The puzzle behind electrical chaos and sudden cardiac death in the structurally normal heart.
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Death, Sudden, Cardiac↗
Biomedical subjects
R Brugada
Publications and source records attributed to R Brugada.
[Brugada syndrome].
In 1992 we described a new syndrome consisting of syncopal episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram displaying a pattern resembling right bundle branch block with an ST segment elevation in leads V1 to V3. In 1998 it was described that the disease is genetically determined with an autosomal dominant pattern of transmission. Three different mutations have been identified. All three mutations affect the structure and the function of the sodium channel SCN5A. 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 disease causes 4 to 10 sudden deaths per 10,000 inhabitants per year in areas like Thailand and Laos. Up to 50% of the yearly sudden deaths in patients with a normal heart might be caused by this syndrome. The diagnosis is easily made by means of the electrocardiogram (ECG). The presence of concealed and intermittent forms, however, makes 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 normalises the ECG, while i.v. ajmaline, flecainide or procainamide accentuate the ST segment elevation and are capable of unmasking concealed and intermittent forms of the disease. The prognosis is poor for patients who do not receive an implantable cardioverter-defibrillator. Antiarrhythmic drugs like amiodarone or beta-blockers do not prevent sudden death in symptomatic or asymptomatic individuals.
Bundle-Branch Block↗
Dominant-negative effect of a mutant cardiac troponin T on cardiac structure and function in transgenic mice.
Hypertrophic cardiomyopathy (HCM) is a disease of sarcomeric proteins. The mechanism by which mutant sarcomeric proteins cause HCM is unknown. The leading hypothesis proposes that mutant sarcomeric proteins exert a dominant-negative effect on myocyte structure and function. To test this, we produced transgenic mice expressing low levels of normal or mutant human cardiac troponin T (cTnT). We constructed normal (cTnT-Arg92) and mutant (cTnT-Gln92) transgenes, driven by a murine cTnT promoter, and produced three normal and five mutant transgenic lines, which were identified by PCR and Southern blotting. Expression levels of the transgene proteins, detected using a specific antibody, ranged from 1 to 10% of the total cTnT pool. M-mode and Doppler echocardiography showed normal left ventricular dimensions and systolic function, but diastolic dysfunction in the mutant mice evidenced by a 50% reduction in the E/A ratio of mitral inflow velocities. Histological examination showed cardiac myocyte disarray in the mutant mice, which amounted to 1-15% of the total myocardium, and a twofold increase in the myocardial interstitial collagen content. Thus, the mutant cTnT-Gln92, responsible for human HCM, exerted a dominant-negative effect on cardiac structure and function leading to disarray, increased collagen synthesis, and diastolic dysfunction in transgenic mice.
Animals↗
Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.
Ventricular fibrillation causes more than 300,000 sudden deaths each year in the USA alone. In approximately 5-12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.
Action Potentials↗
Right bundle-branch block and ST-segment elevation in leads V1 through V3: a marker for sudden death in patients without demonstrable structural heart disease.
BACKGROUND: Five years ago, we described a specific ECG pattern of right bundle-branch block and ST-segment elevation in leads V1 through V3 associated with sudden death in patients without demonstrable structural heart disease. Information on long-term outcome has become available due to pooled data on a large cohort of patients with this syndrome who are followed at 33 centers worldwide. METHODS AND RESULTS: Data on 63 patients (57 men; mean age, 38+/-17 years) with the described ECG pattern were analyzed in terms of arrhythmic events and sudden death. Events were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (symptomatic patients, n=41) and for patients in whom the ECG pattern was recognized by chance or because of screening related to sudden death of a relative (asymptomatic patients, n=22). During a mean follow-up of 34+/-32 months, an arrhythmic event occurred in 14 symptomatic patients (34%) and 6 asymptomatic patients (27%). An automatic defibrillator was implanted in 35 patients, 15 received pharmacological therapy with beta-blockers and/or amiodarone, and 13 did not receive treatment The incidence of arrhythmic events was similar in all therapy groups (log-rank 0.86); however, total mortality was 0% in the implantable defibrillator group, 26% in the pharmacological group, and 31% in the no therapy group (log-rank 0.0005). All mortality was due to sudden death. CONCLUSIONS: Patients without demonstrable structural heart disease and an ECG pattern of right bundle-branch block and ST-segment elevation in leads V1 through V3 are at risk for sudden death. Amiodarone and/or beta-blockers do not protect them against sudden death, and an implantable defibrillator seems to be the present treatment of choice.
