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Maintenance of atrial fibrillation is a complex mechanism, including extensive electrical and structural remodeling of the atria which involves progressive fibrogenesis. Galectin-3 is a biomarker of fibrosis, and, thus, may be involved in atrial remodeling in atrial fibrillation patients. We review the role of galectin-3 in AF mechanisms and its potential therapeutic implications.

Galectin-3 is a biomarker of fibrosis and atrial remodeling, involved in the mechanisms of initiation and maintenance of atrial fibrillation (AF). We sought to study the accuracy of galectin-3 level in predicting recurrences of AF after ablation. Serum concentrations of galectin-3 were determined in a consecutive series of patients addressed for AF ablation in our center. After a 3-month blanking period, recurrences of atrial arrhythmias were collected during the first year in all patients, using Holter monitoring at 3, 6 months and 12 months. A total of 160 patients were included, with a mean galectin-3 rate was 14.4 ± 5.6 ng/mL. At 12-month, 55 patients (34%) had reexperienced sustained atrial arrhythmia. Only higher galectin-3 level (HR = 1.07 [1.01–1.12], p = 0.02) and larger left atrial diameter (HR = 1.07 [1.03–1.12], p = 0.001) independently predicted recurrence. Patients with both galectin-3 level <15 ng/mL and left atrial diameter <40 millimeters had a 1-year arrhythmia-free survival rate − after a single procedure without anti-arrhythmic drug − of 91%, as compared with 41% in patients with galectin-3 ≥ 15 and left trial diameter ≥40 (p < 0.0001), whether AF was paroxysmal or persistent. Galectin-3 and left atrial diameters, rather than clinical presentation of AF, predict recurrences after ablation.

SCN5A Mutations and the Role of Genetic Background in the Pathophysiology of Brugada Syndrome Vincent Probst, MD, PhD ; Arthur A.M. Wilde, MD, PhD ; Julien Barc, MS ; Frederic Sacher, MD ; Dominique Babuty, MD ; Philippe Mabo, MD ; Jacques Mansourati, MD ; Solena Le Scouarnec, PhD ; Florence Kyndt, PharmD, PhD ; Cedric Le Caignec, MD, PhD ; Pascale Guicheney, PhD ; Laetitia Gouas, PhD ; Juliette Albuisson, MD ; Paola G. Meregalli, MD ; Hervé Le Marec, MD, PhD ; Hanno L. Tan, MD, PhD and Jean-Jacques Schott, PhD From the INSERM (V.P., J.B., S.L.S., F.K., H.L.M., J.J.S.), UMR915; CNRS (V.P., J.B., S.L.S., F.K., H.L.M., J.J.S.), ERL3147; Université de Nantes (V.P., J.B., S.L.S., F.K., H.L.M., J.J.S.), l’institut du thorax; CHU Nantes (V.P., H.L.M., J.J.S.), l’institut du thorax, Service de cardiologie, Nantes, France; Department of Cardiology (A.A.M.W., P.G.M., H.L.T.), Academic Medical Center, University of Amsterdam, The Netherlands; Service de rythmologie (F.S.), Hôpital cardiologique du Haut Leveque, Bordeaux, France; Service de cardiologie B (D.B.), Hôpital Trousseau, Tours, France; Departement de cardiologie (P.M.), Hôpital Pontchaillou, Rennes, France; Service de cardiologie (J.M.), centre hospitalo-universitaire de Brest, Brest, France; Service de Génétique Médicale (F.K., C.L.C., J.A.), Institut de Biologie, CHU de Nantes, France; INSERM (P.G., L.G.), U582, Institut de Myologie, Paris, France; and AP-HP (P.G., L.G.), Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Correspondence to Vincent Probst, MD, PhD, Service de cardiologie du CHU de Nantes, CHU de Nantes, Hôpital Nord, Bd Jacques Monod, 44093 Nantes Cedex, France. E-mail vincent.probst{at}chu-nantes.fr Received January 22, 2009; accepted July 14, 2009. Background— Mutations in SCN5A are identified in 20% to 30% of probands affected by Brugada syndrome (BrS). However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families. Methods and Results— Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects. Conclusions— Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels. Key Words: death, sudden (if surviving, use heart arrest) • Brugada syndrome • SCN5A • genetics • tachyarrhythmias • arrhythmia   CLINICAL PERSPECTIVE Drs Probst and Wilde contributed equally to this work. Related Article Nature’s Genetic Gradients and the Clinical Phenotype Ali J. Marian Circ Cardiovasc Genet 2009 2: 537-539. [Extract] [Full Text] [PDF]

