Evaluation of the Safety and Efficacy of Ang-(1-7) to Enhance Cognitive Function in Participants Undergoing CABG

Up to 104 participants (ages 60-80) undergoing elective CABG surgery at the Banner University Medical Center in Tucson, AZ or at Suburban Hospital/NIH Clinical Center in Bethesda, MD, will be enrolled in this randomized, placebo-controlled, double-blind study of Angiotensin-(1-7). Subjects who have a pre-operative neurologic, learning or psychiatric disorder will be excluded. In addition, a concurrent group of 20 age-matched adults will be recruited as a neuropsychological control group and will undergo neuropsychological testing at baseline, Day 21 and Day 90. Participants will be asked to undergo a screening process to confirm eligibility and to rule out depression, dementia and contraindications to MRI. Prior to randomization, baseline measures will include neuropsychological testing, brain MRI, quality of life questionnaires, inflammatory markers and DNA/RNA sample collection. Participants will be treated for 21 days with a daily dose of subcutaneous Ang-(1-7) (100 mcg/kg/day) (n=60) or placebo (n=30). These measures will then be repeated at Day 21 and Day 90. The MRI will be repeated at Day 21 only. Pharmacokinetic measurements will be obtained prior to administration of Ang-(1-7) or placebo and hourly for 6 hours following the first 6 doses. Delirium testing will occur on a daily basis post surgery until discharge. Serum study drug level will be obtained at Day 21. Lastly, subjects will be followed on a weekly basis by telephone for all 12 weeks of the study. 1. Primary Objective: To evaluate the safety and tolerability of 21 days of subcutaneous (s.c.) once daily administration of Ang-(1-7) in eligible participants undergoing first-time, elective coronary artery bypass graft (CABG) surgery. 2. Secondary Objectives: 1. To determine the pharmacokinetics of 21 days of treatment with Ang-(1-7). 2. To determine if 21 days of treatment with 200 mcg/kg/day of Ang-(1-7) improves memory function measured as a change in performance from baseline to follow up on a composite score comprised of memory, executive functioning, language and processing speed in Ang-(1-7) treatment group compared to placebo controls and non-surgical controls. 3. To determine if treatment with 200 mcg/kg/day Ang-(1-7) decreases postoperative delirium length and severity as measured with the Confusion Assessment Method (CAM) D2 to D7 ( or discharge) after surgery as compared to treatment with placebo group. 4. To determine if 21 days of treatment with 200 mcg/kg/day Ang-(1-7) improves participant self-reported outcomes using standardized Kansas City Cardiomyopathy Questionnaire (KCCQ) and Instrumental Activities of Daily Living (IADL) measurement tools. 5. To determine if 21 days treatment with 200 mcg/kg/day Ang-(1-7) results in changes in suicidal ideation and behavior as assessed by The Columbia Suicide Severity Rating Scale (C-SSRS). 6. To compare postoperative mortality and morbidity at 90 days in the 200 mcg/kg/day Ang-(1-7) treatment group with the placebo group. 7. To determine if 21 days of treatment of 200 mcg/kg/day Ang-(1-7) decreases postoperative observable changes in brain fractional anisotropy as measured by diffuse on magnetic resonance imaging (MRI) as compared to placebo.