Eduard Guasch

Cardiac Arrhythmogenic Remodeling in a Rat Model of Long-Term Intensive Exercise Training

Background— Recent clinical studies suggest that endurance sports may promote cardiac arrhythmias. The aim of this study was to use an animal model to evaluate whether sustained intensive exercise training induces potentially adverse myocardial remodeling and thus creates a potential substrate for arrhythmias. Methods and Results— Male Wistar rats were conditioned to run vigorously for 4, 8, and 16 weeks; time-matched sedentary rats served as controls. Serial echocardiograms and in vivo electrophysiological studies at 16 weeks were obtained in both groups. After euthanasia, ventricular collagen deposition was quantified by histological and biochemical studies, and messenger RNA and protein expression of transforming growth factor-&bgr;1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I, and procollagen-III was evaluated in all 4 cardiac chambers. At 16 weeks, exercise rats developed eccentric hypertrophy and diastolic dysfunction, together with atrial dilation. In addition, collagen deposition in the right ventricle and messenger RNA and protein expression of fibrosis markers in both atria and right ventricle were significantly greater in exercise than in sedentary rats at 16 weeks. Ventricular tachycardia could be induced in 5 of 12 exercise rats (42%) and only 1 of 16 sedentary rats (6%; P=0.05). The fibrotic changes caused by 16 weeks of intensive exercise were reversed after an 8-week exercise cessation. Conclusions— In this animal model, we documented cardiac fibrosis after long-term intensive exercise training, together with changes in ventricular function and increased arrhythmia inducibility. If our findings are confirmed in humans, the results would support the notion that long-term vigorous endurance exercise training may in some cases promote adverse remodeling and produce a substrate for cardiac arrhythmias.

Role for MicroRNA-21 in atrial profibrillatory fibrotic remodeling associated with experimental postinfarction heart failure.

Background—Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI). Methods and Results—Large MIs (based on echocardiographic left ventricular wall motion score index) were created by left anterior descending coronary artery ligation in rats. Changes induced by MI versus sham controls were first characterized with echocardiography, histology, biochemistry, and in vivo electrophysiology. Additional MI rats were then randomized to receive anti–miR-21 (KD21) or scrambled control sequence (Scr21) injections into the left atrial myocardium. Progressive left ventricular enlargement, hypocontractility, left atrial dilation, fibrosis, refractoriness prolongation, and AF promotion occurred in MI rats versus sham controls. Atrial tissues of MI rats showed upregulation of miR-21, along with dysregulation of the target genes Sprouty-1, collagen-1, and collagen-3. KD21 treatment reduced atrial miR-21 expression levels in MI rats to values in sham rats, decreased AF duration from 417 (69–1595; median [Q1–Q3]) seconds to 3 (2–16) seconds (8 weeks after MI; P<0.05), and reduced atrial fibrous tissue content from 14.4±1.8% (mean±SEM) to 4.9±1.2% (8 weeks after MI; P<0.05) versus Scr21 controls. Conclusions—MI-induced heart failure leads to AF-promoting atrial remodeling in rats. Atrial miR-21 knockdown suppresses atrial fibrosis and AF promotion, implicating miR-21 as an important signaling molecule for the AF substrate and pointing to miR-21 as a potential target for molecular interventions designed to prevent AF.

Clinical and mechanistic issues in early repolarization of normal variants and lethal arrhythmia syndromes.

Early repolarization, involving ST-segment elevation and, sometimes, prominent J waves at the QRS-ST junction, has been considered a normal electrocardiographic variant for over 60 years. A growing number of case reports and case-control studies indicate that in some instances, early repolarization patterns are associated with increased risk of idiopathic ventricular fibrillation. Epidemiological evidence indicates a dose effect for the risk of cardiac and sudden death with the extent of J-point elevation. This paper reviews present knowledge regarding the epidemiology, presentation, therapeutic response, and mechanisms characteristic of early repolarization. We highlight major unanswered questions relating to our limited ability to determine which individuals with this common electrocardiographic variant are at risk for sudden death, our incomplete understanding of underlying mechanisms, the inadequate information regarding genetic determinants and therapeutic responses, and the unclear relationship between early repolarization and other conditions involving accelerated repolarization and sudden arrhythmic death such as Brugada and short-QT syndromes. This review paper intends to inform the practicing physician about important clinical issues and to stimulate investigators to address the many unresolved questions in this rapidly evolving field.

Efficacy of circumferential pulmonary vein ablation of atrial fibrillation in endurance athletes

Aims Long-term endurance sport practice has been increasingly recognized as a risk factor for lone atrial fibrillation (AF). However, data on the outcome of circumferential pulmonary vein ablation (CPVA) in endurance athletes are scarce. The aim of the study was to evaluate the efficacy of CPVA in AF secondary to endurance sport practice. Methods and results Patients submitted to CPVA answered a questionnaire about lifetime history of endurance sport practice. Endurance athletes were defined as those who engaged in >3 h per week of high-intensity exercise for at least the 10 years immediately preceding their AF diagnosis. A series of 182 consecutive patients was included (51 ± 11 years, 65% with paroxysmal AF, 81% men, 42 ± 6 mm mean left atrial diameter); 107 (59%) patients had lone AF, and 42 of them (23% of the study population) were classified as endurance athletes (lone AF sport group). Freedom from arrhythmia after a single CPVA was similar in the lone AF sport group compared with the remaining patients (P = 0.446). Left atrial size and long-standing AF were the only independent predictors for arrhythmia recurrence after ablation. Conclusion Circumferential pulmonary vein ablation was as effective in AF secondary to endurance sport practice as in other aetiologies of AF.

Expert consensus document: Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.

Emerging risk factors and the dose-response relationship between physical activity and lone atrial fibrillation: a prospective case-control study.

