Study of the Effects of Negative Emotions on Endothelial Function (PUME)

Translational Research of Negative Emotions and Acute Endothelial Dysfunction

Study aims and hypotheses are as follows:

Primary Hypotheses:

Compared to the neutral condition, the anger recall task will acutely induce endothelial dysfunction by impairing endothelium-dependent arterial vasodilation (Hypothesis 1a); increasing circulating levels of EC-derived microparticles (EMPs), a marker of EC injury (Hypothesis 1b); and reducing circulating levels of bone marrow-derived endothelial progenitor cells (EPCs), a marker of EC reparative capacity (Hypothesis 1c).

Secondary Hypotheses:

Compared to the neutral condition, the depressed mood and separately the anxiety recall tasks will acutely impair endothelium-dependent arterial vasodilation, increase circulating levels of EMPs, and reduce circulating levels of bone marrow-derived EPCs. There will be a relation of the level of self-reported anger, depressed mood, and anxiety with endothelial dysfunction.

Study Overview

• Status: Completed
• Conditions: Endothelial Dysfunction; Emotions
• Intervention / Treatment: Other: Anger Induction; Other: Depressed Mood Induction; Other: Anxiety Induction; Other: Neutral emotion task

Detailed Description

Atherosclerosis-related cardiovascular disease (CVD) events remain the leading causes of morbidity and mortality in industrialized nations. Atherosclerosis is a diffuse disease characterized by the deposition of lipid and other blood-borne material within the arterial wall. Evidence demonstrates that disruption of an arterial atherosclerotic plaque and subsequent thrombus formation is responsible for the onset of CVD events. Cardiovascular research efforts have been directed toward the identification of early underlying factors that initiate this cascade.

It has been known for some time that the experience of negative emotions is associated with an increased risk of incident CVD events, independent of traditional risk factors. Among the best-studied negative emotions is anger. Population-based studies have demonstrated that the experience of anger is a trigger of incident CVD events. The mechanism(s) by which provoked anger acutely affects the pathways that underlie atherosclerosis development and progression remain to be fully characterized.

Endothelial dysfunction is a promising mechanism that may explain the link between anger and incident CVD events. Vascular endothelial cells (ECs) play essential roles in maintaining vascular tone and the integrity of blood vessels. Evidence suggests that endothelial dysfunction is an early pathogenic process underlying atherosclerosis development and CVD event onset. Our preliminary findings show in apparently healthy individuals, an anger recall task acutely induces endothelial dysfunction by impairing endothelium-dependent vasodilation, injuring ECs, and disrupting the molecular processes underlying EC reparative capacity. We have additionally found that this task may induce endogenous nitric oxide (NO) inhibition, which plays a central role in aggravating endothelial dysfunction. Therefore, NO inhibition may partially mediate anger-provoked endothelial dysfunction.

Although the strongest data are on anger-provoked CVD events, there is also some evidence that the experience of other core negative emotions such as depressed mood and anxiety may trigger CVD events. Whether the provocation of depressed mood and anxiety acutely induces endothelial dysfunction and NO inhibition remains to be determined. The overall aim of this study is to primarily examine the acute effects of provoked anger and secondarily depressed mood and anxiety on EC health. We will also explore whether NO inhibition partially mediates the acute effects of anger, depressed mood, and anxiety on endothelial function. Examination of these critical pathways will help identify the biological pathways by which the experience of core negative emotions leads to incident CVD risk.

To address these highly significant research questions, we propose a state-of-the-art, laboratory-based, randomized controlled experiment in which 280 participants will be randomized to one of four experimental conditions: an anger recall task (N=70), a depressed mood recall task (N=70), an anxiety recall task (N=70), and an emotionally neutral condition (N=70).