Adolescent↗
The molecular genetics of arrhythmias and sudden death.
The current status of the research in genetics of cardiac diseases causing sudden death is reviewed. Few techniques will impact medicine as will those of molecular biology. The identification of the gene-causing diseases will allow the use of better preventive, diagnostic, and therapeutic options. From genetic counseling at present to gene therapy in the future, the new challenge for the clinician will be to acquire the new information provided by molecular biology and apply it at the bedside to improve the quality of life for the patient.
Arrhythmias, Cardiac↗
[Syndrome of right bundle branch block, ST segment evaluation from V1 to V3 and sudden cardiac death].
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Bundle-Branch Block↗
[Genetic bases of arrhythmias].
We have long known that there are diseases which are inherited from the parents, but it has not been until this last decade, with the introduction of the techniques of molecular biology, that we have been able to study them. These techniques have enable us to localize and detect the gene that causes a disease in the members of a family. The identification of a disease-causing gene does not lead only to the diagnosis and possible treatment of a very select patient population (the one with the familial disease), but also to a better understanding of the molecular basis and pathogenesis of the non-familial forms of the disease. Cardiology, despite having received these techniques more slowly, is now completely. Involved in the study of the molecular basis of cardiac diseases. The first gene to be mapped was that of hypertrophic cardiomyopathy in 1989. Since then, advances have been achieved at all levels in familial cardiac diseases. Hypertension, atherosclerosis, congenital heart diseases, and arrhythmias have all benefitted from the new techniques. Spectacular progress has been achieved in understanding familial heart rhythm disturbances, like long QT syndrome, both as congenital and acquired diseases. In the last five years 4 loci and 3 genes have been identified. The first studies of genetic based therapy have shown that in the near future patients with receive medication depending on the affected gene. Other familial arrhythmias are presently under study. Loci have been detected in some, such as bundle branch block and familial atrial fibrillation. At the speed that the techniques are evolving, and with the impressive advances of the Human Genome Project, we can expect to find the rest of the genes causing familial diseases in the next few years. These results are encouraging and clearly indicate the need for genetic diagnosis in all patients with these diseases. The diagnostic and therapeutic implications of all these discoveries could be of paramount importance.
Adult↗
Identification of a genetic locus for familial atrial fibrillation.
BACKGROUND: Atrial fibrillation, the most common sustained cardiac-rhythm disturbance, affects over 2 million Americans and accounts for one third of all strokes in patients over 65 years of age. The molecular basis for atrial fibrillation is unknown, and palliative therapy is used to control the ventricular rate and prevent systemic emboli. We identified a family of 26 members of whom 10 had atrial fibrillation which segregated as an autosomal dominant disease. We subsequently identified two additional families in which the disease was linked to the same locus. METHODS: We screened the human genome with 300 polymorphic dinucleotide-repeat markers using an unconventional strategy of pooling the DNA samples into two groups (affected and unaffected), which reduced the sample size by approximately 90 percent, before performing linkage analysis to map the locus. This made it possible to identify potential loci within a few weeks. RESULTS: The lod scores for markers D10S569 and D10S607, located at 10q22-q24, were 3.60 in Family 1. The disease locus in Families 2 and 3 was also linked to the same markers, with lod scores of 6.02 and 5.35 for markers D10S569 and D10S607, respectively, when data on all three families were combined. Haplotype analysis of the three families showed that the locus was between D10S1694 and D10S1786, an interval of 11.3 centimorgans. CONCLUSIONS: Identification of the gene for familial atrial fibrillation will help to elucidate the molecular basis of the disease and provide insights into acquired forms. The strategy of pooling DNA samples for analysis is more time and cost effective than conventional screening and should accelerate the process of gene mapping in the future.
Adult↗
A common mutation in methylenetetrahydrofolate reductase gene is not a major risk of coronary artery disease or myocardial infarction.
