Sex-Specific Cerebrovascular Dysfunction in Metabolic Syndrome-Role of COX

University of Wisconsin (UW)

Status and phase: Begins enrollment in 4 months; Early Phase 1

Conditions: Metabolic Syndrome

Treatments: Drug: Indomethacin; Diagnostic Test: MRI; Drug: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT07218653

School of Educ / Kinesiology (Other Identifier)

R01 MetSyn

pending (Other Grant/Funding Number)

Details and patient eligibility

About

This study tests the hypothesis that Metabolic Syndrome (MetSyn) decreases cerebral blood flow (CBF) more in females than males due in part to the sex-specific loss of COX vasodilation. Male and female participants will be enrolled in two groups: Health Controls versus participants with MetSyn.

Full description

The central hypothesis is that MetSyn decreases CBF more in females than males due in part to the sex-specific loss of COX vasodilation. This hypothesis is based on extensive preliminary data demonstrating MetSyn induces: 1) 3-fold larger reductions in CBF in females that abolish sex differences, 2) region-specific CBF reduction patterns, and 3) a greater loss of COX-mediated vasodilation in females.

This hypothesis is tested via three Specific Aims:

• Aim 1: Determine the extent of sex differences in MetSyn-driven CBF reductions. The investigators hypothesize females with MetSyn will demonstrate larger decrements in global, grey matter and white matter CBF versus males.
• Aim 2: Determine the sex-by-region interactions of MetSyn reductions in CBF. The investigators hypothesize females will demonstrate larger regional CBF declines-particularly in regions known to be impacted very early in brain pathologies and/or specifically impaired by insulin resistance.
• Aim 3: Determine the role of COX signaling in mediating CBF changes in MetSyn. The investigators hypothesize COX vasodilation is reduced more in females than males with MetSyn.

All consented participants will conduct a screening visit with a blood panel to identify control vs MetSyn eligibility.

Once eligible, participants complete three laboratory visits (each lasting about 2 hours):

1. Exercise Visit: VO2 Max, DEXA for adiposity quantification, NIH Toolbox to assess neurocognitive function
2. MRI Visit 1: blinded to either Placebo or Indomethacin
3. MRI Visit 2: blinded to either Placebo or Indomethacin

Enrollment: 72 estimated patients

Sex: All

Ages: 18 to 45 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (Healthy Controls):

• non-hypertensive (less than 130/80 mmHg)
• non-obese with a Body Mass Index (BMI) less than 30 kilogram per meter squared (kg/m2)
• Normal blood glucose less than 100 grams per deciliter (g/dl)
• Normal lipids; LDL cholesterol less than130 milligrams per deciliter (mg/dl), triglycerides less than 150 mg/dl.
• Women must have a predictable menstrual cycle for MRI scheduling. Females will be studied on cycle days 1-7 (as presented in all preliminary data) to minimize sex hormone differences and their potential confounding effects on vascular outcomes. Oral contraceptives will be allowed in women to increase translatability in findings.

Inclusion Criteria (Participants with Metabolic Syndrome):

• Meet age criteria plus three or more of the five criteria for MetSyn as defined by ATP, the most common three factors meeting MetSyn criteria will be obesity, prehypertension / hypertension, and low HDL cholesterol.

Exclusion Criteria:

• Subjects with a diagnostic history of:

  • peripheral vascular, hepatic, renal, or hematologic disease
  • stroke
  • type 1 or 2 diabetes
  • sleep apnea
  • hypertension (allowed in MetSyn)
  • regular tobacco users
  • taking cardiovascular medications (e.g., statins, angiotensin II receptor blockers) or metabolic medications (metformin, insulin, semaglutide) or NSAID sensitivity will be excluded.

• In women: pregnancy or polycystic ovarian syndrome (PCOS, to avoid altered testosterone in women).

• A history of a neurocognitive disorder or an intellectual disability will be excluded from the study. A neurocognitive screener (MoCA) will be completed; a score below the normal range (25 or below) is exclusionary. Participants will complete the Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7) to screen for symptoms of depression and anxiety to increase the translatability of data; normal to mildly elevated range (0-9) are included but excluded at higher scores (10-27).

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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72 participants in 2 patient groups

Healthy controls

Experimental group

Description:

Male and female participants 18-45 without Metabolic Syndrome. On study for 3 visits (up to 6 months). Randomized to either Placebo then Indomethacin or Indomethacin then Placebo for 2 MRI visits.

Treatment:

Drug: Placebo

Diagnostic Test: MRI

Drug: Indomethacin

Metabolic Syndrome

Experimental group

Description:

Male and female participants, age-matched with Healthy Controls, who have at least 3 defining symptoms of Metabolic Syndrome. Randomized to either Placebo then Indomethacin or Indomethacin then Placebo for 2 MRI visits.

Treatment:

Drug: Placebo

Diagnostic Test: MRI

Drug: Indomethacin