• Study Type: Interventional
• Enrollment (Actual): 280
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 and over
• Fluent in English

Exclusion Criteria:

• History of any chronic medical condition including prevalent CVD and traditional risk factors
• Active smoking
• Chronic medication use, including over-the-counter drugs or herbal medications
• History of psychosis, a mood disorder, or any overt personality disorder
• Latex allergy
• Poor peripheral veins with low possibility of getting IV access

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Anger induction; The participant will be asked to undergo a validated anger induction task.	Other: Anger Induction; The participant is asked to recall an incident in the recent past during which they became moderately to extremely angry, or is asked to read statements out loud evoking moderate to extreme feelings of anger. The participant is asked to take a few moments to bring the details of the incident to mind and, when ready, to describe the incident in great detail to the experimenter. Participants are asked to describe key elements, such as any dialogue that transpired during the incident, along with other details of the incident, particularly regarding the feelings of that particular emotion experienced at the time. In so doing, the experimenter works to re-elicit the emotions that accompanied the original incident. The duration of the negative emotion induction task is 8 minutes.
EXPERIMENTAL: Depressed Mood Induction; The participant will be asked to undergo a validated depression/sadness induction task.	Other: Depressed Mood Induction; The participant will be asked to undergo a validated depression/sadness induction task.
EXPERIMENTAL: Anxiety Induction; The participant will be asked to undergo a validated anxiety induction task.	Other: Anxiety Induction; The participant will be asked to undergo a validated anxiety induction task.
OTHER: Neutral emotion task; The participant will be asked to undergo a validated neutral task (i.e. count aloud by ones, starting with one and ending with 100, over and over, until the task period has ended).	Other: Neutral emotion task; This is a neutral control task that each of the negation emotion induction tasks will be compared to.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Endothelium-dependent arterial vasodilation	baseline
Circulating EMPs expressing CD62E	baseline
Circulating early EPCs (KDR+, CD34+, CD133+ cells)	baseline
Endothelium-dependent arterial vasodilation	3 mins after end of mood induction
Endothelium-dependent arterial vasodilation	40 mins after end of mood induction
Endothelium-dependent arterial vasodilation	70 mins after end of mood induction
Endothelium-dependent arterial vasodilation	100 mins after end of mood induction
Circulating EMPs expressing CD62E	3 mins after end of mood induction
Circulating EMPs expressing CD62E	40 mins after end of mood induction
Circulating EMPs expressing CD62E	70 mins after end of mood induction
Circulating EMPs expressing CD62E	100 mins after end of mood induction
Circulating early EPCs (KDR+, CD34+, CD133+ cells)	3 mins after end of mood induction
Circulating early EPCs (KDR+, CD34+, CD133+ cells)	40 mins after end of mood induction
Circulating early EPCs (KDR+, CD34+, CD133+ cells)	70 mins after end of mood induction
Circulating early EPCs (KDR+, CD34+, CD133+ cells)	100 mins after end of mood induction

Secondary Outcome Measures

Outcome Measure	Time Frame
Circulating EMPs expressing CD31	baseline; 3 mins, 40 mins, 70 mins, 100 mins after end of mood induction
Circulating EMPs expressing CD51	baseline; 3 mins, 40 mins, 70 mins, 100 mins after end of mood induction
Self-reported anger, depressed mood, and anxiety	baseline; 3 mins, 40 mins, 70 mins, 100 mins after end of mood induction

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nitric oxide(NO) inhibition	Circulating measures of asymmetric dimethylarginine (ADMA) and oxidative stress measures	baseline; 3 mins, 40 mins, 70 mins, 100 mins after end of mood induction
Stress response	Circulating measures of catecholamines, cortisol, endothelin-1; blood pressure and heart rate	baseline; 3 mins, 40 mins, 70 mins, 100 mins after end of mood induction

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Daichi Shimbo, MD, Columbia University

Publications and helpful links

General Publications

• Ensari I, Burg MM, Diaz KM, Fu J, Duran AT, Suls JM, Sumner JA, Monane R, Julian JE, Zhao S, Chaplin WF, Shimbo D. Putative mechanisms Underlying Myocardial infarction onset and Emotions (PUME): a randomised controlled study protocol. BMJ Open. 2018 May 31;8(5):e020525. doi: 10.1136/bmjopen-2017-020525.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2013
• Primary Completion (ACTUAL): November 1, 2020
• Study Completion (ACTUAL): November 1, 2020

Study Registration Dates

• First Submitted: July 25, 2013
• First Submitted That Met QC Criteria: July 26, 2013
• First Posted (ESTIMATE): July 29, 2013

Study Record Updates

• Last Update Posted (ACTUAL): January 27, 2022
• Last Update Submitted That Met QC Criteria: January 12, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: AAAK4250; 1R01HL116470-01 (NIH)

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