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Biomedical subjects

Ramon Brugada

Publications and source records attributed to Ramon Brugada.

At least 37 records · Page 2Linked to original sources
PubMed2005

Is atrial fibrillation a genetic disease?

Atrial fibrillation remains one of the most challenging arrhythmias for the clinician and basic researcher. Different approaches have been undertaken to improve its understanding; from the development of animal models to the analysis of genetic backgrounds in individuals with familial and acquired forms of the disease. In the last few years, a large body of evidence has shown that alterations in ionic currents are involved in the disease. However, it has not been until recently, with the genetic link between mutations in proteins responsible for these ionic currents and the familial disease, that we have been given the final evidence that atrial fibrillation can also be primarily an ion channelopathy. Despite the limited prevalence of the inherited diseases, it has been shown before that the knowledge gained in their study will be helpful in dealing with the most common acquired forms of the disease. Therefore, as data keep unraveling, clinicians can expect that soon better therapeutic and preventive options for atrial fibrillation will emerge from basic science.

Atrial Fibrillation↗
PubMed2004

Cryptic 5' splice site activation in SCN5A associated with Brugada syndrome.

The Brugada syndrome (BS) is characterized by ST segment elevation in the right precordial leads and sudden cardiac death. The disease is linked to mutations in SCN5A in approximately 20% of cases. We collected a large family with BS and have identified a novel intronic mutation. We performed the clinical, genetic, molecular and biophysical characterization of this disease-causing mutation. With direct sequencing we identified an intronic insertion of TGGG 5 bp from the end of the Exon 27 of SCN5A. For transcript analysis, we investigated Epstein-Barr-transformed lymphoblastoid cell lines from patients and controls. Total RNA was extracted and RT-PCR experiments were performed to analyze the splicing patterns in exon 27 and 28. We identified two bands, one of the expected size and the other which showed a 96 bp deletion in exon 27, leading to a 32 amino acid in-frame deletion involving segments 2 and 3 of Domain IV of the SCN5A protein. This finding indicates that the intronic mutation creates a cryptic splice site inside Exon 27. Biophysical analysis using whole-cell patch-clamp techniques showed a complete loss of function of the mutated channels when heterologously expressed. In summary, this is the first report of a dysfunctional sodium channel created by an intronic mutation giving rise to cryptic splice site activation in SCN5A in a family with the BS. The deletion of fragments of segments 2 and 3 of Domain IV leads to complete loss of function, consistent with the biophysical data found in several mutations causing BS.

Arrhythmias, Cardiac↗
PubMed2004

Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations.

BACKGROUND: The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial. METHODS AND RESULTS: We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3% (28:30), and 82.9% (34:41), respectively. Penetrance of the disease phenotype increased from 32.7% to 78.6% with the use of sodium channel blockers. In the absence of ST-segment elevation under baseline conditions, a prolonged P-R interval, but not incomplete right bundle-branch block or early repolarization patterns, indicates a high probability of an SCN5A mutation carrier. CONCLUSIONS: In families with Brugada syndrome, the data suggest that ajmaline testing is valuable in the diagnosis of SCN5A carriers. In the absence of ST-segment elevation at baseline, family members with first-degree atrioventricular block should be suspected of carrying the mutation. An ajmaline test is often the key to making the proper diagnosis in these patients.

Ajmaline↗
PubMed2004

Short QT syndrome: pharmacological treatment.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of various antiarrhythmic drugs at prolonging the QT interval into the normal range and preventing ventricular arrhythmias in patients with short QT syndrome. BACKGROUND: Short QT syndrome is a recently described genetic disease characterized by short QT interval, high risk of sudden death, atrial fibrillation, and short refractory periods. METHODS: Six patients with short QT syndrome, five of whom had received an implantable cardioverter-defibrillator (ICD) and one child, were tested with different antiarrhythmic drugs, including flecainide, sotalol, ibutilide, and hydroquinidine, to determine whether they could prolong the QT interval into the normal range and thus prevent symptoms and arrhythmia recurrences. RESULTS: Class IC and III antiarrhythmic drugs did not produce a significant QT interval prolongation. Only hydroquinidine administration caused a QT prolongation, which increased from 263 +/- 12 ms to 362 +/- 25 ms (calculated QT from 290 +/- 13 ms to 405 +/- 26 ms). Ventricular programmed stimulation showed prolongation of ventricular effective refractory period to > or =200 ms, and ventricular fibrillation was no longer induced. CONCLUSIONS: The ability of quinidine to prolong the QT interval has the potential to be an effective therapy for short QT patients. This is particularly important because these patients are at risk of sudden death from birth, and ICD implant is not feasible in very young children.

