Begoña Benito

Gender Differences in Clinical Manifestations of Brugada Syndrome

OBJECTIVESnWe sought to assess differences in phenotype and prognosis between men and women in a large population of patients with Brugada syndrome.nnnBACKGROUNDnA male predominance has been reported in the Brugada syndrome. No specific data are available, however, concerning gender differences in the clinical manifestations and their role in prognosis.nnnMETHODSnPatients with Brugada syndrome were prospectively included in the study. Data on baseline characteristics, electrocardiogram parameters before and after pharmacological test, and events in follow-up were recorded for all patients.nnnRESULTSnAmong 384 patients, 272 (70.8%) were men and 112 (29.2%) women. At inclusion, men had experienced syncope more frequently (18%) or aborted sudden cardiac death (6%) than women (14% and 1%, respectively, p = 0.04). Men also had greater rates of spontaneous type-1 electrocardiogram, greater ST-segment elevation, and greater inducibility of ventricular fibrillation (p < 0.001 for all). Conversely, conduction parameters and corrected QT intervals significantly increased more in women in response to sodium blockers (p = 0.03 and p = 0.001, respectively). During a mean follow-up of 58 +/- 48 months, sudden cardiac death or documented ventricular fibrillation occurred in 31 men (11.6%) and 3 women (2.8%; p = 0.003). The presence of previous symptoms was the most important predictor for cardiac events in men, whereas a longer PR interval was identified among those women with a greater risk in this series.nnnCONCLUSIONSnMen with Brugada syndrome present with a greater risk clinical profile than women and have a worse prognosis. Although classical risk factors identify male patients with worse outcome, conduction disturbances could be a marker of risk in the female population.

Síndrome de Brugada

El sindrome de Brugada, descrito por primera vez en 1992, se caracteriza por un patron electrocardiografico caracteristico en precordiales derechas y la predisposicion a presentar arritmias ventriculares y muerte subita. El sindrome de Brugada se incluye entre las canalopatias, trastornos electricos primarios que caracteristicamente no asocian cardiopatia estructural concomitante. En los ultimos anos, gracias a una intensa labor cientifica tanto basica como clinica, hemos podido identificar multiples mutaciones causales, y asimismo comprender cuales son los mecanismos implicados en la aparicion del fenotipo caracteristico y los determinantes del pronostico clinico en los pacientes. Sin embargo, todavia persisten multiples preguntas sin resolver que mantienen activa la investigacion sobre el tema. Este articulo revisa nuestro conocimiento actual sobre el sindrome de Brugada y trata de recoger los principales estudios basicos y clinicos que han contribuido mas significativamente a avanzar en nuestra comprension de esta enfermedad.

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.

A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation

BACKGROUNDnType 3 long-QT syndrome (LQT-3) is caused by gain-of-function mutations in the SCN5A encoding the cardiac sodium channel. Familial atrial fibrillation (AF), previously considered a potassium channelopathy, has recently been related to sodium genetic variants, both in isolated forms and in patients with underlying heart disease.nnnOBJECTIVEnThe purpose of this study was to describe the first family associating LQT-3 and AF due to a gain-of-function mutation in SCN5A and assess the usefulness of the sodium blocker flecainide in individuals with both phenotypes.nnnMETHODSnComplete family screening was performed after identifying a proband showing paroxysmal AF and a long QT interval suggestive of LQT-3. Secondary causes of AF were ruled out in all individuals. Flecainide was used in two patients for LQT-3 diagnosis and therapeutic treatment of AF. Genetic screening was performed by direct sequencing of the exons and exon-intron boundaries of SCN5A.nnnRESULTSnWe identified a three-generation family (eight members), all of them showing long QT intervals. Paroxysmal AF initiated between 20 and 35 years of age in all three adults. The flecainide test led to shortening of the QTc interval. Flecainide was also effective in acutely restoring sinus rhythm. A Y1795C mutation was identified in all members.nnnCONCLUSIONnThis is the first report showing an association of familial AF and LQT-3 due to a mutation in SCN5A. This finding provides further evidence of the role of SCN5A in AF. We also confirm the usefulness of flecainide in this particular complex phenotype, both as a diagnostic tool for LQT-3 and as an acute treatment for AF.

