Stress Reactivity: Disturbances of the Neurocardiac Axis Open Access

Abstract

Stress, both physiological and psychological, serve as triggers for cardiovascular events in those with a damaged cardiac substrate, such as ischemic heart disease. The physiological reaction to stress is mediated through the autonomic nervous system, which can be quantified through heart rate variability (HRV).

We measured HRV in three cohorts that had varying burdens of ischemic heart disease, from no known disease, high risk of disease, and known disease after myocardial infarction. Each cohort also had varying types of HRV, from short-term recordings during acute psychological and physiological stress, to longer, diurnal recordings. Two of these cohorts were followed longitudinally to assess for cardiovascular outcomes and mortality. Short-term and cosinor HRV metrics served as the exposure and psychological stress, myocardial ischemia, and major adverse cardiovascular events (MACE) served as outcomes in logistic regression modeling and survival analysis.

Autonomic dysfunction was robustly associated with psychological stress, myocardial ischemia, and MACE. We found a significant relationship between circadian autonomic variability and depression and posttraumatic stress disorder. We found that autonomic dysfunction was also strongly related to mental stress- induced myocardial ischemia. We found that autonomic dysfunction, both to circadian changes and acute mental stress, was associated with an increased, independent risk for MACE.

This suggests that autonomic dysfunction, measured by HRV, plays an important, independent role in the additional cardiovascular risk seen in patients with psychological disease. This association highlights neurocardiac mechanisms as a not yet understood pathological process in both psychiatric and cardiovascular disease that may have implications in diagnosis and therapy. 

Table of Contents

Contents

Acknowledgements v Abbreviations vi

INTRODUCTION 2

1 The Problem 2 2 The Approach 4

BACKGROUND 6

3 Clinical Importance 6 4 Relevant Literature 8

METHODS 11

5 Specific Aims 11 6 Study Design 13 6.1 Population Characteristics and Study Overview . . . . . . . . . . . . 13 6.1.1 Emory Cardiovascular Biobank (Biobank) . . . . . . . . . . . 13 6.1.2 EmoryTwinsStudy(Twins) .................. 13 6.1.3 Mental Stress Ischemia Mechanisms and Prognosis, Myocardial Infarction and Mental Stress (MIMS/MIPS) . . . . . . . . . 14 6.2 Measurements............................... 15 6.2.1 ElectrocardiographyMeasures.................. 15 6.2.2 PsychologicalMeasures ..................... 16 6.2.3 CardiacMeasures......................... 17 6.3 SampleSizeandPowerConsiderations................. 18 7 Analysis 20 7.1 MyocardialIschemia ........................... 20 7.2 PsychologicalStress ........................... 21 7.3 ClinicalOutcomes ............................ 22

RESULTS

8 Study Overview

25

25

ii

CONTENTS iii

9 Psychological Stress 26 10 Myocardial Ischemia 28 11 Clinical Outcomes 30

DISCUSSION 32

12 Principal Findings 32 12.1PsychologicalStress ........................... 32 12.2MyocardialIschemia ........................... 34 12.3ClinicalOutcomes ............................ 37

13 Limitations and Future Direction 39

CONCLUSIONS 43

REFERENCES 45

APPENDIX 56

A TABLES AND FIGURES 56

A.1 ClinicalOverview............................. 56 A.1.1 OverviewofStressReactivity.................. 57 A.1.2 BiobankCohortDescription................... 58 A.1.3 TwinCohortsDescription .................... 59 A.1.4 MentalStressCohortsDescription . . . . . . . . . . . . . . . 60 A.1.5 HRVinTwinsCohorts...................... 61 A.2 PsychologicalStress ........................... 62 A.2.1 HRVandMentalStressChallenge ............... 63 A.2.2 Distribution of HRV and Mental Stress Challenge . . . . . . . 64 A.2.3 Depression and PTSD with Mental Stress Challenge . . . . . 65 A.2.4 DepressionbyPHQ-9andHRV................. 66 A.2.5 HRVandChronicMentalStressinTwins . . . . . . . . . . . 67 A.2.6 Circadian Autonomic Variability and Chronic Mental Stress . 68 A.3 MyocardialIschemia ........................... 69

A.3.1 Relationship Between Obstructive and Non-Obstructive CoronaryArteryDisease..................... 70

A.3.2 Effective of Revascularization on Autonomic Function . . . A.3.3 HRVbyTimingofRevascularization . . . . . . . . . . . . . A.3.4 Relationship of HRV with both Mental and Physical Stress A.3.5 Quantitative Myocardial Perfusion and HRV . . . . . . . . A.3.6 Circadian HRV and Myocardial Perfusion . . . . . . . . . . A.3.7 DistributionofHRVandMSIMI ................ 76 A.3.8 Modeling Mental Stress-Induced Myocardial Ischemia and HRV 77

. 71 . 72 . 73 . 74 . 75

iv CONTENTS

A.4 ClinicalOutcomes ............................ 78 A.4.1 OutcomesinTwins........................ 79 A.4.2 CircadianOutcomesinTwins.................. 80 A.4.3 OutcomesinMIMS/MIPS.................... 81

B Supplementary Files 82 B.0.1 PoincaréPlotofHRV

...................... 83 B.0.2 CosinorMetrics.......................... 84 

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Medicine and Surgery Health Sciences, Epidemiology Health Sciences, Mental Health
Keyword	heart rate variability cardiovascular disease autonomic dysfunction stress
Committee Chair / Thesis Advisor	Matthew Magee, Emory University
Committee Members	Alvaro Alonso, Emory University Amit J. Shah, Emory University

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