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R Brugada

Publications and source records attributed to R Brugada.

At least 37 records · Page 2Linked to original sources
PubMed2000

Role of molecular biology in identifying individuals at risk for sudden cardiac death.

Cardiology has participated in the new developments in molecular biology and the impact of the Human Genome Project. In these last few years, we have observed how the research in human physiology and journal publications have been focusing on the most basic molecular level. Clinicians have likely been having trouble keeping up with the new developments and, more importantly, with the highly publicized discoveries trying to discern what is research and what can already be applied at the bedside. Molecular biology has just started, and there is no doubt that it will have a tremendous impact in the diagnosis, prevention, and therapy of most diseases, including sudden death and cardiac arrhythmia. In the last few years, we have seen new data in the field of genetics and arrhythmia that are already shaping our approach to an inherited disease. Routine clinical tests are not yet available, mainly due to the lack of sufficiently powerful technology, but with the pace of evolution at this turn of the millennium, we can certainly assume that such testing is just a matter of time.

Arrhythmias, Cardiac↗
PubMed2000

Sudden death in high-risk family members: Brugada syndrome.

Brugada syndrome (an electrocardiographic pattern of right bundle branch block, ST segment elevation in leads V1 to V3, and sudden death) is genetically determined and caused by mutations in the cardiac ion channels. The mode of inheritance of the disease is autosomal dominant in half of familial forms. Sudden death may, however, occur from a variety of causes in relatives and patients with this syndrome. Twenty-five Flemish families with this syndrome with a total of 334 members were studied. Affected members were recognized by means of the typical electrocardiogram of the syndrome, either occurring spontaneously or after the intravenous administration of antiarrhythmic drugs. Sudden deaths in these families were classified as related or not to the syndrome by analysis of the data at the time of the event, mode of inheritance of the disease, and data provided by survivors. Of the 25 families with the syndrome, 18 were symptomatic (at least 1 sudden death related to the syndrome) and 7 were asymptomatic (no sudden deaths related to the syndrome). In total, there were 42 sudden cardiac deaths (12% incidence). Twenty-four sudden deaths were related to the syndrome and all happened in symptomatic families. Eighteen sudden deaths (43% of total sudden deaths) were not related to the syndrome (9 cases) or were of unclear cause (9 cases). Three of them occurred in 2 asymptomatic families and the remaining 15 in 5 symptomatic families. A total of 24 of the 50 affected members (47%) and 18 of the 284 unaffected members (6%) had aborted sudden death. This difference in the incidence of sudden death was statistically significant (p <0.0001). Patients with aborted sudden death caused by the syndrome were younger than patients with sudden death of other or unclear causes (38 +/- 4 years vs 59 +/- 3 years respectively; p = 0.0003). In families at high risk of sudden death because of genetically determined diseases, the main cause of sudden death remains the disease itself. However, almost half of sudden deaths are caused by unrelated diseases or from unclear causes. Accurate classification of the causes of sudden death is mandatory for appropriate analysis of the causes of death when designing preventive treatments.

Adolescent↗
PubMed2000

Construction of a high-resolution physical map of the chromosome 10q22-q23 dilated cardiomyopathy locus and analysis of candidate genes.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality and a leading cause of cardiac transplantation worldwide. Multiple loci and three genes encoding cardiac actin, desmin, and lamin A/C have been described for autosomal dominant DCM. Using recombination analysis, we have narrowed the 10q21-q23 locus to a region of approximately 4.1 cM. In addition, we have constructed a BAC contig, composed of 199 clones, which was used to develop a high-resolution physical map that contains the DCM critical region (approximately 3.9 Mb long). Seven genes, including ANX11, PPIF, DLG5, RPC155, RPS24, SFTPA1, and KCNMA1, have been mapped to the region of interest. RPC155, RPS24, SFTPA1, and KCNMA1 were excluded from further analysis based on their known functions and tissue-specific expression patterns. Mutational analysis of ANX11, DLG5, and PPIF revealed no disease-associated mutations. Multiple ESTs have also been mapped to the critical region.

Cardiomyopathy, Dilated↗
PubMed2000

Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts.

BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS: The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a SCN5A mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk.

Adult↗
PubMed2000

Genetic aspects of arrhythmias.

Advances in the treatment and prevention of heart disease have led to consistently declining morbidity and mortality rates over the past 30 years. Despite these advances, therapy remains largely palliative. The development of curative therapies is limited by our lack of knowledge of the basic mechanisms of disease. In the next decade, we will probably change many of these current approaches from treating the crisis to preventing the disease. Molecular biology and genetics have elucidated several basic pathways. It is hoped that targeted therapies will prevent or arrest many of these cardiac diseases, in particular, arrhythmias and sudden death. With the discovery of the genes causing familial diseases like long QT, hypertrophic cardiomyopathy, and Brugada syndrome, we have identified several substrates responsible for triggering malignant arrhythmias.

Adolescent↗
PubMed2000

The Brugada syndrome.

The Brugada syndrome is a hereditary disease causing sudden cardiac death in apparently healthy individuals with a structurally normal heart. The disease is caused by mutations in the cardiac sodium channel gene SCN5A. Patients with this disease have a peculiar electrocardiogram with elevation of the ST segment in leads V1 to V3, an electrocardiogram that every doctor should recognize. There exist variants of the electrocardiogram with minimal ST segment elevation and even concealed forms that can only be unmasked by the administration of class I antiarrhythmic drugs. When left untreated or when treated with all known antiarrhythmic drugs, patients with Brugada syndrome have a high mortality (approximately 10% per year). The only effective treatment to prevent sudden death is the implantable defibrillator.

Anti-Arrhythmia Agents↗
PubMed2000

[Sudden death (VI). The Brugada syndrome and right myocardiopathies as a cause of sudden death. The differences and similarities].

In 1992 we described a new syndrome characterized by syncopal or sudden death episodes in patients with a structurally normal heart and a characteristic electrocardiogram 9 showing a pattern of right bundle branch block and ST segment elevation in right precordial leads V1 to V3. The disease is genetically determined with and autosomic dominant pattern of transmission. Until now three mutations and one polymorphism in the sodium cardiac channel gene have been identified in two families and one sporadic patient. As in many other genetically determined diseases, the disease is heterogeneous, caused by more than one gene. The syndrome has been identified in almost all countries in the world. Its incidence is difficult to evaluate, but it seems to be responsible for 4 to 10 sudden deaths per year per 10,000 inhabitants in areas like Laos or Thailand, and it represents the most frequent cause of death in young male adults in these countries. Up to 50% of all sudden deaths in patients with structurally normal heart are caused by the disease. The diagnosis can be easily made thanks to the characteristic electrocardiographic pattern. In some patients, the presence of concealed and intermittent forms might make the diagnosis more difficult. The electrocardiogram can be modulated by autonomic changes and administration of antiarrhythmic drugs. Beta-adrenergic stimulation normalizes the electrocardiogram, whereas ajmaline, flecainide or procainamide administration increase ST segment elevation. These drugs allow the unmasking of concealed or intermittent forms of the disease. Prognosis of patients with the syndrome is poor without an implantable defibrillator and antiarrhythmic drugs like amiodarone or betablockers do not protect against sudden death. The poor prognosis is similar in patients with a history of aborted sudden death or syncope and in asymptomatic patients in whom the abnormal electrocardiogram characteristic of the syndrome, was identified during a routine examination.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed2000

Sudden death in patients and relatives with the syndrome of right bundle branch block, ST segment elevation in the precordial leads V(1)to V(3)and sudden death.

