflex artery, and not the LAD, group had atrial infarction. The left circumflex artery group demonstrated the following compared with the LAD or control groups: greater slowing in atrial conduction velocity (P<0.0001 and P<0.001); increased absolute range of conduction phase delay (P<0.001 and P<0.001); increased conduction heterogeneity index (P<0.0001 and P<0.001); greater AF vulnerability (P<0.05 for both); and longer AF duration (P<0.05 for both). LAD group had modest but significant slowing in conduction velocity (P<0.01) but no change in conduction heterogeneity index or AF duration compared with control. CONCLUSIONS: Left ventricular infarction, which is known to result in atrial stretch, hemodynamic change, and neurohumoral activation, contributes partially to the atrial abnormalities in MI. Atrial ischemia/infarction results in greater atrial electrophysiological changes and propensity for AF forming the dominant substrate for AF in MI.

Bipolar electrogram shannon entropy at sites of rotational activation: implications for ablation of atrial fibrillation.

BACKGROUND: The pivot is critical to rotors postulated to maintain atrial fibrillation (AF). We reasoned that wavefronts circling the pivot should broaden the amplitude distribution of bipolar electrograms because of directional information encoded in these signals. We aimed to determine whether Shannon entropy (ShEn), a measure of signal amplitude distribution, could differentiate the pivot from surrounding peripheral regions and thereby assist clinical rotor mapping. METHODS AND RESULTS: Bipolar electrogram recordings were studied in 4 systems: (1) computer simulations of rotors in a 2-dimensional atrial sheet; (2) isolated rat atria recorded with a multi-electrode array (n=12); (3) epicardial plaque recordings of induced AF in hypertensive sheep (n=11); and (4) persistent AF patients (n=10). In the model systems, rotation episodes were identified, and ShEn calculated as an index of amplitude distribution. In humans, ShEn distribution was analyzed at AF termination sites and with respect to complex fractionated electrogram mean. We analyzed rotation episodes in simulations (4 cycles) and animals (rats: 14 rotors, duration 80±81 cycles; sheep: 13 rotors, 4.2±1.5 cycles). The maximum ShEn bipole was consistently colocated with the pivot zone. ShEn was negatively associated with distance from the pivot zone in simulated spiral waves, rats, and sheep. ShEn was modestly inversely associated with complex fractionated electrogram; however, there was no relationship at the sites of highest ShEn. CONCLUSIONS: ShEn is a mechanistically based tool that may assist AF rotor mapping.

Stability of complex fractionated atrial electrograms: a systematic review.

UNLABELLED: Stability of CFAE. INTRODUCTION: The efficacy of complex fractionated atrial electrograms (CFAE) ablation as additional substrate modification in atrial fibrillation (AF) patients has been shown to be highly variable. Recently, the validity of sequential CFAE mapping has been challenged by concerns regarding temporal stability of CFAE. Existing studies on CFAE stability are small with very different CFAE definitions. Here, we undertook a systematic literature review to address these controversial findings. METHODS AND RESULTS: A systematic search of the scientific literature was performed through to September 1, 2011. From a total of 162 manuscripts, 7 were identified to contain assessment of the temporal stability of CFAE in human AF. These studies included a total of 96 (80 persistent/16 paroxysmal AF) patients (79% male, mean 58 years old). Varying CFAE mapping techniques or definitions were utilized. CFAE stability averaged 81% between 2 high-density sequential fractionation maps over an average time interval of 19 minutes. However, CFAE stability only averaged at 75% from shorter term continuous recordings (mean 15 comparisons within 75 seconds). Although the variability in CFAE cycle length was small (12-15 ms), coefficients of variation in continuous electrical activity were high (up to 300%). The overall spatial distribution of CFAE was found to be stable. Nevertheless, sequential mapping may not capture all CFAE sites given their dynamic characteristics. CONCLUSION: CFAE are temporally variable in keeping with the diverse mechanisms underlying their existence. The dynamic nature of CFAE will continue to pose a challenge for electrophysiologists in search of critical sites requiring ablation to combat AF. (J Cardiovasc Electrophysiol, Vol. 23, pp. 980-987, September 2012).

Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation.

