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J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 3 , N O . 2 5 , 2 0 1 9

ª 2 0 1 9 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

D

ORIGINAL INVESTIGATIONS

Stress-Associated NeurobiologicalPathway Linking SocioeconomicDisparities to Cardiovascular Disease
Ahmed Tawakol, MD,a,b Michael T. Osborne, MD,a,b Ying Wang, MD, PHD,b,c Basma Hammed, MD,b Brian Tung, MS,b
Tomas Patrich, BA,b Blake Oberfeld, BS,b Amorina Ishai, MD,b Lisa M. Shin, PHD,d Matthias Nahrendorf, MD,e

Erica T. Warner, SCD,f Jason Wasfy, MD,a Zahi A. Fayad, PHD,g Karestan Koenen, PHD,h Paul M Ridker, MD,i

Roger K. Pitman, MD,j Katrina A. Armstrong, MDk

ABSTRACT

ISS

Fro

PE

Me

Un

Bo

Bo

Yo

ow

BACKGROUND Lower socioeconomic status (SES) associates with a higher risk of major adverse cardiac events (MACE)

via mechanisms that are not well understood.

OBJECTIVES Because psychosocial stress is more prevalent among those with low SES, this study tested the

hypothesis that stress-associated neurobiological pathways involving up-regulated inflammation in part mediate the link

between lower SES and MACE.

METHODS A total of 509 individuals, median age 55 years (interquartile range: 45 to 66 years), underwent clinically

indicated whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging and met

pre-defined inclusion criteria, including absence of known cardiovascular disease or active cancer. Baseline hematopoietic

tissue activity, arterial inflammation, and in a subset of 289, resting amygdalar metabolism (a measure of stress-

associated neural activity) were quantified using validated 18F-fluorodeoxyglucose positron emission tomography/

computed tomography methods. SES was captured by neighborhood SES factors (e.g., median household income and

crime). MACE within 5 years of imaging was adjudicated.

RESULTS Over a median 4.0 years, 40 individuals experienced MACE. Baseline income inversely associated with

amygdalar activity (standardized b: �0.157 [95% confidence interval (CI): �0.266 to �0.041]; p ¼ 0.007) and arterial

inflammation (b: �0.10 [95% CI: �0.18 to �0.14]; p ¼ 0.022). Further, income associated with subsequent MACE

(standardized hazard ratio: 0.67 [95% CI: 0.47 to 0.96]; p ¼ 0.029) after multivariable adjustments. Mediation analysis

demonstrated that the path of: Y neighborhood income to [ amygdalar activity to [ bone marrow activity to [ arterial

inflammation to [ MACE was significant (b: �0.01 [95% CI: �0.06 to �0.001]; p < 0.05).

CONCLUSIONS Lower SES: 1) associates with higher amygdalar activity; and 2) independently predicts MACE via a

serial pathway that includes higher amygdalar activity, bone marrow activity, and arterial inflammation. These findings

illuminate a stress-associated neurobiological mechanism by which SES disparities may potentiate adverse health outcomes.

(J Am Coll Cardiol 2019;73:3243–55) © 2019 by the American College of Cardiology Foundation.

N 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.04.042

m the aCardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; bCardiac MR

T CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; cDepartment of Nuclear

dicine, the First Hospital of China Medical University, Heping District, Shenyang, China; dDepartment of Psychology, Tufts

iversity, Medford, Massachusetts; eCenter for Systems Biology, Massachusetts General Hospital and Harvard Medical School,

ston, Massachusetts; fClinical Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School,

ston, Massachusetts; gTranslational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New

rk; hHarvard T.H. Chan School of Public Health, Boston, Massachusetts; iCardiology Division, Brigham and Women’s Hospital

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ABBR EV I A T I ON S

AND ACRONYMS

18F-FDG-PET/CT = 18F-

fluorodeoxyglucose positron

emission tomography/

computed tomography

AmygA = metabolic activity in

the amygdala

CVD = cardiovascular disease

MACE = major adverse cardiac

event

SES = socioeconomic status

and Harvar

Medical Sc

School, Bo

R01HL1379

T32HL0761

Tawakol ha

rendorf has

Biotronik; a

grants from

other autho

MD, served

Manuscript

Tawakol et al. J A C C V O L . 7 3 , N O . 2 5 , 2 0 1 9

Socioeconomic Disparities, Amygdalar Activity, and MACE J U L Y 2 , 2 0 1 9 : 3 2 4 3 – 5 5

