Orthostatic intolerance is the most prevalent autonomic disorder in the United States and the most common autonomic manifestation in the chronic fatigue syndrome (CFS). CFS is a common disorder of unknown cause that incapacitates young individuals in their most productive years. There is evidence that orthostatic intolerance plays a role in the fatigue of some these patients. The long-term objectives of the project are to delineate the pathophysiology and pathogenesis of orthostatic intolerance in patients with chronic fatigue;to investigate the role of orthostatic intolerance in producing the symptoms of fatigue;to use this information to institute physiologically appropriate therapeutic interventions;and thereby decrease the symptoms of fatigue. There is evidence that some patients with POTS have a restricted autonomic neuropathy (neuropathic POTS) while others have POTS unassociated with an autonomic neuropathy. The pathophysiological consequences of these two variants of POTS are not fully understood, however, it is proposed that nitric oxide availability may differ in these two subtypes. Specifically, neuropathic POTS patients may have increased nitric oxide availability whereas patients with non-neuropathic POTS may have decreased nitric oxide availability. It is not known whether nitric oxide abnormalities are merely a biological marker in POTS patients or whether the abnormalities have hemodynamic and pathophysiological significance. It is also not known whether these pathophysiological differences underlie the unsatisfactory response to therapeutic intervention in POTS patients.
The Specific Aims of the application are: in two separate experiments, we will increase and decrease nitric oxide availability, and examine the autonomic cardiovascular effects of this intervention in neuropathic and non- neuropathic POTS. We will also, in two separate therapeutic interventions, increase and decrease sympathetic tone and examine the autonomic cardiovascular effects, fatigue scores, and quality of life in response to these interventions. We anticipate that the responses to changes in nitric oxide availability and the therapeutic interventions will be different in the two POTS subtypes. Public Health Significance: Orthostatic intolerance (the postural tachycardia syndrome;POTS) is the most common autonomic manifestation in patients with chronic fatigue. We will subdivide patients with POTS in to those with and with out neuropathy and determine the role played by nitric oxide in these two subgroups. We will measure the response to therapy and the role played by neuropathy and nitric oxide in determining this response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059459-11
Application #
7876982
Study Section
Special Emphasis Panel (ZRG1-CFS-E (01))
Program Officer
Mcdonald, Cheryl
Project Start
1998-02-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
11
Fiscal Year
2010
Total Cost
$412,046
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Gibbons, Christopher H; Bonyhay, Istvan; Benson, Adam et al. (2013) Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One 8:e84716
Bonyhay, Istvan; Risk, Marcelo; Freeman, Roy (2013) High-pass filter characteristics of the baroreflex--a comparison of frequency domain and pharmacological methods. PLoS One 8:e79513
Simpson, D M; Schifitto, G; Clifford, D B et al. (2010) Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology 74:413-20
Bonyhay, Istvan; Freeman, Roy (2007) Sympathetic neural activity, sex dimorphism, and postural tachycardia syndrome. Ann Neurol 61:332-9
Gibbons, Christopher H; Freeman, Roy (2005) Orthostatic dyspnea: a neglected symptom of orthostatic hypotension. Clin Auton Res 15:40-4
Hunt, Brian E; Farquhar, William B (2005) Nonlinearities and asymmetries of the human cardiovagal baroreflex. Am J Physiol Regul Integr Comp Physiol 288:R1339-46
Bonyhay, Istvan; Freeman, Roy (2004) Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome. Circulation 110:3193-8
Sartipy, Peter; Loskutoff, David J (2003) Expression profiling identifies genes that continue to respond to insulin in adipocytes made insulin-resistant by treatment with tumor necrosis factor-alpha. J Biol Chem 278:52298-306
Sartipy, Peter; Loskutoff, David J (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci U S A 100:7265-70
Risk, Marcelo R; Lirofonis, Vasilios; Armentano, Ricardo L et al. (2003) A biphasic model of limb venous compliance: a comparison with linear and exponential models. J Appl Physiol 95:1207-15

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