Elodie Morel

Identification and distribution of interstitial Cajal cells in human pulmonary veins.

BACKGROUND The major determinant of atrial fibrillation (AF) initiation is focal firing within the muscular portion of the pulmonary veins. We hypothesized that interstitial Cajal cells (ICCs), a known type of pacemaker cells, could underlie the pacemaking activity of isolated pulmonary veins. OBJECTIVE The aim of the study was to characterize the presence and the distribution of ICCs in human pulmonary veins. METHODS Immunohistochemistry was performed on a transversal section of each pulmonary vein of eight adult human hearts obtained at autopsy from January 2005 to December 2005. A history of AF was documented in two of these eight patients. Two immunostainings were performed on successive sections to differentiate ICCs from mast cells (antibody c-kit and antibody AA1). Morphological and distribution analyses were performed manually and automatically. Electron microscopy and immunostaining with HCN4 and smooth muscle alpha-actin antibodies were also used to further characterize Cajal cells. RESULTS ICCs were found in the pulmonary vein sections of three of the eight patients and were mainly identified in sections with a thick muscular sleeve. Two of these three patients had a history of AF. The mean distribution density of these cells was 0.6 ICCs/3 mm(2), with the highest density reaching 14.6 ICCs/3 mm(2) in a pulmonary vein of a patient with a history of AF. A positive immunostaining of Cajal cells with HCN4 was also demonstrated. CONCLUSIONS ICCs may be detected in human pulmonary veins, particularly in patients with AF. Given the electrophysiological attributes of these cells, their role as AF triggers deserve to be more documented.

Increased intracardiac vascular endothelial growth factor levels in patients with paroxysmal, but not persistent atrial fibrillation

AIMS Although inflammation appears to play a pivotal role in the pathophysiology of atrial fibrillation (AF), the source of inflammation is unknown. We hypothesized that multilevel measurement of several inflammatory proteins in AF patients would help assess the extent and the source of inflammation. METHODS AND RESULTS Thirty-nine patients with paroxysmal AF, 33 with persistent AF, and 9 control patients with Wolff-Parkinson-White syndrome were enrolled. Peripheral, left atrial, coronary sinus, and pulmonary vein blood samples were obtained during catheterization. Serum levels of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), soluble intercellular adhesion molecule 1 (sICAM-1), and transforming growth factor-β1 (TGF-β1) were measured at the four sampled sites. Interleukin-8, sICAM-1, and TGF-β1 levels did not differ among groups at any of the sampled sites. Peripheral VEGF levels were higher in both paroxysmal and persistent AF patients than in controls (P ≤ 0.03). Left atrial VEGF levels were higher in paroxysmal AF (P = 0.05), but not in persistent AF (P = 0.32), compared with controls. Coronary sinus and pulmonary vein VEGF levels did not differ significantly among groups. CONCLUSIONS Low levels of several inflammatory markers in both paroxysmal and persistent AF patients suggest that the inflammatory process is of low grade, if present. In the context of normal pulmonary vein VEGF levels, the heart itself is the most likely source of high left atrial VEGF levels in paroxysmal AF patients; however, this disorder appears to be a transient event in the natural history of AF.

Periatrial epicardial fat is associated with markers of endothelial dysfunction in patients with atrial fibrillation.

