Atrial fibrillation affects 3-6 million people in the US. The risk of developing AFib and other cardiac arrhythmias increases with age. Individuals over the age of 65 have a 9% chance of developing AFib with an increased risk of stroke being the primary complication. Currently there are few options for treating AFib, primarily anticoagulation therapy to prevent blood clots and medications to control heart rate but there is no ?cure?. There is evidence that common substrates link AFib with other types of arrhythmia and heart disease. For example, the risk for AF is doubled in LQTS patients and the risk of TdP is much greater in patients with AF when taking ion channel blockers suggesting that AF has an influence on the QT interval. We hypothesize that homeostasis of the dynamic chromatin steady state (a process we have termed ?chromostasis?) of heart cardiomyocytes is critical for maintenance of an appropriate gene expression program, phenotype and function at the cellular and tissue levels over the life span. Using the Drosophila cardiac model, we will identify gene networks/cellular substrates for age-related arrhythmias based on age-dependent changes in transcriptomic signatures. We will first obtain functional data on hearts from young and old wildtype and arrhythmogenic K+ channel mutant flies. Because we anticipate that epigenetic ?drift? occurs over the lifespan and is manifest at several levels we will identify transcriptomics changes in individual hearts with manifest arrhythmia and between sub-regions of individual hearts that exhibit both normal and impaired function. Subsequent bioinformatics analyses will allow us to identify genetic networks that are associated with arrhythmic cardiac function. By comparing data from the wildtype and mutant fly lines at young and old ages, we will identify gene networks that are common to both types of arrhythmia. We will subsequently screen top candidate genes as well as genes previously identified in humans as being associated with AFib. The top hits from this screen will be examined for their ability to suppress arrhythmias in old hearts and in hearts with K+ channel mutations. Identification of the substrates for age-related arrhythmias will provide testable hypotheses that can be further explored to establish targets for therapeutic intervention.

Public Health Relevance

Atrial fibrillation affects 3-6 million people in the US, the incidence of Afib increases with age and treatments are limited with no definitive cure. We propose to use the Drosophila cardiac model to identify cellular substrates for age-related arrhythmias. Identification of these cellular processes will provide testable hypotheses that can be further explored to establish targets for therapeutic intervention.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Kerr, Candace L
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Sanford Burnham Prebys Medical Discovery Institute
La Jolla
United States
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