3244

DownloadedFo

L ife expectancy in the United Statesvaries substantially by socioeconomicstatus (SES), which also contributes to

significant disparities in mortality by geogra-phy and race (1,2). Measures of SES, such asincome and neighborhood environmentalfactors, strongly predict disease outcomes,including cardiovascular disease (CVD)events (3). SES-related disparities in CVDoutcomes are in part attributable to differ-ences in CVD risk factors, access to qualitycare, and health behaviors (3). However,

these factors alone do not explain the large variancein outcomes (4,5), prompting the hypothesis thatlower SES drives health inequalities through yet un-discovered biological mechanisms (6). The discoveryof such mechanisms may reveal new opportunitiesto attenuate the burden of disease in socioeconomi-cally disadvantaged communities.

SEE PAGE 3256

Lower SES associates with greater psychosocialstress (7–9) and systemic inflammation (10–12), bothof which, in turn, are associated with an increasedrisk of diseases that link to low SES, such as cancerand CVD (13,14). Thus, among biological mechanismssuspected of connecting lower SES to physical dis-ease, those involving stress and inflammation loomprominently. The stress response begins in the brain’ssalience network, within which the amygdala is a keycomponent (15–20). Activation of this network in-creases sympathetic nervous system output (21),which triggers increased bone marrow hematopoieticstem and progenitor cell proliferation, andaccelerates innate immune cell output (22). Thisstress-induced leukopoiesis results in greateratherosclerotic inflammation (22), a critical driver ofCVD (23–25). In light of these observations, we pre-viously hypothesized that increased amygdalar ac-tivity associates with an increased risk of CVD, andthat it does so through heightened leukopoiesis and

d Medical School, Boston, Massachusetts; jDepartment of Psych

hool, Boston, Massachusetts; and the kDepartment of Medicine, M

ston, Massachusetts. This study was supported by U.S. Natio

13 (to Dr. Tawakol), R01HL128264 (to Dr. Nahrendorf), R01H

36 and KL2TR002542 (to Dr. Osborne); and by American Heart As

s received grants from Genentech and Actelion; and has receive

served on the Scientific Advisory Board of Verseau and IFM Thera

nd has received a Career Development Award from the American

Novartis, Kowa, and Pfizer; and has consulting agreements with

rs have reported that they have no relationships relevant to the

as Guest Associate Editor for this paper.

received December 19, 2018; revised manuscript received March

for Anonymous User (n/a) at Waikato District Health Board fromr personal use only. No other uses without permission. Copyright

arterial inflammation (20). To test these hypotheses,we used 18F-fluorodeoxyglucose positron emissiontomography/computed tomography (18F-FDG-PET/CT) to objectively quantify metabolic activity in theamygdala (AmygA) (a measure of stress-associatedneural activity), the bone marrow (a measure of he-matopoiesis), and the arterial wall (a measure ofatherosclerotic inflammation) in individuals whowere subsequently followed for the development ofincident CVD. In that study, we observed that AmygArobustly predicts the risk for, and timing of, subse-quent CVD (20). Furthermore, mediation analysisindicated that stress significantly associated withCVD events through a serial pathway of: [ stress to [

AmygA to [ hematopoietic tissue activity to [ arterialinflammation to [ major adverse cardiac events(MACE). Given the association between SES andstress, we hypothesized the existence of a biologicalpathway linking SES to CVD, whereby low SES candrive the front end (YSES to [stress, and so on) of theaforementioned pathway.

Accordingly, we studied individuals who under-went multisystem 18F-FDG-PET/CT imaging, andmeasured amygdalar activity, bone marrow activity,and arterial inflammation. Residence-specific metricswere used to estimate socioeconomic status, afterwhich we assessed for the development of subse-quent incident MACE. We then tested the hypothesesthat lower socioeconomic status: 1) associates withhigher amygdalar activity and arterial inflammation;2) independently associates with MACE; and 3)links to MACE via the prespecified amygdalar-hematopoietic-arterial pathway.

