Exploring Sympathetic Nervous System Function in Individuals With Down Syndrome

NCT ID: NCT07238465

Last Updated: 2025-11-20

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-31
• Study Completion Date: 2029-12-31

Brief Summary

Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with widespread organ dysfunction, including abnormalities in the autonomic nervous system (ANS). The ANS regulates critical functions such as heart rate (HR) and blood pressure (BP), both essential for maintaining homeostasis and supporting physical activity. Individuals with DS often exhibit blunted HR responses to exercise-typically ~30 beats per minute below expected levels-suggesting reduced sympathetic nervous system (SNS) activity. The SNS governs rapid changes in HR and BP during stress by releasing catecholamines: epinephrine (from the adrenal medulla) and norepinephrine (from sympathetic nerve endings). Despite its importance, SNS function has not been comprehensively assessed among individuals with DS.

This study addresses a critical knowledge gap by evaluating SNS responses to physiological stressors in individuals with DS. The investigators will measure beat-to-beat HR and BP, along with plasma catecholamine levels, in response to sympathetic activation, comparing individuals with DS to age- and sex-matched controls. Understanding the mechanisms of SNS dysfunction in DS is vital, as it likely underlies reduced exercise capacity and contributes to broader clinical challenges. These insights may guide targeted interventions to improve cardiovascular function, physical capacity, and overall quality of life in this understudied population.

Detailed Description

Evolution has equipped each species with instinctual defense mechanisms to cope with environmental stressors, ensuring survival. Many of these mechanisms are driven by activation of the sympathetic nervous system (SNS), which orchestrates the "fight or flight" response. Systemic SNS activation extends across all organ systems, triggering the release of catecholamines to elevate heart rate (HR) and increase blood pressure (BP) to meet the heightened metabolic demands of the stressor and ensure the delivery of oxygen-rich blood to active tissues. Exercise, a potent sympathoexcitatory stressor, poses a major challenge to the oxygen transport system, requiring coordinated organ system function to increase both HR and BP. Dysregulated SNS activation can impair oxygen delivery, leading to reduced work capacity, quality of life, and is an independent predictor of morbidity and premature mortality. Therefore, experimental approaches to understand SNS activation in populations with reduced work capacity and premature morbidity, mortality is of upmost importance for improving health outcomes and quality of life on a population level.

Down syndrome (DS) is the most common chromosomal abnormality in the human population, with widespread effects across numerous tissues and organ systems, including accelerated biological aging. Individuals with DS exhibit reduced work capacity, with maximal HRs ~30 beats below normal, and face higher rates of premature morbidity and mortality than the general population. Notably, individuals with DS demonstrate blunted catecholamine response to the sympathetic stressor of maximal exercise, suggesting diminished SNS activation. Recent literature from this PI suggests altered peripheral blood flow and BP regulation among individuals with DS during large muscle mass exercise which immolates walking, or running- critical for survival. These findings align with recent evidence of hypoxic signaling, elevated heme metabolism, and stress erythropoiesis across the lifespan in this population. Together, these data suggest that impaired oxygen delivery, potentially linked to SNS dysregulation, may be more widespread in DS than previously recognized.

However, the role of SNS activation in the context of daily stressors which elevate both HR and BP, remains unclear. Understanding the mechanisms underlying SNS dysfunction in DS is crucial, as it likely contributes to many clinical and developmental challenges, including the underlying reduced work capacity and suggested autonomic dysfunction observed in this population. Addressing this gap may enable targeted therapies to enhance survival, longevity, and quality of life for individuals with DS. The investigators aim to systematically evaluate SNS activation through six stressors which mimic common stressors faced to any individual over the course of a day or lifespan. Through evaluation of plasma catecholamines, the investigators hope to elucidate the mechanisms and impact of catecholamine responses in individuals with DS compared typical responses observed among individuals without DS.