Adolescent↗
PubMed2004

Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A:.

INTRODUCTION: Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V(1) to V(3) of patients with structurally normal hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in SCN5A. METHODS AND RESULTS: We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in SCN5A. The R367H mutation failed to generate any current when heterologously expressed in HEK cells. CONCLUSION: Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false-positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome.

Adult↗
PubMed2004

Brugada syndrome: 12 years of progression.

Brugada syndrome is increasingly being recognized in clinical medicine. What started as an electrocardiographic curiosity has become an important focus of attention for individuals working in the different disciplines related to sudden cardiac death, from basic scientists to clinical cardiac electrophysiologists. In just 12 years, since the description of the disease, clinically relevant information is continuously being provided to physicians to help protect the individuals with Brugada syndrome to the best of our ability. And this information has been gathered thanks to the effort of hundreds of basic scientists, physicians and patients who continue to give their time, effort and data to help understand how the electrocardiographic pattern may cause sudden cardiac death. There are still many unanswered questions, both at the clinical and basic field. However, with the further collection of data, the longer follow-up and the continued interest from the basic science world we will have the necessary tools to the successful unraveling of the disease.

Arrhythmias, Cardiac↗
PubMed2003

Sudden death associated with short-QT syndrome linked to mutations in HERG.

BACKGROUND: Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. METHODS AND RESULTS: Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. CONCLUSIONS: We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.

Adult↗
PubMed2003

Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.

BACKGROUND: Patients with Brugada syndrome who were resuscitated from an episode of ventricular fibrillation are at high risk for recurrent sudden death. There is general agreement about the therapeutic strategy for these patients. Conversely, the prognosis and approach in patients with a diagnostic ECG but without a previous history of sudden cardiac death is controversial. We analyzed a large cohort of patients with Brugada syndrome without previous cardiac arrest to understand the determinants of prognosis. METHODS AND RESULTS: A total of 547 patients with an ECG diagnostic of Brugada syndrome and no previous cardiac arrest were studied. The mean age was 41+/-15 years, and 408 were male. The diagnostic ECG was present spontaneously in 391 patients. In the remaining 156 individuals, the abnormal ECG was noted only after the administration of an antiarrhythmic drug. One hundred twenty-four patients had suffered from at least 1 episode of syncope. During programmed ventricular stimulation, a sustained ventricular arrhythmia was induced in 163 of 408 patients. During a mean follow-up of 24+/-32 months, 45 patients (8%) suffered sudden death or documented ventricular fibrillation. Multivariate analysis identified the inducibility of a sustained ventricular arrhythmia (P<0.0001) and a history of syncope (P<0.01) as predictors of events. Logistic regression analysis showed that a patient with a spontaneously abnormal ECG, a previous history of syncope, and inducible sustained ventricular arrhythmias had a probability of 27.2% of suffering an event during follow-up. CONCLUSIONS: Individuals with Brugada syndrome and no previous cardiac arrest have a high risk of sudden death. Inducibility of ventricular arrhythmias and a previous history of syncope are markers of a poor prognosis.

Adolescent↗
PubMed2003

Brugada syndrome: 1992-2002: a historical perspective.

An intriguing new clinical entity characterized by ST-segment elevation in the right precordial electrocardiographic leads and a high incidence of sudden death in individuals with structurally normal hearts was described by Pedro and Josep Brugada in 1992. The past decade has witnessed an exponential rise in the number of reported cases and a dramatic proliferation of papers serving to define the clinical, genetic, cellular, ionic, and molecular aspects of this disease. The purpose of this brief review is to chronicle the historical highlights that have brought us to our present understanding of Brugada syndrome.

Bundle-Branch Block↗
PubMed2003

Natural history of Brugada syndrome: the prognostic value of programmed electrical stimulation of the heart.

