Mechanisms of Vasovagal Syncope

Vasovagal Syncope (simple postural faint) is the most common cause of acute loss of consciousness. Postural tachycardia syndrome(POTS) is the most common chronic form of postural lightheadedness. Together they afflict many Americans, mostly young women, who are prevented from gainful employ or school attendance. The underlying mechanism is not known. Our past work suggests that a simple molecule, nitric oxide, acts to subvert normal blood flow controls causing blood to pool in the gut when standing. Our proposal will show the mechanism behind this problem and will indicate effective medical treatments. Patients will be compared to healthy control subjects.

Study Overview

• Status: Completed
• Conditions: Postural Tachycardia Syndrome; Vasovagal Syncope
• Intervention / Treatment: Drug: Phenylephrine; Drug: L-Ng-monomethyl Arginine (L-NMMA)

Detailed Description

Vasovagal Syncope (VVS,simple faint) is the most common cause of transient loss of consciousness and is the acute episodic form of orthostatic intolerance(OI). Postural tachycardia syndrome (POTS) is the common chronic form of OI. Both are defined by debilitating symptoms and signs while upright relieved by recumbency. Pathophysiological mechanisms have remained elusive although our past work shows that excessive upright central hypovolemia results from splanchnic pooling due to defective splanchnic arterial and venous constriction. Preliminary data support the hypothesis that production of nitric oxide (NO) is enhanced in these patients resulting in reduced sympathetic noradrenergic neurotransmission at pre-junctional and post-junctional sites. Our approach is two-fold: 1) We will use intradermal microdialysis and laser Doppler flowmetry (LDF) to delineate the microvascular mechanisms of NO modulation of noradrenergic neurotransmission free of confounding systemic reflex changes. 2) We will systemically apply this mechanism to a model of orthostatic stress, lower body negative pressure(LBNP), while measuring cardiac output by inert gas rebreathing, regional blood volume, and regional blood flow using plethysmographic techniques focusing on splanchnic changes, and muscle sympathetic nerve activity by peroneal microneurography. We will study synaptic peripheral neurotransmission of Norepinephrine and how it is affected by supplemental NO and by nitric oxide synthase inhibitor.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Hawthorne, New York, United States, 10532
      • New York Medical College/Bradhurst Building

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 29 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. POTS patients referred for day to day orthostatic intolerance with greater than 3 symptoms for greater than 3 months and will have the diagnosis of symptomatic postural tachycardia made during a screening tilt table test :

   • dizziness
   • nausea and vomiting
   • palpitations
   • fatigue
   • headache
   • exercise intolerance
   • blurred vision
   • abnormal sweating heat.
2. Vasovagal Syncope patients will have at least 3 episodes of fainting episodes in the past year.
3. Healthy control subjects

Cases will be between the ages of 14 and 29 years old Cases will have normal physical examination, and normal electrocardiographic and echocardiographic evaluations.

Only those free from heart disease, and from systemic illness will be eligible to participate.

This excludes patients with illnesses and disease states known to be associated with endothelial cell dysfunction such as diabetes, renal disease, congestive heart failure, systemic hypertension, acute and chronic inflammatory diseases, neoplasm, immune mediated disease, trauma, morbid obesity and peripheral vascular disease.

At the time of testing all patients and control subjects must refrain from vasoactive drugs for two weeks. Please check with us about any medication that you are taking.

Exclusion Criteria:

• Cardiovascular causes of syncope
• An active medical condition that may explain the diagnosis
• A previous medical condition with undocumented resolution that may explain the diagnosis
• Past or present major psychiatric disorder
• Substance abuse within 2 years before onset of symptoms.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Phenylephrine and L-Ng-monomethyl Arginine (L-NMMA)

Drug: Phenylephrine; Phenylephrine dose-response comprises infusion of 0.5, 1, 2, 3, 4 micrograms/kg/min for 10 min at each dose. If bloods pressure increases by 30% or if heart rate decreases below 40 beats per minute we will stop infusion.; Drug: L-Ng-monomethyl Arginine (L-NMMA); Systemic L-NMMA is infused as a 500μg/kg/min loading dose for 15 min followed by a 50μg/kg/min maintenance dose for the remainder of the experiment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Heart rate and blood pressure in response to Lower Body Negative Pressure(LBNP)	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Adrenergic neurotransmission as measured by Muscle Sympathetic Nerve Activity(MSNA), doppler ultrasound blood flow, venous Norepinephrine in response to Phenylephrine infusion	1 year

Collaborators and Investigators

• Sponsor: New York Medical College
• Investigators: Principal Investigator: Julian M. Stewart, M.D., Ph.D., New York Medical College

Publications and helpful links

Helpful Links

• The Center for Hypotension

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): December 1, 2022
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: February 12, 2013
• First Submitted That Met QC Criteria: February 12, 2013
• First Posted (Estimated): February 15, 2013

Study Record Updates

• Last Update Posted (Actual): May 23, 2025
• Last Update Submitted That Met QC Criteria: May 20, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Orthostatic Intolerance; Postural Tachycardia Syndrome; Phenylephrine; Vasovagal Syncope; Nitric Oxide (NO); Orthostatic Stress; L-Ng-monomethyl Arginine (L-NMMA); Sodium Nitroprusside
• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Neurologic Manifestations; Nervous System Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Neurobehavioral Manifestations; Primary Dysautonomias; Autonomic Nervous System Diseases; Orthostatic Intolerance; Consciousness Disorders; Unconsciousness; Tachycardia; Syncope; Postural Orthostatic Tachycardia Syndrome; Syncope, Vasovagal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Neurotransmitter Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Cardiotonic Agents; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Adrenergic alpha-1 Receptor Agonists; Oxymetazoline; Phenylephrine; omega-N-Methylarginine
• Other Study ID Numbers: 1R01HL112736-01A1 (U.S. NIH Grant/Contract)