Mechanisms of maintenance of both atrial fibrillation and structural left ventricular disease are known to include fibrosis. Galectin-3, a biomarker of fibrosis, is elevated both in patients with heart failure and persistent atrial fibrillation. We sought to find whether galectin-3 has a prognostic value in patients with heart failure and a reduced left ventricular ejection fraction undergoing ablation of persistent atrial fibrillation. Serum concentrations of galectin-3 were determined in a consecutive series of patients with an ejection fraction ≤40%, addressed for ablation of persistent atrial fibrillation. Responders to ablation were patients in sinus rhythm and with an ejection fraction ≥50% at 6 months. A combined endpoint of heart failure hospitalization, transplantation and/or death was used at 12 months. Seventy-five patients were included (81% male, age 63±10 years, ejection fraction 34±7%, galectin-3 21±12 ng/mL). During follow-up, eight patients were hospitalized for decompensated heart failure, 1 underwent heart transplantation, and 4 died; 50 patients were considered as responders to ablation. After adjustment, galectin-3 level independently predicted both 6-month absence of response to ablation (OR = 0.89 per unit increase, p = 0.002). Patients with galectin-3 levels <26 had a 95% 1-year event-free survival versus 46% in patients with galectin-3 ≥26 ng/mL (p<0.0001). Galectin-3 levels independently predict outcomes in patients with reduced left ventricular systolic function addressed for ablation of persistent AF, and may be of interest in defining the therapeutic strategy in this population.

Background Cardiac resynchronization therapy (CRT) reduces symptoms, morbidity and mortality in chronic heart failure patients with wide QRS complexes. However, approximately one third of CRT patients are non-responders. Myocardial fibrosis is known to be associated with absence of response. We sought to see whether galectin-3, a promising biomarker involved in fibrosis processes, could predict response and outcomes after CRT. Methods Consecutive patients eligible for implantation of a CRT device with a typical left bundle branch block ≥ 120 ms were prospectively included. Serum Gal-3 level, Selvester ECG scoring, and cardiac magnetic resonance with analysis of late gadolinium enhancement (LGE) were ascertained. Response to CRT was defined by a composite endpoint at 6 months: no death, nor hospitalization for major cardiovascular event, and a significant decrease in left ventricular end-systolic volume of 15% or more. Results Sixty-one patients were included (age 61 ± 5 years, ejection fraction 27 ± 5%), 59% with non-ischemic cardiomyopathy. At 6 months, 49 patients (80%) were considered responders. Responders had a lower percentage of LGE (8 ± 13% vs 22 ± 16%, p = 0.006), and a trend towards lower rates of galectin-3 (16 ± 6 ng/mL vs 19 ± 8 ng/mL, p = 0.13). LGE ≥ 14% and Gal-3 ≥ 22 ng/mL independently predicted response to CRT (OR = 0.17 [0.03–0.62], p = 0.007, and OR = 0.11 [0.02–0.04], p < 0.001, respectively). At 48 months of follow-up, 12 patients had been hospitalized for a major cardiovascular event or had died. Galectin-3 level predicted long-term outcomes (HR = 3.31 [1.00–11.34], p = 0.05). Conclusions Gal-3 serum level predicts the response to CRT at 6 months and long-term outcomes in chronic heart failure patients.

