What is the official name of the SCN5A gene?

The official name of this gene is sodium channel, voltage -gated, type V, alpha subunit.SCN5A is the gene's official symbol. The SCN5A gene is also known by other names, listed below. What is the normal function of the SCN5A gene? The SCN5A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.. The SCN5A gene provides instructions for making a sodium channel that is abundant in heart (cardiac) muscle. These channels open and close at specific times to control the flow of sodium ions into cardiac muscle cells. By changing the electrical properties of these cells, sodium channels play a major role in signaling the start of each heartbeat, coordinating the contractions of the upper and lower chambers of the heart, and maintaining a normal heart rhythm. Does the SCN5A gene share characteristics with other genes? The SCN5A gene belongs to a family of genes called SCN (sodium channels). A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? in the Handbook. How are changes in the SCN5A gene related to health conditions? Brugada syndrome - caused by mutations in the SCN5A gene More than 80 mutations in the SCN5A gene have been identified in people with Brugada syndrome and a condition called sudden unexpected nocturnal death syndrome (SUNDS). SUNDS was originally described in Southeast Asian populations, but researchers have since determined that SUNDS and Brugada syndrome are the same disorder. Some SCN5A mutations change single protein building blocks (amino acids) in the SCN5A protein. These mutations alter the structure of ion channels made with the SCN5A protein and disrupt the flow of sodium ions into cardiac muscle cells. Other mutations prevent the SCN5A gene from producing any functional ion channels, which also reduces the inward flow of sodium ions. A disruption in ion transport changes the way the heart beats, leading to the abnormal heart rhythm (arrhythmia) often found in Brugada syndrome and SUNDS. Romano-Ward syndrome - caused by mutations in the SCN5A gene At least 30 mutations in the SCN5A gene are known to cause a form of Romano-Ward syndrome called long QT syndrome type 3 (LQT3). These mutations include changes in single amino acids and deletions or insertions of a small number of amino acids in the SCN5A protein. Channels made with these altered SCN5A proteins stay open longer than usual, which allows sodium ions to continue flowing into cardiac muscle cells abnormally. This delay in channel closure disrupts the heart's normal rhythm, leading to the irregular heartbeat characteristic of Romano-Ward syndrome. other disorders - caused by mutations in the SCN5A gene Mutations in the SCN5A gene are responsible for several other heart rhythm abnormalities. These conditions include cardiac conduction disease, sick sinus syndrome, sudden infant death syndrome (SIDS), and acquired long QT syndrome. Cardiac conduction disease is a heart condition that increases the risk of fainting (syncope) and sudden death. This condition is caused by SCN5A mutations that lead to a partial or total loss of sodium channel function, reducing or stopping the flow of sodium ions into cardiac muscle cells. Cardiac conduction disease is inherited in an autosomal dominant pattern, which means one altered copy of the SCN5A gene in each cell is sufficient to cause the disorder. Sick sinus syndrome is a disorder of the sinoatrial node, which is a group of specialized cells in the heart that function as a natural pacemaker. The sinoatrial node cannot effectively regulate the heartbeat in people with this condition, leading to an abnormally slow heart rhythm (bradycardia) and an increased risk of dizziness and fainting. Mutations in the SCN5A gene that cause sick sinus syndrome produce nonfunctional sodium channels or abnormal channels that cannot transport ions properly. Sick sinus syndrome is inherited in an autosomal recessive pattern, which means two copies of the gene must be altered in each cell for a person to be affected by the condition. SIDS is a major cause of death in babies younger than one year. It is characterized by sudden and unexplained death, usually during sleep. Although the cause of SIDS is often unknown, researchers have identified mutations in the SCN5A gene in some cases of this condition. Other genetic and environmental factors, many of which have not been identified, also play a part in determining the risk of SIDS.

Certain drugs, including medications used to treat arrhythmias, infections, seizures, and psychotic disorders, can lead to an abnormal heart rhythm in some people. This drug-induced heart condition, which is known as acquired long QT syndrome, increases the risk of cardiac arrest and sudden death. A small percentage of cases of acquired long QT syndrome occur in people who have an underlying mutation in the SCN5A gene. Where is the SCN5A gene located? Cytogenetic Location: 3p21 Molecular Location on chromosome 3: base pairs 38,589,552 to 38,691,163

