Mechanisms of disease: Genetic mechanisms of atrial fibrillation.
Atrial fibrillation is the most common cardiac arrhythmia, and it increases in prevalence with advancing age to about 6% in people older than 65 years. The chance of developing atrial fibrillation at age 40 years or older is about 25% in men and women. This arrhythmia accounts for about one-third of all strokes, and 30% of all patients with atrial fibrillation have a family history of the disease. In 1997, Brugada et al. identified the first locus for familial atrial fibrillation on chromosome 10q22-24 in three different Spanish families. Since that time, seven further loci have been mapped and four relevant genes identified. All these genes encode potassium-channel subunits. The mechanism of action by which all four genes induce atrial fibrillation is via shortening of the action potential duration and atrial effective refractory period. The consistency of the mechanism of action beckons the development of therapy specifically targeted to prevent these molecular events. In addition to monogenic diseases, patients with structural heart disease are predisposed to atrial fibrillation by inherited DNA polymorphisms. The development of chips with hundreds of thousands of single-nucleotide polymorphisms to perform genome-wide scans will elucidate over the next few years the single-nucleotide polymorphisms that predispose to atrial fibrillation. Within the next decade, most of the genes responsible for atrial fibrillation and the single-nucleotide polymorphisms that confer predisposition will probably be identified, and therapies will be developed on the basis of individuals' genomic profiles. In this review I provide an overview of the understanding of the relevant genetic mutations that have been identified so far, and briefly discuss what implications this information might have for practice.
Roberts
Robert
R
University of Ottawa Heart Institute, ON, Canada. rroberts@ottawaheart.ca
D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D005819:Genetic Markers; D015221:Potassium Channels; D004247:DNA