Down SyndromePhase 3DIVENCT07238465
Exploring Sympathetic Nervous System Function in Individuals With Down Syndrome
A Phase 3 study testing Cold Stress, Maximal Dynamic Exercise and Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia in people with Down Syndrome and Autonomic Dysfunction, run by University of Colorado, Denver at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Down Syndrome, Autonomic Dysfunction
- What is being tested?
- Cold Stress, Maximal Dynamic Exercise and Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 200 participants
- Where
- 1 siteUnited States
- Study dates
- 6 Apr 2026to Dec 2030
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 13Show fewer
- Currently pregnant
- Post-menopausal women
- Specific Exclusion Criteria for Certain Stressors:
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Constance Brecl contact
United States1 site, 1 recruiting
- Recruiting
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus
Aurora, Colorado, 80045
Joaquin M Espinosa, PhD, 303-724-7389, DSResearch@cuanschutz.edu
Angela Rachubinski, PhD, DSResearch@cuanschutz.edu
About this study
Official title: Dysautonomia InVestigation in Individuals With Down SyndromE: DIVE Study
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.
Read the 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 four 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) Handgrip with Post-Exercise Muscle Ischemia, C) Head-up Tilt, and D) 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
- Being tested
- Cold Stress, Maximal Dynamic Exercise, Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia, Head-up Tilt Table Test
- Keywords
- Cold Stress, Exercise, Blood Pressure, Heart Rate, Catecholamines, Epinephrine, Norepinephrine, Dopamine, Stress, Post-Exercise Muscle Ischemia, Handgrip, Head Up Tilt Table
- Medical subject headings
- Down Syndrome, Primary Dysautonomias, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cold StressOther
Also called Cold Pressor Test, Cold Water
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.
Maximal Dynamic ExerciseOther
Also called VO2peak, Treadmill 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.
Isometric Handgrip Exercise with Post-Exercise Muscle IschemiaOther
Also called Handgrip, Post-Exercise Muscle Ischemia
The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a isometric handgrip exercise followed by an ischemic period which will be induced by a blood pressure cuff 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.
Head-up Tilt Table TestOther
Also called Tilt Table, Orthostatic Stress
The investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during passive head-up tilt testing which is a standardized, noninvasive clinical and research procedure used to characterize cardiovascular autonomic responses to orthostatic stress, among individuals with Down syndrome, who have proposed autonomic dysfunction.
| Study group | Role | What they receive |
|---|---|---|
| Individuals with Down syndrome | Experimental | The investigators will be recruiting participants between the ages of 18-50 for the study investigating responses to four sympathetic stressors compared to age and sex matched individuals without Down syndrome. Receives: Other: Cold Stress; Other: Maximal Dynamic Exercise; Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia; Other: Head-up Tilt Table Test |
| Individuals without Down syndrome | Experimental | 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 four sympathetic stressors. Receives: Other: Cold Stress; Other: Maximal Dynamic Exercise; Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia; Other: Head-up Tilt Table Test |
What is being measured
The primary outcome is the main question the study is designed to answer.
