Genetic Autonomic Modulation In Vivo to Protect Against Oxidative Stress and Sudden Cardiac Death (SCD)
Abstract
Stress is unpleasant, even when it is transient, e.g., can make the heart pound and breathing quicken. This “fight-or-flight” response by the sympathetic nervous system triggers a cascade of stress hormones that produce well-orchestrated physiological changes throughout most organs in the body. Persistent stress is worse. Whereas transient stress can acutely improve heart function, persistent stress worsens heart function and increases free radicals causing widespread damage throughout the body that, in turn, may alter the stress response itself. This happens most often in patients with poor heart function, thereby triggering a downward spiraling cascade towards disaster. This chronic state of high stress can trigger dangerous heart rhythms known as “ventricular tachyarrhythmias (VT/VF)” that lead to sudden cardiac death (“SCD”). How chronic stress leads to SCD is poorly understood, thereby hampering the development of new and effective therapies. The only effective therapy currently available is the cardioverter-defibrillator, which prevents SCD by delivering shocks for VT/VF. However, surgical implantation of defibrillators is associated with risks, e.g., infection, expensive and palliative, and often, they deliver painful inappropriate shocks for benign rhythms. Further, most people that die from SCD do not have poor heart function. This is important because poor heart function is the best indicator currently available for identifying individuals at high risk for SCD. As such, identifying individuals at risk for SCD remains a clinical challenge and SCD continues to claim 5 million lives per year worldwide, including a large number of men and women in the military. Progress in understanding the mechanisms responsible for SCD and developing new and more effective therapies has been limited by the lack of an animal model that closely resembles the human disease. For example, chronic hypertension is the major cause of poor heart function, which in turn facilitates the triggering of spontaneous VT/VF that leads to SCD. It is rare to find an animal model that mimics this. Further, men and women may differ in the stress response associated with SCD. This has been underexplored because typically, women are underrepresented in studies and have fewer SCD events than men. Stress-induced free radicals have been strongly implicated in putative mechanisms of SCD. However, little is known about the role of free radicals in SCD because prior studies have been limited by the lack of sophisticated methods for measuring free radicals with sufficient accuracy, precision, and subcellular localization. All of these challenges are direct goals of this proposal and addressed through innovative approaches in the specific aims. A bold new systems-based approach is employed for an integrative, yet focused and detailed study of the brain-heart interactions responsible for free radical generation in single heart cells that then is translated to mechanisms as well as therapy for SCD. Our critical new preliminary data suggest that during chronic stress, failing heart cells release signaling substances that induce some of the sympathetic nerves (those releasing stress hormones in the heart) to transform (“transdifferentiate”) into nerves with parasympathetic properties, i.e., those that typically calm and protect the heart. Whether this is an intrinsic protective mechanism remains to be established. If this is truly protective, then exploiting this natural process could result in a new therapy for SCD. To test the effect of enhancing or suppressing transdifferentiation, the proposed studies use cutting-edge molecular tools to transfer genes into the heart of living animals that are at a high risk for SCD. Importantly, both male and female animals are studied, including females with surgically resected ovaries to mimic a post-menopausal state. In this context of sympathetic nerve modulation, the proposed studies also
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910640
Entities
People
- Swati Dey
Organizations
- Johns Hopkins University
- United States Army