Heart-brain-axis and Psychosocial Stress

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

The main study objective is to prospectively determine the influence of sex-related risk factors and psychosocial variables on neuronal stress responses and myocardial perfusion in a population of 64 female and male individuals 50-75 years of age and free of cardiovascular disease.

Study Overview

• Status: Completed
• Conditions: Myocardial Ischemia; Gender; Mental Stress; Sex Role
• Intervention / Treatment: Behavioral: Mental stress

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.

• Study Type: Observational
• Enrollment (Actual): 64

Contacts and Locations

Study Locations

• Switzerland
  • Canton of Zurich
    • Zurich, Canton of Zurich, Switzerland, 8091
      • University Hospital Zurich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

We included healthy volunteers aged between 50-75 years old, post-menopausal in the case of women, recruited mainly in Switzerland.

Description

Inclusion Criteria:

• Women and men that are between 50-75 years of age
• Post-menopausal status in women
• Normal body weight (BMI<30kg/m2)
• Non-smoker or not smoking since ≥ 5 years or occasional smokers.

Exclusion Criteria:

• Written informed consent was not provided
• History of arterial hypertension
• History of diabetes
• History of cardiovascular disease
• History of neurological disorders
• History of cancer (unless considered in remission since at least 5 years and not having necessitated a systemic chemotherapy and/or a brain radiotherapy)
• Use of steroids interfering with biomarker levels

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Female Sex; Healthy volunteer women aged between 50-75 years old, in post-menopausal status.	Behavioral: Mental stress; Two consecutive validated mental stress tests, namely 1) the Montreal Imaging Stress Task consisting of two series of 15-minute mental calculation tests, without (Control Mode) and with (Stress Mode) negative feedback, respectively; and 2) the Trier Social Stress Test consisting of a 5-minute mock job interview (Speech Part) followed by a 5-minute mental calculation test (Mental Arithmetic Part).
Male Sex; Healthy volunteer men aged between 50-75 years old.	Behavioral: Mental stress; Two consecutive validated mental stress tests, namely 1) the Montreal Imaging Stress Task consisting of two series of 15-minute mental calculation tests, without (Control Mode) and with (Stress Mode) negative feedback, respectively; and 2) the Trier Social Stress Test consisting of a 5-minute mock job interview (Speech Part) followed by a 5-minute mental calculation test (Mental Arithmetic Part).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amygdala-to-cerebellum ratio of glycolytic metabolic activities (SUV/SUV)	Sex differences in the stress-related neural activity (SNA) assessed by 18F-FDG-PET and defined as the amygdala metabolic activity (AmygA, expressed as standard uptake value, SUV) corrected to the metabolic activity of the cerebellum (expressed as SUV), following the Trier Social Stress Test. The higher the AmygA/(cerebellum activity) ratio, the higher the SNA (no threshold for normality)	11-10-2021 to 20-11-2023
Difference between the rest and stress amygdala-to-cerebellum perfusion ratios (kBq/kBq)	Sex differences in the amygdala perfusion between rest and stress, assessed by 13N-NH3-PET and defined as the amygdala perfusion (AmygP, expressed as kiloBecquerel, kBq) corrected to the perfusion of the cerebellum (expressed as kBq), following the Montreal Imaging Stress Task. The higher the magnitude of the AmygP/(Cerebellum perfusion) modification at stress compared to rest, the higher the amygdala response to mental stress (no threshold for normality)	11-10-2021 to 20-11-2023
Myocardial flow reserve (MFR, no unit)	Sex differences in myocardial flow reserve (MFR) as determined by 13N-NH3-PET, during the Montreal Imaging Stress Task. MFR is defined as the ratio between MBF at stress and MBF at rest (no unit). The higher the MFR, the higher the myocardial perfusion modification during the stress task (no threshold).	11-10-2021 to 20-11-2023