The SCN5A gene is located on the short (p) arm of chromosome 3 at position 21. More precisely, the SCN5A gene is located from base pair 38,589,552 to base pair 38,691,163 on chromosome 3. See How do geneticists indicate the location of a gene? in the Handbook. Where can I find additional information about SCN5A? You and your healthcare professional may find the following resources about SCN5A helpful. Heart Rhythm Society: Sick Sinus Syndrome PubMed - Recent literature OMIM - Genetic disorder catalog (4 links) Research Resources - Tools for researchers (5 links)

What other names do people use for the SCN5A gene or gene products? HH1 LQT3 Nav1.5 SCN5A_HUMAN Sodium channel protein, cardiac muscle alpha-subunit sodium channel, voltage-gated, type V, alpha (long QT syndrome 3) SSS1

The Brugada Syndrome This site describes most of the available information on a syndrome that causes sudden unexpected cardiac death in apparently healthy individuals. The sudden death is caused by severe disturbances of the rhythm of the heart. This disease is known as Brugada syndrome and is hereditary. The information on this site is only meant for individuals seeking more information on the disease and participating in the collection of data. You should consult your treating physician for any problem related or possibly related to this disease. You should not make any own conclusions or decide upon your or other people's treatment based on the data presented on this site. Any inquiries you may have related to medical problems, should be handled via your treating physician. Definition The syndrome of right bundle branch block, ST segment elevation in V1 to V3 and sudden death is a clinicalelectrocardiographic diagnosis based on syncopal or sudden death episodes in patients with a structurally normal heart with a characteristic electrocardiographic pattern: The electrocardiogram shows ST segment elevation in the precordial leads V1 to V3, with a morphology of the QRS complex resembling a right bundle branch block (picture 1). This pattern of right bundle

branch block has also been called J point elevation. picture 1 Typical electrocardiogram of Brugada syndrome. Note the pattern resembling a right bundle branch block, the P-R prolongation and the ST elevation in leads V1-V3. The episodes of syncope and sudden death (aborted or not) are caused by fast polymorphic ventricular tachycardias or ventricular fibrillation (picture 2). These arrhythmias appear with no warning. There is no prolongation of the QT interval during sinus rhythm. Only in very few cases there is alternation of long-short sequences before the polymorphic ventricular tachycardia, a finding which is very common in other arrhythmias like "torsade de pointes" in the long QT syndrome. There is no preceding acceleration in the heart rate as is the case of cathecolamine-dependent polymorphic ventricular tachycardia

history The first patient with this syndrome was seen in 1986. The patient was a three year old boy from Poland. He had presented multiple episodes of loss of consciousness and had been resuscitated multiple times by his father. The child's sister had died suddenly at age two after multiple episodes of aborted sudden death. When she died, she was receiving amiodarone and had a ventricular pacemaker implanted. The electrocardiograms of the two siblings were very similar and abnormal (picture 3). The identification of two additional patients resulted in the presentation of the preliminary data at the meeting of the North American Society of Pacing and Electrophysiology (NASPE) in 1991. The first paper including 8 patients was published in 1992 . Since then, there has been an exponential increase in the number of patients recognized all over the world. The recent discovery of the genetic abnormalities linked to this syndrome, points to it being a primary electrical disease, providing an important first step in the prevention and effective treatment of this form of sudden death in patients with a structurally normal heart. Several authors have previously reported electrocardiograms similar to the one presented in picture 1. For the most part, these were considered variants of the normal electrocardiogram and no definitive link to sudden death was established. In the 1980's the CDC (Center for Disease Control) in Atlanta, reported an abnormally high incidence of sudden death in young immigrants from Southeast Asia. Interestingly, the natives knew the problem for many decades. In the Northeast of Thailand, this form of death was known as Lai Tai (death during sleep). The indigenous believe that the young men died during sleep because widow ghosts came to take them away. Many young men actually dress still as women to go to sleep at night - a practice carried out for more than 70 years - with the hope that it would mislead the widow ghost, who then would not take these young men. In Philippines the phenomenon was known as Bangungut (scream followed by sudden death during sleep) and in Japan as Pokkuri (unexpected sudden death at night). The incidence of this form of sudden death has been estimated between 26 and 38 cases per 100,000 inhabitants per year. In Laos it may cause 1 sudden death per 1.000 inhabitants per year. Unexpected sudden death is the most common cause of natural death in young Thai people. It has been only recently discovered that many of these patients suffer the Brugada syndrome. The higher prevalence of this syndrome in some areas can be explained by its genetic transmission. Etiology and Genetics This syndrome is genetically determined. Approximately 60% of patients with (aborted) sudden death with the typical electrocardiogram have a family history of sudden death, or have family members with the same electrocardiographic abnormalities. There are also sporadic cases who are probably the patients with a de novo mutation in the family. The pattern of transmission is autosomic dominant. There is a predominance of affected males. In Thailand the disease almost exclusively affects males. The explanation to this predominance is not clear but it is possibly related to some modifier genes. Several mutations linked to this syndrome affecting the gene SCN5A which encodes for the cardiac sodium channel have been described. Some of the families studied do not present these mutations in this gene, indicating that other genetic defects will be found and that this is a genetically heterogeneous disease. The mutations affecting patients in Japan and South Asia are still unknown. The in vitro studies show that the mutant channel has altered function, with a loss of sodium current that is temperature dependent. The loss of current

