Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2002;55:432-7 - Vol. 55 Num.04

Genetics and Arrhythmias

Ramon Brugada a, Josep Brugada b, Pedro Brugada c

a aylor College of Medicine. Houston. Texas. EE.UU.
b Unitat d'Arrítmies. Universitat de Barcelona.
c Cardiovascular Research and Teaching Institute Aalst. Bélgica.


Genetics. Arrhythmias. Sudden death. Molecular biology.


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



Various genetically determined cardiac diseases, some of which produce structural abnormalities while others do not, predispose to arrhythmias (Table 1). These cardiac diseases derive mainly from abnormalities in the encoding of three main families of proteins. The sarcomeric proteins, which are in charge of generating force for the mechanical contraction of myocytes, are responsible for hypertrophic cardiomyopathy.1 The cytoskeletal proteins,2 which transmit this force to neighboring cells for coordinated contraction, are responsible for dilated cardiomyopathy. Finally, ion channels,3 which maintain the ionic balance for generating electrical activity in the myocyte, are responsible for familial arrhythmias. Time has proven, however, that the issue is much more complex. Overlap has been found between diseases, with sarcomeric proteins also being responsible for dilated cardiomyopathy.4 Similarly, sodium-channel SCN5A is responsible for long-QT syndrome, Brugada syndrome, and familial conduction disease.5 Not only at the etiological level, but even when looking at risk stratification in hypertrophic cardiomyopathy, research has found that the mutation-prognosis relationship is not as clear as was once thought.4 Nevertheless, this simplistic classification that has made it possible to gain understanding of the different mechanisms responsible for these three diseases, and the identification of these genetic factors has given us some understanding of arrhythmogenic triggers and the determinants of sudden death. The data is very preliminary, and some of the key genetic factors that could be used to stratify the risk of sudden death or arrhythmias are the result of research in only few families. Longer and more extensive studies are required to validate this data. However, technology is evolving rapidly and it will not be long before we will be able to use genetics to derive information for proper diagnosis and treatment.


Several elements are needed for coordinated cardiac activity. Among them are ion currents, ion channels, structural proteins, and gap junctions, which are responsible for the transmission of electrical and mechanical impulses through the cardiac myocytes. The complexity of this process continues to be a tremendous challenge to our understanding of arrhythmogenesis. With the incorporation of molecular biology in cardiology, we can confront some of these challenges. The discovery of the structure, function, and pathophysiology of the ion channels has helped to unravel in part the role of different ionic currents in electrical activity and electromechanical coupling. While basic mechanisms of arrhythmia have been elucidated by functional analysis of the ion channels involved in generating the cardiac action potential, it was not until the development of genetics and the discovery of mutations that cause familial disease that we could advance from the most elementary level of understanding to the clinical arena. Cardiac arrhythmias that predispose to sudden death, like long-QT and Brugada syndrome, have benefited tremendously from advances in genetics and molecular biology. These single-gene familial diseases, despite being rather uncommon, provide an opportunity for studying a pure form of a disease, in which a single abnormal protein is the trigger responsible for arrhythmogenicity. However, our knowledge of genetics is not confined to inherited forms of disease. It also has brought new insight into how abnormal and, ultimately, normal genes interact with damaged heart muscle, drugs, and the environment to trigger arrhythmias in acquired forms of disease.

Long-QT syndrome

Long-QT syndrome is a repolarization disease characterized by syncopal episodes, malignant ventricular arrhythmias, and ventricular fibrillation that is identified by prolongation of the QT interval on the ECG.3 The most typical ventricular arrhythmia is torsade de pointe. Long-QT syndrome has two main forms, acquired and congenital. A common cause of the acquired disease is iatrogenic, related mainly to medications like antiarrhythmics, antidepressants, and phenothiazides. It can be also due to electrolyte disorders like hypokalemia, hypomagnesemia, and hypocalcemia, especially when associated with the medications just mentioned. Two patterns of inheritance have been described in congenital long-QT syndrome: a) autosomal recessive disease, described by Jervell and Lange Nielsen in 1957, which is associated with deafness,6 and b) autosomal dominant disease, described by Romano and Ward.7,8 In the autosomal dominant syndrome, patients do not have deafness. It is more common than the recessive form.