Determinants of atrial fibrillation in an animal model of obesity and acute obstructive sleep apnea

BACKGROUNDnObesity and obstructive sleep apnea (OSA) are risk factors for atrial fibrillation (AF), but the underlying mechanisms are poorly understood.nnnOBJECTIVEnThe purpose of this study was to assess the mechanisms underlying AF promotion by obesity and OSA in rat models.nnnMETHODSnZucker obese rats (ORs) and lean rats (LRs) were intubated and ventilated with air and 2% isoflurane. OSA was mimicked by stopping the ventilator and closing the airway for 40 seconds. For nonobstructive control periods, the protocol was repeated with an open airway. Fifteen seconds after apnea onset, AF susceptibility was tested with 6 atrial burst pacing cycles (25 Hz, 3 seconds, 1-second intercycle pauses).nnnRESULTSnAF was not inducible in ORs or LRs at baseline or in nonobstructive control periods. AF was induced in 24 of 28 ORs (85.7%) vs 5 of 18 LRs (27.8%) during obstructive apnea (P <.001). Negative intrathoracic pressure generation (esophageal pressure monitoring) was substantial during obstructive apnea. Echocardiography showed left ventricular hypertrophy with diastolic dysfunction in ORs. Obstructive apnea caused acute left atrial (LA) dilation, increasing LA diameter significantly more in ORs than in LRs. To clarify AF mechanisms, 24 AF-inducible ORs were divided into 4 groups: saline (n = 5), pharmacologic autonomic blockade (n = 7), respiratory muscle paralysis with rocuronium (n = 6), and inferior vena cava (IVC) balloon occlusion to unload the LA (n = 6). Balloon catheter-induced IVC occlusion prevented LA distension during obstructive apnea, leading to 83.3% AF prevention (P <.05). Rocuronium also was protective (66.7%), but autonomic blockade had smaller effects (42.9% prevention).nnnCONCLUSIONnObesity and acute obstructive apnea interacted to promote AF in this model. Forced inspiration-induced acute LA distension related to diastolic dysfunction may be an important component of the arrhythmogenic substrate for AF during OSA episodes in obese patients.

Left ventricular systolic dysfunction by itself does not influence outcome of atrial fibrillation ablation.

Aims The objective of the study was to analyse the influence of left ventricular (LV) ejection fraction (EF) on the outcomes of atrial fibrillation (AF) ablation after a first procedure. Pre-procedural predictors of recurrences after AF ablation can be useful for patient information and selection of candidates. The independent influence of LV systolic dysfunction on recurrence rate has not been studied. Methods and results A case–control study (1:1) was conducted with a total of 72 patients: 36 cases (depressed LVEF) and 36 controls (normal LVEF). Patients were matched by left atrial diameter (LAD), the presence of arterial hypertension, and other variables that might influence the results (age, gender and paroxysmal vs. persistent AF). There were no statistical differences in the variables used to perform the matching. Patients with depressed LVEF had higher LV end diastolic diameter (55.6 ± 6.2 vs. 52.4 ± 5.5, P = 0.03), higher LV end systolic diameter (40.3 ± 6.9 vs. 32.6 ± 4.3, P < 0.001), lower LVEF (41.4 ± 8.0 vs. 63.1 ± 5.5, P < 0.001) and were more likely to have structural heart disease. After a mean follow-up of 16 ± 13 months, survival analysis for AF recurrences showed no differences between patients with depressed vs. normal LVEF (50.0 vs. 55.6%, log rank = 0.82). Cox regression analysis revealed LAD to be the only variable correlated to recurrence [OR 1.11 (1.01–1.22), P = 0.03]. Analysis at 6 months showed a significant increase in LVEF (43.23 ± 7.61 to 51.12 ± 13.53%, P = 0.01) for the case group. Conclusion LV systolic dysfunction by itself is not a predictor of outcome after AF ablation. LAD independently correlates with outcome in patients with low or normal LVEF.

