Cardiovascular disease is the leading cause of death and morbidity for individuals with spinal cord injury (SCI). The risk for cardiovascular disease is exacerbated by systemic low grade inflammation as well as abnormal and unstable cardiac and autonomic control. The enhanced inflammation is expected to be due to an attenuated cholinergic anti-inflammatory pathway (CAP). The CAP is an endogenous, physiological mechanism by which acetylcholine from the vagus nerve interacts with the innate immune system to modulate and restrain the inflammatory cascade and promote the reparative process. Accordingly, vagal plasticity, following mid-thoracic SCI (T5X), is expected to attenuate the cholinergic anti-inflammatory pathway and enhance inflammatory responses. Furthermore, the vagal plasticity, associated with SCI, is expected to be a response to pressure and volume unloading as a result of the rapid and sustained reduction in both arterial pressure and end-diastolic volume, secondary to the loss of sympathetic vasoconstrictor tone below the level of the injury. The pressure and volume unloading, is expected to unload arterial baroreceptors with resultant reduced cardiac parasympathetic activity and enhanced cardiac sympathetic activity, which causes cardiac, autonomic and immune dysfunction and structural remodeling. Finally, external lower body compression, by increasing plasma volume, arterial pressure, left ventricular pressure and cardiac output, is expected to maintain contractile function, load arteria baroreceptors and enhance cardiac parasympathetic activity and reduce cardiac sympathetic activity. As a result, cardiac dysfunction and autonomic remodeling are prevented. Furthermore, the enhanced parasympathetic (vagal) tonus is expected to augment the cholinergic anti- inflammatory pathway and attenuate inflammatory responses, and improve post-infarct cardiac remodeling. Therefore, the proposed studies are designed to test the following hypotheses: 1) External lower body compression increases plasma volume, left ventricular pressure, arterial pressure and cardiac output in conscious T5X mice. Consequently, arterial baroreceptors are loaded and enhance cardiac parasympathetic activity and reduce cardiac sympathetic activity. 2) External lower body compression, by normalizing cardiac autonomic control, prevents cardiac and autonomic structural and functional remodeling. 3) External lower body compression, by normalizing cardiac vagal control, reduces infarct expansion by attenuating the inflammatory response following myocardial ischemia/reperfusion and infarction in conscious mice. 4) Finally the responses to external lower body compression] are mediated via the ?7 subunit of the nicotinic acetylcholine receptor. The results from this proposal, using a unique model and innovative telemetric approaches for recording physiological events, have the potential to impact the lives of thousands of individuals and families living with SCI by harnessing endogenous homeostatic control systems to correct autonomic and immune dysfunction with a simple and easily administered therapeutic intervention.

Public Health Relevance

Cardiovascular disease (CVD) is now a leading cause of death and morbidity for individuals with spinal cord injury (SCI). Our long-term goal is to understand the mechanisms contributing to, as well as to develop therapeutic interventions for, the increased susceptibility to CVD following SCI. The objective of this application, which is a necessary step in pursuit of our long-term goal, is to determine the extent to which parasympathetic structural and functional neuroplastic changes within the brainstem and heart alter the cholinergic anti-inflammatory pathway and contribute to cardiovascular dysfunction following SCI. Furthermore, [we will determine the extent to which a simple and safe therapeutic intervention, external lower body compression, attenuates the cardiovascular dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122223-05
Application #
9417048
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Schwartz, Lisa
Project Start
2015-04-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Michigan State University
Department
Physiology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824