METHODS

OVERVIEW. The study’s findings are derived from aretrospective, longitudinal, observational imagingstudy that evaluated the relationship among SES,amygdalar activity, atherosclerotic inflammation, andsubsequent MACE. The study protocol was approvedby the Partners Human Research Committee.

iatry, Massachusetts General Hospital and Harvard

assachusetts General Hospital and Harvard Medical

nal Institutes of Health grants R01HL122177 and

L071021 and 1P01HL131478 (to Dr. Fayad), and

sociation grant 18CDA34110366 (to Dr. Osborne). Dr.

d personal fees from Actelion and Amgen. Dr. Nah-

peutics. Dr. Wasfy has received consulting fees from

Heart Association. Dr. Ridker has received research

Corvidia, VCiviBio, Janssen, Merck, and Amgen. All

contents of this paper to disclose. Philip Greenland,

11, 2019, accepted April 10, 2019.

ClinicalKey.com.au by Elsevier on June 27, 2019. ©2019. Elsevier Inc. All rights reserved.

FIGURE 1 Study Cohort and Measurement of Tissue Activity

Clinical PatientsUndergoing PET/CT

Imaging at MGH2005-2008(N = 6,088)

Clin

ical

Pop

ulat

ion

Subjects Eligible by Clinical Criteria(N = 579)

Datasets Delivered (N = 527)Independently to:

1) Image Analysis Group and2) Event Adjudication Group

Parent Study Population(N = 513)

Brain Imaging Sub-Study (N = 289)

Datasets Available for analysis ofSES Factors vs. MACE Events

(N = 509)

Excluded (N = 52)- Missing images (N = 52)

Excluded (N = 14)- Poor PET image quality (N = 8)

- Insufficient data for eventadjudication (N = 6)

Excluded (N = 4)- SES data unavailable

Excluded (N = 220)- Lack of CT or PET data covering

the brain

Pare

nt S

tudy

Coh

ort

Stud

y Co

hort

Clinical Patientswithout Active Cancerwho underwent FDGPET/CT imaging atMGH 2005-2008

(N = 2,143)Excluded (N = 1,564)

770:

366:164:264:

Chronic inflamm.conditionPrior CVDAge <30 yearsInadequatemedical records

A B

(A) Study cohort. The study cohort was derived from a database of patients who had undergone whole-body 18F-FDG-PET/CT imaging at Massachusetts

General Hospital (MGH). All subjects meeting pre-defined criteria were included. Image analyses, event adjudication, and determination of SES were

performed by mutually blinded investigators. (B) Measurement of tissue activity. Amygdalar activity (corrected for background cerebral activity) and

arterial 18F-FDG uptake (corrected for background blood activity) were measured as validated measures of stress-associated neurobiological activity and

arterial inflammation, respectively. Arrows indicate amygdalar activity (in brain images) and arterial inflammation (in aortic images). CT ¼ computed

tomography; CVD ¼ cardiovascular disease; FDG ¼ fluorodeoxyglucose; MACE ¼ major adverse cardiac event; PET ¼ positron emission tomography;

SES ¼ socioeconomic status.

J A C C V O L . 7 3 , N O . 2 5 , 2 0 1 9 Tawakol et al.J U L Y 2 , 2 0 1 9 : 3 2 4 3 – 5 5 Socioeconomic Disparities, Amygdalar Activity, and MACE

3245

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D

POPULATION. The study population was describedpreviously (25). Subjects were identified from a poolof 6,088 patients who underwent 18F-FDG-PET/CTimaging for clinical evaluation (primarily cancer sur-veillance) at the Massachusetts General Hospital be-tween 2005 and 2008 (Figure 1A). Pre-definedinclusion criteria included: 1) absence of knownCVD; 2) either absence of prior cancer or remissionfrom cancer for at least 1 year prior to imaging andthroughout the follow-up period; 3) absence of acuteor chronic inflammatory or autoimmune disease atthe time of imaging; and 4) age >30 years. To ensureadequate information for MACE adjudication, sub-jects were required to have at least 3 clinicalencounter notes after index imaging in the medicalrecords. All individuals for whom SES data wereavailable and were included in the prior “CVD eventsstudy” (25) were included in the current study.