Background Epicardial adipose tissue (EAT) is associated to atrial fibrillation (AF) burden and outcome after AF ablation. We intended to determine whether global or local EAT is associated with systemic and/or left atrial (LA) inflammation and markers of endothelial dysfunction in AF patients. Methods and Results Total, atrial, and ventricular EAT volume (EATtotal, EATatrial, EATventricular) were measured by multislice cardiac CT in 49 patients with paroxysmal (PAF, n=25) or persistent AF (PeF, n=24). Periatrial epicardial fat thickness at the esophagus (LA-ESO) and thoracic aorta (LA-ThA) were also measured. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), soluble intercellular adhesion molecule 1 (sICAM-1), transforming growth factor-β1 (TGF-β1), and von Willebrand Factor (vWF) levels were measured in peripheral and LA blood samples obtained during catheterization during AF ablation. Patients with PeF had higher EATatrial (P<0.05) and LA-ESO (P=0.04) than patients with PAF. VEGF, IL-8, and TGF-β1 were not associated with EAT. In contrast, after adjusting for LA volume and body mass index, higher LA-ThA was significantly associated with higher sICAM-1 and vWF levels, both in peripheral blood (P<0.05) and in LA (P<0.05). Similar results were found with LA-ESO. Body mass index, EATtotal and EATventricular were not associated with sICAM-1 and vWF. Conclusions Periatrial epicardial fat showed a significant positive association with increased levels of sICAM-1 and vWF, which are biomarkers of endothelial dysfunction. No such associations were found when considering body mass index or EATtotal. These results suggest that local EAT rather than regional or total adiposity may modulate endothelial dysfunction in patients with AF.

Prophylactic Radiofrequency Ablation in Asymptomatic Patients With Wolff–Parkinson–White Is Not Yet a Good Strategy A Decision Analysis

Background—Therapeutic management of asymptomatic patients with a Wolff–Parkinson–White (WPW) pattern is controversial. We compared the risk:benefit ratios between prophylactic radiofrequency ablation and no treatment in asymptomatic patients with WPW. Methods and Results—Decision analysis software was used to construct a risk–benefit decision tree. The target population consisted of 20- to 40-year-old asymptomatic patients with WPW without structural fatal heart disease or a family history of sudden cardiac death. Baseline estimates of sudden death and radiofrequency ablation complication rates were obtained from the literature, an empirical data survey, and expert opinion. The outcome measure was death within 10 years. Sensitivity analyses determined the variables that significantly impacted the decision to ablate or not. Threshold analyses evaluated the effects of key variables and the optimum policy. At baseline, the decision to ablate resulted in a reduction of mortality risk of 8.8 patients for 1000 patients compared with abstention. It is necessary to treat 112 asymptomatic patients with WPW to save one life over 10 years. Sensitivity analysis showed that 3 variables significantly impacted the decision to ablate: (1) complication of radiofrequency ablation, (2) success of radiofrequency ablation, and (3) sudden death in asymptomatic patients with WPW. Conclusions—This study provides a decision aid for treating asymptomatic patients with the WPW ECG pattern. Using the model and the population we tested, prophylactic catheter ablation is not yet ready for widespread clinical use.

Risk of Sprint Fidelis defibrillator lead failure is highly dependent on age.

BACKGROUND In 2007, Medtronic Sprint Fidelis defibrillator leads were taken off the market due to a high rate of lead failure. Current data do not allow for risk stratification of patients with regard to lead failure. AIMS We sought to determine predictors of Sprint Fidelis lead failure. METHODS Between 2004 and 2007, 269 Sprint Fidelis leads were implanted in 258 patients in our centre. Variables associated with lead failure were assessed by the Kaplan-Meier method and a Cox survival model. RESULTS During a median follow-up of 2.80 years (maximum 5.32), we observed 33 (12.3%) Sprint Fidelis lead failures (5-year survival, 65.6% ± 7.5%). In univariate analysis, age was the only predictor of lead failure (hazard ratio [HR] for 1-year increase 0.97; 95% confidence interval [CI] 0.95-0.99; p=0.009). Patients aged<62.5 years (median) had a significantly increased risk of lead failure compared with patients aged>62.5 years (HR 2.80; CI 1.30-6.02; p=0.009). Survival without Sprint Fidelis lead failure was 55.6% ± 10.4%) in patients aged<62.5 years (24/134 leads) vs 78.6% ± 8.8% in patients aged>62.5 years (9/135 leads). The annual incidence of lead failure in patients aged<62.5 years was 11.6% ± 4.9% during the fourth year after implantation and 22.9% ± 13.2% during the fifth year. CONCLUSION Overall, we found a higher rate of Sprint Fidelis lead dysfunction than previously described. Lead failure was much more frequent in younger patients. Our results emphasize the need for close follow-up of younger patients with Sprint Fidelis leads and suggest that, in these patients, the implantation of a new implantable cardioverter defibrillator lead at the time of generator replacement might be reasonable.

