Sex Differences in Heart-brain Crosstalk - Role of Psychosocial Stress

Brief Summary

Detailed Description

The main objective of the project is to prospectively determine the influence of sex on amygdalar metabolic activity and myocardial perfusion in a population of healthy postmenopausal women and aged men under acute psychosocial stress conditions. The primary hypothesis of the study is that women experience disproportionate amygdalar metabolic activity and reduced myocardial perfusion in response to psychosocial stress compared to men. This project is a monocentric prospective observational study involving hybrid positron emission tomography/magnetic resonance (PET/MR) imaging as well as the collection of biological samples in healthy individuals aged 50-75 years (postmenopausal women, and men). To inflict acute psychosocial stress, the investigators applied the Montreal Imaging Stress Test (MIST) when the participants were inside the PET/MR scanner and the Trier Social Stress Test (TSST) when the participants were outside the PET/MR scanner. Both the TSST and the MIST are standardized tests and are widely applied to provoke reliable biological stress responses in a laboratory setting. No follow-up study is planned. At inclusion, individuals have been interviewed and health data have been collected through questionnaires. In addition, biological samples, including blood, nail and saliva have been collected. Volunteers underwent myocardial blood flow (MBF) and cerebral perfusion imaging using ammonia (13NH3)-PET, as well as functional imaging using magnetic resonance imaging (MRI), both routinely used imaging techniques. 13NH3-PET/MR has been conducted at rest and under stress (MIST). Subsequently, the study participants underwent a TSST, followed by whole body metabolic imaging with fluor-18-deoxyglucose (18F-FDG)-PET/MRI, allowing to study brain and bone marrow metabolism, among other parameters. In parallel, the heart rate response (HRR) has been monitored throughout the study and catecholamines were collected at baseline and after stress to assess the autonomic influence on the heart. The total radiation exposure was below 5 mSv. In detail, each participant was asked to complete questionnaires to assess their psychometric baseline characteristics at the study visit. Two blood samples were collected from a peripheral intravenous catheter, at the beginning of the study and the end of the TSST. Blood glucose levels were measured using a finger prick. In addition, saliva samples of approximately 1 mL each were taken at different time points, notably before and after each of the mental stress tests. Nail samples were collected by clipping nails from the fingers and/or toes. All biological samples from the participants were immediately processed to allow sample conservation. Project data and samples were handled with the uttermost discretion and only accessible to authorized personnel. On project-specific documents, participants are only identified by a unique participant number. Coded data were used and the participant identification list is only accessible by the investigators. Data is protected from unauthorized or accidental disclosure, alteration, deletion, copying, and theft by using the built-in mechanisms of Redcap®. Biological material in this project is not identified by participant name but by a unique participant number. Participants were asked to fast for at least 2.5 hours prior to the study visit and refrain from strong physical activity for at least 24 hours. All study participants underwent serial imaging on a dedicated hybrid PET/MR scanner (GE Healthcare) using 13N-NH3 and 18F-FDG as validated tracers, according to daily clinical routine. Whole-body (18F-FDG) or brain and heart (13-NH3) MRI were recorded simultaneously with all PET scan acquisitions. Beginning with an intravenous bolus administration of 200 MBq of 13N-NH3, serial dynamic and static PET images were acquired for 30 minutes. In parallel, subjects underwent the Control (rest) part of the MIST (mathematical task, inside the scanner). A second dose of 400 MBq of 13N-NH3 was given, and images were recorded in the same acquisition sequence for 30 minutes, in parallel to the Stress part of the MIST. After a break, all individuals were injected with 150 MBq of 18F-FDG, followed by a TSST outside of the scanner. During the first part of the TSST, a panel of two to three judges (trained staff), equipped with a video camera, ask the participant to prepare a 5-minute presentation. To do that, participants can use paper and pen but must hand out their notices at the beginning of the presentation. During the 5-minute presentation, the judges observe the participants without giving any comments or facial expressions. The participants are asked to continue if they stop before the entire 5 minutes run out. For the second part of the TSST, participants undergo a mental arithmetic task during which they are asked to count backward from 1022 in steps of 11. Subsequently, participants were allowed to rest in a designated separate dark room (rest phase), and the 18F-FDG-PET scan was performed ca. 60 min after tracer injection to assess metabolic activity in the brain, according to routine procedures at the Department of Nuclear Medicine of the University Hospital Zurich. Heart rate and blood pressure were recorded at baseline and throughout the procedure. The procedure from the initial scan to the end of the final scan takes about 3.5 hours. Together with the 2 hours of preparation, participants spent about 5.5 hours on the study in total.

Primary Outcomes

Secondary Outcomes

• Difference between the rest and stress amygdala-to-vmPFC perfusion ratios (kBq/kBq)(11-10-2021 to 20-11-2023)
• Noradrenaline (mL/min)(11-10-2021 to 20-11-2023)
• Interleukin-2 (IL-2, pg/mL)(11-10-2021 to 20-11-2023)
• Interleukin-4 (IL-4, pg/mL)(11-10-2021 to 20-11-2023)
• Tumor necrosis factor (TNF, pg/mL)(11-10-2021 to 20-11-2023)
• Salivary cortisol (mol/L)(11-10-2021 to 20-11-2023)
• Adrenaline (mL/min)(11-10-2021 to 20-11-2023)
• Bone marrow metabolic activity (SUV)(11-10-2021 to 20-11-2023)
• Amygdala-to-vmPFC ratio of glycolytic metabolic activities (SUV/SUV)(11-10-2021 to 20-11-2023)
• Myocardial blood flow (MBF) at rest (mL/g/min)(11-10-2021 to 20-11-2023)
• Gender score questionnaire(11-10-2021 to 20-11-2023)
• Left ventricular ejection fraction (LVEF, %)(11-10-2021 to 20-11-2023)
• Heart-rate response (HRR, no unit)(11-10-2021 to 20-11-2023)
• Dopamine (mL/min)(11-10-2021 to 20-11-2023)
• Vascular Cell Adhesion Molecule (VCAM)(11-10-2021 to 20-11-2023)
• Myocardial blood flow (MBF) at stress (mL/g/min)(11-10-2021 to 20-11-2023)
• Spleen metabolic activity (SUV)(11-10-2021 to 20-11-2023)
• Aorta metabolic activity (SUV)(11-10-2021 to 20-11-2023)
• Interleukin-10 (IL-10, pg/mL)(11-10-2021 to 20-11-2023)
• C-reactive protein (CRP, mg/L)(11-10-2021 to 20-11-2023)
• Interleukin-6 (IL-6, pg/mL)(11-10-2021 to 20-11-2023)
• Interleukin-8 (IL-8, pg/mL)(11-10-2021 to 20-11-2023)
• Matrix metalloproteinase-9 (MMP9, pg/mL)(11-10-2021 to 20-11-2023)
• Monocyte Chemoattractant Protein-1 (MCP1, pg/mL)(11-10-2021 to 20-11-2023)