BACKGROUND: There is a known association between obstructive sleep apnea (OSA) and atrial fibrillation (AF); however, how OSA affects the atrial myocardium is not well described. OBJECTIVE: To determine whether patients with OSA have an abnormal atrial substrate. METHODS: Forty patients undergoing ablation of paroxysmal AF and in sinus rhythm (20 with OSA [apnea-hypopnea index ≥ 15] and 20 reference patients with no OSA [apnea-hypopnea index < 15] by polysomnography) were studied. Multipolar catheters were positioned at the lateral right atrium (RA), coronary sinus, crista terminalis, and RA septum to determine the effective refractory period at 5 sites, conduction time along linear catheters at the RA and the coronary sinus, conduction at the crista terminalis, and sinus node function (corrected sinus node recovery time). Biatrial electroanatomic maps were created to determine the voltage, conduction, and distribution of complex electrograms (duration ≥ 50 ms). RESULTS: The groups had no differences in the prevalence of established risk factors for AF. Patients with OSA had the following compared with those without OSA: no difference in effective refractory period (P = .9), prolonged conduction times along the coronary sinus and RA (P = .02), greater number (P = .003) and duration (P = .03) of complex electrograms along the crista terminalis, longer P-wave duration (P = .01), longer corrected sinus node recovery time (P = .02), lower atrial voltage (RA, P <.001; left atrium, P <.001), slower atrial conduction velocity (RA, P = .001; left atrium, P = .02), and more widespread complex electrograms in both atria (RA, P = .02; left atrium, P = .01). CONCLUSION: OSA is associated with significant atrial remodeling characterized by atrial enlargement, reduction in voltage, site-specific and widespread conduction abnormalities, and longer sinus node recovery. These features may in part explain the association between OSA and AF.

Atrial protective effects of n-3 polyunsaturated fatty acids: a long-term study in ovine chronic heart failure.

BACKGROUND: It has been suggested that omega-3 polyunsaturated fatty acids (n-3 PUFAs) may prevent the development of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the impact of these agents on development of the AF substrate in heart failure (HF). METHODS: In this study, HF was induced by intracoronary doxorubicin infusions. Twenty-one sheep [7 with n-3 PUFAs treated HF (HF-PUFA), 7 with olive oil-treated HF controls (HF-CTL), 7 controls (CTL)] were studied. Open chest electrophysiologic study was performed with assessment of biatrial effective refractory period (ERP) and conduction. Cardiac function was monitored by magnetic resonance imaging. Atrial n-3 PUFAs levels were quantified using chromatography. Structural analysis was also performed. RESULTS: Atrial n-3 PUFAs levels were twofold to threefold higher in the HF-PUFA group. n-3 PUFAs prevented the development of HF-related left atrial enlargement (P = .001) but not left ventricular/atrial dysfunction. Atrial ERP was significantly lower in the HF-PUFA group (P <.001), but ERP heterogeneity was unchanged. In addition, n-3 PUFAs suppressed atrial conduction abnormalities seen in HF of prolonged P-wave duration (P = .01) and slowed (P <.001) and heterogeneous (P <.05) conduction. The duration of induced AF episodes in HF-PUFA was shorter (P = .02), although AF inducibility was unaltered (P = NS). A 20% reduction of atrial interstitial fibrosis was seen in the HF-PUFA group (P <.05). CONCLUSION: In this ovine HF study, chronic n-3 PUFAs use protected against adverse atrial remodeling by preventing atrial enlargement, fibrosis, and conduction abnormalities leading to shorter AF episodes despite lower ERP.

Assessment of myocardial fibrosis by endoventricular electromechanical mapping in experimental nonischemic cardiomyopathy.

Cardiac fibrosis plays an important prognostic role in nonischemic cardiomyopathy (NICM), making it a potential therapeutic target. Although electromechanical mapping has been used to identify myocardial scar and facilitate intramyocardial intervention in the setting of ischemic heart disease, its application has not been described in NICM. We assessed the detection of myocardial fibrosis by endoventricular electromechanical mapping in an experimental model of NICM. The NOGA® XP system was used to perform left ventricular mapping in twelve sheep that had undergone intracoronary doxorubicin dosing to induce NICM and in six healthy control animals. Results for endocardial voltage and mechanical shortening were evaluated against myocardial fibrosis burden, as determined by delayed-enhancement cardiac magnetic resonance and quantitative histomorphometry. Doxorubicin treatment resulted in dilated cardiomyopathy with moderate-severe impairment of left ventricular ejection fraction. Late gadolinium uptake was present in 9/12 doxorubicin animals, while histological fibrosis was approximately doubled compared to controls and was distributed multisegmentally throughout the left ventricle. Cardiomyopathy was associated with widespread reductions in unipolar and bipolar voltage amplitude and endocardial shortening. Each parameter showed an inverse relationship with the burden of fibrosis. Moreover, unipolar voltage and linear local shortening ratio displayed moderate accuracy for identifying myocardial segments with delayed contrast enhancement or increased fibrosis content, with optimal discriminatory thresholds of 7.5 mV and 11.5%, respectively. In this model of NICM, electromechanical mapping shows potential for delineating segmental differences in fibrosis. Pending clinical evaluation, it may therefore have applicability for directing targeted intramyocardial interventions in nonischemic heart disease.

Characterization of atrial remodeling studied remote from episodes of typical atrial flutter.