leaves Ito unopposed, creating heterogeneity of refractory periods and a perfect substrate for arrhythmias based on phase 2 re-entry. Incidence Because the syndrome has been identified only recently, it is difficult to ascertain its incidence and distribution in the world. When we analyze the data from the different publications, the disease is responsible for 4 to 12 % of unexpected sudden deaths, and for up to 50% of all sudden death in patients with an apparently normal heart. The incidence may even be higher in the younger population. Indeed, this syndrome is the most common cause of sudden death in individuals younger than 50 in South Asia with no underlying cardiac disease. It is important to stress that the physician plays an important role in the identification of the syndrome to estimate its real prevalence. This syndrome is possibly more prevalent, but the magnitude of it has yet to be determined. The difficulty to estimate the incidence and prevalence of the disease becomes more complicated as we unravel the syndrome and some of its peculiar characteristics. It is a syndrome that can present with a typical electrocardiogram but in some other cases the patient can present concealed forms or intermittent forms, meaning that the electrocardiogram is normal at certain times. The electrocardiogram of the syndrome may be unmasked by the administration of ajmaline, flecainide or procainamide. The pharmacologic test is so specific, that it is recommended in all patients who present with a history of syncope of unknown origin or ventricular fibrillation of unknown cause. Unfortunately, these tests are not applied routinely. Without a doubt this is one of the reasons why the prevalence of the disease probably is underestimated. Recent data from France and Japan show a prevalence of 1 per 1000 electrocardiograms compatible with the syndrome in the normal adult population. This syndrome has already been recognized in virtually all parts of the world. We suspect that the lack of cases in some countries is due more to the lack of recognition than to the absence of the disease. With present data, the disease seems spread all over the world, a not surprising finding, given the high mobility of the population and the genetic basis of the disease. In the future we only can expect a sizeable increase in the number of identified cases as the recognition of the disease grows. A prospective study of an adult Japanese population (22.027 subjects) showed an incidence of 0.05% of electrocardiograms compatible with the syndrome (12 subjects). A second study of adults in Awa (Japan) showed an incidence of 0.6 % (66 cases out of 10.420). However, a third study in children from Japan showed an incidence of electrocardiograms compatible with the syndrome of only 0.0006% (1 case in 163.110). These results suggest that the syndrome is manifested during adulthood, which is in accordance to the mean age of the sudden death victims (35 to 40 years). The youngest patient known was 6 months old at the time of sudden death, and the oldest 74. In the Dutch area of Belgium (6 million inhabitants) already 44 families with the syndrome have been identified. About 15% of members are affected. That gives an incidence of 1:30.000 in that area. Pathological Findings Pathological data are available from many patients with the syndrome. None of the patients have any structural abnormality. Despite other authors suggestions, there is no indication that the disease is arrhythmogenic right ventricular dysplasia. Other non-invasive studies like nuclear magnetic resonance of the heart and echocardiography (which are available in the majority of the patients) are normal. The genetic defects in Brugada syndrome are not related to the loci of right ventricular dysplasia, and none of the families studied is linked to these loci Clinical Manifestations The complete syndrome is characterized by episodes of fast polymorphic VT (picture 2) in patients with an electrocardiogram showing a pattern of right bundle branch block and ST segment elevation in leads V1 to V3 (picture 1,3). The manifestations of the syndrome are caused by episodes of polymorphic ventricular tachycardiaventricular fibrillation. When the episodes terminate spontaneously the patient develops syncopal attacks. When the episodes are sustained, full blown cardiac arrest and eventually sudden death occur. Thus, these manifestations can range widely: at the one end of the spectrum we have asymptomatic individuals and at the other end those who die suddenly. As it is seen in other clinical-electrocardiographic syndromes, there are other different presentations of the disease. There exist asymptomatic individuals in whom the typical electrocardiogram is detected during routine examination. This electrocardiogram cannot be distinguished from that of symptomatic patients. In other patients, the characteristic electrocardiogram is recorded during screening after the sudden death of a family member with the disease. On the other hand, there is the group of symptomatic patients who have been diagnosed as suffering syncopal episodes of unknown cause or vaso-vagal origin, or have a diagnosis of idiopathic ventricular fibrillation. Some of these patients are diagnosed at follow-up, when the electrocardiogram changes spontaneously from normal to the typical pattern of the syndrome (picture 5). This is also the case for those individuals in whom the disease is unmasked by the administration of an antiarrhythmic drug given for other arrhythmias, for instance atrial fibrillation. It really does not make a difference, this electrocardiogram, with or without symptoms, appearing spontaneously or after the administration of medications, is a marker of sudden death: Up to 40% of the individuals will develop a new or a first episode of polymorphic ventricular tachycardia or sudden death during the next 2-3 year follow-up.

