ダウン症候群の個人における交感神経系機能の探求 (DIVE)
ダウン症候群患者における自律神経障害の調査：DIVE研究
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.
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
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.
研究の種類
研究の種類
入学 (推定)
入学
段階
段階
- フェーズ 3
連絡先と場所
研究連絡先
研究連絡先
- 名前：Sara R Sherman, PhD
- 電話番号：303-724-0598
- メール：sara.r.sherman@cuanschutz.edu
研究連絡先のバックアップ
- 名前：Constance Brecl
- メール：DSResearch@cuanschutz.edu
研究場所
-
-
Colorado
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Aurora、Colorado、アメリカ、80045
- 募集
- Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus
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コンタクト：
- Joaquin M Espinosa, PhD
- 電話番号：303-724-7389
- メール：DSResearch@cuanschutz.edu
-
コンタクト：
- Angela Rachubinski, PhD
- メール：DSResearch@cuanschutz.edu
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-
参加基準
適格基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：防止
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
|---|---|
|
実験的：Individuals with Down syndrome
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. |
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.
他の名前：
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.
他の名前：
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.
他の名前：
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.
他の名前：
|
|
実験的：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 four sympathetic stressors. |
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.
他の名前：
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.
他の名前：
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.
他の名前：
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.
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Seated Baseline Concentration of Plasma Catecholamines
時間枠：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. |
Seated baseline blood draw, prior to stressors
|
|
Standing Baseline Concentration of Plasma Catecholamines
時間枠：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. |
Blood draw will occur in standing position, prior to head up tilt table testing
|
|
Concentration of Plasma Catecholamines During Cold Pressor Test
時間枠：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. |
During the cold stress test, around or up to 5 minutes
|
|
Concentration of Plasma Catecholamines During Handgrip Test
時間枠：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. |
Blood draws occur around or up to 2-3 minutes into handgrip test
|
|
Concentration of Plasma Catecholamines During Post Exercise Muscle Ischemia
時間枠：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. |
Seated blood draw to occur, around or about 2-3 minutes into post exercise muscle ischemia
|
|
Supine Concentration of Plasma Catecholamines
時間枠：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. |
Blood draws during or around 10 minutes of supine rest
|
|
Supine Concentration of Plasma Catecholamines, 5 Minutes into Head-Up Tilt
時間枠：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. |
At or around 5 minutes into the head-up tilt table stimulus
|
|
Supine Concentration of Plasma Catecholamines, 10 Minutes into Head-Up Tilt
時間枠：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. |
At or around 10 minutes into the head-up tilt table stimulus
|
|
Baseline Standing Concentration of Plasma Catecholamines Prior to Maximal Exercise Test
時間枠：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 baseline blood draw, prior to maximal exercise test
|
|
Standing Concentration of Plasma Catecholamines at End of Maximal Exercise Test
時間枠：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. |
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
時間枠：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. |
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
時間枠：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. |
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
時間枠：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. |
Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
|
|
Heart Rate Collected During Cold Pressor Test
時間枠：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. |
Collected throughout the Cold Pressor Test, around 6 minutes in total
|
|
Heart Rate, Maximal Exercise Test
時間枠：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. |
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
時間枠：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. |
Resting seated baseline, prior to cold pressor test, up to or around 5 minutes
|
|
Blood Pressure Collected During Cold Pressor Test
時間枠：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. |
Collected throughout the Cold Pressor Test, around 6 minutes in total
|
|
Heart Rate Collected During Handgrip with Post-Exercise Muscle Ischemia
時間枠：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. |
Collected throughout the Handgrip tests with Post-Exercise Muscle Ischemia, around 12 minutes in total
|
|
Heart Rate Collected During Head-Up Tilt Table Test
時間枠：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. |
Collected throughout the Head-Up Tilt Table Test, around 25 minutes in total
|
|
Blood Pressure Collected During Handgrip Test with Post-Exercise Muscle Ischemia
時間枠：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. |
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
時間枠：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. |
Collected throughout the head-up tilt table test, around 25 minutes in total
|
二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Facial Affective Scale Score, Baseline Assessment
時間枠：Baseline Assessment of Facial Affective Scale, this will occur prior to any stressors.
|
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. |
Baseline Assessment of Facial Affective Scale, this will occur prior to any stressors.
|
|
Facial Affective Scale Score, Cold Pressor Test, 1.5 Minutes
時間枠：Assessment occurs around or up to 90 seconds (1.5 minutes) into cold water immersion
|
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. |
Assessment occurs around or up to 90 seconds (1.5 minutes) into cold water immersion
|
|
Facial Affective Scale Score, Cold Pressor Test, Finale
時間枠：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
|
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. |
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
|
協力者と研究者
協力者
協力者
研究記録日
主要日程の研究
研究開始 (実際)
研究開始
一次修了 (推定)
一次修了
研究の完了 (推定)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (実際)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
その他の研究ID番号
- 25-0503
- T32AG000279 (米国 NIH グラント/契約)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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