M. Alasady

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 β1, 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 β1 (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.

Effect of Atrial Fibrillation on Atrial Thrombogenesis in Humans: Impact of Rate and Rhythm

OBJECTIVES We sought to assess the effect of atrial fibrillation (AF) on atrial thrombogenesis in humans by determining the impact of rate and rhythm. BACKGROUND Although AF is known to increase the risk of thromboembolic stroke from the left atrium (LA), the exact mechanisms remain poorly understood. METHODS We studied 55 patients with AF who underwent catheter ablation while in sinus rhythm; 20 patients were induced into AF, 20 patients were atrial paced at 150 beats/min, and 15 were control patients. Blood samples were taken from the LA, right atrium, and femoral vein at baseline and at 15 min in all 3 groups. Platelet activation (P-selectin) was measured by flow cytometry. Thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric dimethylarginine [ADMA]), and platelet-derived inflammation (soluble CD40 ligand [sCD40L]) were measured using enzyme-linked immunosorbent assay. RESULTS Platelet activation increased significantly in both the AF (p < 0.001) and pacing (p < 0.05) groups, but decreased in control patients (p < 0.001). Thrombin generation increased specifically in the LA compared with the periphery in both the AF (p < 0.01) and pacing (p < 0.01) groups, but decreased in control patients (p < 0.001). With AF, ADMA (p < 0.01) and sCD40L (p < 0.001) levels increased significantly at all sites, but were unchanged with pacing (ADMA, p = 0.5; sCD40L, p = 0.8) or in control patients (ADMA, p = 0.6; sCD40L, p = 0.9). CONCLUSIONS Rapid atrial rates and AF in humans both result in increased platelet activation and thrombin generation. Prothrombotic activation occurs to a greater extent in the human LA compared with systemic circulation. AF additionally induces endothelial dysfunction and inflammation. These findings suggest that although rapid atrial rates increase the thrombogenic risk, AF may further potentiate this risk.

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.

Long-term mechanical consequences of permanent right ventricular pacing: Effect of pacing site

Optimal Right Ventricular Pacing Introduction: Long‐term right ventricular apical (RVA) pacing has been associated with adverse effects on left ventricular systolic function; however, the comparative effects of right ventricular outflow tract (RVOT) pacing are unknown. Our aim was therefore to examine the long‐term effects of septal RVOT versus RVA pacing on left ventricular and atrial structure and function.

Time course of inflammation, myocardial injury, and prothrombotic response after radiofrequency catheter ablation for atrial fibrillation

Background—Inflammation has been linked to the genesis of stroke in atrial fibrillation (AF) and is implicated in early recurrent arrhythmia after AF ablation. We aimed to define the time course of inflammation, myocardial injury, and prothrombotic markers after radiofrequency ablation for AF and its relation to AF recurrence. Methods and Results—Ninety consecutive AF patients (53% paroxysmal) undergoing radiofrequency ablation were recruited. High-sensitivity C-reactive protein (hs-CRP), Troponin-T, creatine kinase-MB, fibrinogen, and D-Dimer concentrations were measured at baseline, at 1, 2, 3, 7 days, and at 1 month after ablation. AF recurrence was documented at 3 days and at 1, 3, and 6 months follow-up. Troponin-T and creatine kinase-MB peaked at day 1 after procedure (both P<0.05). Hs-CRP peaked at day 3 after procedure (P<0.05). Fibrinogen (P<0.05) and D-Dimer (P<0.05) concentrations were significantly elevated at 1 week after procedure. Ln hs-CRP elevation correlated with Ln Troponin-T and fibrinogen elevation. The extent of Ln hs-CRP, Ln Troponin-T, and fibrinogen elevation predicted early AF recurrence within 3 days after procedure (P<0.05, respectively), but not at 3 and 6 months. Conclusions—Patients undergoing radiofrequency ablation for AF exhibit an inflammatory response within 3 days. The extent of inflammatory response predicts early AF recurrence but not late recurrence. Prothrombotic markers are elevated at 1 week after ablation and may contribute to increased risk of early thrombotic events after AF ablation.

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.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.

New-onset atrial fibrillation and acute coronary syndrome

Despite advances in the diagnosis and management of acute coronary syndrome (ACS), atrial fibrillation (AF) remains a commonly encountered complication leading to adverse short- and long-term outcomes across the whole spectrum of ACS. At present, the underlying mechanisms of AF in myocardial ischemia remain incompletely understood. This article evaluates the incidence and trends of new-onset AF in ACS, its impact on ACS management and the associated prognostic significance in patients with acute ischemic heart disease. The safety and use of oral anticoagulation treatment in ACS patients on multiple antiplatelet agents are also explored. Further experimental and clinical studies are needed to improve current understanding and management of new-onset AF in ACS patients.