The only excepcion seem to be carriers who are asymptomatic and in whom the electrocardiogram is only found after administration of drugs. Diagnosis The diagnosis of the syndrome is easily obtained by electrocardiography as long as the patient presents the typical electrocardiographic pattern (picture 1) and there is a history of aborted sudden death or syncopes caused by a polymorphic ventricular tachycardia. It is difficult to forget such a typical electrocardiogram. The ST segment elevation in V1 to V3 with the right bundle branch block pattern is characteristic. The ST changes are different from the ones observed in acute septal ischemia, pericarditis, ventricular aneurysm and in some normal variants like early repolarization. There are though, electrocardiograms which are not as characteristic (picture 6), and they are only recognized by a physician who is thinking of the syndrome. There are also many patients with a normal electrocardiogram in whom the syndrome can only be recognized a posteriori when the typical pattern appears in a follow-up electrocardiogram or after the administration of ajmaline, procainamide or flecainide (picture 7).

It is possible that the electrocardiographic patterns are different depending on the genetic abnormality. This is the case in other genetic diseases like the long QT syndrome. The mutations that have been discovered in two families give proof of this fact: their electrocardiograms are similar, but not identical (picture 8). Even though in both cases the affected gene was the same, the exact mutation was different. It will be necessary to identify more mutations and make close genotype-phenotype correlation to establish the links. However, we cannot forget the great variability of the electrocardiogram in this syndrome, something which will certainly not facilitate analysis. Additional diagnostic problems are caused by the changes in the electrocardiogram induced by the autonomous system and by antiarrhythmic drugs. The study by Miyazaki et al was the first one to show the variability of the electrocardiographic pattern in the syndrome. Despite the fact that the syndrome was initially described as a persistent electrocardiographic pattern, it was soon recognized that the electrocardiogram is variable over time, depending on the autonomic interaction and the administration of antiarrhythmic drugs. Adrenergic stimulation decreases the ST segment elevation, while vagal stimulation worsens it. The administration of class Ia, Ic and III drugs increases the ST segment elevation, and also fever. Exercise decreases ST segment elevation in some patients but increases it in others (after exercise when the body temperature has risen). The changes in heart rate induced by atrial pacing are accompanied by changes in the degree of ST segment elevation. When the heart rate decreases, the ST segment elevation increases and when the heart rate increases the ST segment elevation decreases. However, the contrary can also be observed.

Picture 8 Leads V1 to V3 are shown from two patients with two different mutations in the sodium channel. It is possible that the electrocardiogram varies depending upon the type of mutation. Patients with syncope of unknown cause must be challenged with antiarrhythmic drugs in order to exclude the possibility of this syndrome as a cause of ventricular arrhythmias and syncope.

Origin of the Electrocardiogram and Ventricular Arrhythmias It is unclear whether the right bundle branch block in this syndrome is real or whether it represents an early repolarization of right ventricular epicardium. The clinical and electrophysiologic data suggest that both possibilities exist. Some electrocardiograms clearly show a right bundle branch block after normalization of the ST segment (picture 9, panel C). There is frequently a prolongation of the H-V interval in these patients, which supports an abnormality of the conduction system. On the other hand, we can find electrocardiograms without right bundle branch block after normalization of the ST segment elevation (picture 10). Moreover, not all the patients have a prolongation of the H-V interval.

Approximately 10% of patients with this syndrome suffer from paroxysmal atrial fibrillation. It is possible that similar genetic defects alter atrial and ventricular electrophysiology in some patients.

