Atrial fibrillation following cardiac surgery is the most prevalent complication occurring in from 30-50% of patients. It is associated with increased mortality, increased incidence of stroke, and an increased length of intensive care unit and hospital stay. Treatment with standard antiarrhythmic therapies has failed to reduce the incidence. The long term objective of this research is to develop a treatment for postoperative atrial fibrillation that is effective, can be used in the majority of patients undergoing surgery, and has minimal side effects. In a novel canine surgical model, we have shown that there is an increased inhomogeneity of conduction and inducibility of atrial fibrillation that is dependent on the degree of inflammation and can be prevented by treatment with steroids. We will test the overall hypothesis that inflammation is a significant causative factor in postoperative atrial fibrillation.
The specific aims of this grant for this funding period are: 1) to test the hypothesis that inhomogeneous inflammation increases the inhomogeneity of atrial conduction and refractory period distribution in a canine surgical model of postoperative atrial fibrillation. 2) To test the hypothesis, that INa, Ito, Iks, and Ica,L will be downregulated and the inward NaCa exchanger current will be upregulated by inflammation and these changes are the underlying mechanisms for changes in conduction and refractory periods. To test the first hypothesis, the inhomogeneity of conduction, refractory periods, and inflammation will be determined in intact dogs preoperatively and on post operative day 2 following various surgical interventions. The experimental groups will include: control animals with no surgery;anesthesia alone;pericardotomies, atriotomies, and atriotomies with steroids. To test specific aim 2, myocytes will be isolated from the same groups of animals to record action potential and ion current densities. Data from these studies will provide a functional mechanistic framework to study the signal transduction pathways to determine where therapy can be directed to prevent the proarrhythmic changes. The study also has implications beyond postoperative atrial fibrillation. Inflammation has been implicated in non-operative atrial fibrillation. Understanding how inflammation affects the underlying substrates in postoperative atrial fibrillation may provide insights into the underlying mechanisms of non-surgical atrial fibrillation and could provide a mechanistic framework for development of novel treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085113-05
Application #
8085873
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lathrop, David A
Project Start
2007-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$353,924
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Weimar, Timo; Lee, Anson M; Ray, Shuddhadeb et al. (2012) Evaluation of a novel cryoablation system: in vivo testing in a chronic porcine model. Innovations (Phila) 7:410-6
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Schuessler, Richard B; Ishii, Yosuke; Khagi, Yulian et al. (2012) The effects of inflammation on heart rate and rhythm in a canine model of cardiac surgery. Heart Rhythm 9:432-9

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