This proposal describes the five-year mentored training program designed to facilitate the career development of Kimberly Howard-Quijano MD MS into an independent physician-scientist capable of high-level scientific investigation. Dr. Howard has a long-standing interest in cardiovascular science and a demonstrated commitment to research. She is currently a junior faculty member in the division of Cardiothoracic Anesthesiology at the University of California at Los Angeles (UCLA) and has joined the laboratory of Drs. Aman Mahajan and Yibin Wang, investigating neuraxial modulation of ventricular arrhythmias. Dr. Howard has a strong background in academic science, completed a Masters of Research at UCLA, and seeks to develop a research path beginning with mentored investigations into the mechanisms of spinal control of myocardial excitability, which will lead to an independent research career devoted to investigating neuraxial therapies in treatment of ventricular arrhythmias. Sudden cardiac death (SCD) due to ventricular tachyarrhythmias is the leading cause of mortality in the United States. Neuraxial interventions at the spinal level have been demonstrated to provide an important avenue for novel therapies aimed at ventricular arrhythmias and SCD. However, the mechanisms through which neuraxial modulation are affecting myocardial arrhythmogenesis remain to be defined. The objective of this proposal is to determine how spinal cord processing of cardiac neural impulses controls ventricular excitability after Chronic MI and to explain how spinal cord stimulation (SCS) therapy works, thus providing a rational basis for optimizing its efficacy in preventing cardiac dysfunction. The central hypothesis of this proposal is that Chronic MI triggers pathologic remodeling of cardiospinal neural circuits which increase myocardial sympathoexcitation. SCS therapy reduces sympathetic output through inhibitory cardioneural pathways (e.g. GABA), reducing ventricular excitability and arrhythmias after Chronic MI. The proposed studies will use an innovative preclinical model of Chronic MI which mimics ischemic heart disease in the human condition, to address the current gap in knowledge regarding the cardiospinal neural interactions that control myocardial sympathoexcitation after Chronic MI. The results of the proposed studies with acute ischemia in chronic MI hearts (Aim 1), will establish the cardiospinal neural network through which myocardial excitability is controlled and will reveal important cellular and molecular mechanisms responsible for the abnormal excitability in the diseased heart. Understanding the spinal neural pathways, through which ischemia induces myocardial sympathoexcitation, will provide the foundation to define the neurochemical signaling pathways and molecular mechanisms through which SCS reduces cardiac arrhythmias (Aim 2). Achievement of these investigations will yield important insights into the mechanisms of neuromodulation therapies, allowing expansion of their use and further development of novel treatments to prevent cardiac dysfunction and SCD.

Public Health Relevance

Sudden cardiac death due to abnormal ventricular rhythms is the leading cause of death in the United States. After a myocardial infarction or a heart attack, imbalances in the neural signaling/communication between the heart and the spinal cord are fundamental to the development of these abnormal heart rhythms. In this proposal we will first investigate the mechanisms by which neural signals from the heart affect its electrical function during myocardial ischemia or infarction and study the novel techniques that target these adverse neural events so that we can develop the most effective therapies for preventing sudden cardiac death.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL135418-01A1
Application #
9527596
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Huang, Li-Shin
Project Start
2018-07-01
Project End
2023-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095