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Prof. Josep Brugada
Molecular biology and genetics are giving and will continue to give new insights into the development of cardiac diseases. Arrhythmias like AF will undoubtedly benefit from the discovery of the genes that cause the familial forms of the disease and from the understanding of the altered gene expression as a consequence of it.
The interaction of all these genes with the structural cardiac abnormalities will probably shed light not only on the factors that induce the first episode but on the determinants that prolong this episode into a chronic form.
Limited success in the therapy of AF is partly due to our poor understanding of its molecular pathophysiology. Advances in genetics and molecular biology are likely to give new insights into the development of the disease. AF is the most common sustained arrhythmia encountered in clinical practice. Its prevalence increases with age to about 6% in people over the age of 65. The disease doubles the mortality and accounts for over one third of all cardioembolic episodes. In addition, AF is usually associated with cardiac pathology including hypertensive heart disease, cardiomyopathy, valvular disease, or atherosclerotic cardiovascular disease. AF can be transient (paroxysmal) or persistent. Paroxysmal AF accounts for 35-40% of all cases of AF seen by physicians and is not a benign entity in individuals with underlying cardiac pathology. The disease carries a high mortality and high incidence of stroke, and despite it being a self-terminating arrhythmia, there is a 30-50% chance of it converting to a chronic state depending on the underlying pathology. In some instances, especially in the young, the disease has no apparent etiology, and is called “lone” AF. In the “lone” AF group falls the familial forms of the disease, in which a genetic basis and no cardiac pathology are the main characteristics. Limited studies have shown that the familial form has also a higher risk of embolism after the age of 65, data supports the use of anticoagulation in these individuals .
Several elements are needed for a coordinated cardiac activity. Among them, ion currents, ion channels, structural proteins and gap junctions, which are responsible for the transmission of the electrical and mechanical impulse across the cardiac myocites. The complexity of this process continues to be a tremendous limitation to our understanding of arrhythmogenesis. With the incorporation of molecular biology in cardiology, we are able to resolve some of the challenges. The discovery of the structure of the ion channels, their function and pathophysiology have helped unravel part of the role played by the different ionic currents in both the electrical activity and electromechanical coupling. While basic mechanisms of arrhythmia have been provided by the functional analysis of the ion channels involved in the generation of the cardiac action potential, it has not been until the development of genetics and the discovery of mutations causing familial diseases that we have been able to jump from the most basic level to the clinical arena. Cardiac arrhythmias predisposing to sudden death, like Long QT, Short QT and Brugada syndrome, have benefited tremendously from the advances in genetics and molecular biology. Most importantly, these discoveries have provided the possibility for genetic diagnosis. These familial diseases due to a single gene, despite being rather uncommon, allow the study of a pure form of a disease, in which a single abnormal protein is the trigger responsible for the arrhythmogenecity. Atrial Fibrillation was first reported as a familial form in 1943 , and while it is probably very uncommon, there has been no systematic study to determine the overall prevalence of the disease. With techniques of linkage analysis in 5 large Spanish families, a locus was identified in 10q22, which was segregating with the affected individuals . The gene has not been identified yet. The first gene for atrial fibrillation has been identified in the last months. A family from China was segregating the disease with a locus on chromosome 11. The analysis of KVLQT1 (KCNQ1) identified a missense mutation S140G which revealed a gain of function effect for the channel .
The familial form of AF is uncommon. The majority of the cases are acquired and related to structural abnormalities. Though, it is still important to remember that not all individuals with the same cardiac pathology develop AF, and probably, among other things, there are genetic factors that predispose for the development of the arrhythmia. Few centers have been trying to uncover some of these genetic backgrounds, but the results have been disappointing to date. Some reports [5, 6] tested the hypothesis that genetic factors that increase cardiac fibrosis would be a determinant for the development of lone AF. The investigators analysed a polymorphism in the ACE gene, an enzyme that interacts with angiotensin II and affects cardiac remodeling. The ACE gene can be inherited with an intronic deletion, which has been linked to higher circulating levels of enzyme and a higher degree of hypertrophy and myocardial fibrosis. While this cardiac fibrosis has been described at the ventricular level, they hyposthesis was that it would also affect the atria and cause the arrhythmia. No differences in the distribution of the ACE genotypes between the affected individuals and controls were found and there was no correlation with the type of AF, namely, paroxysmal or chronic and the genotype.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Girona J, Domingo A, Albert D, Casaldàliga J, Mont L, Brugada J, Brugada R. Fibrilacion auricular familiar. Rev. Esp. Cardiol 1997;50:548-551 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9340695 2. Wolf L. Familial auricular fibrillation. New Engl J Med 1943;229:396 3. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, Brugada J, Girona J, Domingo A, Bachinski LL, Roberts R. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med 1997;336:905-911 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9070470 4. Chen YH, Xu, SJ, Bendahhou S et al. KCNQ1 Gain of function mutation in familial atrial fibrillation. Science 2003, 299:251-254 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12522251 5. Yamashita T, Hayami N, Ajiki K, Oikawa N, Sezaki K, Inoue M, Omata M, Murakawa Y. Is ACE gene polymorphism associated with lone atrial fibrillation? Jpn Heart J 1997;38:637-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9462412 6. Nakai K, Itoh C, Miura Y, Hotta K, Musha T, Itoh T, Miyakawa T, Iwasaki R, Hiramori K. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese. Circulation 1994;90:2199-202. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7955173
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