Impact of T Cells on Age-related Vascular Dysfunction: A Translational Approach

Study Overview
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Brief Summary
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Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and other industrialized societies, and advanced age is the major risk factor for development of CVD. Advancing age appears to exert its pathological influence primarily via adverse functional and structural effects on arteries. Aging is associated with increased stiffness (reduced compliance) of large elastic arteries and impaired arterial endothelial function that is characterized by reductions in nitric oxide (NO)- mediated endothelium-dependent dilation (EDD). While several changes to arteries may contribute to age-associated increases in CVD risk; the development of endothelial dysfunction and stiffening of the large elastic arteries are among the most important contributors. Both are predictors of CV events and clinical CVD with increasing age. Although the importance of endothelial dysfunction and arterial stiffening with age are well established, the initiating events of these deleterious changes are elusive.

Detailed Description
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Advanced age is the primary and most predictive risk factor for CVD. The investigators have demonstrated that there is a pronounced age-associated increase in T cell infiltration into the perivascular space around large elastic arteries and small resistance arteries. The objective of this study is to determine if and how T cells contribute to age-related arterial inflammation and dysfunction. Although there is evidence from rodent studies that T cells play a critical role in arterial dysfunction, it is unknown whether this occurs in humans. Abatacept, a T cell co-stimulation inhibitor, is FDA approved for treatment of rheumatoid arthritis. Importantly, Abatacept decreases the inflammatory phenotype of circulating T cells. Abatacept will be used in older adults to be the first to determine if T cell inflammation contributes to arterial dysfunction in older adults. The investigators hypothesize that older adults treated with Abatacept will exhibit greater flow-mediated dilation, decreased pulse wave velocity, decreased or unchanged blood pressure, decreased inflammatory and oxidative stress markers in endothelial cells, decreased plasma free radicals, decreased proportion of memory T cells, and experience a shift away from a pro-inflammatory T cell phenotype compared to placebo. These results will be interpreted to mean that T cells play a role in mediating age-related arterial dysfunction in humans.

Official Title
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Impact of T Cells on Age-related Vascular Dysfunction: A Translational Approach

Conditions
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Aging, Cardiovascular Diseases, Inflammation

Intervention / Treatment
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* Other: Placebo
* Drug: Abatacept 10 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Older adults (55-75 years old). Women will be at least two years postmenopausal, not using hormone therapy and have a follicle stimulating hormone (FSH) concentration of >30 IU/L. Exclusion Criteria: Autoimmune disorders, Hypertension (blood pressure >140/90mmHg), Body mass index of >30 kg/m2, Clinical CVD, Diabetes Current tobacco use, Regular aerobic exercise (>30 mins per day, > 2 days per week for the at least the last 2 years), Current or recurring infections within 12 weeks of the baseline visit, A positive tuberculosis (TB) test or subjects at risk of TB, Positive test for Hepatitis B, C, or cytomegalovirus (CMV), Use of immunosuppressive medication, Vaccination within 4 weeks of the baseline visit, Major surgery within 8 weeks of the baseline visit, Previous lymphoid irradiation or bone marrow transplant, Subjects at risk for diverticulitis, Any laboratory test result that, in the opinion of the overseeing physician (Dr. Frech) might place a participant at unacceptable risk.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective placebo controlled crossover design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Older Adult participants<br>Older adult participants (ages 55-75) will be assessed for arterial function using FMD analysis, PWV calculations, T Cell phenotyping, and proportion of inflammatory biomarkers after injections of placebo and abatacept. | Other: Placebo<br>* Placebo injection at day one and day fourteen.<br>Drug: Abatacept 10 mg/kg<br>* Abatacept injection at day twenty eight and day forty two.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in brachial arterial diameter after abatacept injection. |  | 7 weeks | 
| Change in brachial arterial flow rate after abatacept injection. |  | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pulse wave velocity as measured by doppler ultrasound after abatacept injection. |  | 7 weeks | 
| Change in proportion of memory T-Cells after abatacept injection |  | 7 weeks | 
| Change in proportion of inflammatory biomarker Tumour Necrosis Factor alpha (TNF-α) after abatacept injection |  | 7 weeks | 
| Change in proportion of inflammatory biomarker Interferon gamma (IFN-γ) after abatacept injection |  | 7 weeks | 
| Change in proportion of inflammatory biomarker interleukin 10 (IL-10) after abatacept injection |  | 7 weeks | 
| Change in proportion of inflammatory biomarker interleukin 17 (IL-17) after abatacept injection |  | 7 weeks | 
| Change in proportion of inflammatory biomarker forkhead box P3 (FoxP3) after abatacept injection |  | 7 weeks | 
| Change in proportion of inflammatory biomarker perforin after abatacept injection |  | 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aging, Inflammation, Cardiovascular disease