Abstract Aims The role of high-intensity exercise and other emerging risk factors in lone atrial fibrillation (Ln-AF) epidemiology is still under debate. The aim of this study was to analyse the contribution of each of the emerging risk factors and the impact of physical activity dose in patients with Ln-AF. Methods and results Patients with Ln-AF and age- and sex-matched healthy controls were included in a 2:1 prospective case–control study. We obtained clinical and anthropometric data transthoracic echocardiography, lifetime physical activity questionnaire, 24-h ambulatory blood pressure monitoring, Berlin questionnaire score, and, in patients at high risk for obstructive sleep apnoea (OSA) syndrome, a polysomnography. A total of 115 cases and 57 controls were enrolled. Conditional logistic regression analysis associated height [odds ratio (OR) 1.06 [1.01–1.11]], waist circumference (OR 1.06 [1.02–1.11]), OSA (OR 5.04 [1.44–17.45]), and 2000 or more hours of cumulative high-intensity endurance training to a higher AF risk. Our data indicated a U-shaped association between the extent of high-intensity training and AF risk. The risk of AF increased with an accumulated lifetime endurance sport activity ≥2000 h compared with sedentary individuals (OR 3.88 [1.55–9.73]). Nevertheless, a history of <2000 h of high-intensity training protected against AF when compared with sedentary individuals (OR 0.38 [0.12–0.98]). Conclusion A history of ≥2000 h of vigorous endurance training, tall stature, abdominal obesity, and OSA are frequently encountered as risk factors in patients with Ln-AF. Fewer than 2000 total hours of high-intensity endurance training associates with reduced Ln-AF risk.

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.

A proposal for new clinical concepts in the management of atrial fibrillation

Atrial fibrillation (AF) represents a growing public health burden. It is a complex condition, involving a number of etiologic factors and arrhythmia mechanisms associated with atrial remodeling. Greater understanding of these mechanisms may improve therapy. Current AF classification schemes are limited by simplicity. A number of risk factors predict AF onset, and additional factors are being evaluated in registry studies. Doppler imaging and Holter monitoring in high-risk patients to predict the onset of AF and progression from paroxysmal to permanent AF are promising. There is a need for a novel multifactorial classification model encompassing AF duration, symptoms, markers of atrial remodeling, and a risk score for AF onset, persistence, progression, and complications to guide treatment and prognostication. Preventing AF onset with upstream therapy is of great interest, but current data are conflicting. More study is needed to optimize rhythm control with antiarrhythmic drugs and targeted ablation to specific patient populations at an earlier stage. There is little consensus on optimal rate control and no information relating to optimum rate control in specific populations. This article highlights new concepts in AF and directions for future research.

Circumferential pulmonary vein ablation: does use of a circular mapping catheter improve results? A prospective randomized study.

BACKGROUND The best method for performing atrial fibrillation (AF) ablation is still under debate. The importance of using a circular mapping (CM) catheter for assessing isolation of the pulmonary vein (PV) antrum on the outcome of the procedure has not been clearly established. OBJECTIVE The purpose of this study was to evaluate whether use of a CM catheter improves the arrhythmia-free proportion after circumferential pulmonary vein ablation (CPVA). METHODS A series of 146 consecutive patients (83% males, age 53 +/- 10 years, 53% paroxysmal AF) were randomized to two ablation strategies. In both groups, ipsilateral PV encirclement was performed until disappearance or dissociation of the local electrogram within the surrounded area. In the first group, only the radiofrequency catheter was used to both map and ablate (CPVA group, n = 73). In the other group, a CM catheter was added to assess the electrical activity of the PV antrum (CPVA-CM group, n = 73). An ablation line along the left atrial roof was also created in all patients. RESULTS Procedural and fluoroscopic times were longer in the CPVA-CM group (P <.05). Severe procedure-related complications occurred in 1 (1.4%) patient in the CPVA group and in 3 (4.1%) patients in the CPVA-CM group (P = .317). After mean follow-up of 9 +/- 3 months, 31 (42.5%) patients in the CPVA group and 47 (64.4%) patients in the CPVA-CM group were arrhythmia-free without antiarrhythmic medication (P = .008). CONCLUSION Use of a CM catheter to ensure isolation of the PV antrum improved the success of CPVA but increased some procedural requirements.

Evolución de la mejora en los resultados y las complicaciones de la ablación por catéter de la fibrilación auricular: aprendizaje, técnicas y metodología

INTRODUCTION AND OBJECTIVES The outcomes of atrial fibrillation ablation procedures vary widely between different centers. Our objective was to analyze the results and complications of this procedure in our center and identify factors predicting the efficacy and safety of atrial fibrillation ablation. METHODS In total, 726 atrial fibrillation ablation procedures were performed in our center between 2002 and 2009. Beginning in January 2008, a protocol for anticoagulation and conscious sedation was systematically applied. Outcomes and complications could therefore be compared in 2 well-differentiated groups: group A included 419 procedures performed prior to 2008 and group B included 307 procedures completed after 2008 using the new protocol. RESULTS During an average follow-up of 8.7 months, 60.9% of patients were arrhythmia-free after one or repeat procedures. After only 1 procedure, the success rate was 41% and significantly higher in group B (51.6% vs 35.2% in group A; P=.001). There were 31 major complications (4.2%), 26 in group A (6.2%) and 5 in group B (1.6%) (P=.002). The implementation of the new protocol was an independent predictor of the absence of complications (odds ratio=0.406; 95% confidence interval, 0.214-0.769; P<.006). CONCLUSIONS Systematic application of an anticoagulation and conscious sedation protocol is associated with improved results and fewer complications of atrial fibrillation ablation. Factors not evaluated in the present study, such as operator experience and ongoing improvements in atrial fibrillation ablation technology, could have influenced these findings.