Atrial fibrillation is associated with hypermethylation in human left atrium, and treatment with decitabine reduces atrial tachyarrhythmias in spontaneously hypertensive rats

&NA; Atrial fibrillation (AF) is the most common cardiac arrhythmia. As the molecular mechanisms underlying the pathology are largely unknown, this cardiac arrhythmia remains difficult to treat. To identify specific molecular actors involved in AF, we have performed a transcriptomic analysis on left atrium (LA) from patients with valvular heart disease with or without AF. We showed that 1627 genes had altered basal expression level in LA tissue of AF patients compared with the control group. The significantly enriched gene ontology biological process “anatomical structure morphogenesis” contained the highest number of genes in line with changes in structure that occur when the human heart remodels following AF development (ie, LA dilatation and interstitial fibrosis). We then focused the study on Pitx2 (paired‐like homeodomain 2), being the most altered transcription factor in LA from AF patients and from which compelling evidence have indicated that its reduced expression can be considered as a marker for the disease. In addition, its expression was inversely correlated with LA size. We demonstrated that AF is associated with Pitx2 promoter hypermethylation both in humans and arrhythmic aging spontaneously hypertensive rats. Chronic administration of a DNA methylation inhibitor (ie, 5‐Aza‐2′‐deoxycitidine) improved ECG arrhythmic profiles and superoxide dismutase activities and reduced fibrosis in the left ventricle of spontaneously hypertensive rats. Taken together, these data support the notion that AF is associated with epigenetic changes in LA and provide a proof‐of‐concept that hypomethylating agents have to be considered in the treatment of atrial arrhythmias.

Chronic oral amiodarone but not dronedarone therapy increases ventricular defibrillation threshold during acute myocardial ischemia in a closed-chest animal model.

Abstract: Dronedarone, a recently approved antiarrhythmic drug, has been shown to have fewer side effects than amiodarone, particularly with regard to thyroid and neurologic events. Since the effects of either drug on ventricular defibrillation threshold during ischemia are unknown, the aim of this study was to compare the effects of dronedarone and amiodarone on defibrillation efficacy during ischemia in a closed-chest animal model. Dronedarone (30 mg·kg−1·d−1) and amiodarone (20 mg·kg−1·d−1) were administered orally for 3 weeks to 19 and 21 pigs, respectively. A control group (no treatment) comprised 19 pigs. A 2-lead endovascular defibrillation system was used. Each biphasic shock was delivered after 8 seconds of ventricular fibrillation. A step-up/step-down protocol was used to calculate mean defibrillation threshold before and 10 minutes after coronary artery occlusion using an angioplasty balloon in the left descending artery. At basal state, defibrillation threshold did not differ between the control (20.8 ± 4.8 J), amiodarone (21.2 ± 2 J), and dronedarone (19.5 ± 3 J) groups. After ischemia, the amiodarone group had a significantly higher defibrillation threshold than the control group (29.6 ± 3 J vs. 21.8 ± 5 J, respectively; P = 0.015), but the dronedarone (22.8 ± 4 J) and control groups had similar defibrillation threshold values. These data indicate that oral dronedarone treatment, unlike oral amiodarone, does not affect defibrillation threshold during ischemia in pigs.

The impact of acute myocardial ischemia on the ventricular defibrillation threshold during chronic oral azimilide therapy.