Seated Baseline Concentration of Plasma Catecholamines
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Seated baseline blood draw, prior to stressors
Standing Baseline Concentration of Plasma Catecholamines
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Blood draw will occur in standing position, prior to head up tilt table testing
Concentration of Plasma Catecholamines During Cold Pressor Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: During the cold stress test, around or up to 5 minutes
Concentration of Plasma Catecholamines During Handgrip Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Blood draws occur around or up to 2-3 minutes into handgrip test
Concentration of Plasma Catecholamines During Post Exercise Muscle Ischemia
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Seated blood draw to occur, around or about 2-3 minutes into post exercise muscle ischemia
Supine Concentration of Plasma Catecholamines
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Blood draws during or around 10 minutes of supine rest
Supine Concentration of Plasma Catecholamines, 5 Minutes into Head-Up Tilt
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: At or around 5 minutes into the head-up tilt table stimulus
Supine Concentration of Plasma Catecholamines, 10 Minutes into Head-Up Tilt
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: At or around 10 minutes into the head-up tilt table stimulus
Baseline Standing Concentration of Plasma Catecholamines Prior to Maximal Exercise Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Standing baseline blood draw, prior to maximal exercise test
Standing Concentration of Plasma Catecholamines at End of Maximal Exercise Test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: This blood draw will occur at the very end or immediately following the maximal exercise test on the treadmill
Standing Concentration of Plasma Catecholamines, 30 Minutes Post Maximal Exercise
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: This blood draw will occur around 30 minutes following the maximal exercise test on the treadmill
Standing Concentration of Plasma Catecholamines, 60 Minutes Post Maximal Exercise
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Measured: This blood draw will occur at the around 60 minutes following the maximal exercise test on the treadmill
Seated Baseline Heart Rate, Prior to Cold Pressor Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during (in some stressors), and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
Heart Rate Collected During Cold Pressor Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Collected throughout the Cold Pressor Test, around 6 minutes in total
Heart Rate, Maximal Exercise Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Continuous heart rate recordings will take place throughout the maximal aerobic exercise test on the treadmill, up to or around 20 minutes
Seated Baseline Blood Pressure, Prior to Cold Pressor Test
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
Blood Pressure Collected During Cold Pressor Test
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Collected throughout the Cold Pressor Test, around 6 minutes in total
Heart Rate Collected During Handgrip with Post-Exercise Muscle Ischemia
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Collected throughout the Handgrip tests with Post-Exercise Muscle Ischemia, around 12 minutes in total
Heart Rate Collected During Head-Up Tilt Table Test
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Collected throughout the Head-Up Tilt Table Test, around 25 minutes in total
Blood Pressure Collected During Handgrip Test with Post-Exercise Muscle Ischemia
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Collected throughout the handgrip test with post-exercise muscle ischemia, up to or around 12 minutes
Blood Pressure Collected During Head-Up Tilt Table Test
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Measured: Collected throughout the head-up tilt table test, around 25 minutes in total
Secondary outcomes (3)
Facial Affective Scale Score, Baseline Assessment
Investigators will use the validated 'Facial Affective Scale', which uses a series of nine drawn faces showing various degrees of emotional distress to help participants assess their emotional state. The nine faces represent a range of negative to positive affect, and each face having a specific value between 0.04 (maximum positive affect) and 0.97 (maximum negative affect). The chosen face's corresponding value is the Facial Affective Score. This will take up to or around approximately 5 minutes to complete.
Measured: Baseline Assessment of Facial Affective Scale, this will occur prior to any stressors.
Facial Affective Scale Score, Cold Pressor Test, 1.5 Minutes
Investigators will use the validated 'Facial Affective Scale', which uses a series of nine drawn faces showing various degrees of emotional distress to help participants assess their emotional state. The nine faces represent a range of negative to positive affect, and each face having a specific value between 0.04 (maximum positive affect) and 0.97 (maximum negative affect). The chosen face's corresponding value is the Facial Affective Score.
Measured: Assessment occurs around or up to 90 seconds (1.5 minutes) into cold water immersion
Facial Affective Scale Score, Cold Pressor Test, Finale
Investigators will use the validated 'Facial Affective Scale', which uses a series of nine drawn faces showing various degrees of emotional distress to help participants assess their emotional state. The nine faces represent a range of negative to positive affect, and each face having a specific value between 0.04 (maximum positive affect) and 0.97 (maximum negative affect). The chosen face's corresponding value is the Facial Affective Score.
