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Biomedical subjects

Josep Brugada

Publications and source records attributed to Josep Brugada.

At least 19 recordsLinked to original sources
PubMed2006

Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada syndrome.

BACKGROUND: Loss-of-function mutations in SCN5A have been associated with the Brugada syndrome. We report the first Brugada syndrome family with compound heterozygous mutations in SCN5A. The proband inherited 1 mutation from each parent and transmitted 1 to each daughter. METHODS AND RESULTS: The effects of the mutations on the function of the sodium channel were evaluated with heterologous expression in TSA201 cells, patch-clamp study, and confocal microscopy. Genetic analysis revealed that the proband carried 2 heterozygous missense mutations (P336L and I1660V) on separate alleles. He displayed a coved-type ST-segment elevation and a prolonged PR interval (280 ms). One daughter inherited P336L and exhibited a prolonged PR (210 ms). The other daughter inherited mutation I1660V and displayed a normal PR interval. Both daughters had a slightly elevated, upsloping ST-segment elevation. The parents had normal ECGs. Patch-clamp analysis showed that the P336L mutation reduced I(Na) by 85% relative to wild type. The I1660V mutation produced little measurable current, which was rescued by room temperature incubation for 48 hours. Sodium channel blockers also rescued the I1660V current, with mexiletine proving to be the most effective. Confocal immunofluorescence showed that I1660V channels conjugated to green fluorescent protein remained trapped in intracellular organelles. CONCLUSIONS: Mutation P336L produced a reduction in cardiac I(Na), whereas I1660V abolished it. Only the proband carrying both mutations displayed the Brugada syndrome phenotype, whereas neither mutation alone produced the clinical phenotype. I1660V channels could be rescued pharmacologically and by incubation at room temperature. The present data highlight the role of compound heterozygosity in modulating the phenotypic expression and penetrance of Brugada syndrome.

Brugada Syndrome↗
PubMed2006

Electrocardiogram interpretation and class I blocker challenge in Brugada syndrome.

Brugada syndrome is characterized by the presence of an electrocardiographic pattern of ST-segment elevation in leads V1 to V3 and a history of sudden cardiac death in the absence of structural heart disease [Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol 1992;20(6):1391]. The disease usually affects individuals in their 40s, at the prime of their life, and the appearance of cardiac arrest in these otherwise healthy individuals brings an important burden to families and to health care. Brugada syndrome is in several instances a familial disease, caused by mutations in SCN5A in up to 25% of the individuals [Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392(6673):293]. The identification of the electrocardiographic pattern in an individual will therefore trigger an important cascade of events in the families. Several family members, including children, will be under the scrutiny of a cardiologist to decide on preventive measures, especially if there is a history of sudden death in the family. The presence of abnormal repolarization patterns, which in otherwise sporadic individuals might be classified under normal variations, have become a diagnostic challenge for clinicians facing a family with the disease [Hong K, Brugada J, Oliva A, Berruezo-Sanchez A, Potenza D, Pollevick GD, et al. Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation 2004;110(19):3023].

Bundle-Branch Block↗
PubMed2006

Relation of response to cardiac resynchronization therapy to left ventricular reverse remodeling.

Cardiac resynchronization therapy (CRT) reverses left ventricular (LV) remodeling in patients with congestive heart failure. However, the mechanisms leading to the clinical response to CRT remain unclear. The aim of this study was to analyze whether patients who improve clinically have greater LV reverse remodeling than nonresponders after a 12-month follow-up period. The sample comprised 64 consecutive patients with heart failure, complete left bundle branch block, and LV ejection fractions (EFs) < or =35% who were treated with CRT. Doppler echocardiographic scans were taken just before and immediately after the implantation of the pacemakers and at 6- and 12-month follow-up examinations. LV diameters, volumes, and EFs were compared. Responders were defined as those patients who were alive without cardiac transplantation and with > or =10% improvement in the 6-minute walking test after 1 year of follow-up. There were no clinical differences at baseline between responders and nonresponders. At 6- and 12-month follow-up, LV dimensions decreased significantly in responders but did not change in nonresponders. Furthermore, LVEFs improved only in responders. In conclusion, patients who clinically respond to CRT have greater LV reverse remodeling than nonresponders after 6 and 12 months of follow-up. The effect of CRT on LV remodeling may explain, at least in part, the clinical benefit of this therapy.