Atrial electrical remodeling has been shown after termination of atrial flutter (AFL); however, whether abnormalities persist beyond an arrhythmic episode is not known. We aimed to characterize the atrial substrate, remote from arrhythmia, in patients with typical AFL. We compared 20 patients, studied remote from episodes of typical AFL and without a history of atrial fibrillation, to 20 reference patients. Multipolar catheters placed at the lateral right atrium (RA), coronary sinus, crista terminalis, and septal RA measured the effective refractory period at 5 sites; conduction characteristics at the crista terminalis; and the conduction time along the lateral RA and coronary sinus. Electroanatomic right atrial maps were created to determine regional differences in voltage and conduction. Patients with AFL demonstrated the following compared to the reference patients: a larger right atrial volume (121 +/- 30 vs 83 +/- 24 ml, p = 0.005); a prolonged P-wave duration (122 +/- 18 vs 102 +/- 11 ms, p = 0.007); a longer right atrial activation time (107 +/- 23 vs 85 +/- 14 ms, p = 0.02); a prolonged conduction time along the lateral RA (67 +/- 4 vs 47 +/- 3 ms, p <0.001); a slower mean conduction velocity (1.2 +/- 0.2 vs 2.1 +/- 0.6 mm/ms, p <0.001); a greater proportion of fractionated electrographic findings (16 +/- 4% vs 10 +/- 6%, p = 0.006); more frequent abnormal electrographic findings at the crista terminalis (4.1 +/- 2.6 vs 1.0 +/- 1.1, p = 0.001); a prolonged corrected sinus node recovery time (318 +/- 71 vs 203 +/- 94 ms, p = 0.02); a trend toward greater effective refractory period (232 +/- 29 vs 213 +/- 12 ms, p = 0.06); and a lower voltage (2.1 +/- 0.5 vs 3.0 +/- 0.5 mV, p <0.001). In conclusion, studied remote from arrhythmia, patients with AFL demonstrated significant and diffuse atrial abnormalities characterized by structural changes, conduction abnormalities, and sinus node dysfunction. These persisting abnormalities characterize the substrate underlying typical AFL and may account for the subsequent development of atrial fibrillation.

Feasibility of high-density electrophysiological study using multiple-electrode array in isolated small animal atria.

1. High-density cardiac electrophysiological study (EPS) of small animal atria has been limited to optical mapping techniques, which require complex and expensive equipment setup. We aim to evaluate the feasibility of carrying out EPS in isolated atrial tissues using a custom made high-density multiple-electrode array (MEA). 2. Isolated rat atrial preparations were studied. The MEA (4 × 5 mm) consisted of 90 silver chloride coated electrodes (0.1 mm diameter, 0.5 mm pitch) and was connected to a conventional EP system yielding 80 bipolar signals. Atrial tissues were placed over the MEA in a dish bubbled with 100% oxygen and superfused with modified HEPES solution at pH 7.35 and 37°C. Then, 1 mmol of 2,3-butanedione monoxime was added to suppress motion artifacts from muscle contractions. Custom plaque analysis software was used for offline conduction analysis. 3. Isolated atrial tissues showed good viability of > 30 min, allowing ample time for complete EPS. High quality electrograms with excellent signal to noise ratio were obtained. All electrophysiological parameters showed good reproducibility: effective refractory period, conduction velocity and heterogeneity index. Tachycardia was also inducible in these normal atria. 4. The present study shows the feasibility of performing high-density EPS of small isolated atrial tissues with a conventional electrode-based technique. The MEA system is compatible with standard electrophysiology recording systems and provides a novel, inexpensive option for detailed EPS in small animal models. In particular, it presents new research avenues to further explore the mechanisms of atrial arrhythmias in various transgenic and knockout rodent models.

Hypertension and atrial fibrillation: evidence of progressive atrial remodeling with electrostructural correlate in a conscious chronically instrumented ovine model.

BACKGROUND: Hypertension accounts for more atrial fibrillation (AF) than any other predisposing factor. OBJECTIVE: The purpose of this study was to characterize the time course, extent, and electrostructural correlation of atrial remodeling in chronic hypertension. METHODS: Thirty-two sheep were studied: 21 with induced "one-kidney, one-clip" hypertension and 11 controls. Sequential closed-chest electrophysiologic studies were performed in 12 conscious animals (6 hypertensive, 6 controls) to evaluate progressive remodeling over 15 weeks. Additional atrial structural/functional analyses were performed in 5 controls and at 5, 10, and 15 weeks of hypertension (five per time point) via histology/cardiac magnetic resonance imaging to correlate with open-chest electrophysiologic parameters. RESULTS: The hypertensive group developed a progressive increase in mean arterial pressure (P <.001). Mean effective refractory periods were uniformly higher at all time points (P <.001). Progressive biatrial hypertrophy (P = .003), left atrial dysfunction (P <.05) and greater AF inducibility were seen early with increased inflammation from 5 weeks of hypertension. In contrast, significant conduction slowing (P <.001) with increased heterogeneity (P <.001) along with increased interstitial fibrosis resulted in longer and more fractionated AF episodes only from 10 weeks of hypertension. Significant electrostructural correlation was seen in conduction abnormalities and AF inducibility with both atrial inflammation and fibrosis. CONCLUSION: Hypertension is associated with early and progressive changes in atrial remodeling. Atrial remodeling occurs at different time domains in chronic hypertension with significant electrostructural correlation of the remodeling cascade. Early institution of antihypertensive treatment may prevent formation of substrate capable of maintaining AF.