Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction

February 16, 2024 updated by: The University of Texas at Arlington

Mechanism and Modulation of Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction

To test the specific research questions, healthy men and age-matched healthy premenopausal females will be enrolled. Subjects will undergo cardiac magnetic resonance imaging and spectroscopy (MRI/MRS) to evaluate cardiac morphology/function and fat metabolism. To acutely elevate myocardial triglyceride content, subjects will be asked to abstain from eating for 2 days (reproducibly causes a significant and physiological increase in myocardial fat deposition, transiently). Subjects will be allowed water and/or an isotonic saline solution in order to maintain hydration status. After screening, subjects will meet with the research coordinator or an investigator for a discussion, with opportunity for questions, before applicable consent forms are obtained. The subject will be screened for metal in or on their body and claustrophobia using a standard MR screening form. A venous blood sample will be taken for measurement of metabolic health, circulating hormones, and systemic inflammation. Imaging will include cine imaging for global morphology and function, tissue tagging for regional tissue deformation, spectroscopy for fat quantification. After baseline images of the heart are obtained, the subject will be asked to squeeze a MR-safe handgrip dynamometer at 30% of their maximum while images of the heart are obtained. Blood pressure will also be measured at rest and during stress. Each MRI will take approximately 90-120 minutes.

Aim 1 will test the hypothesis that cardiac steatosis induced left ventricular dysfunction is sexually dimorphic, by comparing age-matched men and premenopausal women before and after 48 of fasting. Subjects will complete the MRI/MRS protocol described above before and after the fasting intervention.

Aim 2 will test the hypothesis that estrogen is protective against cardiac steatosis-induced dysfunction, by suppressing ovarian sex hormones with a GnRH antagonist and repeating the fasting studies with and without estrogen add-back. 30 female subjects will be treated with GnRH antagonist and repeat the 48 hour fasting intervention and cardiac MRI/MRS protocol. 15 of the subjects will receive estrogen add-back using a transdermal patch, the other 15 subjects will receive a placebo patch.

Aim 3 will test whether plasma and myocardial fatty acid composition is sexually dimorphic, by performing comprehensive plasma and myocardial lipidomics assessment.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

100

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Texas
      • Arlington, Texas, United States, 76019
        • Recruiting
        • University of Texas at Arlington
        • Contact:
        • Contact:
        • Principal Investigator:
          • Michael Nelson, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 30 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • blood pressure <140/90 mmHg
  • BMI between 18.5 and 30 kg/m2
  • sedentary or recreationally active (<3 days of vigorous aerobic exercise each week)
  • no use of oral contraceptives hormone therapy, or other medications that might influence cardiovascular function
  • nonsmokers.

Exclusion Criteria:

  • Women will be excluded with

    1. history of or active estrogen-dependent neoplasms, acute liver or gallbladder disease, vaginal bleeding, venous thromboembolism, hypertriglyceridemia, and CVD
    2. known allergy to transdermal patch, GnRHant (i.e., hypersensitivity to cetrorelix, extrinsic peptide hormones, mannitol, GnRH, benzyl alcohol - the vehicle for injection of cetrorelix)
    3. history of stomach ulcer or bleeding
    4. other contraindications to hormone replacement therapy or GnRHant, (i.e., taking Levodopa, medications that can inhibit folate metabolism including methotrexate).

Other conditions for which individuals will be excluded from the study include:

diabetes active infection history of seizures or disease that affects the nervous system sepsis an abnormal resting ECG contraindications to MRI pregnant or planning to become pregnant smoking history illicit drug use (excluding occasional marijuana).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Fasting only
To acutely elevate myocardial triglyceride content, subjects will be asked to abstain from eating for 2 days (reproducibly causes a significant and physiological increase in myocardial fat deposition, transiently). Subjects will be allowed water and/or an isotonic saline solution in order to maintain hydration status.
Other: Fasting
Subjects will abstain from food for 48 hours. Subjects will be allowed water and/or an isotonic saline solution in order to maintain hydration status.
Experimental: LBNP Only
Subjects undergo lower body negative pressure at 40 mmHg.
Other: Lower Body Negative Pressure
This test simulates Earth's gravity. The subject will rest on his/her back, with their lower body sealed in an air-tight chamber from the waist down. The chamber is connected to a vacuum that sucks air from the chamber and creates negative pressure inside and around the subject's lower body. As a result, the subject's blood pool shifts towards their legs, away from their chest and arms.
Other Names:
  • LBNP
Experimental: Estrogen add back with GnRHant
Subjects are given estradiol patch.
Other: Fasting
Subjects will abstain from food for 48 hours. Subjects will be allowed water and/or an isotonic saline solution in order to maintain hydration status.
Drug: Estradiol patch
Brand name Climara for estrogen add back portion of study. Premenopausal women treated with a GnRH antagonist will be randomized to estrogen add-back or placebo. Thus, for women without contradictions to estrogen use, the risks associated with their use for the duration proposed in these studies (i.e., 6 days) are small. The respective estradiol regimen is a standard approved dose for treatment of hot flashes and the prevention of osteoporosis, and this dose will increase E2 to concentrations typically observed during the mid to late follicular phase of the menstrual cycle.
Drug: Cetrotide
Premenopausal women will be treated with the gonadotropin-releasing hormone (GnRH) antagonist Cetrorelix for 6 days in order to suppress ovarian sex hormones. Cetrorelix may cause an anaphylactic reaction in volunteers with hypersensitivity to cetrorelix, GnRH or any other GnRH analogs, or extrinsic peptide hormones or mannitol. It may also cause hot flashes, headaches, and nausea. These are typically transient and of mild intensity. These effects are all reversible upon cessation of cetrorelix. Absence of pregnancy will be confirmed before drug administration.
Experimental: Placebo add back with GnRHant
Subjects are given placebo patch.
Other: Fasting
Subjects will abstain from food for 48 hours. Subjects will be allowed water and/or an isotonic saline solution in order to maintain hydration status.
Drug: Cetrotide
Premenopausal women will be treated with the gonadotropin-releasing hormone (GnRH) antagonist Cetrorelix for 6 days in order to suppress ovarian sex hormones. Cetrorelix may cause an anaphylactic reaction in volunteers with hypersensitivity to cetrorelix, GnRH or any other GnRH analogs, or extrinsic peptide hormones or mannitol. It may also cause hot flashes, headaches, and nausea. These are typically transient and of mild intensity. These effects are all reversible upon cessation of cetrorelix. Absence of pregnancy will be confirmed before drug administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in left ventricular relaxation rate
Time Frame: 1 week
Measured at each of the 4 MRIs by tissue tagging
1 week
Comprehensive plasma lipidomics
Time Frame: 1 week
Measured from blood drawn at each of the 4 MRIs
1 week

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Texas at Arlington

Collaborators

University of Texas Southwestern Medical Center

Investigators

  • Principal Investigator: michael nelson, PhD, University of Texas at Arlington

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 13, 2018

Primary Completion (Estimated)

December 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

December 3, 2020

First Submitted That Met QC Criteria

December 11, 2020

First Posted (Actual)

December 17, 2020

Study Record Updates

Last Update Posted (Actual)

February 20, 2024

Last Update Submitted That Met QC Criteria

February 16, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STU 112017-013

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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