Aged↗
PubMed2006

Recurrent syncope: an unusual presentation of Brugada syndrome.

BACKGROUND: A 55-year-old man presented at hospital with recurrent syncope. He did not have any prodromic symptoms and did not report having palpitations, dizziness or chest pain before, during or after the syncopal episodes. He had no family history of either syncope or sudden cardiac death. The patient was initially diagnosed with carotid sinus hypersensitivity and received a dual-chamber, rate-modulated pacemaker. Several months later, he presented at hospital again having had two more syncopal episodes. INVESTIGATIONS: Physical examination, electrocardiography, echocardiography, cerebral CT scan, and carotid sinus massage. DIAGNOSIS: Syncope associated with Brugada syndrome. MANAGEMENT: Implantation of a cardioverter-defibrillator.

Bundle-Branch Block↗
PubMed2006

Anodal capture in cardiac resynchronization therapy implications for device programming.

INTRODUCTION: Right ventricular (RV) anodal capture (AC) has been reported in cardiac resynchronization therapy (CRT), when left ventricular (LV) pacing uses pseudobipolar (LV tip to RV proximal electrode) configuration. The aim of the study was to analyze the prevalence of AC and its implications for device programming. METHODS AND RESULTS: When AC occurred, the resulting QRS morphology was evaluated with the following pacing modes: (1) LV tip pacing plus RV AC, (2) Biventricular (BiV) pacing (i.e., both LV and RV tip pacing), and (3) BiV pacing plus RV AC. Several interventricular pacing (VV) intervals from 50 ms of LV preactivation to 30 ms of RV preactivation were tested in modes 2 and 3. From 38 consecutive patients, AC was achieved in 14 (in 74% of the pacemakers and in none of the defibrillators). LV tip pacing plus RV AC obtained narrower QRS than BiV pacing at all VV intervals in seven of the patients with AC (50%). When BiV pacing is combined with RV AC, it produced a ventricular depolarization through two wave fronts (one from the LV tip and the second from either the ring or the tip of the RV lead depending on the VV interval programmed). CONCLUSIONS: AC obtained the narrowest QRS of all tested pacing modes in a significant proportion of patients undergoing CRT. Though the stimulus was delivered from three sites (BiV pacing plus RV AC mode), only two wave fronts of ventricular activation were seen by ECG.

Aged↗
PubMed2006

Familial pseudo-Wolff-Parkinson-White syndrome.

INTRODUCTION: PRKAG2 plays a role in regulating metabolic pathways, and mutations in this gene are associated with familial ventricular preexcitation, hypertrophic cardiomyopathy, and atrioventricular conduction disturbances. Clinico-pathologic and experimental data suggest the hypothesis of a glycogen storage disease. OBJECTIVE: To report a unique pattern of clinical features observed in individuals with a mutant PRKAG2 from two unrelated families. METHODS AND RESULTS: We studied two large families and found a total of 20 affected individuals showing a combination of sinus bradycardia, short PR interval, RBBB, intra and infrahisian conduction disturbances often requiring a pacemaker, and atrial tachyarrhythmias. Three individuals died suddenly at a young age. No patient had the Wolff-Parkinson-White (WPW) syndrome, and only two patients (10%) had myocardial hypertrophy. We performed screening of the exons and exon-intron boundaries of PRKAG2. Genetic analysis revealed a missense mutation (Arg302Gln) in the affected individuals from both families. This mutation had been described before and has been associated with the familial form of the WPW syndrome and with a high prevalence of left ventricular hypertrophy. CONCLUSION: PRKAG2 mutations are responsible for a diverse phenotype and not only the familial form of the WPW syndrome. Familial occurrence of right bundle branch block, sinus bradycardia, and short PR interval should raise suspicion of a mutant PRKAG2 gene.

Adult↗
PubMed2005

Potential proarrhythmic effects of biventricular pacing.