Picture 10 In contrast to picture 9, this patient shows no right bundle branch block when the electrocardiogram normalizes during followup. The polymorphic ventricular tachycardia can be often reproduced by programmed electrical stimulation of the heart in these patients, suggesting a re-entrant mechanism. Phase 2 re-entry is believed to undelie ventricular arrhythmias in this syndrome. Cellular Mechanisms There exist a lot of variation in the intensity of cellular electrophysiologic currents between the different animal species. Ito, for instance, is very intense in the human being, dog, rabbit, cat, and rat, but very weak in other species. Within the same animal, there exist also a large variation in the intensity of electrophysiologic currents from endocardium to epicardium. Ito is much more expressed at epicardial than at endocardial level. Because of this heterogeneity, it is easy to understand that the effects of antiarrhythmic drugs also vary from species to species and from endocardium to epicardium. Several physiologic, and not necessarily pathologic electrophysiologic changes may result in an electrophysiologic and electrocardiographic pattern as observed in the syndrome under discussion. At birth, rats show an isoelectric repolarization between QRS and T wave, but they develop a progressive ST elevation after the second week of life. The ST elevation coincides with an increase in the intensity of the Ito. In man, this happens around 6 months of life. However, like in other large mammalians, no elevation of the ST segment is observed under normal circumstances. Hypothermia results in ST segment elevation. Experimental application of cold at the epicardium, or application of pressure also results in ST segment elevation. Pharmacologic interventions blocking the sodium channel or the calcium channel, or the activation of ATP-dependent potassium currents also result in elevation of the ST segment because of shortening of the duration of the action potential of cells with an intense Ito. When inward Ca currents (ICa) are overwhelmed by Ito, a reduction of up to 70% in the duration of the action potential is possible. This causes loss of the dome of the action potential at some areas at epicardial level, while other areas maintain the normal duration of the action potential. This results in severe heterogeneity of duration of action potentials and consequently in refractory periods. Cells with a short duration of action potential can be reexcited by adjacent cells with a normal duration of the action potential (phase 2 re-entry, picture 11). These mechanisms have been elegantly shown by Antzelevitch and co-workers in the dog's heart with the administration of flecainide, potassium channel openers, increase in extracellular calcium, metabolic inhibition and simulated ischemia. When Ito is blocked under these circumstances, homogeneity is recovered and phase 2 re-entry disappears.

Picture 11 Schematic drawing showing the mechanism of phase 2 re-entry in Brugada syndrome. A selective shortening of the duration of the action potential on the epicardium because of an increased activity of the Ito results in an electric gradient and re-entry.

The cellular mechanisms underlying this syndrome of right bundle branch block, ST segment elevation from V1 to V3 and sudden death have been recently extensively reviewed. The loss of the dome of the action potential occurs because of a disequilibrium between Ito and ICa during phase 1 of the action potential. Any influences which come to alter this disequilibrium in one or another sense, will result in changes in the degree of ST segment elevation. For instance, interventions increasing the potassium current will increase ST segment elevation, while interventions increasing calcium current will decrease the amount of ST elevation. On the contrary, a decrease in potassium current will decrease ST segment elevation, and block of calcium currents will increase the amount of ST segment elevation. The observations by Miyazaki and co-workers and by others in patients with this syndrome are in agreement with these predictions (picture 9). Relation With "Early Repolarisation" Because of some possible similarities between early repolarisation and this syndrome, and because some patients with the syndrome have been misdiagnosed as early repolarisation, a discussion of the similarities, differences and electrophysiologic mechanisms of these two syndromes is justified. Early repolarisation is a frequent finding in healthy, usually sportive, young men. The Brugada syndrome also frequently affects active, sportive, and apparently healthy young men. During exercise, there is a normalization of the ST segment in both situations. Adrenergic stimulation with isoproterenol normalizes the ST segment in both syndromes, while beta-adrenergic blockade increases the ST segment elevation. Which are the differences between the two syndromes then? The first and very much important difference is that normal individuals with early repolarisation do not develop sudden death because of ventricular arrhythmias. There exist also electrocardiographic differences between the two syndromes, like the type and localization in the precordial leads of the ST segment elevation (picture 12).

Picture 12 Early repolarization. Compare with the electrocardiograms of patients with Brugada syndrome to note the important differences. Although the underlying cellular electrophysiologic mechanisms of early repolarisation are not completely clear, some electrophysiologic similarities between the two syndromes may exist. From a discussion with Dr. Antzelevitch, picture 13 was drawn to try to understand the differences between early repolarisation, long QT syndrome and Brugada syndrome, and why arrhythmias do not occur in the first situation but do occur in the other two.