A common mutation (C677-->T) in methylenetetrahydrofolate (MTHFR) gene, involved in the metabolism of homocysteine, has been suggested to play a role in increasing cardiovascular disease risk. We determined the frequency of C677-->T genotypes and alleles in 155 Caucasian patients with angiographically documented coronary artery disease (CAD) and in 155 age and sex matched normal Caucasian individuals. DNA was extracted from the blood and genotypes were determined by polymerase chain reaction, restriction mapping with HinfI and gel electrophoresis. The distribution of MTHFR C677-->T genotypes followed the Hardy-Weinberg equilibrium. The distribution of MTHFR genotypes and the frequency of alleles were similar in cases and controls. The TT genotype was present in 8% of controls as compared to 6% of cases (P = 0.50, OR = 0.82; 95% CI: 0.34-1.96). The frequency of T allele was also similar in patients with CAD compared with controls (0.29 vs. 0.33; P = 0.29). There was also no significant association between C677-->T genotypes and the risk of myocardial infarction. In a subgroup of 44 cases and 89 controls who had no conventional risk factors for CAD (hyperlipidemia, hypertension, diabetes mellitus, and smoking), the frequency of TT genotype was similar (11% vs. 8%, respectively, P = 0.71, OR: 0.67, 95% CI: 0.20-2.23). Thus, the MTHFR TT genotype is not a major genetic risk factor for predisposition to CAD and its thrombotic complications in this population.
Alleles↗
[Atrial fibrillation: is the solution in the genes?].
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Atrial Fibrillation↗
[Arrhythmogenic dysplasia of the right ventricle].
Arrhythmogenic right ventricular dysplasia is a disease of the cardiac muscle of unknown etiology. Landmarks of this disease are the presence of muscular atrophy and replacement of ventricular myocardium by adipous and fibroadipous tissue. This disease was originally described by Fontaine et al in 1977 during surgical ablation of drug refractory ventricular tachycardias in patients without evident structural heart disease. During surgery anomalies in contractility of the right ventricle and the presence of adipous tissue were documented. Some years later, Markus et al reported the first clinical series of patients with arrhythmogenic right ventricular dysplasia. Since then, this disease has been widely recognized and must be considered in the differential diagnosis of all patients with ventricular arrhythmias originating in the right ventricle.
Arrhythmias, Cardiac↗
[Familial auricular fibrillation].
INTRODUCTION AND OBJECTIVE: We present two families with atrial fibrillation in 20 of 50 members, during three generations, with known cardiac rhythms, in order to communicate their infrequent existence and the most relevant clinical facts. METHOD: Clinical situation, evolution, ECG and ECHO findings, treatments and complications related with the disease are investigated. RESULTS: The presence of atrial fibrillation in 20 members is demonstrated, although one of them was on sinus rhythm at the time of the study; 3 patients had left ventricular enlargement on the ECHO study; the clinical situation was good in all patients except two who died because of complications related to the arrythmia and a third patient that had a brain stroke. The patients received different treatments because they where controlled by different physicians; the possible lethal proarrythmic effect in such cases must be taken into account. CONCLUSION: Familiar atrial fibrillation is a very infrequent arrythmia, usually well tolerated, that follows a dominant autosomic hereditary pattern. The use of antiagregants is advised because of the risk of embolism, or the use of anticoagulants in the presence of associated risk factors. Electric cardioversion has been show not be useful. The possible proarrythmic effect of some antiarrythmic agents, used in the control of cardiac frequency, must be taken into account.
Adolescent↗
Role of candidate modifier genes on the phenotypic expression of hypertrophy in patients with hypertrophic cardiomyopathy.
