Sex Differences in Myocardial Steatosis Induced Left Ventricular Dysfunction

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.

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).