Picture 13 Electrophysiologic differences between early repolarization, long QT syndrome and Brugada syndrome. In early repolarization there exists a voltage gradient but no dispersion of duration of action potentials. That is why these patients show ST elevation but do not develop arrhythmias. In the long QT syndrome there exist a voltage gradient because of prolongation of the action potential in some areas because of early afterdepolarizations. The voltage gradient results in phase 2 re-entry. In Brugada syndrome re-entry occurs because of the voltage gradient caused by the shortening of the duration of the action potential. Relation With Other Syndromes There exist a lot of concern about a possible relation between the syndrome under discussion and other syndromes, particularly right ventricular dysplasia. The recent discovery of the genetic abnormalities of Brugada syndrome in the gene SCN5A located in chromosome 3 should be sufficient to finish this discussion, because the loci so far described in right ventricular dysplasia are located in other chromosomes. In spite of these considerations, of course it is perfectly possible that some patients manifest two different diseases at the same time, and also there exists electrocardiograms that look similar to Brugada syndrome, but are not caused by the disease (pseudo-Brugada syndrome). Ikeguchi and co-workers (personal communication) have studied a patient with Wolff-Parkinson-White syndrome who was successfully treated by means of radiofrequency catheter ablation. The patient died suddenly two years after ablation. Analysis of the electrocardiograms of this case shows that he also suffered from Brugada syndrome. Thus, he had two syndromes at the same time. It is not unthinkable, therefore, that some patients may suffer from right ventricular dysplasia and Brugada syndrome simultaneously. Other diseases may result in electrocardiographic manifestations similar to Brugada syndrome. For instance, it is interesting to observe the pictures published from Buenos Aires in 1982 (picture 14). In patients with Chagas' disease Chiale et al. showed that the intravenous administration of ajmaline was of value to uncover latent conduction disturbances, but also what they called "latent disease". In patients with positive serology severe conduction disturbances occurred in one third after the administration of intravenous ajmaline. In 8% of patients

they observed the appearance of ventricular arrhythmias and in 7% elevation of the ST segment in the right precordial leads (picture 14). The question arises of the relation between Chagas' disease and Brugada syndrome in these patients. Chiale and co-workers actually considered the ajmaline challenge as a non-specific test capable of detecting myocardial damage. On the light of the recent discovery of the genetic defect underlying Brugada syndrome, the question also arises about the possible occurrence of damage to the sodium channel by Chagas' disease. Although there exist major differences between Chagas' disease and Brugada syndrome, the final common pathway leading to sudden death may be the same: damage to the sodium channel (infectious and inmunologic in Chagas' disease, genetic in Brugada syndrome) with conduction and repolarisation disturbances leading to electrical chaos and ventricular fibrillation. Picture 14 Effects of ajmaline in a patient with Chagas' disease. Ajmaline produces ST segment elevation in the right precordial leads (arrows). It is not clear whether this patient suffered from two diseases at the same time or whether Chagas' disease causes the same abnormalities as Brugada. Other conditions may result in electrocardiograms simulating Brugada syndrome: Steinert's disease (picture 15), pectus excavatum, and mediastinal tumors (Farre J). These should be excluded before diagnosing Brugada syndrome. Effects of Changes in Heart Rate and Exercise As already discussed in part, this syndrome is characterized by a great variability in the electrocardiographic pattern. The electrocardiogram may be completely abnormal at times, but completely normal at others . This variability has many causes and several explanations. Autonomic changes and body temperature influence the electrocardiogram. So do spontaneous or induced changes in heart rate. An artificial increase in heart rate (by atrial pacing) decreases ST segment elevation, while a decrease in heart rate increases it. These data are again in agreement with the loss of the dome of the action potential at epicardial level as the cause of ST segment elevation. Ito becomes more prominent at slow rates increasing heterogeneity and ST segment elevation. These data are also in agreement with the clinical observations documenting a bradycardia -dependency and a higher incidence of sudden death during sleep in patients with this syndrome. Normalization of the ST segment during exercise is the most common finding in patients with this syndrome. These are logical findings because both an increase in heart rate and adrenergic stimulation decrease ST segment elevation Picture 15 Electrocardiogram of a patient with Steinert's disease.Some disease may result in electrocardiographic patterns resembling Brugada syndrome. However, the differences are usually evident,both clinically and electrocardiographically. On this electrocardiogram we do not observe the typical ST segment elevation in leads V1 to V3 although the right bundle branch block is evident. Electrophysiologic and Hemodynamic Findings During invasive electrophysiologic investigations sinus node function has been normal in the large majority of the patients. However, isolated patients have manifest sinus node disease and are pacemaker dependent. As already discussed, about 10% of patients has paroxysmal atrial fibrillation. There exist no detailed studies on the ability to induce this arrhythmia by programmed electrical stimulation. All published studies agree on the inducibility of polymorphic ventricular tachycardia by programmed electrical stimulation in symptomatic patients. About 80% of them are inducible by giving 1 or 2 ventricular premature beats during ventricular pacing. In some patients three premature stimuli are required. The induced arrhythmia is sustained in practically all cases, results in hemodynamic collapse and has to be terminated by an external DC shock. It can be criticized that polymorphic ventricular tachycardia or ventricular fibrillation induced by programmed stimulation is a non-specific finding, because these arrhythmias can sometimes be induced in patients with a normal heart. There exist, however, major differences between the two situations: 1.- The clinical context, with symptomatic patients with Brugada syndrome having suffered from spontaneous ventricular arrhythmias, 2.- The percentage of patients inducible to a sustained polymorphic ventricular arrhythmia in Brugada syndrome (80%) as compared to individuals without the syndrome where a sustained polymorphic ventricular tachycardia or ventricular fibrillation is only exceptionally induced. The same studies coincide in the frequent finding of conduction disturbances in patients with the disease. The H-V interval is prolonged in about the half of the patients. The prolongation is not marked, rarely exceeding the 70 ms, but being clearly abnormal in this population with an average age of 40 years. The H-V prolongation explains the slight prolongation of the P-R interval during sinus rhythm (picture 1). Hemodynamic studies have been systematically normal. Prognosis and Treatment This syndrome has a very poor prognosis when left untreated: One third of patients having suffered from syncopal episodes or resuscitated from near-sudden death develops a new episode of polymorphic ventricular tachycardia within 2 years. Unfortunately, prognosis of asymptomatic individuals with typical electrocardiogram is also poor. In spite of not having any previous symptoms, also one third of these individuals presents a first polymorphic ventricular tachycardia or ventricular fibrillation within 2 years of follow-up (picture 16).