Implantable cardioverter-defibrillators (ICD) are meant to fight life-threatening ventricular arrhythmias and reduce overall mortality. Ironically, life-saving shocks themselves have been shown to be independently associated with an increased mortality. We sought to identify myocardial changes at the protein level immediately after ICD electrical shocks using a proteomic approach. ICD were surgically implanted in 10 individuals of a healthy male sheep model: a control group (N = 5) without any shock delivery and a shock group (N = 5) with the delivery of 5 consecutive shocks at 41 J. Myocardial tissue samples were collected at the right-ventricle apex near to the lead coil and at the right ventricle basal free wall region. Global quantitative proteomics experiments on myocardial tissue samples were performed using mass spectrometry techniques. Proteome was significantly modified after electrical shock and several mechanisms were associated: protein, DNA and membrane damages due to extreme physical conditions induced by ICD-shock but also due to regulated cell death; metabolic remodeling; oxidative stress; calcium dysregulation; inflammation and fibrosis. These proteome modifications were seen in myocardium both \"near\" and \"far\" from electrical shock region. N-term acetylated troponin C was an interesting tissular biomarker, significantly decreased after electrical shock in the \"far\" region (AUC: 0.93). Our data support an acute shock-induced myocardial tissue injury which might be involved in acute paradoxical deleterious effects such as heart failure and ventricular arrhythmias.

Management of antithrombotic therapy in patients with atrial fibrillation (AF) and coronary stenting remains challenging, and there is a need for efficient tools to predict their risk of different types of cardiovascular events and death. Several scores exist such as the CHA2DS2-VASc score, the Global Registry of Acute Coronary Events (GRACE) score, the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score, the Anatomical and Clinical Syntax II Score and the Reduction of Atherothrombosis for Continued Health score. These 5 scores were investigated in patients with AF with coronary stenting with the aim of determining which was most predictive for stroke/thromboembolic (TE) events, nonlethal coronary events, all-cause mortality, and major adverse cardiac events (MACE). Among 845 patients with AF with coronary stenting seen from 2000 to 2014, 440 (52%) were admitted for acute coronary syndrome and 405 (48%) for elective percutaneous coronary intervention. The rate of cardiovascular complication was at 14.1% per year, and nonlethal coronary events were the most frequent complications with a yearly rate of 6.5%. CHA2DS2-VASc score was the best predictor of stroke/TE events with a c-statistic of 0.604 (95% CI 0.567 to 0.639) and a best cut-off point of 5. SYNTAX score was better to predict nonlethal coronary events and MACE with c-statistics of 0.634 (95% CI 0.598 to 0.669) and 0.612 (95% CI 0.575 to 0.647), respectively, with a best cut-off point of 9. GRACE score appeared to be the best to predict all-cause mortality with a c-statistic of 0.682 (95% CI 0.646 to 0.717) and a best cut-off point of 153. In conclusions, among validated scores, none is currently robust enough to simultaneously predict stroke/TE events, nonlethal coronary events, death, and MACE in patients with AF with stents. The CHA2DS2-VASc score remained the best score to assess stroke/TE risk, as was the SYNTAX score for nonlethal coronary events and MACE, and finally, the GRACE score for all-cause mortality in this study population.

The benefit of implantable cardioverter-defibrillators (ICDs) remains controversial in elderly patients and may be attenuated by a greater risk of nonarrhythmic death. We examined the effect of age on outcomes after prophylactic ICD implantation. All patients with coronary artery disease or dilated cardiomyopathy implanted with an ICD for primary prevention of sudden cardiac death in 12 French medical centers were included in a retrospective observational study. The 5,534 ICD recipients were divided according to age: 18 to 59 years (n = 2,139), 60 to 74 years (n = 2,693), and ≥75 years (n = 702). Greater prevalences of coronary artery disease and atrial fibrillation at the time of implant were observed with increasing age (both p <0.0001). During a mean follow-up of 3.1 ± 2.0 years, the annual mortality rate increased with age: 3.1% per year for age 18 to 59 years, 5.7% per year for age 60 to 74 years, and 7.5% per year for age ≥75 years (p <0.001). Older age was independently associated with a greater risk of death (adjusted odds ratio 1.43, 95% confidence interval 1.14 to 1.80 for age 60 to 74 years; and adjusted odds ratio 1.65, 95% confidence interval 1.22 to 2.22 for age >75 years). Proportions of cardiac deaths (55.2%, 57.6%, and 57.0%, p = 0.84), including ICD-unresponsive sudden death (9.9%, 6.0%, and 10.6%, p = 0.08), and rates of appropriate ICD therapies were similar in the 3 age groups. Older age was independently associated with a higher rate of early complications and a lower rate of inappropriate therapies. In conclusion, older patients exhibited higher global mortality after ICD implantation for primary prevention, whereas rates of sudden deaths and of appropriate device therapies were similar across age groups.