The first locus of the autosomal dominant disease was mapped on chromosome 11 in 1991.9 Since then, a total of 6 loci and 5 genes have been identified (Table 1). All the genes encode proteins that are responsible for the automaticity of electrical activity in cardiac cells. DNA mutations that have been described disrupt the formation of these proteins, altering the cardiac action potential and generating a voltage gradient, especially at the ventricular level, that is responsible for re-entrant arrhythmias.3 The genes responsible for the disease that have been described to date are the following: genes that encode for potassium channels, KVLQT1 and minK, which interact to form the cardiac IKs current;10 HERG and MiRP1, which integrate to form the IKr current;11 and the gene that encodes for the sodium channel SCN5A,12 which has also been linked to Brugada syndrome13 and familial conduction disease14. There is still one gene that has not been identified, LQT4, which is present on chromosome 4.15 The autosomal recessive forms of the disease have been linked to mutations in the genes that encode for the IKs current, KVLQT1 and minK.16 In order to develop dominant disease, patients must inherit a mutation from both parents.

Genetic therapy

Since the different channels were identified and an understanding of their function was obtained from functional analysis, investigators have been considering the possibility of a therapy aimed at the specific channel affected. Some researchers have used this information to guide specific therapy to the defect. Sodium blockers have been used by different investigators to reduce repolarization abnormalities in a few patients with long-QT syndrome. The use of mexiletine17 in patients with sodium-channel mutations and the use of intravenous potassium18 in patients with mutations in the HERG potassium channel have achieved electrocardiographic improvement of the QT interval. However, these studies are too small to draw any conclusions as to whether improving the QT interval with antiarrhythmic agents would actually decrease the incidence of sudden death in this disease. While preliminary, these first studies are an important step toward genetic therapy.


Since its initial description in 1992, the syndrome of right bundle-branch block, ST-segment elevation in V1 to V3, and sudden death («Brugada syndrome») is gaining recognition worldwide.19 Its diagnosis is clinical-electrocardiographic and based on syncopal or sudden death episodes that occur in patients with a structurally normal heart and characteristic ECG pattern. Episodes of syncope and sudden death (aborted) are caused by fast polymorphic ventricular tachycardia.

It has been known for many years that there is an abnormally high incidence of sudden death in some Southeast Asian countries.20 The fatal event usually appears at night and only affects males. It is known as Sudden Unexpected Death Syndrome (SUDS). The incidence of this form of sudden death has been estimated at 26 to 38 per 100 000 inhabitants per year. In countries like Thailand, it is the most common cause of death in persons under 50, second only to traffic accidents. It has only recently been discovered that SUDS patients suffer from Brugada syndrome.21

While the average age of cardiac events is 40 years, sudden death can strike at any age. Actually, in the original publication, the first patient ever seen was only 2 years old when he had his first cardiac arrest. His sister, who had the same ECG pattern, had died at the same age a few years earlier.19 The observation that this disease can cause death in very young children has been confirmed recently by other investigators.22

Some cases of the syndrome are genetically determined. So far, the pattern of transmission described is autosomal dominant. Genetic defects have been described in the cardiac sodium channel SCN5A,13 the same gene that causes LQT3. Many mutations have been reported to date. As is the case with other familial cardiac diseases, some of the families studied are not linked to the gene, indicating that it is genetically heterogeneous. Basic functional analysis in Xenopus oocytes have shown interesting results compared with mutations causing LQT3. While the functional defect in the sodium channel in LQT3 is incomplete inactivation, which allows continuous leakage of Na ions into the cell, in Brugada syndrome the Na channel is more rapidly inactivated, leaving the Ito potassium current unopposed in phase 1 of the action potential.23 Nevertheless, the end result in both LQT3 and Brugada syndrome is the same, the generation of a voltage gradient and substrate for reentrant arrhythmias. Further electrophysiological studies have shown that the function of the mutated channel worsens at temperatures approaching physiological range.24 This observation has clinical implications because many patients suffer cardiac arrest during febrile episodes.

The identification of the persons at risk is complicated by the variability of the electrocardiogram, which can normalize over time. For the same reason, it is difficult to estimate the real prevalence of the disease.25 The use of modulators has improved the diagnosis of these individuals. Intravenous ajmaline, flecainide, or procainamide are very sensitive and specific for the identification of carriers with a normal ECG, at least among persons with a mutation in SCN5A.26

Since the initial description of individuals with sudden death, the ECG pattern has been recognized in symptomatic and asymptomatic family members and in patients with a persistent or variable EKG pattern. While clinical observations have shown that persons who are not inducible during EP testing or require IV antiarrhythmic agents to elicit the EKG probably have a better prognosis,27 but it is still a very premature conclusion and requires further follow-up.