These data are of extreme importance for the delineation of treatment policies of these patients. Because antiarrhythmic drugs (amiodarone or beta-blockers) do not protect against sudden cardiac death, the only available treatment is the implantable cardioverter-defibrillator (picture 16). This device effectively recognizes and treats the ventricular arrhythmias. When provided with the implantable defibrillator total mortality in patients with Brugada syndrome has been 0% with up to 10 years follow-up. These results are not surprising. These patients are young and usually devoid from other diseases. Because the heart is structurally normal, and there is no coronary artery disease, these patients do not die from heart failure or complications of ischemic events. Thus, they are the most ideal candidates for treatment with an implantable defibrillator. Symptomatic patients must receive this device.

On the other hand, major concerns arise in the treatment of asymptomatic individuals. In our previous report six asymptomatic patients died suddenly during follow-up. Four patients were members of affected families, but two were sporadic cases. Data from electrophysiologic investigations did not help us to predict prognosis at that time. Recent data support the fact that this may have been caused by a type II error (not sufficient number of patients to prove a statistically significant difference). At present, we believe three different groups of patients can be distinguished: 1.- Symptomatic individuals with the disease who require an implantable cardioverter-defibrillator. Patients with transient normalization of the electrocardiogram during follow-up have the same prognosis as compared to patients with a permanently abnormal electrocardiogram. 2.- Asymptomatic patients with a spontaneous abnormal electrocardiogram, and inducible polymorphic ventricular tachycardia or ventricular fibrillation who also require an implantable defibrillator. 3.- Asymptomatic individuals with an abnormal electrocardiogram only after drug chanllenge and no inducible ventricular arrhythmias who should not be treated but followed-up carefully for development of symptoms suggesting arrhythmias (particularly syncope). One has to realize, however, that these recommendations may rapidly change depending upon the availability of new data Conclusions The syndrome of right bundle branch block, ST segment elevation from V1 to V3 and sudden death is a new entity. This disease is genetically determined. The incidence of sudden death in this syndrome is very high and, at present, can only be prevented by implanting a cardioverter-defibrillator. The electrocardiogram is a marker of sudden death in symptomatic, but also in asymptomatic individuals. Protocol of Study of Brugada Syndrome.