Resynchronization therapy involving right ventricular endocardial and left ventricular epicardial pacing improves cardiac output, quality of life, and New York Heart Association functional class in patients with congestive heart failure. Although a great deal of attention has been directed at showing the mechanical benefits and in fine-tuning the biventricular pacing configuration and protocol, little attention has been focused on the consequences of reversing the direction of activation of the left ventricular wall. Recent basic science and clinical studies have shown a proarrhythmic effect of reversing the direction of activation of the left ventricular wall. Reversal of the normal activation sequence prolongs the QT interval and increases the existing transmural dispersion of repolarization, creating the substrate and trigger for re-entrant arrhythmias under long QT conditions. A number of case reports of R-on-T extrasystoles and ventricular tachyarrhythmia induction as a result of biventricular pacing support this observation, and raise concern that biventricular pacing may be proarrhythmic in select cases, particularly when associated with a prolonged QT interval. Our focus in this review is on current understanding of transmural heterogeneity of repolarization that exists across the left ventricular wall, how this dispersion of repolarization is amplified as a consequence of reversal of the normal activation sequence, and how these basic experimental findings may apply to patients receiving cardiac resynchronization therapy.

Animals↗
PubMed2005

De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero.

OBJECTIVE: We describe a genetic basis for atrial fibrillation and short QT syndrome in utero. Heterologous expression of the mutant channel was used to define the physiological consequences of the mutation. METHODS: A baby girl was born at 38 weeks after induction of delivery that was prompted by bradycardia and irregular rythm. ECG revealed atrial fibrillation with slow ventricular response and short QT interval. Genetic analysis identified a de novo missense mutation in the potassium channel KCNQ1 (V141M). To characterize the physiological consequences of the V141M mutation, Xenopus laevis oocytes were injected with cRNA encoding wild-type (wt) KCNQ1 or mutant V141M KCNQ1 subunits, with or without KCNE1. RESULTS: Ionic currents were recorded using standard two-microelectrode voltage clamp techniques. In the absence of KCNE1, wtKCNQ1 and V141M KCNQ1 currents had similar biophysical properties. Coexpression of wtKCNQ1+KCNE1 subunits induced the typical slowly activating and voltage-dependent delayed rectifier K(+) current, I(Ks). In contrast, oocytes injected with cRNA encoding V141M KCNQ1+KCNE1 subunits exhibited an instantaneous and voltage-independent K(+)-selective current. Coexpression of V141M and wtKCNQ1 with KCNE1 induced a current with intermediate biophysical properties. Computer modeling showed that the mutation would shorten action potential duration of human ventricular myocytes and abolish pacemaker activity of the sinoatrial node. CONCLUSIONS: The description of a novel, de novo gain of function mutation in KCNQ1, responsible for atrial fibrillation and short QT syndrome in utero indicates that some of these cases may have a genetic basis and confirms a previous hypothesis that gain of function mutations in KCNQ1 channels can shorten the duration of ventricular and atrial action potentials.

Action Potentials↗
PubMed2005

Sport practice and the risk of lone atrial fibrillation: a case-control study.

BACKGROUND: Lone atrial fibrillation (LAF) is characterized by the presence of atrial fibrillation in the absence of structural heart disease or other identifiable cause of arrhythmia. In a recent study, we reported sport practice to be more frequent in LAF patients than in the general population. The aim of the study was to determine the association between sport practice and the prevalence of LAF in men. METHODS: An age-matched case-control study was designed. Cases were identified from consecutive patients who attended an outpatient clinic; 51 men with LAF were included, 20 of them with vagal characteristics. Controls were selected from the general population (n=109). A questionnaire to assess former and current sport practice and the number of lifetime hours of sport practice was administered. Conditional logistic regression was used for statistical analysis. RESULTS: The proportion of patients with LAF who reported current sport practice (31%) was higher than that observed in controls (14%). In the logistic regression, current practice of sport was associated with a higher prevalence of LAF (OR=3.13; 95% CI: 1.39-7.05). The practice of more than 1500 lifetime hours of sport appears to be the threshold for the observed association. Current practice of sport with a lifetime practice greater than 1500 h was associated with LAF (OR=2.87; 95% CI: 1.20-6.91). CONCLUSION: In men, the combination of current and prolonged lifetime sport practice is associated with higher risk of LAF.

Adult↗
PubMed2005

Predictors of lack of response to resynchronization therapy.