No pharmacological therapy has been shown to be useful in the prevention of sudden death in these individuals. Only implantable defibrillators have been beneficial.

Familial polymorphic ventricular tachycardia

Calcium channels are critical to normal cardiac function. They are involved in the generation of the action potential and in myocyte contraction, making calcium a key ion in excitation-contraction coupling. Calcium intervenes in the depolarizing current to create the plateau, or phase 2 of the action potential, trigger the release of calcium from the sarcoplasmic reticulum, and activate the cardiac contractile apparatus. The sarcoplasmic reticulum (SR) functions primarily as an intracellular store of calcium in skeletal muscle cells.

Experience with other ion channels and diseases caused by channel defects prepared the way to hypothesize that defects in proteins interacting with calcium could also impair cardiac electrical and contractile function. This process starts in the cell membrane, where few calcium ions enter the cell through the voltage-gated L-type calcium channels during phase 2 of the action potential. These channels are in close proximity to the calcium-release channels of the sarcoplasmic reticulum, also called ryanodine receptors, and are activated by incoming calcium. Calcium ions then bind to troponin C and initiate the contraction process in the sarcomere. The ryanodine receptor in the sarcoplasmic reticulum of most muscle cells (smooth, cardiac, skeletal) is then a Ca+2-activated Ca+2 channel. In other words, the Ca+2 that enters the voltage-gated Ca+2 channel from outside the cell triggers the opening of the Ca+2-release channel, resulting in an efflux of Ca+2 from the sarcoplasmic reticulum into the cytoplasm.

In the heart, RYR2 is also associated with two different diseases, arrhythmogenic right ventricular dysplasia type 2 (ARVD2)28 and familial polymorphic ventricular tachycardia (FPVT).29

FPVT is also an autosomal-dominant inherited disease with a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by runs of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease.

What is most intriguing is how the same gene can cause these two cardiac diseases, keeping in mind that there is an important difference between them. ARVD2 is accompanied by structural abnormalities that are absent in FPVT. Whether this is due to the effect of the mutations, genetic background, or some other environmental modifiers has yet to be determined.


A balance between structural and ionic components is required for the orderly propagation of the electromechanical impulse through the myocardial cells. When structural heart disease or genetic or iatrogenic factors modify this interaction, the result can be chaotic electrical activity, or fibrillation, which can affect any chamber of the heart, atria or ventricles. Atrial chaos, or atrial fibrillation (AF), is defined as an erratic activation of the atria, causing an irregular heart rhythm at the ventricular level. AF continues to be the Achilles´ heel of cardiac rhythmology. Despite the overall advance in the treatment of the cardiac dysrhythmias with the introduction of radiofrequency ablation, therapeutic options in AF have remained largely unchanged and are aimed at controlling heart rate and providing anticoagulation. New surgical and ablation techniques are being developed but, while promising, they are still extremely laborious and available to only a handful of patients.

Genetic background

In humans, research efforts to elucidate the molecular basis of AF focus on three main areas: genetic defects that cause familial forms of atrial fibrillation, genetic backgrounds that predispose to the disease, and disturbances in the gene expression of ion-channel currents that are involved in the formation of the atrial action potential. Research into the gene expression of ion-channel currents should provide some understanding on the molecular changes triggered by the disease and may explain some of the mechanisms that perpetuate the arrhythmia in chronic form. However, it will be very difficult to prove whether the molecular changes that occur in the atria cause the disease or are one of its consequences. This hypothesis could be clarified in part by identifying the genetic defects that cause the familial form of the disease. In this case, the genetic defect triggers the development of the pathology and provides definitive insight into the etiology of the disease.

Atrial fibrillation as a monogenic disease

It is not generally appreciated that AF may be familial. It was first reported as a familial form in 1943. In 1996 we identified five families with hereditary AF and an autosomal dominant pattern of transmission.30 These families had a total of 103 members, 42 of which had AF. The age of diagnosis of the arrhythmia ranged from 1 to 45 years. The penetrance of the disease was very high; in latter generations three members were diagnosed in the first month of life.

Using linkage analysis techniques, we were able to identify an area of 28 cM in chromosome 10q22, which was secreted by the affected individuals. Analysis of other families from the same geographic area confirmed linkage and gave us an opportunity to narrow the region to around 800 000 base pairs, thus allowing us to undertake positional cloning to identify the gene and the underlying mutation. At this point, eight genes have been identified in the area and are presently being characterized.