OUTCOME EVENTS. Event adjudication was per-formed by 2 cardiologists blinded to clinical and im-aging data. MACE was defined as: cardiac death,myocardial infarction, unstable angina, cerebrovas-cular accident, peripheral artery disease with revas-cularization, or heart failure.

ESTIMATION OF SOCIOECONOMIC STATUS. Popu-lation-based SES measures were derived from the U.S.Census Bureau’s 2015 American Community Survey5-Year Estimates and Massachusetts Uniform CrimeReporting database by the Federal Bureau of Inves-tigation. We utilized subjects’ residential addresses toderive residence-specific metrics at the zip code level.Although zip-code SES measures may be less preciseas a proxy for individual SES, we hypothesized thatthe larger area level measure would be particularlysalient to the relationship between neighborhoodcrime and income and amygdalar activity (26).Further details are provided in the Online Appendix.18F-FDG PET/CT IMAGING PROTOCOL. 18F-FDG-PET/CTimaging was performed with a Biograph 64 (orsimilar) scanner (Siemens Healthcare, Erlangen,Germany). Following an overnight fast, w370 MBqof intravenous fluorodeoxyglucose (FDG) wasadministered. Individuals sat in a quiet waitingroom after radiotracer administration until imagingwas performed after approximately 1 h. A nongated,noncontrast-enhanced computed tomography(120 keV, w50 mAs) was acquired for attenua-tion correction.

MEASUREMENT OF REGIONAL BRAIN 18F-FDG

UPTAKE. Image analyses was conducted by aninvestigator (A.I.) who was blinded to all clinical andSES data. Analysis of AmygA (Figure 1B) was

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performed using validated approaches (20). AmygAassociates with anxious temperament (18,27), clinicalmanifestations of stress-related disorders (27–30),risk of subsequent incident diabetes (31), noncalcifiedcoronary artery plaques (32), and risk of MACE (20).Using a dedicated workstation (Leonardo–TrueD,Siemens Solutions), circular regions of interest (ROI)were placed in the right and left amygdalae, as well asin background cerebral regions (the right and lefttemporal lobes). 18F-FDG accumulation was recordedas the mean standardized uptake value (SUV) for eachROI. AmygA was calculated as the average mean SUVof both amygdalae, divided by background cerebralactivity (20). Further details are provided in theOnline Appendix.

MEASUREMENT OF ARTERIAL INFLAMMATION AND

HEMATOPOIETIC ACTIVITY. Arterial inflammationand bone marrow metabolic activity (Figure 1B) weremeasured according to previously validated methods(25,33). 18F-FDG, a radioactive glucose analogue, ac-cumulates within tissues in proportion to theirglycolytic rates (34). Because inflammatory cells(especially pro-inflammatory macrophages) haverelatively high glycolytic rates (34), there is substan-tial accumulation of 18F-FDG within inflamed tis-sues.18F-FDG uptake within the arterial wall providesa validated measure of atherosclerotic inflammation(34), measured as the SUV in the wall of the aortaadjusted for background venous blood activity (bycalculating a target-to-background ratio [TBR]).Similarly, hematopoietic tissue activity was assessedby deriving the SUV from ROIs placed within verte-brae (from T1 to L5) (33). Coronary artery calciumscore was derived from the computed tomographyimages (35,36).

STATISTICAL ANALYSIS. Statistical analyses wereperformed using SPSS version 25 (IBM Corp, Armonk,New York). Continuous variables are presented asmean � SD or as median (25th to 75th percentile[interquartile range]) when not normally distributed.Multivariable associations were evaluated usinglinear regression models. Where variables were non-normally distributed, bootstrapping was employed.To assess associations with MACE, Cox proportionalhazards models were used to derive hazard ratios(HRs) and 95% confidence intervals (CIs). Addition-ally, Kaplan-Meier estimates of event-free survivalwere generated; statistical significance was evaluatedusing log-rank tests. The models incorporated timebetween imaging and the date of MACE event or lastfollow-up.

