Postural tachycardia syndrome (POTS) is the most common cause of chronic orthostatic intolerance affecting at least one million Americans. POTS is not a single disease but rather a pathophysiological category characterized by decreased cardiac venous return related to impaired vascular regulation. Our long-term objective is to identify and treat vascular dysfunction in POTS. Preliminary data indicate that POTS in the young segregates into three groups: a) reduced adrenergic-mediated vasoconstriction producing peripheral vasodilation; b) defective splanchnic venoconstriction producing venous pooling; and c) abnormal local vascular control producing peripheral arterial vasoconstriction, venoconstriction and decreased peripheral blood flow. This last group is the focus of the current proposal. We hypothesize that local vascular defects relate to endothelial dysfunction and reduced nitric oxide (NO) secretion which is demonstrable in the skin. We will identify 30 low flow POTS patients and 30 high flow POTS patients by upright tilt tests of 200 potential subjects comparing them to 30 healthy volunteers: 1) To test the hypothesis that local NO release is impaired we will use laser Doppler flowmetry (LDF) combined with reactive hyperemia and thermal hyperemia measurements (local heating to 42 degrees C) to show defective flow mediated vasodilation. We predict reduced tissue levels of NO metabolites (NOx) by microdialysis, decreased effects of the NO synthase inhibitor nitro-L-arginine (NLA) on NOx production and LDF, and blunted dose-response to cutaneous acetylcholine but not to sodium nitroprusside (SNP) as receptor mediated endothelial-dependent and independent vasodilators; we will determine if local SNP restores flow mediated hyperemia; and we will administer phentolamine to verify that adrenergic mechanisms are not the primary cause of vasoconstriction. 2) We will use intravital microscopy of the hand and foot nailbeds to test for microanatomic evidence of vasoconstriction and venoconstriction related to microvascular size or enhanced leukocyte adhesion. 3) We will test the hypotheses that calf venous hypertension, venous capacitance and venous resistance are related to local vascular dysfunction by measuring blood volume, fractional excretion of sodium, vascular capacitance, peripheral blood flow, arterial and venous resistance, and local vascular properties in the forearm and calf and relate these to microvascular measurements using venous occlusion plethysmography in the forearm and calf. Verifying these hypotheses will improve our ability to diagnose and treat an important cause of vascular pathophysiology in man.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074873-05
Application #
7448458
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Mcdonald, Cheryl
Project Start
2004-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2008
Total Cost
$369,790
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
Stewart, Julian M; Boris, Jeffrey R; Chelimsky, Gisela et al. (2018) Pediatric Disorders of Orthostatic Intolerance. Pediatrics 141:
Medow, Marvin S; Kothari, Mira L; Goetz, Amanda M et al. (2017) Decreasing cerebral oxygen consumption during upright tilt in vasovagal syncope. Physiol Rep 5:
Rowe, Peter C; Underhill, Rosemary A; Friedman, Kenneth J et al. (2017) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Front Pediatr 5:121
Medow, Marvin S; Merchant, Sana; Suggs, Melissa et al. (2017) Postural Heart Rate Changes in Young Patients With Vasovagal Syncope. Pediatrics 139:
Stewart, Julian M; Medow, Marvin S; Sutton, Richard et al. (2017) Mechanisms of Vasovagal Syncope in the Young: Reduced Systemic Vascular Resistance Versus Reduced Cardiac Output. J Am Heart Assoc 6:
Stewart, Julian M; Suggs, Melissa; Merchant, Sana et al. (2016) Postsynaptic ?1-Adrenergic Vasoconstriction Is Impaired in Young Patients With Vasovagal Syncope and Is Corrected by Nitric Oxide Synthase Inhibition. Circ Arrhythm Electrophysiol 9:
Wieling, Wouter; Jardine, David L; de Lange, Frederik J et al. (2016) Cardiac output and vasodilation in the vasovagal response: An analysis of the classic papers. Heart Rhythm 13:798-805
Ross, Amanda J; Stewart, Julian M (2015) Prospects for droxidopa in neurogenic orthostatic hypotension. Hypertension 65:34-5
Sheldon, Robert S; Grubb 2nd, Blair P; Olshansky, Brian et al. (2015) 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 12:e41-63
Kizilbash, Sarah J; Ahrens, Shelley P; Bruce, Barbara K et al. (2014) Adolescent fatigue, POTS, and recovery: a guide for clinicians. Curr Probl Pediatr Adolesc Health Care 44:108-33

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