Testosterone Deficiency and Endothelial Dysfunction After Spinal Cord Injury

Testosterone Deficiency and Endothelial Dysfunction in Spinal Cord Injury Related Cardiovascular Disease Mechanistic Insights and Therapeutic Prospects

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.

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 plasminogen activator (t-PA). Importantly, endothelial dysfunction often precedes detectable atherosclerosis and predicts future major vascular events.

Low testosterone (T) is a common secondary complication that occurs early after SCI, with hypogonadism being four times more prevalent in men with SCI. Testosterone has known antioxidant properties and its deficiency may contribute to endothelial dysfunction. Testosterone deficiency may represent a modifiable risk factor for vascular impairment after SCI.

This cross-sectional study will include 48 adults with subacute (<6 months), motor-complete (AIS A/B) paraplegia (neurological level T3 or below). 24 with testosterone deficiency and 24 with normal T levels. Endothelium-dependent vasodilation and t-PA capacity will be assessed via intra-arterial infusion of vasoactive drugs, with total forearm blood flow measured using venous occlusion plethysmography.

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 more than low-risk history of alcohol consumption
• History of drug abuse
• History of use of cardiovascular-acting (i.e. statins, beta-blockers) therapeutics
• History of other health habits, medications, and supplements that could influence the outcome measures deemed by principal investigators and investigative team.