Novel Sex-Specific Strategy for Tuning the Fight or Flight Reflex to Reduce Oxidative Stress, Reduce Ventricular Tachyarrhythmias, and Prevent SCD
Abstract
Sudden cardiac death (SCD) from abnormal heart rhythms such as “ventricular tachyarrhythmias (VT)” claim over a quarter million lives each year in the USA, including those of men and women in the military. The link between SCD and the “fight-or-flight” stress response of the sympathetic nervous system (SNS) is quite strong. The underlying mechanisms are poorly understood, thereby limiting the design of new, more effective therapies. Implantable cardioverter-defibrillators (ICDs), the only effective therapy, prevent SCD by delivering shocks for VT. However, ICDs do not reverse or prevent the underlying disease. While poor heart function is currently the best available clinical indicator for receiving an ICD, its use as a risk stratifier for primary prevention of SCD results in an abysmally low rate of appropriate ICD therapy (~5% per year). Thus, many patients are exposed to ICD-related risks (e.g., infection, inappropriate shocks) without deriving health benefit. While this poses a large socioeconomic burden, current clinical indicators also fail to identify the majority of SCD victims who typically do not have a history of poor heart function and remain asymptomatic until catastrophic clinical presentation. Men and women also differ in the stress responses associated with SCD. This has been underexplored because women have typically been underrepresented in studies of SCD. Indeed, SCD is the leading cause of death during military training in young premenopausal women with structurally normal hearts. The need for improved SCD risk stratification and therapy remains a clinical, research, and public health priority. Progress has been limited by the lack of a suitable animal model that resembles human SCD. For example, chronic stress causes high blood pressure, which is the most common cause of poor heart function and SCD in humans. It is rare to find an animal model that mimics this. Through a prior Department of Defense award, the Principal Investigator (PI) and Co-PI have collaboratively developed male and female animal models that uniquely mimic human stress-induced SCD. Further, we developed sophisticated new tools and identified critical new regulators of the SNS. About 90% of the SNS input to the heart originate from the “stellate ganglia,” a bundle of nerve cells in front of the last cervical vertebrae. Our recent publication in Circulation Research showed that stress-induced hyperactivity of the stellate ganglia increases free radicals in the heart, leading to electrical instability and SCD. We further identified that stress causes heart cells to release signaling molecules that transform (“transdifferentiate”) SNS nerves from the stellate ganglia into nerves with parasympathetic (PSNS) properties (i.e., those that typically calm the heart). Our preliminary studies reveal, for the first time, that transdifferentiation is a natural response to stress that protects against SCD. Our provocative new findings add a new dimension to the classical teaching that the SNS and PSNS are discrete in structure, function, and connections, and how their change (“plasticity”) during stress impacts SCD. We exploited these fundamental new insights to design and validate novel artificial intelligence (AI) signal processing algorithms for robust, rapid, and highly accurate detection of electrical instability and predicting imminent SCD in our animal model, and in large multicenter prospective human studies. Leveraging these powerful new tools, we hypothesized that during chronic stress, AI-based modulation of stellate ganglia activity reduces free radicals and SCD while optimizing cardiac function in freely ambulating animals. In the proposed studies, we will determine how modulating stellate ganglia activity in male and female animals during chronic stress affects transdifferentiation, free radicals, heart function, and SCD risk (Aim 1). Because permanent activation or inhibition of SNS activity can have del
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010701
Entities
People
- Swati Dey
Organizations
- United States Army
- Vanderbilt University