About 30% of patients treated with cardiac resynchronization therapy (CRT) do not respond to treatment. The aim of this study was to identify clinical predictors of lack of improvement in patients receiving CRT. From 197 consecutive patients scheduled to receive CRT, 143 fulfilled the inclusion criteria. Mean age was 68 +/- 7 years and 79% were men. Heart failure was due to ischemic heart disease in 49 patients (34%). Mean QRS duration was 165 +/- 26 ms, and left ventricular ejection fraction was 27 +/- 7%. Nonresponder patients were defined as those who died of heart failure, underwent heart transplantation, or did not increase the distance walked in 6 minutes >10%. At 6-month follow-up, there were 28 nonresponders (20%). Among nonresponders, 2 patients received a heart transplantation and 9 patients died of heart failure. In logistic regression analysis, independent predictors of lack of response to CRT were ischemic heart disease (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.2 to 7; p = 0.023), severe mitral regurgitation (OR 3.5, 95% CI 1.3 to 9; p = 0.014), and left ventricular end-diastolic diameter > or =75 mm (OR 3.1, 95% CI 1.1 to 8; p = 0.026). Patients with these 3 predictors had a probability response of 27%.

Aged↗
PubMed2005

Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.

Since its introduction as a clinical entity in 1992, the Brugada syndrome has progressed from being a rare disease to one that is second only to automobile accidents as a cause of death among young adults in some countries. Electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. Patients with a spontaneously appearing Brugada ECG have a high risk for sudden arrhythmic death secondary to ventricular tachycardia/fibrillation. The ECG manifestations of Brugada syndrome are often dynamic or concealed and may be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hypo- and hyperkalemia, hypercalcemia, and alcohol and cocaine toxicity. In recent years, an exponential rise in the number of reported cases and a striking proliferation of articles defining the clinical, genetic, cellular, ionic, and molecular aspects of the disease have occurred. The report of the first consensus conference, published in 2002, focused on diagnostic criteria. The present report, which emanated from the second consensus conference held in September 2003, elaborates further on the diagnostic criteria and examines risk stratification schemes and device and pharmacological approaches to therapy on the basis of the available clinical and basic science data.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2005

Incidence of pulmonary vein stenosis in patients submitted to atrial fibrillation ablation: a comparison of the Selective Segmental Ostial Ablation vs the Circumferential Pulmonary Veins Ablation.

INTRODUCTION: Pulmonary vein (PV) stenosis is an important complication of the AF ablation and could be underestimated if their assessment is not systematically done. Selective Segmental Ostial Ablation (SSOA) and Circunferential Pulmonary Veins Ablation (CPVA) have demonstrated efficacy in atrial fibrillation (AF) treatment. In this study the real incidence of PV stenosis in patients (pts) submitted to both SSOA and CPVA was compared. METHODS: Those pts with focal activity and normal left atrial size were submitted to SSOA, remaining pts were submitted to CPVA to treat refractory, symptomatic AF. Contrast enhanced magnetic resonance angiography (MRA) was routinely performed in all patients 4 months after the procedure. RESULTS: A series of 73 consecutive patients (mean age of 51 +/- 11 years; 75% male) were included. SSOA was performed in 32 patients, and the remaining 41 patients underwent to CPVA, obtaining similar efficacy rates (72% vs 76% arrythmia free probability at 12 months; log rank test p = NS). Six patients had a significant PV stenosis, all in SSOA group none in CPVA group (18.8% vs 0%; p = 0.005). All patients were asymptomatic and the stenosis was detected in routine MRA. No predictors of stenosis has been identified analysing patient procedure characteristics. CONCLUSION: PV stenosis is a potential complication of SSOA not seen in CPVA. The study confirms than MRA is useful for identifying patients with asymptomatic PV stenosis.

Atrial Fibrillation↗
PubMed2005

Brugada syndrome: from cell to bedside.

Since its introduction as a new clinical entity in 1992, the Brugada syndrome has attracted great interest because of its high incidence in many parts of the world and its association with high risk for sudden death in infants, children, and young adults. Recent years have witnessed an exponential rise in the number of reported cases and a striking proliferation of articles serving to define the clinical, genetic, cellular, ionic, and molecular aspects of the disease. A consensus report published in 2002 delineated diagnostic criteria for the syndrome. A second consensus conference was held in September 2003. This review provides an in-depth overview of the clinical, genetic, molecular, and cellular aspects of the Brugada syndrome, incorporating the results of the two consensus conferences, and the numerous clinical and basic publications on the subject. The proposed terminology, diagnostic criteria, risk stratification schemes, and device and pharmacologic approach to therapy discussed are based on available clinical and basic studies and should be considered a work-in-progress that will without doubt require fine-tuning as confirmatory data from molecular studies and prospective trials become available.

Arrhythmogenic Right Ventricular Dysplasia↗