Psychosocial Distress: Cardiovascular Outcomes, Underlying Mechanisms, and Sex Differences Restricted; Files Only

Pimple, Pratik (Summer 2018)

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Background: While depression is a well-established risk factor for cardiovascular disease (CVD), results on post-traumatic stress disorders, anxiety, anger, hostility and perceived-stress are mixed. Even though these psychosocial phenotypes are correlated, previous studies have treated them as independent factors. Examining these factors together may provide new insights.

Objectives: This dissertation evaluated the association between an integrated indicator of chronic psychosocial distress and CVD outcomes, including future CVD events and mental stress-induced myocardial ischemia (MSIMI) with a specific focus on sex differences. To better understand vulnerability to MSIMI and the underlying pathophysiology, we also evaluated genetic determinants of MSIMI.

Methods: We used data from two observational studies at Emory University (N=950). For aim 1, we examined the association between the psychosocial distress indicator, created using latent-class analysis (LCA), and a composite CVD endpoint at 3 years of follow-up. For aim 2, we examined the association between the psychosocial distress indicator and MSIMI severity. For aim 3, we examined the association between a-priori selected 286 candidate-genes and MSIMI.


Aim 1: As compared to women in the lowest psychosocial distress class (LCA class-1), women in the highest class (LCA class-4) had 2.8-times the hazard of CVD events (95% CI: 1.2-6.6). No association was found in men.

Aim 2: As compared to women in the lowest psychosocial distress class, women in the highest class had 4.0-points higher summed rest score (95% CI: 0.2-7.7). This association was not observed in men. There was no association between psychosocial distress and MSIMI in either women or men.

Aim 3: Of 286 candidate-genes, the FGF5 (Fibroblast Growth Factor-5) gene on chromosome 4 was associated with MSIMI at the Bonferroni-adjusted significant threshold (P=4.7×10-5). 

Conclusion: A higher level of psychosocial distress is associated with the risk of cardiovascular events and higher resting perfusion abnormalities in women, but not in men. We also uncovered a signaling pathway related to tissue growth and repair and with links to the brain as being possibly involved in MSIMI. Overall, our findings suggest a prominence of the psychosocial sphere in CVD risk pathways especially for women.

Table of Contents

Chapter 1: Introduction, Study Background, Objectives & Hypotheses      1

Brief Overview: 1

Background: Association Between Psychosocial Distress Indicators & Cardiovascular Outcomes    4

Aim 1: Psychosocial Distress and Future Cardiovascular Events: Objective & Hypothesis   9

Background: Association Between Psychosocial Distress Indicators & Stress-Induced Ischemia      9

Aim 2: Psychosocial Distress & MSIMI: Objective & Hypothesis    11

Background: Genetic Determinants of Stress-Induced Ischemia   12

Aim 3: Genetic Determinants of Stress-Induced Ischemia: Objective & Hypothesis              14

Chapter 2: Methods       15

Brief Overview  15

Data Source and Population characteristics:         16

Exposure Assessment: Composite Psychosocial Distress Indicator (Aim 1, & 2)       18

Exposure Assessment: Genetic Determinants (Aim 3)       25

Outcome Assessment: Future Cardiovascular Events (Aim 1)         27

Outcome Assessment: Mental-Stress Induced Myocardial Ischemia (Aim 2 & 3)    28

Adjustment Factors        29

Data Analysis Plans          30

Chapter 3: Psychological Distress and Future Cardiovascular Events           36

Key Points:          37

Abstract               38

Introduction:     40

Methods:            41

Results: 45

Discussion:          47

Chapter 4: Psychosocial Distress and Stress Induced Myocardial Ischemia               65

Abstract               67

Introduction:     68

Methods:            69

Results: 74

Discussion:          76

Chapter 5: Genetic Determinants of Mental Stress Induced Myocardial Ischemia 94

Abstract               95

Introduction:     97

Methods:            98

Results: 101

Discussion:          104

Chapter 6: Implications  128

Key Findings:      128

Strengths & Limitations 129

Conclusion & Future Directions  131

References:        132

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