BACKGROUND: The phenotypic expression of left ventricular hypertrophy (LVH) in patients with hypertrophic cardiomyopathy (HCM) is variable. This phenotypic variability is not completely explained by the responsible mutations or other known factors. Recent data denote a role for the modifier genes and environmental factors. We studied the role of 3 potential modifier genes, i.e., angiotensinogen (AGT), angiotensin II receptor 1a (AT1a), and endothelin-1 (END1) on the phenotypic expression of LVH in patients with hypertrophic cardiomyopathy (HCM). METHODS: The study population was comprised of 108 genetically independent patients with HCM. Left ventricular mass index (LVMI) and LVH score were determined per published protocols. The genotypes of AGT (M235T, T174M, and G-6A), AT1a, and END1 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or mutation-specific PCR (MS-PCR). RESULTS: Male patients had higher mean LVMI and LVH score than female patients (146.0 +/- 33.5 vs 129.4 +/- 33.6, p = 0.01 and 6.0 vs 5.0, p = 0.010, respectively). Gender accounted for 4.8% and 5.4% of the variability of LVMI and LVH score, respectively. The END1 genotypes also had a significant influence on LVH scores accounting for 2.9% of their variability (p = 0.042). The median LVH score was greater in patients with the AA and AG genotypes, as compared to patients with the GG genotype (7.0 vs 5.0, p = 0.034). Neither the AGT nor the AT1 genotypes had a significant influence on the expression of LVH. In multivariate regression analysis, END1 and gender accounted for 7.3% of the variability of the LVH score (p = 0.007). CONCLUSIONS: Our results show that gender and the END1 gene modify the phenotypic expression of hypertrophy in patients with HCM.
Adult↗
Platelet glycoprotein IIIa PlA polymorphism and myocardial infarction.
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Angina, Unstable↗
Which ventricular tachycardia is dangerous?
The treatment of ventricular arrhythmias remains a major challenge in cardiology. Several very helpful pieces of information can be obtained from the clinical history. The left ventricular function and the hemodynamic effects of a ventricular tachycardia are the two main factors affecting survival. Therefore, if a patient with sustained ventricular tachycardia presents with syncope or cardiac arrest, or if his functional class for dyspnea is III-IV (NYHA classification), he is a candidate for an implantable defibrillator while otherwise medical therapy is advised.
Decision Trees↗
Changes in plasma cholesterol levels after hospitalization for acute coronary events.
UNLABELLED: To retrospectively assess the changes in total cholesterol levels after a hospital admission for an acute coronary event, 287 patients were identified who had one isolated event: 130 patients with acute myocardial infarction, 122 patients after coronary artery bypass graft surgery, 35 patients after percutaneous transluminal coronary angioplasty. To be included, patients had to have a total cholesterol measurement within the 3 months prior to hospitalization and periodically after the acute coronary event. Total cholesterol measurements were recorded during four time periods: 0-3 months before hospital admission (baseline); and 0-3, 3-6, and 6-9 months after the hospitalization. Mean total cholesterol value was used if a patient had multiple measurements during a time period. RESULTS: There was no significant difference in the baseline total cholesterol levels among the three groups (acute myocardial infarction, coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty). In all three groups, there was a decrease in total cholesterol level after hospital admission compared to baseline (p < 0.0001). This decrease was significantly greater in coronary artery bypass graft surgery patients compared to the other two groups. Total cholesterol levels returned to baseline levels by 3 months after the hospitalization in all three groups. Total cholesterol decreased significantly from baseline in patients after an acute myocardial infarction; this decrease was significantly greater if they received thrombolytic therapy (p < 0.05). Total cholesterol returned to baseline 3 months after hospitalization in both groups. CONCLUSIONS: During the 3 months following hospital admission for an acute coronary event, total cholesterol levels are not representative of the patient's baseline values. Management of hypercholesterolemia in this setting requires the use of baseline (preadmission) total cholesterol values.
Aged↗
[ST segment elevation, right bundle branch block and sudden death: Brugada's syndrome].
Brugada's syndrome is one of the main causes of sudden death in young adults without a structural heart disease. This is an electrical cardiac illness secondary to a mutation of SCN5A gene of chromosome 3 that has a dominant autosomic transmission pattern. This mutation implies the dysfunction of the sodium channel that increases the Ito, loosing the dome of the epicardiac action potential phase two. An "all or none" repolarization pattern ensues and gives rise to a phase two reentry. This kind of reentry is responsible for the initiation and perpetuation of malignant ventricular arrhythmias among these patients. The clinical characteristics of the syndrome are the right bundle branch block, ST segment elevation from V1 to V3 leads and sudden death or syncope. In some patients, a pharmacological test must be done with ajmaline or procainamide to unmask the electrocardiographic changes. At present, the only effective treatment is the implantable cardioverter defibrillator (ICD). This device has the capability to reduce mortality from 40% annually to 0% at ten years. Pharmacological treatment is not useful.
Adult↗