INTRODUCTION: The prognostic value of electrophysiologic studies in individuals with the syndrome of right bundle branch block and ST segment elevation in precordial leads V1 to V3 (Brugada syndrome) remains controversial. Our previous data from 252 individuals with the syndrome suggested that programmed ventricular stimulation had a good overall accuracy to predict events. However, studies from independent investigators questioned our results. We report here the largest population with Brugada syndrome ever studied by programmed electrical stimulation of the heart. METHODS AND RESULTS: Four hundred forty-three individuals with an ECG diagnostic of Brugada syndrome were studied by programmed electrical stimulation of the heart. The diagnosis was made because of the classic ECG showing a coved-type ST segment elevation in precordial leads V1 to V3. Of the 443 individuals, 180 had developed spontaneous symptoms (syncope or aborted sudden cardiac death) and 263 were asymptomatic at the time the diagnosis was made. The ventricular stimulation protocol included a minimum of two basic pacing cycle lengths with two ventricular premature beats from the right ventricular apex. A sustained ventricular arrhythmia was induced in 217 cases (49%). Symptomatic patients were more frequently inducible [126/180 (70%)] than asymptomatic individuals [91/263 (34%); P = 0.0001]. Males were more frequently inducible than females (54% vs 32%, P < 0.0001). Inducible individuals had a longer HV interval than noninducible patients (50 +/- 12 msec vs 46 +/- 10 msec, P < 0.002). HV interval and number of premature beats needed to induce VF were not related to outcome. Inducibility was statistically a powerful predictor of arrhythmic events during follow-up. Sixty of 217 inducible patients (28%) had spontaneous ventricular fibrillation compared with 5 of 221 noninducible patients (2%; P = 0.0001). CONCLUSION: Inducibility of sustained ventricular arrhythmias during programmed ventricular stimulation of the heart is a good predictor of outcome in Brugada syndrome.

Adolescent↗
PubMed2002

Genetics and arrhythmias.

The availability of chromosomal markers that span the human genome and improved high-throughput technology for genotyping and sequencing have led to major advances against genetic diseases. Genes have been identified for several disorders responsible for arrhythmias and sudden death. These genes all encode ion channels and are referred to as channelopathy genes. Congenital long QT syndrome is caused by mutations in genes encoding sodium or potassium channels. Brugada syndrome, only recently described, is due to mutations in a sodium channel and is an important cause of sudden death, particularly in Southeast Asia. Familial polymorphic ventricular tachycardia is due to a defect in the ryanodine receptor. A locus mapped to 10q32 is responsible for familial atrial fibrillation. Treatments based on knowledge of the molecular defect are being implemented for long QT syndrome and will probably provide paradigms for targeted treatment of acquired arrhythmias.

Arrhythmias, Cardiac↗
PubMed2002

The cloning, genomic organization and tissue expression profile of the human DLG5 gene.

BACKGROUND: Familial atrial fibrillation, an autosomal dominant disease, was previously mapped to chromosome 10q22. One of the genes mapped to the 10q22 region is DLG5, a member of the MAGUKs (Membrane Associated Gyanylate Kinase) family which mediates intracellular signaling. Only a partial cDNA was available for DLG5. To exclude potential disease inducing mutations, it was necessary to obtain a complete cDNA and genomic sequence of the gene. METHODS: The Northern Blot analysis performed using 3' UTR of this gene indicated the transcript size to be about 7.2 KB. Using race technique and library screening the entire cDNA was cloned. This gene was evaluated by sequencing the coding region and splice functions in normal and affected family members with familial atrial fibrillation. Furthermore, haploid cell lines from affected patients were generated and analyzed for deletions that may have been missed by PCR. RESULTS: We identified two distinct alternately spliced transcripts of this gene. The genomic sequence of the DLG5 gene spanned 79 KB with 32 exons and was shown to have ubiquitous human tissue expression including placenta, heart, skeletal muscle, liver and pancreas. CONCLUSIONS: The entire cDNA of DLG5 was identified, sequenced and its genomic organization determined.

Journal Article↗
PubMed2002

Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.

Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST-segment elevation in leads V1-V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome. We screened patients with SUNDS for mutations in SCN5A, the gene known to cause Brugada syndrome, as well as genes encoding ion channels associated with the long-QT syndrome. Ten families were enrolled, and screened for mutations using single-strand DNA conformation polymorphism analysis, denaturing high-performance liquid chromatography and DNA sequencing. Mutations were identified in SCN5A in three families. One mutation, R367H, lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments of SCN5A. A second mutation, A735V, lies in the first transmembrane segment of domain II (DIIS1) close to the first extracellular loop between DIIS1 and DIIS2, whereas the third mutation, R1192Q, lies in domain III. Analysis of these mutations in Xenopus oocytes showed that the R367H mutant channel did not express any current and the likely effect of this mutation is to depress peak current due to the loss of one functional allele. The A735V mutant expressed currents with steady state activation voltage shifted to more positive potentials. The R1192Q mutation accelerated the inactivation of the sodium channel current. Both mutations resulted in reduced sodium channel current (I(Na)) at a time corresponding to the end of phase 1 of the action potential, as described previously in the Brugada syndrome. Based upon these observations we suggest that SUNDS and Brugada syndrome are phenotypically, genetically and functionally the same disorder.

Alleles↗
PubMed2002

Long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3.

BACKGROUND: The electrocardiographic pattern of right bundle-branch block with ST-segment elevation in leads V1 to V3 is increasingly recognized among patients who have aborted sudden cardiac death, but also in asymptomatic individuals, raising questions about its prognostic significance. METHODS AND RESULTS: The clinical, electrophysiological, and follow-up data of 334 patients with the Brugada phenotype were analyzed. A total of 79 women and 255 men with a mean age at diagnosis of 42+/-16 years were studied. The abnormal ECG was recognized after a resuscitated cardiac arrest in 71 patients (group A), after a syncopal episode in 73 patients (group B), and in 190 asymptomatic individuals (group C). Sustained ventricular arrhythmias were inducible in 83%, 63%, and 33% of patients in group A, group B, and group C, respectively. During 54+/-54 and 26+/-36 months of follow-up, respectively, 62% of patients in group A and 19% of group B patients had a new arrhythmic event. Inducibility of ventricular arrhythmias was the only predictor of arrhythmia occurrence in both groups. During a mean follow-up of 27+/-29 months, 8% of group C individuals had a first arrhythmic event. In these individuals, inducibility of ventricular arrhythmias and a basal abnormal ECG were predictors of arrhythmia occurrence. CONCLUSIONS: An ECG showing right bundle-branch block and ST-segment elevation in the right precordial leads is a marker of malignant ventricular arrhythmias and sudden death. Recurrence of malignant arrhythmias is high after the occurrence of symptoms. Among asymptomatic individuals, those with a spontaneously abnormal ECG and inducible to ventricular arrhythmias have the poorer prognosis.

Adult↗
PubMed2002

[Genetics and arrhythmias].

In the last 50 years we have been very successful at prolonging survival and improving the quality of life of patients with cardiac disease. The innovations in technology and pharmacology, better preventive and diagnostic tools have provided tremendous breakthroughs. However, despite our best efforts, the majority of cardiac diseases are structural in origin and will progress to their ultimate outcome. Curative therapies are not available due in part to our poor understanding of the basic mechanisms responsible for these diseases. The new developments in molecular genetics and biology are likely to change the way we approach a cardiac patient in the future. The diseases are presently being deciphered at the most basic level, and the information obtained opens new possibilities not only for better therapeutic and diagnostic measures but also for prevention of the disease.

Arrhythmias, Cardiac↗
PubMed2002

Novel mutations in domain I of SCN5A cause Brugada syndrome.

Brugada syndrome, an autosomal dominantly inherited form of ventricular fibrillation characterized by ST-segment elevation in leads V1-V3 and right bundle-branch block on surface electrocardiogram, is caused by mutations in the cardiac sodium channel gene SCN5A. Patients with Brugada syndrome were studied using single-strand conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing of SCN5A. Mutations were identified in SCN5A in two families and one sporadic case. In one family, a missense mutation leading to a glycine to valine substitution (G351V) in the pore region between the DIS5 and DIS6 transmembrane segments was detected. Biophysical analysis demonstrated that this mutation caused significant current reduction. In the other family, a 20-bp deletion of the exon 5 splice acceptor site was identified; as exon 5 encodes part of the intracellular loop between DIS2 and DIS3, this portion of the channel is disrupted. In the sporadic patient, a missense mutation resulting in the substitution of lysine by glutamic acid (K126E) in the intracellular loop at the boundary with DIS1 was identified. These three new SCN5A mutations in Brugada syndrome patients are all located within domain I of SCN5A, a region not previously considered important in the development of ventricular arrhythmias.

Animals↗