Postural tachycardia syndrome (POTS) often afflicts younger CFS patients. We classified POTS patients into three flow regimes - low, normal, and high flow based on supine blood flow. Data suggest the involvement of nitric oxide (NO) and angiotensin in producing redistributive hypovolemia and sympathoexcitation. The overall objective of the application is to define mechanisms of CFS/POTS related to bioavailable NO, and to explore the subclinical microvascular abnormalities in CFS without POTS (CFS/~POTS). We will subset CFS patients (16-29 years) by POTS using upright tilt, and subgroup POTS based on peripheral blood flow. We will compare low flow POTS (N=30) and normal flow POTS (N=30), to CFS/~POTS (N=30) and control (N=30) with and without POTS to explore the following hypotheses: 1) Low flow CFS/POTS is due to decreased bioavailable NO produced by nNOS related to increased angiotensin-II (A-II) and oxidative stress. This increases isoprostanes, 3- nitrityrosine, and IL-6 increasing angiotensinogen. We will measure skin blood flow with laser flowmetry, NO and its metabolites by intradermal microdialysis, and use local heating (nNOS dependent) and acetylcholine response (eNOS dependent) combined with isoform selective NOS inhibitors to demonstrate isoform dependence of low flow CFS/POTS. We will test whether A-II receptor blocker, losartan, corrects cutaneous flow. 2) Oral losartan increases regional circulation and cutaneous microvascular NO dependent responses in low flow CFS/POTS. We will simultaneously measure regional blood flows/volumes, and perform cutaneous local heating and acetylcholine before and after losartan administration in low flow CFS/POTS patients. 3) NO is increased in normal flow CFS/POTS producing nitrosative stress. As in 1) we will measure NO and use local heating and acetylcholine response combined with isoform selective NOS inhibitors to ascertain isoform dependence of normal flow CFS/POTS. Cutaneous somatostatin administration can reduce skin NO excess. 4) Subcutaneous octreotide, a somatostatin analog, reduces orthostatic splanchnic pooling and cutaneous microvascular NO dependent responses in normal flow CFS/POTS. We will smeasure changes in regional blood flows and blood volumes, and perform cutaneous local heating and acetylcholine dose-response before and after octreotide administration and during tilt in normal flow CFS/POTS patients. Blood flow abnormalities associated with the postural tachycardia syndrome (POTS) produce major disability in younger CFS patients. These may be due to defects in a fundamental signaling molecule called nitric oxide (NO). In the current application we will determine how NO produces POTS in CFS patients and whether drugs that alter NO can improve patient health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087803-03
Application #
7790653
Study Section
Special Emphasis Panel (ZRG1-CFS-E (01))
Program Officer
Thrasher, Terry N
Project Start
2008-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$397,500
Indirect Cost
Name
New York Medical College
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Ross, Amanda J; Ocon, Anthony J; Medow, Marvin S et al. (2014) A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (Lond) 126:289-96
Stewart, Julian M; Medow, Marvin S; DelPozzi, Andrew et al. (2013) Middle cerebral O? delivery during the modified Oxford maneuver increases with sodium nitroprusside and decreases during phenylephrine. Am J Physiol Heart Circ Physiol 304:H1576-83
Schwartz, Christopher E; Medow, Marvin S; Messer, Zachary et al. (2013) Spontaneous fluctuation indices of the cardiovagal baroreflex accurately measure the baroreflex sensitivity at the operating point during upright tilt. Am J Physiol Regul Integr Comp Physiol 304:R1107-13
Medow, Marvin S; Aggarwal, Arun; Baugham, Ila et al. (2013) Modulation of the axon-reflex response to local heat by reactive oxygen species in subjects with chronic fatigue syndrome. J Appl Physiol (1985) 114:45-51
Stewart, Julian M (2013) Common syndromes of orthostatic intolerance. Pediatrics 131:968-80
Ross, Amanda J; Medow, Marvin S; Rowe, Peter C et al. (2013) What is brain fog? An evaluation of the symptom in postural tachycardia syndrome. Clin Auton Res 23:305-11
Shungu, Dikoma C; Weiduschat, Nora; Murrough, James W et al. (2012) Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 25:1073-87
Stewart, Julian M (2012) Update on the theory and management of orthostatic intolerance and related syndromes in adolescents and children. Expert Rev Cardiovasc Ther 10:1387-99
Ocon, Anthony J; Messer, Zachary R; Medow, Marvin S et al. (2012) Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome. Clin Sci (Lond) 122:227-38
Stewart, Julian M; Medow, Marvin S; Messer, Zachary R et al. (2012) Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. Am J Physiol Heart Circ Physiol 302:H1185-94

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