Testosterone Deficiency and Endothelial Dysfunction in Spinal Cord Injury Related Cardiovascular Disease Mechanistic Insights and Therapeutic Prospects
Craig Hospital
Summary
Heart attacks and strokes are among the most common causes of premature death in individuals living with spinal cord injury (SCI) and appear to occur earlier in life. The factors that lead to the heighten and accelerated risk of heart attacks and strokes in adults living with SCI remain poorly understood. The investigators aim to uncover why this happens and find ways to prevent it. Our research focuses on how important cells which line blood vessels, called endothelial cells, function after SCI. The investigators test endothelial function in live conscious people with SCI. The investigators also study signaling molecules endothelial cells release called endothelial cell derived microvesicles (EMVs), which the investigators can measure in blood to tell us the health of endothelial cells. By using these rigorous tests of vascular function, the investigators have determined that endothelial cells appear dysfunctional after SCI. The investigators also know that many men with SCI have low testosterone levels. Our team has studied testosterone's effects on endothelial dysfunction and believe low testosterone may be contributing to endothelial dysfunction after SCI. By understanding these mechanisms, the investigators hope to improve the lives of those living with SCI and reduce their risk for heart attacks and strokes. The investigators propose to study the influence of testosterone on endothelial function by using state-of-the-art clinical and laboratory experiments to assess endothelial function in men with SCI with low and normal testosterone levels.
Description
The vascular endothelium plays a central role in atherosclerotic cardiovascular disease and may contribute to the increased risk of myocardial infarction and stroke following spinal cord injury (SCI). Endothelial dysfunction is characterized by impaired vasodilator function and reduced fibrinolytic capacity. Endothelium-dependent vasodilation is primarily mediated by nitric oxide (NO), which induces rapid relaxation of vascular smooth muscle. Fibrinolysis is the breakdown of thrombi within blood vessels, and is facilitated by endothelial cells through the synthesis and release of tissue-type…
Eligibility
- Age range
- 18–89 years
- Sex
- Male
- Healthy volunteers
- No
Inclusion Criteria: * Between ages 18-89 years of age * Male Sex * History of motor complete (AIS A/B) paraplegia (NLI T3 or Below) * Time since injury \<6 months at time of enrollment (Subacute injury) * Testosterone Deficiency defined as \< 300ng/dL Exclusion Criteria: * Overt cardiovascular disease assessed by a) medical history, b) physical examination c) electrocardiogram * Anaphylaxis to betadine, lidocaine, iodine * Active infection at time of enrollment. * Recent surgery (\<1 month) at time of enrollment. * History smoking tobacco (currently or in the past 12 months) * History of mo…
Interventions
- Diagnostic TestIntra-arterial Infusion of Vasoactive Agents
A catheter is placed in the brachial artery of the non-dominant arm, and small doses of vasoactive drugs acetylcholine, isoproterenol, sodium nitroprusside are infused. Forearm blood flow will be measured using venous occlusion plethysmography. The purpose of this procedure is to assess endothelium-dependent and independent vasodilation by stimulating different vascular pathways. The acetylcholine infusion is to test muscarinic receptor, nitro oxide dependent, endothelium-dependent vasodilation. Isoproterenol was selected to stimulate tissue plasminogen activator based on its specificity and effectiveness at eliciting local and rapid tissue plasminogen activator release in adult humans. Sodium nitroprusside infusion is to assess endothelium-independent vasodilation.
- Diagnostic TestIntra-arterial Vitamin C Infusion
Vitamin C, a potent antioxidant, will be infused into the forearm and forearm blood flow will be re-evaluated to determine whether oxidative stress contributes to endothelial dysfunction.
- Diagnostic TestBlood Sampling
Blood will be sampled from the antecubital vein (\~50 mL) for biomarker analysis. This is to assess circulating biochemical and molecular indicators of vascular health and inflammation including levels of endothelial cell derived microvesicles.
Location
- Craig HospitalEnglewood, Colorado