Aim 1. Characterize the catecholamine response to physiological stressors among individuals with DS. The investigators will assess SNS responses in individuals with DS and age- and sex-matched controls. Beat-to-beat HR and BP, along with plasma catecholamine levels will be collected in response to the following sympathetic stressors: A) Cold Stress, B) Fear (i.e., virtual reality), C) Pain (i.e., capsicum patch), D) Caffeine, E) 12-Hour Fast, and F) Maximal Dynamic Exercise (VO2peak). Metabolomics and proteomics will be performed on the plasma samples and these efforts will help define the manifestations of hormonal SNS dysfunction in individuals with DS.

Conditions

Down Syndrome; Autonomic Dysfunction

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Individuals with Down syndrome

The investigators will be recruiting participants between the ages of 18-50 for the study investigating responses to six sympathetic stressors compared to age and sex matched individuals without Down syndrome.

Group Type: EXPERIMENTAL

Cold Stress

Intervention Type: OTHER

Cold triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during a cold stress test.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a cold stress test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Fear Response

Intervention Type: OTHER

Fear triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine the cardiovascular physiology of how individuals with DS will respond during a scary simulation.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a fear simulation using virtual reality goggles in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Pain Response

Intervention Type: OTHER

Pain triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to the perceived threat (i.e., hurt) by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during application of a painful patch.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during application of a pain patch in individuals with Down syndrome, who have proposed autonomic dysfunction. This pain patch is similar to what someone would buy at the drug store for sore muscles. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Caffeine

Intervention Type: OTHER

Caffeine acts as a stimulant to the sympathetic nervous system leading to an increase in blood pressure, heart rate, and release of catecholamines.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed following ingestion of a caffeine pill (similar to ~2 cups of coffee) in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

12-Hour Fast

Intervention Type: OTHER

Fasting-induced hypoglycemia triggers a 'fight-or-flight' response as the body attempts to raise low blood glucose levels to bring them back to 'normal'. These measurements will be taken to examine how individuals with DS will respond following a 12-hour abstinence from food, inducing low blood sugar.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed following a 12-hour fast in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Maximal Dynamic Exercise

Intervention Type: OTHER

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a treadmill maximal exercise test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Individuals without Down syndrome

The investigators will be recruiting individuals without Down syndrome between the ages of 18-50 to serve as the comparisons for individuals with Down syndrome across the six sympathetic stressors.

Group Type: EXPERIMENTAL

Cold Stress

Intervention Type: OTHER

Cold triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during a cold stress test.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a cold stress test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Fear Response

Intervention Type: OTHER

Fear triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine the cardiovascular physiology of how individuals with DS will respond during a scary simulation.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a fear simulation using virtual reality goggles in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Pain Response

Intervention Type: OTHER

Pain triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to the perceived threat (i.e., hurt) by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during application of a painful patch.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during application of a pain patch in individuals with Down syndrome, who have proposed autonomic dysfunction. This pain patch is similar to what someone would buy at the drug store for sore muscles. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Caffeine

Intervention Type: OTHER

Caffeine acts as a stimulant to the sympathetic nervous system leading to an increase in blood pressure, heart rate, and release of catecholamines.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed following ingestion of a caffeine pill (similar to ~2 cups of coffee) in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

12-Hour Fast

Intervention Type: OTHER

Fasting-induced hypoglycemia triggers a 'fight-or-flight' response as the body attempts to raise low blood glucose levels to bring them back to 'normal'. These measurements will be taken to examine how individuals with DS will respond following a 12-hour abstinence from food, inducing low blood sugar.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed following a 12-hour fast in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Maximal Dynamic Exercise

Intervention Type: OTHER

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a treadmill maximal exercise test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Interventions

Cold Stress

Cold triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during a cold stress test.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a cold stress test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Intervention Type: OTHER

Fear Response

Fear triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to a perceived threat by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine the cardiovascular physiology of how individuals with DS will respond during a scary simulation.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a fear simulation using virtual reality goggles in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Intervention Type: OTHER

