Clinical Genetic Testing for Familial Atrial Fibrillation: Is it Time?

Michael H. Gollob, MD
Director, Inherited Arrhythmia Clinic and Arrhythmia Research Laboratory
University of Ottawa Heart Institute
Ottawa, Ontario, Canada

Michael H. Gollob, MD
Director, Inherited Arrhythmia Clinic and Arrhythmia Research Laboratory
University of Ottawa Heart Institute
Ottawa, Ontario, Canada

Atrial fibrillation (AFIB), the most common sustained cardiac arrhythmia, is a growing health epidemic associated with a substantial clinical and economic burden. The direct costs for treating the arrhythmia in the United States alone have been estimated at $6.65 billion annually. This economic burden will likely grow dramatically in the coming years due in part to a rapidly expanding prevalence. Secular trends in the incidence of AFIB project that the number of affected Americans may surge from 2.3 million in 2001 to nearly 16 million by 2050.

Epidemiologic studies previously confirmed the role of genetics in the development of the arrhythmia. Data from the Framingham Heart Study has shown that a parental history of AFIB is associated with a 1.85-fold increased risk of developing the arrhythmia in offspring. The risk of developing the arrhythmia in the presence of a sibling with lone AFIB is increased 70-fold in males and 34-fold in females. Over the last 5 years, genetics research has led to a surge in the identification of genetic culprits responsible for lone, familial AFIB, or sporadic loan AFIB (Table 1). At present, 8 genes are now recognized as a cause of sporadic or familial AFIB. Most interestingly, these identified genes/proteins predict a vulnerability to AFIB by gene-specific, heterogeneous mechanisms, including the development of arrhythmogenic substrates of prolonged action potential duration (KCNQ1), shortened action potential duration and effective refractory period (KCNA5), and promotion of tissue conduction velocity heterogeneity (GJA5), and cellular hyperexcitability (SCN5A), to name a few. This heterogeneity may underlie the variable efficacy of non-specific pharmacologic, contemporary treatment strategies for AFIB, thereby reinforcing the need for improved insight into the subtypes of lone AFIB in order to facilitate targeted therapy that carries maximal efficacy and minimal risk.

This ‘pharmacogenomic approach’ as a future management strategy to AFIB is now within grasp. Clinical genetic testing for the currently known culprit genes for AFIB are now commercially available from Transgenomic, Inc. (FAMILION Familial Atrial Fibrillation Test, Transgenomic, Inc., Omaha, NE). Although yield of comprehensive genetic testing in familial AFIB cases has not been firmly established, based on individual gene studies in unselected AFIB cohorts, the estimated yield should exceed 10%. Future goals should be aimed at correlating genetic-specific subtypes of AFIB with the response to medical therapy and ablation. Such studies will require large cohorts, perhaps through registry design, but may ultimately lead to a more personalized approach to rhythm management. At the present time, clinical utility of identifying disease-causing familial mutations may be aimed at enhancing medical surveillance of asymptomatic gene carriers. This may facilitate earlier arrhythmia detection and stroke prevention and rhythm control strategies.

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