Measured: Assessment occurs immediately following or during the last minute of the Cold Pressor Test, up to or around 6 minutes following placement of arm into cold
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2025
- Study start6 Apr 2026
- Primary completionDec 2029 (estimated)
- Study completionDec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Down SyndromeStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA), Linda Crnic Institute for Down Syndrome, GLOBAL Down Syndrome Foundation, University of Colorado Colorado Clinical and Translational Sciences Institute
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07238465
- Sponsor's protocol ID
- 25-0503
- Other IDs
- T32AG000279
- Acronym
- DIVE
- Status last verified
- Sep 2026
- First submitted
- 22 Oct 2025
- Last updated
- 13 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dysautonomia InVestigation in Individuals With Down SyndromE: DIVE Study
- ClinicalTrials.gov ID
- NCT07238465
- Acronym / sponsor ID
- DIVE / 25-0503
- Conditions
- Down Syndrome, Autonomic Dysfunction
- Keywords
- Cold Stress, Exercise, Blood Pressure, Heart Rate, Catecholamines, Epinephrine, Norepinephrine, Dopamine
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA), Linda Crnic Institute for Down Syndrome, GLOBAL Down Syndrome Foundation, University of Colorado Colorado Clinical and Translational Sciences Institute
- Study start
- 6 Apr 2026 (actual)
- Primary completion
- Dec 2029 (estimated)
- Study completion
- Dec 2030 (estimated)
- First posted
- 20 Nov 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 four 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) Handgrip with Post-Exercise Muscle Ischemia, C) Head-up Tilt, and D) 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Individuals with Down syndrome | Experimental | Other: Cold Stress, Other: Maximal Dynamic Exercise, Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia, Other: Head-up Tilt Table TestThe investigators will be recruiting participants between the ages of 18-50 for the study investigating responses to four sympathetic stressors compared to age and sex matched individuals without Down syndrome. |
| Individuals without Down syndrome | Experimental | Other: Cold Stress, Other: Maximal Dynamic Exercise, Other: Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia, Other: Head-up Tilt Table TestThe 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 four sympathetic stressors. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cold StressAlso: Cold Pressor Test, Cold WaterCold 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. | Other | Individuals with Down syndrome, Individuals without Down syndrome |
| Maximal Dynamic ExerciseAlso: VO2peak, Treadmill ExerciseThe 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. | Other | Individuals with Down syndrome, Individuals without Down syndrome |
| Isometric Handgrip Exercise with Post-Exercise Muscle IschemiaAlso: Handgrip, Post-Exercise Muscle IschemiaThe investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during a isometric handgrip exercise followed by an ischemic period which will be induced by a blood pressure cuff 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. | Other | Individuals with Down syndrome, Individuals without Down syndrome |
| Head-up Tilt Table TestAlso: Tilt Table, Orthostatic StressThe investigators are looking at how plasma catecholamines (i.e., Epinephrine, Norepinephrine, and Dopamine), blood pressure, and heart rate are expressed during passive head-up tilt testing which is a standardized, noninvasive clinical and research procedure used to characterize cardiovascular autonomic responses to orthostatic stress, among individuals with Down syndrome, who have proposed autonomic dysfunction. | Other | Individuals with Down syndrome, Individuals without Down syndrome |
Primary outcome
Seated Baseline Concentration of Plasma Catecholamines
Time frame: Seated baseline blood draw, prior to stressors
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Standing Baseline Concentration of Plasma Catecholamines
Time frame: Blood draw will occur in standing position, prior to head up tilt table testing
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Concentration of Plasma Catecholamines During Cold Pressor Test
Time frame: During the cold stress test, around or up to 5 minutes
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Concentration of Plasma Catecholamines During Handgrip Test
Time frame: Blood draws occur around or up to 2-3 minutes into handgrip test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Concentration of Plasma Catecholamines During Post Exercise Muscle Ischemia
Time frame: Seated blood draw to occur, around or about 2-3 minutes into post exercise muscle ischemia
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Supine Concentration of Plasma Catecholamines
Time frame: Blood draws during or around 10 minutes of supine rest
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Supine Concentration of Plasma Catecholamines, 5 Minutes into Head-Up Tilt
Time frame: At or around 5 minutes into the head-up tilt table stimulus
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Supine Concentration of Plasma Catecholamines, 10 Minutes into Head-Up Tilt
Time frame: At or around 10 minutes into the head-up tilt table stimulus
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Baseline Standing Concentration of Plasma Catecholamines Prior to Maximal Exercise Test
Time frame: Standing baseline blood draw, prior to maximal exercise test
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Standing Concentration of Plasma Catecholamines at End of Maximal Exercise Test
Time frame: This blood draw will occur at the very end or immediately following the maximal exercise test on the treadmill
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Standing Concentration of Plasma Catecholamines, 30 Minutes Post Maximal Exercise
Time frame: This blood draw will occur around 30 minutes following the maximal exercise test on the treadmill
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Standing Concentration of Plasma Catecholamines, 60 Minutes Post Maximal Exercise
Time frame: This blood draw will occur at the around 60 minutes following the maximal exercise test on the treadmill
Investigators will use metabolomic techniques to quantify plasma concentrations of epinephrine, norepinephrine, and dopamine in all participants before, during (in some stressors), and after the four stressor tests. These metabolites will provide insight into sympathetic nervous system activation in individuals with Down syndrome compared to those without Down syndrome.
