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USING GENE THERAPY TO PREVENT ATRIAL FIBRILLATION

Liu, Zhao
http://orcid.org/0000-0002-9847-7098
http://rave.ohiolink.edu/etdc/view?acc_num=case1481231548493874

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Postoperative AF (POAF), a specific form of AF, is the most common complication after cardiac surgery. Current therapies are suboptimal with a limited efficacy and significant toxicity, suggesting the need to develop novel and more effective therapies. Gene therapy becomes an attractive alternative to prevent or ablate AF. AF is considered to be sustained by reentrant mechanisms that are promoted by atrial remodeling. We studied the two major forms of atrial remodeling: structural and electrical remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a role in structural remodeling in several tissues, but its role in sustaining AF remains undefined. We tested the hypothesis that increased CaMKII activity is a cause of structural remodeling in AF. We assessed the effects of CaMKII inhibition in our porcine AF-heart failure model after atrial gene transfer with an adenovirus encoding a potent and specific inhibitor of CaMKII (the inhibitory peptide CaMKIIn). Inhibition of CaMKII preserved atrial contractile function and attenuated atrial structural remodeling, including hypertrophy, fibrosis and apoptosis but did not affect inflammation or myolysis. These observations were accompanied by significantly decreased phosphorylation of HDAC4 and decreased expression of p38MAP-Kinase, but no change in JNK or ERK1/2. Action potential duration (APD) shortening is an important aspect of electrical remodeling. Our previous work showed that KCNH2-G628S gene therapy eliminated AF by prolonging APD. In this study, we examined the efficacy and safety of KCNH2-G628S gene therapy to prevent POAF. We found that the gene transfer reduced AF burden without any evident toxicity in extensive safety analysis. The timing of adenovirus-mediated gene expression is such that the method can be directly applicable to prevent POAF, which supports further study in a Phase I clinical trial. Furthermore, to improve the efficiency and accuracy of histological analysis, we developed and validated automatic and semi-automatic image processing algorithms. In summary, this work demonstrated that in a clinically relevant large mammalian model of persistent AF and heart failure, gene therapy successfully disrupted atrial structural and electrical remodeling and prevented AF.
J. Kevin Donahue (Advisor)
Andrew Rollins (Committee Chair)
Xin Yu (Committee Member)
Kenneth Laurita (Committee Member)
David Van Wagoner (Committee Member)
175 p.
Biomedical Engineering
Atrial fibrillation; gene therapy; atrial remodeling; CaMKII; post-operative atrial fibrillation; electrophysiology; KCNH2

Recommended Citations

Citations

  • Liu, Z. (2017). USING GENE THERAPY TO PREVENT ATRIAL FIBRILLATION [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1481231548493874

    APA Style (7th edition)

  • Liu, Zhao. USING GENE THERAPY TO PREVENT ATRIAL FIBRILLATION . 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1481231548493874.

    MLA Style (8th edition)

  • Liu, Zhao. "USING GENE THERAPY TO PREVENT ATRIAL FIBRILLATION ." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481231548493874

    Chicago Manual of Style (17th edition)

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© 2017, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.