The effects of chronic oral azimilide therapy on the ventricular defibrillation threshold (DFT) during ischemia are unknown. The effects of azimilide on defibrillation efficacy under ischemic condition were investigated in a closed-chest animal model. Azimilide (20 mg/kg/d) was administered orally for 7 days to 10 pigs (20 to 25 kg). The control group (no treatment) comprised 15 pigs. A 2-lead defibrillation system was used. Each shock was delivered after 8 seconds of ventricular fibrillation. A step-up and step-down protocol was used to calculate mean DFT before and 10 minutes after coronary artery occlusion using an angioplasty balloon in the left descending artery. The basal DFT of the azimilide group did not differ from controls (20.8 ± 4.8 versus 18.8 ± 2.8; P = 0.33). After ischemia, the mean DFT of the azimilide-treated animals was similar to controls (21.8 ± 5.2 versus 23.2 ± 3.8 J; P = 0.54), despite significant lengthening of ventricular repolarisation (428.2 ± 51.8 versus 494.1 ± 46.6 msec; P = 0.005) and significant prolongation of the ventricular fibrillation cycle length (85.1 ± 13 versus 104.7 ± 24 msec; P < 0.04). Chronic oral azimilide treatment does not affect the DFT at baseline or during acute myocardial ischemia.

Blockade of the renin-angiotensin-aldosterone system in patients with arrhythmogenic right ventricular dysplasia: A double-blind, multicenter, prospective, randomized, genotype-driven study (BRAVE study)

Arrhythmogenic right ventricular dysplasia (ARVD) is a rare cardiomyopathy characterized by the progressive replacement of cardiomyocytes by fatty and fibrous tissue in the right ventricle (RV). These infiltrations lead to cardiac electrical instability and ventricular arrhythmia. Current treatment for ARVD is empirical and essentially based on treatment of arrhythmia. Thus, there is no validated treatment that will prevent the deterioration of RV function in patients with ARVD. The aim of the BRAVE study is to evaluate the effect of ramipril, an angiotensin‐converting enzyme inhibitor, on ventricular myocardial remodeling and arrhythmia burden in patients with ARVD. Despite the fact that myocardial fibrosis is one of the structural hallmarks of ARVD, no study has tested an antifibrotic drug in ARVD patients. The trial is a double‐blind, parallel, multicenter, prospective, randomized, phase 4 drug study. Patients will be randomized into 2 groups, ramipril or placebo. The 120 patients (60 per group) will be enrolled by 26 centers in France. Patients will be followed up every 6 months for 3 years. The 2 co–primary endpoints are defined as the difference of telediastolic RV volume measured by magnetic resonance imaging between baseline and 3 years of follow‐up, and the change in arrhythmia burden during the 3 years of follow‐up. A decrease in RV and/or left ventricular deterioration and in arrhythmia burden are expected in ARVD patients treated with ramipril. This reduction will improve quality of life of patients and will reduce the number of hospitalizations and the risk of terminal heart failure.

Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation

Atrial fibrillation (AF) is a common arrhythmia for which the genetic studies mainly focused on the genes involved in electrical remodeling, rather than left atrial muscle remodeling. To identify rare variants involved in atrial myopathy using mutational screening, a high-throughput next-generation sequencing (NGS) workflow was developed based on a custom AmpliSeq™ panel of 55 genes potentially involved in atrial myopathy. This workflow was applied to a cohort of 94 patients with AF, 76 with atrial dilatation and 18 without. Bioinformatic analyses used NextGENe® software and in silico tools for variant interpretation. The AmpliSeq custom-made panel efficiently explored 96.58% of the targeted sequences. Based on in silico analysis, 11 potentially pathogenic missense variants were identified that were not previously associated with AF. These variants were located in genes involved in atrial tissue structural remodeling. Three patients were also carriers of potential variants in prevalent arrhythmia-causing genes, usually associated with AF. Most of the variants were found in patients with atrial dilatation (n=9, 82%). This NGS approach was a sensitive and specific method that identified 11 potentially pathogenic variants, which are likely to play roles in the predisposition to left atrial myopathy. Functional studies are needed to confirm their pathogenicity.