Cardiovascular diseases such as heart failure, arrhythmias, and hypertension are leading causes of morbidity and mortality in the United States and world-wide. The autonomic nervous system plays a critical role in the pathophysiology of these diseases and neuraxial modulation provides an important avenue for therapeutic intervention. The major goal of our research team is to precisely define the cardiac neural hierarchy and develop circuit diagrams from the macroscopic to cellular and molecular levels and share these data on an ongoing basis with the scientific community. This effort will also provide verified methods and tools for assessing neuromodulation. The research team will make them freely available to the scientific community. A multiscale, multidisciplinary approach across various species, highly relevant to human disease, will be used to define the anatomy of cardiac innervation in high definition. Neural structure will be linked to cardiac function. The complexity of cardiac neural control necessitates an integrative approach that will represent a tour de force in this field. State-of-the-art anatomical, physiological, and pharmacological approaches from `cells to man' must be combined in order to achieve the above goals. This approach will be utilized at each level of the neuraxis (heart, extracardiac intrathoracic neural structures and extrathoracic neural structures). The techniques proposed will allow, for the first time, a detailed description of the anatomical and molecular interactions at the synaptic and cell body levels in cardiac and extracardiac ganglia. The techniques used and the integration of these pathways represents the most innovative attempt to understand cardiac neural control ever undertaken. Understanding these pathways has the potential to accelerate development of therapies that will be able to precisely target neural structures and also guide methods to re-purpose already available therapies (e.g. nerve stimulators) for therapeutic purposes. Ultimately, these approaches are required to develop novel, effective, and affordable interventions for the management and prevention of heart disease and sudden cardiac death.

Public Health Relevance

Cardiovascular diseases such as heart failure and sudden cardiac death are the leading cause of mortality in the United States, resulting in over 800,000 deaths a year (1 in 3 deaths). The proposed mechanistic research studies will provide much needed knowledge about the anatomy and function of the nerves that control the heart. These studies can have an immediate clinical impact, by guiding treatments to reduce mortality by controlling life threatening abnormal heart rhythms, and improving quality of life for patients with heart failure by preventing the progression of heart disease and reducing hospitalization.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Project #
3OT2OD023848-01S4
Application #
9864228
Study Section
Anatomical and Functional Mapping of the Innervation of Marjor Internal Organs (AFMI)
Program Officer
Qashu, Felicia M
Project Start
2016-09-24
Project End
2019-07-31
Budget Start
2019-04-06
Budget End
2019-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Liu, Kun; Li, Dan; Hao, Guoliang et al. (2018) Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivity. JCI Insight 3:
Hanna, Peter; Shivkumar, Kalyanam; Ardell, Jeffrey L (2018) Calming the Nervous Heart: Autonomic Therapies in Heart Failure. Card Fail Rev 4:92-98
Bayles, R G; Olivas, A; Denfeld, Q et al. (2018) Transcriptomic and neurochemical analysis of the stellate ganglia in mice highlights sex differences. Sci Rep 8:8963
Li, Anthony; Hayase, Justin; Do, Duc et al. (2018) Hybrid surgical vs percutaneous access epicardial ventricular tachycardia ablation. Heart Rhythm 15:512-519
Morotti, Stefano; Grandi, Eleonora (2018) Quantitative systems models illuminate arrhythmia mechanisms in heart failure: Role of the Na+ -Ca2+ -Ca2+ /calmodulin-dependent protein kinase II-reactive oxygen species feedback. Wiley Interdiscip Rev Syst Biol Med :e1434
Bardsley, Emma N; Davis, Harvey; Ajijola, Olujimi A et al. (2018) RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity. Sci Rep 8:8633
Grandi, Eleonora; Morotti, Stefano; Pueyo, Esther et al. (2018) Editorial: Safety Pharmacology - Risk Assessment QT Interval Prolongation and Beyond. Front Physiol 9:678
Vaseghi, Marmar; Hu, Tiffany Y; Tung, Roderick et al. (2018) Outcomes of Catheter Ablation of Ventricular Tachycardia Based on Etiology in Nonischemic Heart Disease: An International Ventricular Tachycardia Ablation Center Collaborative Study. JACC Clin Electrophysiol 4:1141-1150
Agarwal, Shailesh R; Gratwohl, Jackson; Cozad, Mia et al. (2018) Compartmentalized cAMP Signaling Associated With Lipid Raft and Non-raft Membrane Domains in Adult Ventricular Myocytes. Front Pharmacol 9:332
Davis, Harvey; Bardsley, Emma N; Paterson, David J (2018) Transcriptional profiling of stellate ganglia from normotensive and spontaneously hypertensive rat strains. Sci Data 5:180123

Showing the most recent 10 out of 25 publications