Exploring Sympathetic Nervous System Function in Individuals With Down Syndrome

Official title

Dysautonomia InVestigation in Individuals With Down SyndromE: DIVE Study

Overview

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.

Interventions

• 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 a
• Other 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
• 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 exp
• 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 individua
• 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 w
• 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.

Primary outcome measures

• Seated Baseline Concentration of Plasma Catecholamines [Time frame: Seated baseline blood draw, prior to stressors]
• Concentration of Plasma Catecholamines During Cold Pressor Test [Time frame: During the cold stress test, around or up to 5 minutes]
• Baseline Standing Concentration of Plasma Catecholamines [Time frame: Standing baseline blood draws, prior to fear simulation]
• First Fear Simulation, Concentration of Plasma Catecholamines [Time frame: During the first virtual reality fear stressor, around 5 minutes]
• Second Fear Simulation, Concentration of Plasma Catecholamines [Time frame: During the second fear simulation, around 15 minutes into the test]
• First Minute of Pain Patch, Concentration of Plasma Catecholamines [Time frame: Blood draw will take place within 1-minute of the application of the pain patch.]
• 15 Minutes into Pain Patch Application, Concentration of Plasma Catecholamines [Time frame: Blood draw will occur about 15 minutes after the application of the pain patch.]
• 12-Hour Fast, Concentration of Plasma Catecholamines [Time frame: Blood draw will occur following a 12-hour fast inducing hypoglycemia]
• Seated Baseline Blood Draw, Concentration of Plasma Catecholamines [Time frame: Blood draw will occur prior to ingestion of caffeine pill]
• 30 Minutes Following Ingestion of Caffeine Pill(s), Concentration of Plasma Catecholamines [Time frame: Blood draw will occur around 30 minutes following participant ingestion of caffeine pill(s)]

Secondary outcome measures (9)

• 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]
• Facial Affective Scale Score, During Pain Response, 1-Minute [Time frame: Assessment will take place approximately 1-minute following administration of the pain patch]
• Facial Affective Scale Score, Pain Response, 5 Minutes [Time frame: Up to or around 5 minutes into pain patch]
• Facial Affective Scale Score, Pain Response, 10 Minutes [Time frame: Up to or around 10 minutes into pain patch application]
• Facial Affective Scale Score, Pain Response, 15 Minutes [Time frame: Up to or around 15 minutes following the application of the pain patch]
• Blood Glucose, Baseline Without 12-Hour Fast [Time frame: Baseline without fast, Prior to 12-Hour fast condition to confirm low blood sugars]
• Blood Glucose, 12-Hour Fast [Time frame: Measurement will be conducted prior to the 12-Hour fast condition to confirm low blood sugars]

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

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
• Chronic caffeine drinkers for caffeine stressor (consumption of caffeine in the last 7 days)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

United States · 1 center

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

Identifiers

NCT: NCT07238465 · 25-0503 · T32AG000279

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