Project Number: 5R01HL087803-02
Principal Investigator (PI): STEWART, JULIAN M
Title: Vascular Dysfunction In CFS
Organization: NEW YORK MEDICAL COLLEGE
Abstract Text:
DESCRIPTION (provided by applicant): 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.
Other Information:
RFA/PA: PA-07-265
Study Section: ZRG1 Project Start Date: 1-APR-2008 Project End Date:
31-MAR-2012
Fiscal Year: 2009 Budget Start Date: 1-APR-2009 Budget End Date: 31-MAR-2010
Administering Institutes or Centers: NATIONAL HEART, LUNG, AND BLOOD
INSTITUTE
Project Funding Information for 2009: Total Funding: $385,700
Year Funding IC FY Total Cost by IC
2009 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $385,700
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