BACKGROUND: The syndrome with an electrocardiographic pattern of right bundle branch block, ST segment elevation in leads V(1)to V(3)and sudden death is genetically determined and caused by mutations in the cardiac sodium channel. The inheritance of the disease is autosomal dominant. Sudden death may, however, occur from a variety of causes in relatives and patients with this syndrome. PATIENTS AND METHODS: Twenty-five Flemish families with this syndrome with a total of 334 members were studied. Affected members were recognized by means of a typical electrocardiogram either occurring spontaneously or after the intravenous administration of antiarrhythmic drugs. Sudden deaths in these families were classified as related or not to the syndrome by analysis of the data at the time of the event, mode of inheritance of the disease, and data provided by survivors. Results Of the 25 families with the syndrome, 18 were symptomatic (at least one sudden death related to the syndrome) and seven were asymptomatic (no sudden deaths related to the syndrome). In total, there were 42 sudden cardiac deaths (12% incidence). Twenty-four sudden deaths were related to the syndrome and all occurred in symptomatic families. Eighteen sudden deaths (43% of total sudden deaths) were not related to the syndrome (nine cases) or were of unclear cause (nine cases). Three of them occurred in two asymptomatic families and the remaining 15 in five symptomatic families. Twenty-four of the 50 affected members (47%) suffered (aborted) sudden death and 18 of the 284 unaffected members (6%). This difference in the incidence of sudden death was statistically significant (P<0.0001). Patients with (aborted) sudden death caused by the syndrome were younger than patients with sudden death of other or unclear causes (38+/-4 years vs 59+/-3 years respectively, P=0.0003). CONCLUSIONS: In families at high risk of sudden death because of genetically determined diseases, the main cause of sudden death remains the disease. However, almost the half of sudden deaths are caused by unrelated diseases or are of unclear cause. Accurate classification of the causes of sudden death is mandatory for appropriate analysis of the causes of death when designing preventive treatments.

Adolescent↗
PubMed2000

A reply

Explore the source record for details and available documents.

Journal Article↗
PubMed2000

Pharmacological and device approach to therapy of inherited cardiac diseases associated with cardiac arrhythmias and sudden death.

A genetic origin in diseases like the long QT syndrome, the Brugada syndrome, or hypertrophic cardiomyopathy have been identified over the past years. These diseases have in common that they may result in sudden cardiac death of the patient. Recognition of patients based on their phenotype and application in clinical practice of the knowledge acquired on the genetic basis may have a major impact on how we approach them. In the long QT syndrome several mutations have been identified both in the sodium and in the potassium channels. The different electrophysiological effects of the mutations lead to a common phenotype: prolongation of the QT interval; but also to a common clinical impact: occurrence of malignant ventricular arrhythmias. Genetics should help us in treating in a more rational way our patients depending on the type of mutation. In the Brugada syndrome, mutations affecting the sodium channel have been so far identified. The results are electrophysiologically opposite to the ones observed in the long QT syndrome. Thus different mutations in the same gene lead to different functional consequences. Again, identification and study of the right mutation may lead to a more rational treatment directed to correct the malfunction of the channel.

Anti-Arrhythmia Agents↗
PubMed1999

Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.

The Brugada syndrome is a major cause of sudden death, particularly among young men of Southeast Asian and Japanese origin. The syndrome is characterized electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation. Our group recently linked the disease to mutations in SCN5A, the gene encoding for the alpha subunit of the cardiac sodium channel. When heterologously expressed in frog oocytes, electrophysiological data recorded from the Thr1620Met missense mutant failed to adequately explain the electrocardiographic phenotype. Therefore, we sought to further characterize the electrophysiology of this mutant. We hypothesized that at more physiological temperatures, the missense mutation may change the gating of the sodium channel such that the net outward current is dramatically augmented during the early phases of the right ventricular action potential. In the present study, we test this hypothesis by expressing Thr1620Met in a mammalian cell line, using the patch-clamp technique to study the currents at 32 degrees C. Our results indicate that Thr1620Met current decay kinetics are faster when compared with the wild type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 degrees C, and steady-state activation was significantly shifted. Our findings explain the features of the ECG of Brugada patients, illustrate for the first time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed only at temperatures approaching the physiological range, and suggest that some patients may be more at risk during febrile states.

Adult↗
PubMed1999

Use of the prophylactic implantable cardioverter defibrillator for patients with normal hearts.

