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Autonomic remodeling and modulation as mechanism and therapy for spontaneous sudden cardiac death

Crocker, Jeffrey
http://orcid.org/0000-0003-3315-6602
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1669649024849304

Abstract Details

2022, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
Ventricular tachyarrhythmias resulting in sudden cardiac death (SCD) continue to claim over 350,000 lives per year in the United States. Though several modes of treatment exist, these are palliative and do not address the root pathology of the disease. Treatment is further complicated by adverse side effects which increase mortality and decrease patient quality of life. Recent clinical trials have explored vagus nerve stimulation (VNS) as a potential therapy for patients with heart failure, though findings are mixed. VNS has yet to be explored in the context of SCD in the clinical setting. VNS has been shown to augment antioxidant capacity and may confer protection from ROS-induced cardiac remodeling, preventing SCD. However, VNS is known to decrease cardiac contractility and heart rate while prolonging ventricular repolarization, all of which could exacerbate symptoms of heart failure, increasing patient susceptibility to SCD. To better discern whether VNS is a potential candidate for patients with heart failure or SCD, insight into the molecular mechanisms of both VNS and SCD is essential. The results of this dissertation suggest that vagal signaling is cardioprotective. Using a unique guinea pig model of SCD, it was observed that animals dying from SCD experienced tachyarrhythmias resulting from prolonged and disperse ventricular repolarization, both of which are hallmarks of SCD. Further, animals that did not reach premature endpoints in the SCD group were observed to have undergone cardiac remodeling, resulting in prolonged and heterogeneous cardiac conduction. Reactive oxygen species (ROS) have been shown to play a critical role in the mechanism of SCD, leading to widespread damage, electrical instability, and cardiac electromechanical dysfunction. Using a ROS scavenger, we were able to abolish arrhythmia in ex vivo failing hearts. Importantly, studies have found that vagal stimulation confers anti-oxidant activity, suggesting a potential means of alleviating ROS-related damages to the cardiac environment. Administration of a parasympathomimetic, carbachol, rescued arrhythmia in sham animals. Although SCD animals treated with optogenetic afferent VNS appear to experience prolonged QT intervals, the salutary effects of VNS may help to stabilize the QT interval, decreasing dispersion of repolarization and lowering SCD risk through boosted antioxidant signaling. In summary, this dissertation further characterizes the guinea pig SCD model and provides preclinical insight into how VNS therapy may affect not only pre-existing heart failure patients, but also those at risk of SCD.
Roger Worrell, Ph.D. (Committee Member)
Karthickeyan Chella Krishnan, Ph.D. (Committee Member)
Margaret Powers-Fletcher, Ph.D. (Committee Member)
Sarah Pixley, Ph.D. (Committee Member)
Onur Kanisicak, PhD (Committee Member)
244 p.
Physiological Psychology
sudden cardiac death; vagus nerve stimulation; reactive oxygen species; arrhythmia; autonomic dysfunction; optogenetics

Recommended Citations

Citations

  • Crocker, J. (2022). Autonomic remodeling and modulation as mechanism and therapy for spontaneous sudden cardiac death [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1669649024849304

    APA Style (7th edition)

  • Crocker, Jeffrey. Autonomic remodeling and modulation as mechanism and therapy for spontaneous sudden cardiac death. 2022. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1669649024849304.

    MLA Style (8th edition)

  • Crocker, Jeffrey. "Autonomic remodeling and modulation as mechanism and therapy for spontaneous sudden cardiac death." Doctoral dissertation, University of Cincinnati, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1669649024849304

    Chicago Manual of Style (17th edition)

ucin1669649024849304
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This open access ETD is published by University of Cincinnati and OhioLINK.