Similar predisposing factors are found in most types of atrial arrhythmias. The incidence of atrial fibrillation (AF) among patients with atrial flutter is high, suggesting similar outcomes in patients with those arrhythmias. We sought to investigate the long-term outcomes and prognostic factors of patients with AF and/or atrial flutter with contemporary management using radiofrequency ablation. In an academic institution, we retrospectively examined the clinical course of 8,962 consecutive patients admitted to our department with a diagnosis of AF and/or atrial flutter. After a median follow-up of 934 ± 1,134 days, 1,155 deaths and 715 stroke and/thromboembolic (TE) events were recorded. Patients with atrial flutter undergoing cavotricuspid isthmus ablation (n = 875, 37% with a history of AF) had a better survival rate than other patients (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.25 to 0.49, p <0.0001). Using Cox proportional hazards model and propensity score model, after adjustment for main other confounders, ablation for atrial flutter was significantly associated with a lower risk of all-cause mortality (HR 0.55, 95% CI 0.36 to 0.84, p = 0.006) and stroke and/or TE events (HR 0.53, 95% CI 0.30 to 0.92, p = 0.02). After ablation, there was no significant difference in the risk of TE between patients with a history of AF and those with atrial flutter alone (HR 0.83, 95% CI 0.41 to 1.67, p = 0.59). In conclusion, in patients with atrial tachyarrhythmias, those with atrial flutter with contemporary management who undergo cavotricuspid isthmus radiofrequency ablation independently have a lower risk of stroke and/or TE events and death of any cause, whether a history of AF is present or not. •The impact of catheter ablation for typical atrial flutter on mortality and thromboembolic events is poorly known.•In patients with atrial arrhythmias, we found a lower mortality in patients with ablation for atrial flutter, even after adjusting for confounding factors.•Atrial flutter with cavotricuspid isthmus ablation was also associated with a lower risk of stroke.•These findings were similar in patients with atrial flutter and a history of atrial fibrillation.•Ablation for atrial flutter is thus effective to maintain sinus rhythm and likely to be associated with a better prognosis on clinical end points.

In some pathological conditions carnitine concentration is high while in others it is low. In both cases,cardiac arrhythmias can occur and lead to sudden cardiac death. It has been proposed that in ischaemia, acylcarnitine (acyl-CAR), but not carnitine, is involved in arrhythmias through modulation of ionic currents. We studied the effects of acyl-CARs on hERG, K(IR)2.1 and K(v)7.1/minK channels (channels responsible for I(KR), I(K1) and I(KS) respectively). HEK293 cells stably expressing hERG, K(IR)2.1 or Kv7.1/minK were studied using the patch clamp technique. Free carnitine (CAR) and acyl-CAR derivatives from medium- (C8 and C10) and long-chain (C16 and C18:1) fatty acids were applied intra- and extracellularly at different concentrations. For studies on hERG, C16 and C18:1 free fatty acid were also used. Extracellular long-chain (LCAC), but not medium-chain, acyl-CAR,induced an increase of I(hERG) amplitude associated with a dose-dependent speeding of deactivation kinetics. They had no effect on K(IR)2.1 or Kv7.1/minK currents.Computer simulations of these effects were consistent with changes in action potential profile. CONCLUSIONS AND APPLICATIONS: Extracellular LCAC tonically regulates I(hERG) amplitude and kinetics under physiological conditions. This modulation may contribute to the changes in action potential duration that precede cardiac arrhythmias in ischaemia, diabetes and primary systemic carnitine deficiency.