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amygdala-to-vmPFC ratio of glycolytic metabolic activities (SUV/SUV)	Sex differences in the stress-related neural activity (SNA) assessed by 18F-FDG-PET and defined as the amygdala metabolic activity (AmygA, expressed as standard uptake value, SUV) corrected to the metabolic activity of the ventromedial prefrontal cortex vmPFC (expressed as SUV), following the Trier Social Stress Test. The higher the AmygA/(vmPFC activity) ratio, the higher the SNA (no threshold for normality)	11-10-2021 to 20-11-2023
Difference between the rest and stress amygdala-to-vmPFC perfusion ratios (kBq/kBq)	Sex differences in the amygdala perfusion between rest and stress, assessed by 13N-NH3-PET and defined as the amygdala perfusion (AmygP, expressed as kiloBecquerel, kBq) corrected to the perfusion of the ventromedial prefrontal cortex (vmPFC, expressed as kBq), following the Montreal Imaging Stress Task. The higher the magnitude of the AmygP/(vmPFC perfusion) modification at stress compared to rest, the higher the amygdala response to mental stress (no threshold for normality)	11-10-2021 to 20-11-2023
Myocardial blood flow (MBF) at rest (mL/g/min)	Sex differences in myocardial blood flow (MBF, in mL/g/min) as determined by 13N-NH3-PET, during the control mode of the Montreal Imaging Stress Task. The higher the MBF, the higher the myocardial perfusion (no threshold).	11-10-2021 to 20-11-2023
Myocardial blood flow (MBF) at stress (mL/g/min)	Sex differences in myocardial blood flow (MBF, in mL/g/min) as determined by 13N-NH3-PET, during the stress mode of the Montreal Imaging Stress Task. The higher the MBF, the higher the myocardial perfusion (no threshold).	11-10-2021 to 20-11-2023
Heart-rate response (HRR, no unit)	Sex differences in the heart rate response (HRR), a surrogate for cardiac sympathetic activity, following each of the Montreal Imaging Stress Task and the Trier Social Stress Test. The HRR is defined as follows: HRR = ((Heart Rate at Stress) - (Heart Rate at Rest)/(Heart Rate at Rest)). The higher the HRR, the higher the cardiac sympathetic response to stress.	11-10-2021 to 20-11-2023
Salivary cortisol (mol/L)	Sex differences in the salivary cortisol response, a surrogate marker for the hypothalamic-pituitary-axis (HPA), to each of the Montreal Imaging Stress Task and the Trier Social Stress Test. The higher the cortisol increase, the higher the HPA response (no threshold).	11-10-2021 to 20-11-2023
Noradrenaline (mL/min)	Sex differences in the blood noradrenaline increase (mL/min) following the Trier Social Stress Task.	11-10-2021 to 20-11-2023
Adrenaline (mL/min)	Sex differences in the blood adrenaline increase (mL/min) following the Trier Social Stress Task.	11-10-2021 to 20-11-2023
Dopamine (mL/min)	Sex differences in the blood dopamine increase (mL/min) following the Trier Social Stress Task.	11-10-2021 to 20-11-2023
Spleen metabolic activity (SUV)	Sex differences in the spleen metabolic activity, a surrogate for systemic inflammation, following the Trier Social Stress Test, as assessed by 18F-FDG-PET, and expressed in standard uptake value (SUV). The higher the spleen SUV, the higher systemic inflammation.	11-10-2021 to 20-11-2023
