An observational study in Spinal Cord Injuries, Cardiovascular Diseases and Endothelial Dysfunction, sponsored by Craig Hospital. Recruiting at 1 site in United States. Open to participants aged 18 Years to 89 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-08-20.
Sponsored by Craig Hospital · Observational
Individuals with spinal cord injury have heart attacks and strokes more frequently, and much earlier in life. People with spinal cord injuries develop plaque in vessels much faster, and the reasons why are unclear. Doctors generally attributed the increased risk with weight gain and developing diabetes, but many studies have shown that even without these common factors, plaque in vessels is developing more often and faster. Endothelial cells are a single layer of cells that line all vessels in the body and plays an important role in vessel health. Damage to endothelial cells is known to lead to heart attacks and strokes. Past studies on endothelial cells of people with spinal cord injury have been unclear. The investigators have new data that these cells are unhealthy after spinal cord injury a measurement. This includes measuring endothelial health by directly altering its function using a catheter in the arm and measuring small particles in blood called endothelial microvesicles. If the project is successful, the investigators will learn important information on the health of endothelial cells after spinal cord injury. The investigators will also be able to use these markers of endothelial cell function to create treatments to improve vessel health and prevent heart attacks and strokes later in life in people with spinal cord injury.
Adults with spinal cord injury (SCI) demonstrate accelerated atherosclerotic cardiovascular disease (ASCVD) occurring \~4 fold more often, and decades earlier in life. Importantly, atherosclerosis has been detected in people with SCI independent of traditional risk factors, much earlier in life, and appear recalcitrant to conventional risk mitigating inventions such as exercise and diet. Also, as disease is silent, many individuals are not screened for this atherosclerotic burden and only aware after the major vascular event of a myocardial infarction or stroke. The mechanisms which drive early ASCVD is unknown. Endothelial cell dysfunction precedes radiographic or angiographic evidence of atherosclerosis, and plays a central role in the development, progression and severity of atherosclerotic vascular disease. While it has been suggested that SCI results in compromised endothelial health, there is little empirical data on the degree or scope of impairment as well as mechanisms underlying any potential impairment. Endothelial dysfunction may be an important factor underlying the increased risk and prevalence of ASCVD and associated events in adults with SCI and a viable target for therapeutic intervention. Preliminary data suggests primary endothelial cell impairment related to its vasodilator function and provide potential mechanisms related to oxidative stress burden. The investigators also present the potential of endothelial cell derived microvesicles as a biomarker and mediator of endothelial cell dysfunction. The aim of this proposal is to determine whether endothelial function is impaired in adults with SCI. Our hypothesis is that endothelium-dependent vasodilation is impaired in adults with SCI and oxidative stress and endothelial cell derived microvesicles contribute to this dysfunction. Results supporting this hypothesis will: 1) provide mechanistic insight into the excess risk of ASCVD in adults with SCI; 2) identify therapeutic targets for reducing cardiovascular risk in this population; and 3) provide scientific rationale for vascular-related treatment clinical trials aimed at improving vascular health and reducing cardiovascular risk in individuals with SCI.
1,988 studies on the registry are indexed under Spinal Cord Injuries; 516 are open to participants now.
This study's planned enrollment of 60 is close to the median of 60 across 332 observational studies indexed under Spinal Cord Injuries.
Browse Spinal Cord Injuries studies →Craig Hospital is the lead sponsor of 38 studies on the registry; 11 are open to participants now.
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Men and women of all races, ethnic backgrounds, over the age of 18 years with history chronic motor complete paraplegia, but free of overt chronic diseases assessed by clinically documented medical history, physical examination, and blood chemistries and hematological evaluation.
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Exclusion Criteria:
Men and women of all races, ethnic backgrounds, over the age of 18 years: adults with chronic (\>12 months), motor complete (AIS A/B) SCI with paraplegia (neurological level of injury \[NLI\] at T2 or below).
Procedure: Brachial intra-arterial infusion of vasoactive and antioxidant drugs (acetylcholine, nitroprusside, ascorbic acid) · Procedure: venous occlusion plethysmography · Drug: Acetylcholine · Drug: Sodium Nitroprusside · Drug: Ascorbic acid · Procedure: venous phlebotomy
Non-injured men and women of all races, ethnic backgrounds, over the age of 18 years.
