Novel genetics and insights related to supraventricular arrhythmias

Keith C. Ferdinand, MD

Tulane University School of Medicine

Cardiology Review® Online, August 2008, Volume 25, Issue 8

One of the many highlights of the 21st Annual Scientific Sessions of the Association of Black Cardiologists held in Chicago, Illinois, on March 29, 2008, was a discussion held by Dawood Darbar, MD, PhD, Assistant Professor of Medicine and Pharmacology, Vanderbilt University, Nashville, Tennessee. Dr Darbar identified 2 prevailing mechanisms underlying atrial fibrillation (AF) and discussed the role of genetics. He also listed ion channel genes that have been linked with familial AF and discussed the role of common polymorphisms in identifying individuals at increased risk for developing AF.

As a basis for his discussion, he noted that therapeutic options for most AF patients are suboptimal and that the etiology of AF remains elusive. AF is often considered to occur secondary to other conditions; however, up to 30% of patients have no obvious cause and are thought to have idiopathic or lone AF. Dr Darbar indicated that clinical and basic investigation suggests that the mechanisms underlying AF are heterogeneous, with multiple factors contributing to the initiation or maintenance of the arrhythmia. Furthermore, there is increasing support for a prominent familial component to AF. Dr Darbar noted that identification of genetic loci for AF may provide further insight into the pathophysiology of this common condition and help identify novel therapeutic strategies. While isolated kindreds with familial AF have been reported, the genetic contribution to AF is underappreciated and may actually be much more common. For instance, in the Framingham Heart Study, 30% of subjects with AF had a parent with this condition. In a Mayo Clinic study, 15% of lone AF patients had a positive family history.

Dr Darbar suggested that while most clinicians are aware that AF is a heterogeneous disease, a better way to classify AF must be devised before the common AF genes can be identified. One way to do this is by identifying intermediate or endophenotypes that cosegregate with the AF phenotype. Such intermediate phenotypes include signal-averaged P-wave duration, pulmonary vein morphology, and biomarkers, such as the natriuretic peptides.

Dr Darbar proceeded to discuss the reasons why identifying common AF genes has been difficult. One factor is reduced penetrance, such that not all members of a family who carry the AF gene manifest the disease because additional genes or environmental triggers (such as high blood pressure) are required before a person develops AF. Another reason relates to the sporadic or paroxysmal nature of AF and the fact that not all patients have arrhythmia symptoms. Nevertheless, Dr Darbar contended that identifying causal genes may be aided by intermediate phenotypes and markers for a reduced AF threshold, which may be both clinically useful and also accelerate identification of common AF genes. So far, the genes that have been shown to cause AF have been ion channel genes, and AF has been called an “ion channelopathy.” Importantly, defects in these ion channels have shown that shortening of the cardiac action potential predisposes individuals to developing AF. For instance, during the lecture, it was noted that genes that encode for subunits of cardiac K+ channels and for a majority of mutations have been identified, and that these genes confer a gain-of-function with shortening of the atrial action potential duration and atrial effective refractory period. The first gene linked with AF is KCNQ1, a cardiac K+ channel gene, discovered in a very large Chinese four-generation family, which included 16 family members with AF. The age of onset was extremely variable in these individuals, and not only did they have AF, but also appeared to have a prolonged QT interval on the electrocardiogram, suggesting their genetic defect may also affect the ventricle. Furthermore, 2 common variants on chromosome 4q25 have recently been identified that increase the risk of AF. Importantly, these common variants are very close to a gene that is critical for the development of the left atrial pulmonary myocardium. Although multiple polymorphisms have been associated with AF, the precise physiologic effect of each polymorphism is unclear. Nevertheless, they appear to predispose some individuals to AF.

Dr Darbar concluded by noting that familial AF is clinically and genetically a heterogeneous disease and that phenotype classification is the key to unraveling mechanisms and identification of AF genes. Although numerous AF loci have been identified, the major AF genes remain elusive. Overall, common AF is likely the result of complex interactions of several genes with environmental triggers, which lower the threshold for developing AF. Improved understanding of the molecular basis of AF may lead to new therapeutic strategies for prevention and treatment of this common and morbid condition.