Bone marrow metabolic activity (SUV)	Sex differences in the bone marrow metabolic activity, a surrogate for systemic inflammation, following the Trier Social Stress Test, as assessed by 18F-FDG-PET, and expressed in standard uptake value (SUV). The higher the bone marrow SUV, the higher systemic inflammation.	11-10-2021 to 20-11-2023
Aorta metabolic activity (SUV)	Sex differences in the thoracic aorta metabolic activity, a surrogate for aortic inflammation, following the Trier Social Stress Test, as assessed by 18F-FDG-PET, and expressed in standard uptake value (SUV). The higher the aorta SUV, the higher aorta inflammation.	11-10-2021 to 20-11-2023
Left ventricular ejection fraction (LVEF, %)	Sex differences in the left ventricular ejection fraction (LVEF, %) following the control and stress phases of the Montreal Imaging Stress Task.	11-10-2021 to 20-11-2023
C-reactive protein (CRP, mg/L)	Sex differences in C-reactive protein (CRP, in mg/L) collected at baseline and after the Trier Social Stress Test. The higher the CRP, the higher the inflammation.	11-10-2021 to 20-11-2023
Interleukin-2 (IL-2, pg/mL)	Sex differences in Interleukin-2 (IL-2), collected at baseline and after the Trier Social Stress Test. The higher the IL-2, the higher the inflammation.	11-10-2021 to 20-11-2023
Interleukin-4 (IL-4, pg/mL)	Sex differences in Interleukin-4 (IL-4) collected at baseline and after the Trier Social Stress Test. The higher the IL-4, the higher the inflammation.	11-10-2021 to 20-11-2023
Interleukin-6 (IL-6, pg/mL)	Sex differences in Interleukin-6 (IL-6) collected at baseline and after the Trier Social Stress Test. The higher the IL-6, the higher the inflammation.	11-10-2021 to 20-11-2023
Interleukin-8 (IL-8, pg/mL)	Sex differences in Interleukin-8 (IL-8) collected at baseline and after the Trier Social Stress Test. The higher the IL-8, the higher the inflammation.	11-10-2021 to 20-11-2023
Interleukin-10 (IL-10, pg/mL)	Sex differences in Interleukin-10 (IL-10) collected at baseline and after the Trier Social Stress Test. The higher the IL-10, the higher the inflammation.	11-10-2021 to 20-11-2023
Tumor necrosis factor (TNF, pg/mL)	Sex differences in Tumor necrosis factor (TNF, pg/mL) collected at baseline and after Trier Social Stress Test. The higher the TNF, the higher the inflammation.	11-10-2021 to 20-11-2023
Matrix metalloproteinase-9 (MMP9, pg/mL)	Sex differences in Matrix metalloproteinase-9 (MMP9, pg/mL), collected at baseline and after Trier Social Stress Test. The higher the MMP9, the higher the inflammation.	11-10-2021 to 20-11-2023
Monocyte Chemoattractant Protein-1 (MCP1, pg/mL)	Sex differences in Monocyte Chemoattractant Protein-1 (MCP1, pg/mL), collected at baseline and after Trier Social Stress Test. The higher the MCP1, the higher the inflammation.	11-10-2021 to 20-11-2023
Vascular Cell Adhesion Molecule (VCAM)	Sex differences in Monocyte Chemoattractant Protein-1 (MCP1, pg/mL), collected at baseline and after Trier Social Stress Test. The higher the VCAM, the higher the inflammation.	11-10-2021 to 20-11-2023
Gender score questionnaire	Sex differences in the self-perceived gender identity on a 0-to-100 scale, lower scores indicating a more pronounced "male gender" identity, higher scores indicating a more pronounced "female gender" identity. In addition to stratifying the analysis by sex, the role of gender on the results will be explored.	11-10-2021 to 20-11-2023