Since the beginning of the project, we have collected more than 100 probands with familial AF and we have finished the phenotypic characterization in 32 families. The analysis of these families has shown that AF is a heterogeneous disease that is caused by more than one gene.31


The first gene responsible for causing a cardiac disease was discovered only ten years ago. Genetics has tremendous potential in all fields of medicine, as well as cardiology. In 10 years we have learned a great deal about the pathophysiological mechanisms involved in monogenic diseases. With the Human Genome Project, several new lines of research and molecular interactions have opened, which will be targeted to improve therapy. Ten years have passed, but this is just the beginning.

Dr. R. Brugada.
Assistant Professor of Medicine. Baylor College of Medicine.
One Baylor Plaza, 533D. Houston, TX 77030. USA.


1. Marian AJ, Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 1995;92:1336-419.
2. Olson TM, Michels VV, Thibodeau SN, Tai YS, Keating MT. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 1998;280:750-2.
3. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps and future directions. Circulation 1996;94: 1996-2012.
4. Li D, Czernuszewicz GZ, González O, Tapscott T, Karibe A, Durand JB, et al. Novel cardiac troponin T mutation as a cause of familial dilated cardiomyopathy. Circulation 2001;104:2188-93.
5. Brugada R, Roberts R. Brugada syndrome: why are there multiple answers to a simple question? Circulation 2001;104:3017-9.
6. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, function heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957;54:59-68.
7. Romano C, Gemme G, Pongiglione R. Arritmie cardiache rare in eta pediatrica. Clin Pediatr 1963;45:656-83.
8. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc 1964;54:103-6.
9. Keating MT, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991;252:704-6.
10. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. KVLQT1 and IsK (minK) proteins associate to form the Iks cardiac potassium current. Nature 1996;384:78-80.
11. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 1995;81:299-307.
12. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-11.
13. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature 1998;392:293-6.
14. Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, et al. Cardiac conduction defects associate with mutations in SCN5A. Nature Genetics 1999;23:20-1.
15. Schott JJ, Charpentier F, Peltier S, Foley P, Drouin E, Bouhour JB, et al. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet 1995;57:1114-22.
16. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, et al. A novel mutation on the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genet 1997;15:186-9.
17. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na channel blockade and to increases in heart rate. Circulation 1995;92:3381-6.
18. Compton SJ, Lux RL, Ramsey MR. Genetically defined therapy of inherited long-QT syndrome. Circulation 1996;94:1018-22.
19. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol 1992;20:1391-6.
20. Baron RC, Thacker SB, Gorelkin L, Vernon AA, Taylor WR, Choi K. Sudden death among Southeast Asian refugees: an unexplained nocturnal phenomenon. JAMA 1983;250:2947-51.
21. Nademanee K, Veerakul G, Nimmannit S, Chaowakul V, Bhuripanyo K, Likittanasombat K, et al. Arrhythmogenic marker for the sudden unexplained death syndrome in Thai men. Circulation 1997;96:2595-600.
22. Priori SG, Napolitano C, Giordano U, Collisani G, Memmi M. Brugada syndrome and sudden cardiac death in children. Lancet 2000;355:808-9.
23. Antzelevitch C. The Brugada syndrome: ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268-72.
24. Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 1999;85:803-9.
25. Brugada J, Brugada R, Brugada P. Right bundle branch block and ST segment elevation in leads V1-V3: a marker for sudden death in patients with no demonstrable structural heart disease. Circulation 1998;97:457-60.
26. Brugada R, Brugada J, Antzelevitch A, Kirsch GE, Potenza D, Towbin JA, et al. Sodium channel blockers identify risk for sudden death in patients with ST segment elevation and right bundle branch block but structurally normal hearts. Circulation 2000;101:510-5.
27. Brugada P, Geelen P, Brugada R, Mont L, Brugada J. The prognostic value of electrophysiologic investigation in Brugada syndrome. J Cardiovasc. Electrophysiol 2001;12:1004-7.
28. Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001;10:189-94.
29. Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 2001;103:485-90.
30. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias AM, Mont L, et al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med 1997;336:905-11.
31. Brugada R, Bachinski L, Hill R, Roberts R. Familial atrial fibrillation is a genetically heterogeneous disease. J Am Coll Cardiol 1998;31:349A.

1885-5857/© 2002 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved

To improve our services and products, we use cookies (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.
Cookies policy
To improve our services and products, we use cookies (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.