Disruption or loss of axonal myelin in the central nervous system (CNS) with multiple sclerosis (MS) can lead to a myriad of symptoms including fatigue, spasticity, dizziness and vertigo, and balance and coordination problems in individuals with MS. The hypothalamus is frequently affected by MS, resulting in impaired control of autonomic and endocrine function. Autonomic dysfunction involving the genito-urinary, gastrointestinal, cardiovascular, and thermoregulatory systems are commonly observed and described in MS. Preliminary evidence suggests impairments in the neural control of blood pressure and heart rate in individuals with MS, as well as reductions in orthostatic tolerance. In addition, heat stress is known to exacerbate clinical signs and neurological symptoms of MS. Given that orthostatic tolerance is markedly reduced during heat stress in otherwise healthy individuals, in part due to impairments in arterial baroreflex control, it is likely that heat stres in this patient population would further impair neural control of cardiovascular function and orthostatic tolerance.
Two aims will examine the physiologic consequences of MS on dynamic blood pressure control (i.e., baroreflex function) and the associated control mechanisms (i.e., neural, cardiac, and peripheral vascular responsiveness), as well as orthostatic tolerance in this population: 1. Is resting arterial baroreflex function impaired in MS patients? 2. Is orthostatic tolerance and arterial baroreflex responsiveness to orthostatic challenge during thermoneutral and heat stress conditions impaired in MS patients? Important basic and clinical information will be gained from the proposed studies through the novel application of established techniques that have not been previously used in the study of this disease. The findings obtained from these studies should provide novel information about the mechanisms contributing to the impaired blood pressure response in MS patients. Understanding these mechanisms may provide valuable information to clinicians for potential treatment strategies and improve the day-to-day lives of individuals with MS. Further, important information will be garnered in regard to the potential influences of heat stress in modulating neural cardiovascular responses in MS. Overall, the findings from the proposed work have the potential to lead to development of novel therapeutic strategies targeted at countering the deleterious cardiovascular and neural alterations in individuals with MS during thermoneutral and heat stress conditions. Indeed, if as preliminary data suggest, impairments in the arterial baroreflex function are identified as the underlying mechanism for impairments in orthostatic tolerance in MS patients, we will then be able to pursue therapies/interventions that could improve blood pressure regulation and potentially offset the deleterious neural cardiovascular responsiveness that manifests with this disease.

Public Health Relevance

Autonomic dysfunction in multiple sclerosis involves cardiovascular and thermoregulatory systems leading to impairments in the control of blood pressure and heart rate, as well as reductions in orthostatic tolerance in individuals with MS. This research project will examine the consequences of MS on dynamic blood pressure control (i.e., baroreflex control of arterial blood pressure and the associated end organ responses mediated by the baroreflex control mechanisms, including neural, cardiac, and peripheral vascular responsiveness) and orthostatic tolerance not only during resting thermoneutral conditions, but also during heat stress in MS patients. The proposed studies may lead to the development of novel therapeutic strategies targeted at improving cardiovascular and hemodynamic responses during thermoneutral and heat stress conditions in MS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15HL117224-01
Application #
8434554
Study Section
Special Emphasis Panel (ZRG1-CVRS-B (90))
Program Officer
Maric-Bilkan, Christine
Project Start
2013-01-11
Project End
2014-12-31
Budget Start
2013-01-11
Budget End
2014-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$378,338
Indirect Cost
$79,654
Name
Southern Methodist University
Department
Physiology
Type
Schools of Education
DUNS #
001981133
City
Dallas
State
TX
Country
United States
Zip Code
75205
Keller, David M; Fadel, Paul J; Harnsberger, Melissa A et al. (2014) Reduced spontaneous sympathetic nerve activity in multiple sclerosis patients. J Neurol Sci 344:210-4