Adults with Down syndrome (Ds) are often thought to have a lower risk of heart and blood vessel disease because they tend to have lower blood pressure and fewer heart attacks than people without Ds. However, recent research suggests that heart and blood vessel diseases, including stroke, are becoming a more common cause of death in adults with Ds as life expectancy increases. Despite these findings, studies examining heart and blood vessel health in adults with Ds have produced mixed results, making it difficult to determine their true risk and whether preventive strategies are needed. This study will investigate the health of blood vessels in adults with Ds and compare the results with those of adults without Ds. Healthy blood vessels are important because they help deliver blood and oxygen throughout the body. Changes in blood vessel function and stiffness can occur with aging and may increase the risk of heart disease, stroke, kidney disease, and memory problems. The study aims to determine whether adults with Ds experience changes in blood vessel health that may place them at increased cardiovascular risk. Specifically, the study will: (1) Examine how well blood vessels function in adults with Ds; (2) Measure the stiffness of arteries in adults with Ds; (3) Compare two methods used to assess blood vessel function to determine whether a simpler exercise-based test provides results similar to a commonly used standard test.

The findings may improve understanding of cardiovascular risk in adults with Ds and help guide future strategies to promote healthy aging in this population.

This proposal challenges the conventional wisdom that adults with Down syndrome (Ds) are at a lower risk for cardiovascular disease (CVD) because they have low blood pressure and fewer heart attacks than their peers without DS. Recent studies show a larger and increasing contribution of non-congenital CVD (including stroke) to mortality in adults with Ds, likely due to the increased life expectancy. Despite this, studies on traditional cardiovascular risk indicators in adults with DS are conflicting. This currently results in limited urgency for implementing risk-lowering strategies. To address this gap in knowledge and methodology, our overall aim is to demonstrate accelerated vascular aging in adults with Ds, defined by age-related yet Ds-specific endothelial dysfunction and arterial stiffness. Vascular aging directly measures the disease progression towards organ damage, such as the brain and the kidneys, which leads to cardiovascular disease, stroke, and Alzheimer's disease (AD) in the general population. Adults with Ds experience excessive syndrome-specific chronic vascular adaptations, which may accelerate vascular aging. However, this has not yet been investigated.

This project aims to provide a more direct and accurate measure to determine cardiovascular risk by comprehensively characterizing vascular health in adults with Ds compared to adults without Ds.

Aim 1: To identify the effect of Ds on endothelial function. Aim 2: To identify the impact of Ds on arterial stiffness. Aim 3: To compare measurements of endothelial function using a hand grip exercise protocol and the gold standard flow-mediated dilation protocol.

A cross-sectional research design is used for all aims and includes a comprehensive evaluation of endothelial function and arterial stiffness. Both participants with DS and a sex-matched control group of participants without DS or other intellectual disabilities (from here on control participants) will be included.

Familiarization. We involve parents/caregivers to provide a supportive environment for participants and to enhance the parent's/caregiver's understanding of the research with videos and practicing sessions.

Description of data collection visits. Data collection will be completed in two study visits of maximal 2h each. We will first obtain a signed informed consent form explaining our study procedures, potential risks, and benefits of the study from the participants and/or their legally authorized representative, if present. During the first data collection visit, after discussing the study and potential questions, participants and/or legally authorized representative will complete the International Physical Activity Questionnaire (IPAQ) to confirm eligibility. Participants will be tested in a postprandial state (>3 h) and will refrain from drinking or eating caffeine and drinking alcohol and from exercise 24 h before both the test days. Females will be studied during the first 3-5 days of menses to control for hormonal variation. Baseline measurements will include anthropometric assessments of height, weight, and circumference. Body composition will be measured with a DEXA scan to record forearm composition and mass. For arterial stiffness assessment, participants will lie down while their arterial Pulse Wave Velocity (PWV) and Augmentation Index are measured using a brachial blood pressure monitor (Mobil-O-Graph) and carotid-femoral tonometry (PulsePen). Carotid Beta-Stiffness and intima-media thickness (IMT) will be evaluated via carotid ultrasonography (Hitachi Arietta 70). The second visit will include an assessment of endothelial function. Participants will lie down and perform a 2-minute isometric hand grip test (HG) at 30% MVC, followed by a flow-mediated dilation (FMD) protocol with a cuff occlusion of 50 mmHg above systolic blood pressure on the forearm for 5 minutes. Brachial artery dilation and blood flow will be assessed after HG and FMD using high-resolution ultrasonography (Arietta 70, Hitachi, Tokyo, Japan).

Inclusion Criteria:

• between 18 and 35 years old
• generally healthy
• sedentary (defined as being involved in less than 30 minutes of moderately-intense physical activity per day)

Additionally, for the participants with Down syndrome:

• diagnosis of Down syndrome trisomy 21
• normal thyroid function or stable thyroid function (and medications) for at least 6 mo.

Exclusion Criteria:

• unresolved congenital heart disease;
• atherosclerotic or other vascular disease (such as blood clot history or clotting disorders);
• asthma or other pulmonary disease;
• hypertension (defined BP >140/90 mmHg); blood pressure below 90/60 mmHg;
• history of pre-syncope or syncope;
• diabetes (defined as Hba1c of >7.5% or use of glucose lowering medication);
• severe obesity (defined as BMI >40);
• heart medications affecting heart rate, blood pressure or arterial function, including blood thinners; anti-inflammatory medication including NSAIDS;
• current smoking;
• currently pregnant or planning to become pregnant during the study period;
• currently breastfeeding;
• unable or unwilling to use an acceptable method of contraception during the study timeframe;
• positive pregnancy test at screening.

The population being evaluated by the protocol consists of a convenience sample of individuals with Down syndrome (Ds) between the ages of 18 and 35 years old, and a group of controls without Ds matched for age and sex, living in the community. 24 participants will be enrolled in the study at UNLV; 12 individuals with Down syndrome and 12 individuals without Down syndrome.

De-identified IPD will be made available to other researchers upon request.