About 10-20% of patients dying suddenly and unexpectedly do not have structural heart disease. The major causes of sudden death in this population are acute ischemia, the syndrome of right bundle branch block, and ST-elevation from V1 to V3, the long QT-syndrome, and the Wolff-Parkinson-While syndrome. In some patients, none of these syndromes can be recognized and ventricular fibrillation is classified as idiopathic. There are good preventive and therapeutic methods against acute ischemia and there are also curative treatments for the Wolff-Parkinson-White syndrome. Patients with idiopathic ventricular fibrillation cannot be recognized beforehand. However, there are electrocardiographic and genetic markers for the Brugada syndrome and the long QT syndrome. It is, therefore, justified to discuss the possible role of the prophylactic defibrillator to prevent sudden death in these 2 syndromes for which no effective treatment exists. Patients with Brugada syndrome have a high incidence of sudden death, and prophylactic defibrillators are indicated in patients with inducible arrhythmias at electrophysiologic study, irrespective of symptoms. On the contrary, the incidence of sudden death in the long QT syndrome is very low, making prophylactic defibrillator implantation not cost-effective.

Bundle-Branch Block↗
PubMed1999

Lipoprotein lipase gene mutations, plasma lipid levels, progression/regression of coronary atherosclerosis, response to therapy, and future clinical events. Lipoproteins and Coronary Atherosclerosis Study.

Mutations in human lipoprotein lipase (LPL) gene are potential risk factors for susceptibility to coronary artery disease (CAD). The objectives of this study were to determine the influence LPL mutations Asn291Ser and Ser447Ter on plasma lipid levels, regression and progression of CAD, clinical events rate, and response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. LCAS is a double blind, randomized, placebo-controlled study designed to test the influence of fluvastatin on progression or regression of CAD. The Asn291Ser and Ser447Ter genotypes were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. Fasting plasma lipid profiles were measured and quantitative coronary angiography was performed at baseline and 2.5 years following randomization. Fatal and non-fatal cardiovascular events during the follow-up period were recorded. A total of 4% (14/363) and 18% (62/352) of the subjects had the Asn291Ser and Ser447Ter mutations, respectively. Overall, there was no statistically association between the Asn291Ser and Ser447Ter mutations and the baseline or final mean plasma levels of lipids, number of coronary lesions, total occlusions, the mean minimal lumen diameter (MLD) stenoses and the clinical events rate. However, patients with the Ser447Ter variant had a slightly higher baseline high density lipoprotein-cholesterol (HDL-C) level (46.2 +/- 12 vs 43.2 +/- 11, P = 0.057), less increase in plasma HDL levels in response to fluvastatin therapy (3 vs 11%, P = 0.056) and a higher cardiovascular events rate (23 vs 13%, P = 0.056). Thus, the Ser447Ter variant had a modest influence on plasma HDL levels and the rate of cardiovascular events. These changes were of borderline statistical significance. Neither the Ser447Ter nor the Asn291Ser mutation had a major impact on susceptibility to CAD, progression or regression of CAD, clinical events rate or response to fluvastatin therapy in LCAS population.

Adult↗
PubMed1999

Genetics of cardiovascular disease with emphasis on atrial fibrillation.

Cardiology has embraced the techniques of molecular genetics later than other medical disciplines but is now completely submerged in the genetic mapping of cardiac diseases. The techniques of molecular biology, and in particular, their application to the genetics of inherited diseases, have brought the clinician and the scientist together in an unparalleled dependence. The chromosomal mapping of genes responsible for disease requires the identification of families with inherited diseases. This step involves the cooperation of the clinician. In order to continue improving our understanding of the molecular basis, it is imperative to raise the clinician awareness of the role of genetics in cardiac diseases. Arrhythmias can also have a familial origin and it is not generally appreciated that atrial fibrillation could be inherited. In the last two years, we have identified more than 100 families all over the world with individuals affected by the familial form of the disease. With the techniques of genetic mapping we have identified an area on chromosome 10 that carries a gene causing the disease in some of the families and there is ongoing research to identify the specific mutation. The clinician/scientist relationship has just started and the application of the discoveries in molecular genetics will probably have a direct role on how to approach medicine in the future, from prevention of diseases in patients carrying the susceptibility genes to gene therapy in those individuals with the disease.

Atrial Fibrillation↗
PubMed1999

The syndrome of right bundle branch block ST segment elevation in V1 to V3 and sudden death--the Brugada syndrome.