Pain Response

Pain triggers the sympathetic nervous system, known as the 'fight-or-flight' response, which prepares the body to respond to the perceived threat (i.e., hurt) by increasing heart rate, blood pressure, and releasing catecholamines. These measurements will be taken to examine how individuals with DS will respond during application of a painful patch.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during application of a pain patch in individuals with Down syndrome, who have proposed autonomic dysfunction. This pain patch is similar to what someone would buy at the drug store for sore muscles. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Intervention Type: OTHER

Caffeine

Caffeine acts as a stimulant to the sympathetic nervous system leading to an increase in blood pressure, heart rate, and release of catecholamines.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed following ingestion of a caffeine pill (similar to ~2 cups of coffee) in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Intervention Type: OTHER

12-Hour Fast

Fasting-induced hypoglycemia triggers a 'fight-or-flight' response as the body attempts to raise low blood glucose levels to bring them back to 'normal'. These measurements will be taken to examine how individuals with DS will respond following a 12-hour abstinence from food, inducing low blood sugar.

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed following a 12-hour fast in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Intervention Type: OTHER

Maximal Dynamic Exercise

The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a treadmill maximal exercise test in individuals with Down syndrome, who have proposed autonomic dysfunction. This study will compare responses among individuals with Down syndrome to a control group without Down syndrome.

Intervention Type: OTHER

Other Intervention Names

Physiological Fear Response; Virtual Reality Simulation; Cold Pressor Test; Cold Water; Capsaicin Patch; Caffeine Pill; Coffee; Low Blood Sugar; Hypoglycemia; VO2peak; Treadmill Exercise

Eligibility Criteria

Inclusion Criteria

• 18-50 yrs old and apparently healthy individuals
• Ability to understand the study and give assent to participate
• Has a study partner who can attend all visits for the individuals with DS, and answer questionnaires, provide consent when necessary
• Corrected or non-existent congenital heart disease
• Euthyroid or on stable thyroid medication dose for at least 6 months
• Free from cardiovascular, pulmonary, inflammatory, or metabolic disease in the past 6 months that would prevent participation in study procedures
• BMI <45kg/m2
• Ability to tolerate repeated blood draws / catheter placement

Exclusion Criteria

• Hypertension (resting systolic blood pressure [SBP] ≥140 and/or diastolic blood pressure [DBP] ≥90 mmHg) this includes those on medications to treat hypertension
• Hypotension (resting BP of <90/60 mmHg)
• Cancer in the last six months
• Any heart-rate-altering medications or any other medication that may modify metabolic responses
• Self-reported diabetes or use of glucose-lowering medication
• Tobacco products, including vaping, or marijuana use
• Currently pregnant
• Post-menopausal women

• Orthopedic limitations that would prohibit exercise or movement for exercise
• Fracture of limb to be immersed for CPT
• Open cut or sore on hand to be immersed for CPT
• Raynaud's syndrome for CPT
• Chronic caffeine drinkers for caffeine stressor (consumption of caffeine in the last 7 days)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Linda Crnic Institute for Down Syndrome

UNKNOWN

Sponsor Role: collaborator

GLOBAL Down Syndrome Foundation

UNKNOWN

Sponsor Role: collaborator

University of Colorado Colorado Clinical and Translational Sciences Institute

UNKNOWN

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States

Countries

United States

Central Contacts

Sara R Sherman, PhD

Role: CONTACT

sara.r.sherman@cuanschutz.edu

303-724-0598

Constance Brecl

Role: CONTACT

constance.brecl@cuanschutz.edu

Facility Contacts

Joaquin M Espinosa, PhD

Role: primary

joaquin.espinosa@cuanschutz.edu

303-724-7389

Angela Rachubinski, PhD

Role: backup

angela.rachubinski@cuanschutz.edu

Other Identifiers

T32AG000279

Identifier Type: NIH

Identifier Source: secondary_id

View Link

25-0503

Identifier Type: -

Identifier Source: org_study_id