Left Ventricular Outflow Tract Ventricular Tachycardia Originating from the Noncoronary Cusp: Electrocardiographic and Electrophysiological Characterization and Radiofrequency Ablation

Noncoronary cusp (NCC) ventricular tachycardia is a rare form of monomorphic outflow tract tachycardia, and its electrocardiographic and electrophysiological characteristics have not been well described previously. The NCC should be considered for catheter ablation if attempts to eliminate ventricular tachyarrhythmia were unsuccessful in the other common anatomical sites of the left ventricular outflow tract.

Accuracy and clinical outcomes of CT image integration with Carto-Sound compared to electro-anatomical mapping for atrial fibrillation ablation: A randomized controlled study

BACKGROUND Carto-Sound integrates 2D intra-cardiac ultrasound imaging into a 3D environment to allow left atrial mapping from the right atrium without fluoroscopic assistance. We conducted an open randomized controlled study to compare procedural, clinical and accuracy parameters between CT integrated Carto-Sound and electro-anatomic mapping (EAM) for AF ablation. METHODS Sixty index AF ablation patients were randomized equally to either the Carto-Sound or EAM mapping/navigation for their procedure performed at a single institution. Procedure and X-ray times, X-ray dose, navigational accuracy and clinical success were assessed. The study was powered to the primary outcome of fluoroscopy time. RESULTS Total procedure (232 ± 60 vs 223 ± 48 min; p = 0.51), ablation (p = 0.84) and mapping times (p = 0.11) were similar in each group. In contrast, Carto-Sound reduced total X-ray time (65 ± 18 vs 51 ± 12 min; p = 0.001), via a reduction in both mapping (p<0.001) and remaining procedure X-ray time (p = 0.03). Left atrial access time (p = 0.03) was also reduced using Ultra-sound assisted 3D mapping compared to the EAM group. Carto-Sound maps demonstrated equivalent mean navigational accuracy (p>0.17) compared to EAM. Ultra-sound assisted 3D mapping did not improve single procedure drug free clinical success (EAM: 13/30 [43%] vs Carto-Sound: 15/30 [50%]) at a mean of 13 ± 5 months (p = 0.79). CONCLUSIONS In the context of long left atrial procedures with high radiation doses, reduced X-ray and left atrial access times using CT integrated Carto-Sound mapping/navigation may have implications for patients and laboratory staff, albeit at an extra financial cost and the requirement of an additional access site for a right sided catheter. TRIAL REGISTRATION NUMBER ACTRN12612000089831.

Successful catheter ablation decreases platelet activation and improves endothelial function in patients with atrial fibrillation

BACKGROUND Nonvalvular atrial fibrillation (AF) confers a five-fold increased risk of stroke. Whether catheter ablation (CA) subsequently decreases prothrombotic risk is unknown. OBJECTIVE The purpose of this study was to assess the long-term effects of CA for AF on prothrombotic risk. METHODS Fifty-seven patients undergoing CA for AF were prospectively studied. Platelet activation (CD62P [platelet P-selectin] and PAC-1 [glycoprotein IIb/IIIa] expression) and endothelial function (asymmetric dimethylarginine [ADMA] levels) were measured at baseline and 6-months postablation. RESULTS Thirty-seven (65%) patients remained in sinus rhythm (SR group) and 20 (35%) sustained AF recurrence (AF recurrence group) at 6-months. Patients with AF-recurrence were older, had a higher proportion of hypertension and long-standing persistent AF. There were no significant differences in CD62P (P = .3), PAC-1 (P = .1) and ADMA (P = .7) levels at baseline between the two groups. In the SR group, markers of platelet activation decreased significantly at 6-month follow-up compared to baseline; log CD62P % 0.79 ± 0.28 vs 1.03 ± 0.27 (P <.05) and log PAC-1 % 0.22 ± 0.58 vs 0.89 ± 0.31 (P <.01). This was not significant in the AF-recurrence group (P = .8, log CD62P; P = .1, log PAC-1). For endothelial function, ADMA levels decreased significantly at 6-months compared to baseline in the SR group (log ADMA μM/L 0.15 ± 0.02 vs 0.17 ± 0.04; P <.05), but did not alter significantly in the AF-recurrence group (P = .4, log ADMA). CONCLUSION Catheter ablation and successful maintenance of SR leads to a decrease in platelet activation and improvement in endothelial function in patients with AF. These findings suggest that AF is an important determinant of the prothrombotic state and that this may be reduced by successful catheter ablation.