Angiotensin (1-7) Treatment to Improve Cognitive Functioning in Heart Failure Patients

In this non-randomized pilot study 16 heart failure patients will be enrolled. Adults (ages
55-75) with chronic HF will be recruited who do not have neurologic or psychiatric disorders
expected to interfere with memory function. Patients must have been diagnosed with HF ≥ 90
days prior to enrollment, be clinically stable, and on stable medications. Participants have
a medical history and examination, with documentation of evidence of HF, and screening to
rule out dementia (Mini-Mental State Exam score less than 25), and depression (Geriatric
Depression Scale score greater than 10. Participants will be treated for 12 weeks with a
daily dose of subcutaneous Ang-(1-7) (100 mcg/kg/day). Half of the group will be given memory
training in 2-hr sessions twice weekly for two weeks beginning at 6 weeks of drug treatment.
Prior to drug treatment, baseline measures will include memory and neuropsychological tests
and inflammatory markers. Memory and neuropsychological tests will be repeated at 3 weeks, 6
weeks and 12 weeks. Inflammatory biomarkers will be reassessed at 6 weeks and 12 weeks. Blood
draws for pharmacokinetic (PK) measurements will be obtained at baseline and Day 7. MRI scans
will be obtained from all participants who do not have an ICD, pacemaker or other
contraindication to MRI at baseline with repeat scans at 12 weeks. Lastly Self-Care Efficacy
testing will be obtained at 12 weeks from all participants.

Aim 1 Primary Outcome: Changes in performance on the Memory Intentions Test (MIST, a test of
PM) between baseline and 12 weeks27 will be the primary endpoint to test effectiveness of PMT
in the presence or absence of Ang-(1-7) treatment.MIST scores have been shown to predict
medication adherence.

Aim 1 Secondary Outcomes:

1. Safety of the treatment will be assessed by careful collection of standard serious
adverse events, and comparison of events across treatment arms. In addition, patients
will be asked about difficulties associated with the therapy, and medication vials
collected to assess compliance with therapy.

2. Self-care efficacy at 12 weeks will be measured using the SCHFI, a validated tool.

3. Other neuropsychological measures of memory, executive functions, and psychomotor speed
will be assessed at baseline, 3 weeks, 6 weeks, and at the 12 week follow-up.

4. HF quality of life will be assessed using the Kansas City Cardiomyopathy Questionnaire
(KCCQ) at baseline and 12 weeks.

5. Adjudicated HF hospitalizations, all-cause hospitalizations and death will be assessed
by treatment arm.

Aim 2: Systemic Inflammation Assay: At baseline, and after 6 and 12 weeks of Ang-(1-7)
treatment, blood will be collected for assessment of systemic inflammation. Blood will be
placed in lavender-top EDTA tubes, centrifuged to obtain plasma, and rapidly frozen in liquid
nitrogen.

Cytokines, chemokines, and additional circulating inflammatory analytes will be detected and
quantified by multiplex immunoassay using a MAGPIX®. Each sample will be measured in
duplicate. Data will be analyzed by ANOVA across all groups.

Aim 2 Primary Outcome: Immunosuppressive cytokines TGFα and IL-1 will be measured as they
play an important role in the anti-inflammatory actions of Ang-(1-7) and are widely used as
functional indicators of systemic inflammation. The more common clinical inflammatory marker
of systemic inflammation C-reactive protein, will also be measured.

Inclusion Criteria:

- Diagnosed with chronic HF ≥ 90 days prior to enrollment

- Be clinically stable and on stable medications

- Stable NYHA Class II-III HF or symptoms during mild or moderate exercise but not at
rest (i.e. shortness of breath)

- Fluent in English or formal education in English starting from at least the age of 5

- Able and willing to provide informed consent

Exclusion Criteria:

- Evidence of decompensated HF

- Symptoms or signs of active coronary ischemia

- Criteria for DSM-IV diagnosis or history of serious psychiatric disease, or diagnosed
learning disabilities. May have psychological problem that has been well controlled on
medication for a sustained period of more than 2 years.

- Any other neurological, psychiatric, or medical illness or injury expected to
interfere with cognitive function or memory including but not limited to stroke
(diagnosed with evidence of stroke), head injury, epilepsy, Alzheimer's, Parkinson's,
brain cancer, depression (current, but ok in past). Migraines OK. May have TIAs with
no sign of impairment and no sequelae following the event

- Active substance abuse disorder i.e. alcohol, nicotine. Previous substance abuse of
cocaine, Ecstasy, LSD, IV drugs

- History of seizure disorder as child or currently experiencing or on medications for
seizures. Exception is febrile seizures as a child.

- Any condition which may prevent the subject from adhering to the study protocol, as
determined by the Investigator i.e. reported learning disability, cataracts impairing
vision, colorblindness.

- Movement disorders that prevent the subject from being still for the MRI

- The presence of any metallic implant or foreign body, including dental bridges
excludes patients from MRI. Removable body piercings/implants okay. Patients with a
metal implant or foreign body will still be enrolled; however these patients will not
undergo MRI testing.

- Professional metalworker or welder

- Recurring panic attacks or claustrophobic

- Abnormally high weight or height to fit in scanner (Bore 70cm)