Medical knowledge changes very fast. You may consider contacting us directly at the enclosed email before taking any decisions or making recommendations, or for the purpose to sent blood samples for genetic studies. The following strategy is recommended at present: 1.- From each individual seen because of the diagnosis or suspicion of Brugada syndrome take a medical history with special attention to symptoms that may suggest arrhythmias like syncope, presyncope, dizziness, palpitations. Special attention must also be given to a family history of unexplained syncope, sudden death and unexplained traumatic deaths like car accidents that may result from loss of consciousness. Do not accept a diagnosis of the causes of sudden death or syncope unless proven. In 50% of the cases of sudden death in families with Brugada syndrome the cause of sudden death is Brugada syndrome, but in the other half the cause is a myocardial infarction or is unclear. 2.- Physical examination will usually be normal, but it should be carefully done to exclude any condition that may simulate Brugada syndrome. 3.- Record a 12-lead resting electrocardiogram and an electrocardiogram after the administration of either: a.- ajmaline 1mg/kg body weight iv in 5 minutes, or b.- flecainide 2 mg/Kg body weight iv in 10 minutes, or c.- procainamide, 10 mg/kg body weight iv in 10 min. These tests should be performed in an environment with facilities for CPR because in 0.5% of tests the patient may develop ventricular fibrillation. Ajmaline is the preferred drug because of the very short half-life. If necessary, consider approval of the test by your local ethical committee before performing it. A pharmacologic test is considered positive if an additional 1 mm ST segment elevation appears in leads V1, V2 and V3. The ST segment elevation is measured 0.08 s after the J wave. 4.- All positive individuals should undergo programmed ventricular stimulation to assess inducibility of ventricular arrhythmias and to measure the conduction intervals (the H-V interval is frequently prolonged in Brugada syndrome). Programmed ventricular stimulation should at least include two different pacing cycle lengths from the right ventricular apex and at least two ventricular premature beats. Drawing, preparation and shipment of the samples.

Draw 3 tubes of 8 cc(ml) blood to fill three green top tubes (sodium heparin) or yellow top tubes (citrate). Invert the tube several times after drawing to prevent blood from clotting. Label each tube with full name and birthday. Place the samples into a Styrofoam shipping box and seal tightly with tape. Place the box into the shipping bag provided by your Airborne Express Company. Seal lightly with tape. DO NOT SEND ON ICE OR DRY ICE, SEND AT AMBIENT (ROOM) TEMPERATURE. Insert the following information on the box for customs. This message must be seen from the outside.This package contains blood samples being transported in a vial with no media. This is non-infectious, non-contagious, and for research only. It contains no animal origin or no additives and is for genetic research. Please do not refrigerate. Please include the consent form and the clinical information form.Please send an email to the address enclosed to notify of the shipping and tracking number of the package. Please contact Dr Brugada for any questions and additional information. The diagnosis of Brugada syndrome is confirmed in an individual with the following: Type 1 ECG (elevation of the J wave 2 mm with a negative T wave and ST segment that is coved type and gradually descending) in more than one right precordial lead (V1-V3)*, with or without administration of a sodium channel blocker (i.e., flecainide, pilsicainide, ajmaline, or procainamide) and

A and/or B: A At least one of the following findings: Documented ventricular fibrillation Self-terminating polymorphic ventricular tachycardia A family history of sudden cardiac death Coved-type ECGs in family members Electrophysiologic inducibility Syncope or nocturnal agonal respiration B An SCN5A mutation * No other factor(s) should account for the ECG abnormality. Brugada syndrome should be strongly considered in individuals with either of the two following ECG types: Type 2 ECG (elevation of the J wave 2 mm with a positive or biphasic T wave; ST segment has a saddle-back configuration and is elevated 1 mm) in more than one right precordial lead under baseline conditions with conversion to type 1 ECG following challenge with a sodium channel blocker (considered equivalent to a positive finding in A.). Note: Drug-induced ST-segment elevation to a value greater than 2 mm should raise the possibility of Brugada syndrome when one or more of the clinical criteria are present (see A.). Based on current limited knowledge, whether an individual with a negative drug test (i.e., no change observed in the ST segment in response to a sodium channel blocker) has Brugada syndrome is unknown because the sensitivity of the test is 80% with the sodium channel blocker ajmaline, and probably lower for the other class 1 blockers [Hong, Brugada et al 2004].

Type 3 ECG (elevation of the J wave 2 mm with a positive T wave; ST segment has a saddle-back configuration and is elevated <1 mm) in more than one lead under baseline conditions with conversion to type 1 ECG following challenge with a sodium channel blocker (considered equivalent to a positive finding in A.).