Post-operative atrial fibrillation (POAF) is the most common complication following cardiac surgery. POAF increases morbidity and mortality after surgery, increases length of stay in the ICU and hospital, and increases risks of stroke, congestive heart failure, myocardial infarction and death. The impact on public health is substantial. In particular, POAF is a problem of the elderly, because the need for cardiac surgery, and the incidence, morbidity and mortality of POAF all increase as a function of age. Currently available preventative strategies still allow a 30% incidence of POAF. To combat this problem, we propose gene therapy as a new strategy to prevent POAF. We have efficacy and safety data in a pig model of POAF that shows prevention of sustained AF for 2 weeks after atrial gene painting of AdKCNH2-G628S, a time that coincides with the window of risk for POAF. We saw no proarrhythmia or other negative effects after atrial gene painting. Here, we propose formal preclinical testing of AdKCNH2-G628S with the following specific aims: (1) to successfully complete a dose-ranging study that defines minimum effective dose, and (2) to successfully complete a formal preclinical biodistribution and toxicology testing that defines maximum safe dose. Successful completion of these aims will complete the necessary preclinical testing before moving this potential life-saving therapy to clinical trial.

Public Health Relevance

Atrial fibrillation after cardiac surgery (post-op AF) is the most common complication of those procedures. For patients older than 70, almost 50% will develop post-op AF, and for those over 80 year old, greater than 60% will have post-op AF. These patients stay in the intensive care unit and in the hospital longer, they die sooner, and they have more strokes, heart attacks and respiratory failure than patients without AF. The impact on public health is equally substantial, with considerable expense related to the complications caused by post-op AF. Adding to the problems caused by AF is the lack of fully effective preventive therapies for this rhythm disorder. This proposal focuses on formal preclinical testing of a new therapy for post-op AF. We have preliminary data showing that gene therapy can eliminate AF. In this proposal, we will assess minimum effective dose and maximum safe dose for this therapy before contemplating clinical trial.

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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Zieman, Susan
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University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
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Finet, J Emanuel; Wan, Xiaoping; Donahue, J Kevin (2018) Fusion of Anthopleurin-B to AAV2 increases specificity of cardiac gene transfer. Virology 513:43-51
Donahue, J Kevin (2017) Current state of the art for cardiac arrhythmia gene therapy. Pharmacol Ther 176:60-65
Donahue, J Kevin (2016) Biological Therapies for Atrial Fibrillation: Ready for Prime Time? J Cardiovasc Pharmacol 67:19-25
Wolfram, Julie A; Donahue, J Kevin (2013) Gene therapy to treat cardiovascular disease. J Am Heart Assoc 2:e000119