Increase in sudden death from coronary artery disease in young adults

BACKGROUNDnSudden cardiac death (SCD) is the most common cause of death in adults aged <65 years, making it a major public health problem. A growing incidence in coronary artery disease (CAD) in young individuals has been predicted in developed countries, which could in turn be associated with an increase in SCD in this population. The aim of the study was to assess the prevalence of CAD among autopsies of young individuals (<40 years) who had sudden death (SD).nnnMETHODSnWe selected all the autopsies referred to the Montreal Heart Institute and Maisonneuve-Rosemont Hospital from January 2002 to December 2006 that corresponded to individuals <40 years old who had died suddenly. For each decedent, the following data were collected: cause of death, autopsy findings, available clinical history, toxicological findings, and cardiovascular risk factors.nnnRESULTSnFrom a total of 1,260 autopsies, 243 fulfilled the inclusion criteria. Coronary artery disease was the main cause of SCD from age 20 years, representing the 37% of deaths in the group of 21 to 30 years old, and up to 80% of deaths in the group of 31 to 40 years old. Among individuals who died of CAD, 3-vessel disease was observed in 39.7% of cases. Moreover, among the whole population <40 years old, at least 1 significant coronary lesion was observed in 39.5% of cases, irrespective to the cause of death. In the multivariable analysis, an increased BMI (hazard ratio 1.1 for each kg/m(2), 95% CI 1.01-1.1) and hypercholesterolemia (hazard ratio 2.4, 95% CI 1.7-333.3) showed to be the modifiable factors related to an increased risk of SD from CAD.nnnCONCLUSIONSnIn our population, CAD was the main cause of SD from age 20 years. These data bring into question whether present prevention strategies are sufficient and reinforce the need to extend prevention to younger ages.

Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Barahona‐Dussault C, Benito B, Campuzano O, Iglesias A, Leung TL, Robb L, Talajic M, Brugada R. Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model

Rationale Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise. Objective This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise. Methods and Results Male Wistar rats were randomly distributed into 4 experimental groups: Exercise, Exercise plus losartan, Sedentary and Sedentary plus losartan. Exercise groups were conditioned to run vigorously for 16 weeks. Losartan was orally administered daily before each training session (50 mg/kg/day). Time-matched sedentary rats served as controls. After euthanasia, heart hypertrophy was evaluated by histological studies; ventricular collagen deposition was quantified by histological and biochemical studies; and messenger RNA and protein expression of transforming growth factor-β1, fibronectin-1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, procollagen-I and procollagen-III was evaluated in all 4 cardiac chambers. Daily intensive exercise caused hypertrophy in the left ventricular heart wall and originated collagen deposition in the right ventricle. Additionally long-term intensive exercise induced a significant increase in messenger RNA expression and protein synthesis of the major fibrotic markers in both atria and in the right ventricle. Losartan treatment was able to reduce all increases in messenger RNA expression and protein levels caused by exercise, although it could not completely reverse the heart hypertrophy. Conclusions Losartan treatment prevents the heart fibrosis induced by endurance exercise in training animals.

Sleep Disordered Breathing in Patients with the Brugada Syndrome

We investigated breathing patterns and the occurrence of arrhythmias and ST-segment changes during sleep in patients with Brugada syndrome. Patients with Brugada syndrome are more likely to die from ventricular arrhythmias during sleep. ST-segment changes have been correlated with risk of sudden cardiac death. Whether sleep disturbances may contribute to arrhythmogenesis is unknown. Patients with Brugada syndrome underwent overnight polysomnography with simultaneous 12-lead electrocardiographic recording. A control group matched by age, gender, and body mass index (BMI) also underwent polysomnography. Twenty patients were included (50 ± 15 years old, 75% men). Despite their normal BMI (24.7 ± 2.7 kg/m(2)), 45% had sleep-disordered breathing (SDB), with a mean apnea-hypopnea index of 17.2 ± 14 events/hour. In patients with a high risk of arrhythmias, 5 (63%) had SDB. In the control group, 27% had SDB. Atrial or ventricular arrhythmias were not observed. Spontaneous ST-segment changes occurred in 2 patients over 45 different time points. Most ST-segment changes were observed during rapid eye movement sleep (31%) or within 1 minute of arousals (44%). Regarding respiratory events, 25 (56%) of ST-segment changes were related to occurrence of apnea or hypopnea. In conclusion, patients with Brugada syndrome have a high prevalence of SDB even in the setting of normal BMI. The higher incidence of nocturnal death in patients with Brugada syndrome may be conceivably related to co-morbid SDB. Moreover, autonomic instability encountered in rapid eye movement sleep and arousals could potentiate the risk of arrhythmias.