Procedure: Brachial intra-arterial infusion of vasoactive and antioxidant drugs (acetylcholine, nitroprusside, ascorbic acid) · Procedure: venous occlusion plethysmography · Drug: Acetylcholine · Drug: Sodium Nitroprusside · Drug: Ascorbic acid · Procedure: venous phlebotomy
The brachial artery in the non-dominant arm will be catheterized to infuse endothelium-dependent vasodilator acetylcholine, endothelium-independent vasodilator nitroprusside, and antioxidant ascorbic acid at concentrations to have isolated effect in the forearm.
Whole forearm blood flow will be measured by mercury-strain gauge while venous occlusion is applied to the forearm and hand by rapid-cuff inflation to sub-arterial pressures. Changes in whole forearm blood flow with be measured at baseline, endothelial agonists, and removal of oxidative stress via acorbic acid.
Endothelium-dependent vasodilation will then be assessed by changes in FBF in response to intra-arterial infusions of the endothelial agonist acetylcholine infused at rates of 4.0, 8.0, 16.0 μg/100 mL of forearm tissue/min to generate a dose-response curve.
Endothelium-independent vasodilation will be assessed by changes in forearm blood flow in response to intra-arterial infusions of sodium nitroprusside at 1.0, 2.0, 4.0 μg/100 mL forearm tissue/min.
Ascorbic acid will be infused at a constant rate (12 mg/100 mL tissue/min) and maintained at the same rate while the acetylcholine and sodium nitroprusside dose-response curves are repeated.
Venous blood samples will be collected to measure baseline cardiometabolic characteristics and isolate endothelial cell microvesicles for characterizations and in vitro experiments.
Endothelium-dependent vasodilation
Total forearm blood flow with be measured by strain gauge venous plethysmography under baseline conditions and under pharmacological manipulation with acetylcholine at increasing concentrations (8, 16, 32ug/ml).
Time frame: Measured at baseline (without acetylcholine) and immediately after each acetylcholine dose for 3-5 minutes.
Endothelium-independent vasodilation
Total forearm blood flow with be measured by strain gauge venous plethysmography under baseline conditions and under pharmacological manipulation with sodium nitroprusside at increasing concentrations (1, 2, 4ug/ml).
Time frame: Measured at baseline (without sodium nitroprusside) and immediately after each sodium nitroprusside dose for 3-5 minutes.
Endothelial cell-derived microvesicles concentration
Endothelial cell-derived microvesicles will be collected from venous blood samples and counted used flow cytometry to determine a circulating concentration.
Time frame: Baseline
Association of Endothelial cell-derived microvesicles to Endothelium-dependent vasodilation
Time frame: Baseline
Endothelial cell-derived microvesicles effects of human coronary artery endothelial cells nitric oxide bioavailability
Endothelial cell-derived microvesicles will be sorted and collected by fluorescence-activated cell sorting (FACS) flow cytometry. The endothelial cell-derived microvesicles will be co-cultured with human coronary artery endothelial cells. Endothelial Nitric Oxide Synthase and phosphorylation sites of interest will be measured by intracellular protein expression quantification of whole cell lysates by capillary electrophoresis immunoassays. Nitric oxide production will be assessed by total nitric oxide and nitrate/nitrite parameter assays.
Time frame: Baseline
Endothelial cell-derived microvesicles effects of human coronary artery endothelial cells reactive oxygen species and antioxidant capacity
Endothelial cell-derived microvesicles will be sorted and collected by fluorescence-activated cell sorting (FACS) flow cytometry. The endothelial cell-derived microvesicles will be co-cultured with human coronary artery endothelial cells. Super oxide dismutase and catalase expression will be measured by intracellular protein expression quantification of whole cell lysates by capillary electrophoresis immunoassays. Intracellular oxidative stress will be assessed by ROS-Glo H2O2 assay.
Time frame: Baseline
Plan to share: Yes — Data sharing will be facilitated through active participation in Open Data Commons for SCI (ODC-SCI). ODC-SCI is a cloud-based community-governed repository to store, share, and publish research data on Spinal Cord Injury and is compliant with requirements for FAIR and trustworthy repositories established by NIH.
Start is estimated for Sep 2024; primary completion for Mar 2027, 30 months later.
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