In 1992 a new syndrome was described consisting of syncopal episodes and/or sudden death in patients with a structurally normal heart and an electrocardiogram (ECG) characteristic of right bundle branch block with ST segment elevation in leads V1 to V3. The disease is genetically determined, with an autosomal dominant pattern of transmission. Three different mutations that affect the structure and function of the cardiac sodium channel gene SCN5A have been identified. Two mutations result in total loss of function of the sodium channel. The other mutation results in acceleration of the recovery of the sodium channel from inactivation. The incidence of the disease is difficult to estimate, but it causes 4 to 10 sudden deaths per 10000 inhabitants per year in areas like Thailand and Laos. In these countries, the disease represents the most frequent cause of death in young adults. Up to 50% of the yearly sudden deaths in patients with a structurally normal heart are caused by this syndrome. The diagnosis is easily made by means of the ECG. The presence of concealed and intermittent forms, however, make the diagnosis difficult in some patients. The ECG can be modulated by changes in autonomic balance and the administration of antiarrhythmic drugs. Beta-adrenergic stimulation normalizes the ECG, while intravenous ajmaline, flecainide or procainamide accentuate ST segment elevation and are capable of unmasking concealed and intermittent forms of the disease. Recent data suggest that loss of the action potential dome in the right ventricular epicardium but not the endocardium underlies ST segment elevation seen in the Brugada syndrome. Also, electrical heterogeneity within the right ventricular epicardium leads to the development of closely coupled extrasystoles via a phase 2 reentrant mechanism, which then precipitates ventricular tachycardia-ventricular fibrillation. Right ventricular epicardium is preferentially affected because of the predominance of transient outward current in this tissue. Antiarrhythmic drugs like amiodarone and beta-blockers do not prevent sudden death in symptomatic or asymptomatic individuals. Gene therapy may offer a cure in future years. Implantation of an automatic cardioverter-defibrillator is the only currently proven effective therapy.

Bundle-Branch Block↗
PubMed1999

Molecular biology and atrial fibrillation.

Atrial fibrillation remains one of the most challenging arrhythmias in cardiology. Despite the overall advance in the treatment of patients with cardiac dysrhythmias with the introduction of radiofrequency ablation, therapeutic options in atrial fibrillation have remained largely unchanged and aimed at controlling the heart rate and anticoagulation. New surgical and ablation compartmentalization techniques are being developed that are promising, but to date these techniques are still extremely laborious and available only to a handful of patients. Advances in genetics and molecular biology will likely give new insights into the development of the disease. Molecular biology research is presently focused into two main fields: 1) identification of the genes that cause familial forms of the disease, and 2) altered gene expression during the disease state. These studies are aimed at identifying not only the triggering factors in the acute form but also those that prolong the arrhythmia and convert it into a chronic form.

Animals↗
PubMed1999

A transgenic rabbit model for human hypertrophic cardiomyopathy.

Certain mutations in genes for sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). We have developed a transgenic rabbit model for HCM caused by a common point mutation in the beta-myosin heavy chain (MyHC) gene, R400Q. Wild-type and mutant human beta-MyHC cDNAs were cloned 3' to a 7-kb murine beta-MyHC promoter. We injected purified transgenes into fertilized zygotes to generate two lines each of the wild-type and mutant transgenic rabbits. Expression of transgene mRNA and protein were confirmed by Northern blotting and 2-dimensional gel electrophoresis followed by immunoblotting, respectively. Animals carrying the mutant transgene showed substantial myocyte disarray and a 3-fold increase in interstitial collagen expression in their myocardia. Mean septal thicknesses were comparable between rabbits carrying the wild type transgene and their nontransgenic littermates (NLMs) but were significantly increased in the mutant transgenic animals. Posterior wall thickness and left ventricular mass were also increased, but dimensions and systolic function were normal. Premature death was more common in mutant than in wild-type transgenic rabbits or in NLMs. Thus, cardiac expression of beta-MyHC-Q(403) in transgenic rabbits induced hypertrophy, myocyte and myofibrillar disarray, interstitial fibrosis, and premature death, phenotypes observed in humans patients with HCM due to beta-MyHC-Q(403).

Animals↗