Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction

Summary

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.

Conditions

• Heart Diseases
• Left Ventricular Dysfunction

Interventions

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.

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.

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.

Sponsors & Collaborators

• University of Texas Southwestern Medical Center

  collaborator OTHER

• The University of Texas at Arlington

  lead OTHER

Principal Investigators

• michael nelson, PhD · University of Texas at Arlington

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

30 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2018-09-13

Primary Completion

2024-12-31

Completion

2024-12-31

FDA Drug

Yes

Countries

• United States

Study Locations