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate-Pressure-Product (RPP, in beats per minute x mmHg)	Sex differences in the rate-pressure-product (RPP, in beats per minute x mmHg) following the Montreal Imaging Stress Task, defined as the ratio between heart rate and systolic blood pressure. The higher the RPP, the higher the myocardial workload.	11-10-2021 to 20-11-2023
vmPFC-to-cerebellum ratio of glycolytic metabolic activities (SUV/SUV)	Sex differences in the metabolic activity of the ventromedial prefrontal cortex, assessed by 18F-FDG-PET, and defined as the vmPFC metabolic activity (expressed as standard uptake value, SUV) corrected to the metabolic activity of the cerebellum (expressed in SUV), following the Trier Social Stress Test. The higher the AmygA/(vmPFC activity) ratio, the higher the SNA (no threshold for normality)	11-10-2021 to 20-11-2023
Nail cortisol value (pg/mg)	Cortisol (pg/mg) as measured in the nails, a surrogate for chronic stress exposure.	11-10-2021 to 20-11-2023
General Anxiety Disorder (GAD-7) Questionnaire	Sex differences in the General Anxiety Disorder (GAD-7) questionnaire measuring anxiety severity on a 0-to-21 scale. The higher the score, the more pronounced anxiety symptoms.	11-10-2021 to 20-11-2023
Patient Health Questionnaire (PHQ-8)	Sex differences in the Patient Health Questionnaire (PHQ-8) assessing depressive symptoms on a 0-to-27 score. The higher the score, the more pronounced depressive symptoms.	11-10-2021 to 20-11-2023
Shortened Maastricht Exhaustion Questionnaire	Sex differences in the Shortened Maastricht Exhaustion Questionnaire assessing exhaustion levels on a 0-to-18 score. The higher the score, the more pronounced exhaustion symptoms.	11-10-2021 to 20-11-2023
Type D Personality (DS14) questionnaire	Sex differences in the Type D Personality (DS14) questionnaire on a 0-to-56 score. The higher the score, the more pronounced type D personality features.	11-10-2021 to 20-11-2023
Wagnild & Young Score resilience questionnaire	Sex differences in the Wagnild & Young Score resilience questionnaire on a 0-to-77 score. The higher the score, the more pronounced features of a resilient personality.	11-10-2021 to 20-11-2023
Perceived Stress Scale (PSS-4) questionnaire	Sex differences in the Perceived Stress Scale (PSS-4) questionnaire assessing stress levels in the previous months on a 0-to-16 scale. The higher the score, the higher the perceived stress.	11-10-2021 to 20-11-2023
Jenkins Sleep Scale (JSS-4)	Sex differences in the Jenkins Sleep Scale (JSS-4) evaluating sleep quality on a 0-to-16 scale.The higher the score the higher the sleep disturbances.	11-10-2021 to 20-11-2023
Trier Inventory for Chronic Stress (TICS)	Sex differences in the Trier Inventory for Chronic Stress (TICS) evaluating stress exposure in the preceding three months on a 0-to-228 scale. The higher the score, the more pronounced stress exposure.	11-10-2021 to 20-11-2023
Perceived stress	Sex differences in the perceived stress following each of the Montreal Imaging Stress Task and the Trier Social Stress Test, as self-assessed by the participants on a 0 to 7 Likert scale (0 indicating no perceived stress, and 7 indicating the highest possible stress perception).	11-10-2021 to 20-11-2023
Left ventricular stroke volume (LVSV, mL)	Sex differences in the left ventricular stroke volume (LVSV, mL), as measured by cardiac magnetic resonance, following the control and stress phases of the Montreal Imaging Stress Task.	11-10-2021 to 20-11-2023
Left ventricular end-systolic volume (LVESV, mL)	Sex differences in the left ventricular end-systolic volume (LVESV, mL), as measured by cardiac magnetic resonance, following the control and stress phases of the Montreal Imaging Stress Task.	11-10-2021 to 20-11-2023
Left ventricular end-diastolic volume (LVEDV, mL)	Sex differences in the left ventricular end-diastolic volume (LVEDV, mL), as measured by cardiac magnetic resonance, following the control and stress phases of the Montreal Imaging Stress Task.	11-10-2021 to 20-11-2023
Estradiol levels (pmol/L)	Estradiol levels (pmol/L) in blood collected at baseline.	11-10-2021 to 20-11-2023
Progesterone levels (nmol/L)	Progesterone levels (nmol/L) in blood collected at baseline.	11-10-2021 to 20-11-2023
Sex Hormone Binding Globulin (SHBG) levels (nmol/L)	Sex Hormone Binding Globulin (SHBG) levels (nmol/L) in blood collected at baseline.	11-10-2021 to 20-11-2023
Total testosterone levels (nmol/L)	Total testosterone levels (nmol/L) in blood collected at baseline.	11-10-2021 to 20-11-2023
Free testosterone levels (pmol/L)	Free testosterone levels (pmol/L) in blood collected at baseline.	11-10-2021 to 20-11-2023

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Cathérine Gebhard, Professor, University of Zurich

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2021
• Primary Completion (Actual): November 20, 2023
• Study Completion (Actual): November 20, 2024

Study Registration Dates

• First Submitted: March 5, 2024
• First Submitted That Met QC Criteria: March 27, 2024
• First Posted (Actual): April 3, 2024

Study Record Updates

• Last Update Posted (Actual): May 7, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Behavioral Symptoms; Behavior; Sexual Behavior; Myocardial Ischemia; Stress, Psychological; Coitus
• Other Study ID Numbers: BASEC 2020-02922

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No