Seated Baseline Heart Rate, Prior to Cold Pressor Test
Time frame: Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
Investigators will collect beat-to-beat heart rate recordings in all participants before, during (in some stressors), and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Heart Rate Collected During Cold Pressor Test
Time frame: Collected throughout the Cold Pressor Test, around 6 minutes in total
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Heart Rate, Maximal Exercise Test
Time frame: Continuous heart rate recordings will take place throughout the maximal aerobic exercise test on the treadmill, up to or around 20 minutes
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Seated Baseline Blood Pressure, Prior to Cold Pressor Test
Time frame: Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Blood Pressure Collected During Cold Pressor Test
Time frame: Collected throughout the Cold Pressor Test, around 6 minutes in total
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Heart Rate Collected During Handgrip with Post-Exercise Muscle Ischemia
Time frame: Collected throughout the Handgrip tests with Post-Exercise Muscle Ischemia, around 12 minutes in total
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Heart Rate Collected During Head-Up Tilt Table Test
Time frame: Collected throughout the Head-Up Tilt Table Test, around 25 minutes in total
Investigators will collect beat-to-beat heart rate recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Blood Pressure Collected During Handgrip Test with Post-Exercise Muscle Ischemia
Time frame: Collected throughout the handgrip test with post-exercise muscle ischemia, up to or around 12 minutes
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
Blood Pressure Collected During Head-Up Tilt Table Test
Time frame: Collected throughout the head-up tilt table test, around 25 minutes in total
Investigators will collect beat-to-beat blood pressure recordings in all participants before, during, and after the four stressor tests. These cardiovascular perturbations will provide insight into sympathetic nervous system modulation in individuals with Down syndrome compared to those without Down syndrome.
3 secondary outcomes
Facial Affective Scale Score, Baseline Assessment
Time frame: Baseline Assessment of Facial Affective Scale, this will occur prior to any stressors.
Facial Affective Scale Score, Cold Pressor Test, 1.5 Minutes
Time frame: Assessment occurs around or up to 90 seconds (1.5 minutes) into cold water immersion
Facial Affective Scale Score, Cold Pressor Test, Finale
Time frame: Assessment occurs immediately following or during the last minute of the Cold Pressor Test, up to or around 6 minutes following placement of arm into cold
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Oct 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Constance Brecl contact
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Cold Stress, Maximal Dynamic Exercise and Isometric Handgrip Exercise with Post-Exercise Muscle Ischemia in people with Down Syndrome and Autonomic Dysfunction, run by University of Colorado, Denver at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 13 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sara R Sherman, PhD (303-724-0598, sara.r.sherman@cuanschutz.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Seated Baseline Concentration of Plasma Catecholamines (time frame: Seated baseline blood draw, prior to stressors). The study lists 21 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Oct 2026.