Sudden cardiac death (SCD) due to ventricular arrhythmias is the leading cause of mortality in the United States, resulting in 250,000 deaths/year. The autonomic nervous system plays a major role in the pathophysiology of arrhythmias leading to SCD and neuraxial modulation provides an important venue for therapeutic intervention. The major goal of our research is to investigate the role of cardiac sympathetic innervations in the genesis of arrhythmias, and that of neuraxial modulation in prevention of these arrhythmias in humans. The mechanisms underlying sympathetic control of myocardial excitability in normal and diseased human hearts, and specifically, regional differences (apex versus base, epicardium versus endocardium, right versus left stellate ganglion innervation) remain unknown and need to be studied. Further, myocardial scars seen in ischemic and non-ischemic cardiomyopathy show nerve sprouting at the border zone of scars due to neural remodeling, which has been implicated in the pathophysiology of ventricular arrhythmias. The functional effects of nerve stimulation in this setting and how neuraxial blockade works in humans in these diseases are still unknown and this knowledge can help guide therapy. In this proposal, electrophysiological effects of direct regional cardiac nerve stimulation and neuraxial modulation of the thoracic sympathetic ganglia will be investigated. Areas of the heart regulated by the right and left stellate ganglia will be delineated in patients undergoing interventional electrophysiology procedures and cardiac transplantation. Understanding neuraxial modulation has the potential to further develop therapies that target these pathways in the very near term. Therapies such as right, left, or bilateral cerviocothoracic sympathectomy which has been 're-introduced'into clinical practice (by our group and others) already show a lot of promise and could emerge as novel/elegant therapies that are also cost-effective for the prevention of SCD. Therefore, neuraxial modulation is an approach that has the potential to have a global impact given the prohibitive high cost and morbidity associated with implantable defibrillators which prevent their expanded use.

Public Health Relevance

The project seeks to identify the pathways that regulate sympathetic output to the heart and study its modulation and role in ventricular arrhythmias. Ventricular tachycardia and fibrillation are thought to be the major cause of sudden cardiac death resulting in over 250,000 deaths/year in the USA. By defining the regulation of these nerves in humans we can improve the treatment of these arrhythmias and prevent sudden cardiac death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084261-07
Application #
8603270
Study Section
Special Emphasis Panel (ZRG1-CVRS-E (02))
Program Officer
Lathrop, David A
Project Start
2006-05-15
Project End
2016-12-31
Budget Start
2014-01-24
Budget End
2014-12-31
Support Year
7
Fiscal Year
2014
Total Cost
$348,763
Indirect Cost
$118,021
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
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