Mediation analysis was performed with the SPSSPROCESS macro (version 2.16.3), which uses an




TABLE 1 Baseline Characteristics

Full Cohort(n ¼ 509)

No MACE(n ¼ 469)

MACE(n ¼ 40) p Value

Age, yrs 55 (45–66) 54 (44–65) 68 (61–78) <0.001

Men 213 (42) 197 (42) 16 (40) 0.805

Caucasian 461 (91) 425 (91) 36 (90) 0.898

Current smoker 54 (11) 43 (9) 11 (28) <0.001

Hypertension 179 (35) 154 (33) 25 (63) <0.001

Diabetes mellitus 45 (9) 37 (8) 8 (20) 0.010

Hyperlipidemia 141 (28) 125 (27) 16 (40) 0.072

Total cholesterol, mg/dl 192 � 43 192 � 43 186 � 40 0.445

LDL cholesterol, mg/dl 110 � 39 111 � 37 104 � 34 0.698

Statin therapy 101 (20) 84 (18) 16 (40) 0.001

FRS 3.0 (1.0–8.0) 2.0 (1.00–6.75) 8.0 (3.00–13.50) <0.001

BMI, kg/m2 26.4 (23.4–30.9) 26.3 (23.3–30.9) 27.9 (24.1–31.3) 0.585

Coronary artery calcium score <0.001

0–10 327 (74) 314 (76) 13 (43)

11–99 60 (14) 51 (12) 9 (30)

$100 57 (13) 49 (12) 8 (27)

History of cancer 427 (84) 403 (86) 24 (60) <0.001

History of clinically documented depression or anxiety* 29 (10) 27 (10) 2 (13) 0.740

Local median household income, $ 82,017 � 27,974 82,815 � 28,419 72,657 � 20,100 0.027

Local total crime rate per thousand 24.6 � 12.4 24.1 � 12.2 30.2 � 13.6 0.008

Values are median (interquartile range), n (%), or mean � SD. Bold p values are significant. *Data on depression/anxiety are available on 288 subjects.

BMI ¼ body mass index; FRS ¼ Framingham risk score; LDL ¼ low-density lipoprotein; MACE ¼ major adverse cardiovascular event.

TABLE 2 Associations Between SES Indexes and Amygdalar Activity

Predictors

Associations Between SES Indexes andAmygdalar Activity

b (95% CI) p Value

Local socioeconomic factors

% high school graduates �0.116 (�0.227 to 0.002) 0.046

Median household income �0.156 (�0.264 to �0.042) 0.007

% living below poverty 0.098 (�0.016 to 0.211) 0.092

Population 0.116 (0.003 to 0.220) 0.045

Total housing units 0.129 (0.015 to 0.230) 0.026

Crime statistics

Violent crime rate 0.109 (�0.021 to 0.226) 0.104

Murder rate 0.008 (�0.125 to 0.140) 0.912

Rape rate 0.049 (�0.078 to 0.168) 0.471

Robbery rate 0.097 (�0.033 to 0.210) 0.151

Aggravated assault rate 0.118 (�0.013 to 0.237) 0.079

Property crime rate 0.144 (0.013 to 0.265) 0.031

Burglary rate 0.064 (�0.064 to 0.181) 0.345

Larceny and theft rate 0.150 (0.018 to 0.272) 0.025

Motor vehicle theft rate 0.125 (�0.007 to 0.261) 0.062

Arson rate �0.075 (�0.199 to 0.055) 0.264

Total crime rate 0.141 (0.009 to 0.260) 0.035

All associations were adjusted for age and sex. Unadjusted analyses yielded similarly significantassociations. Bold p values are significant.

CI ¼ confidence interval; SES ¼ socioeconomic status.


3247

ordinary least squares or logistic regression-basedpath framework to estimate direct and indirect ef-fects and produces CIs from bias-corrected bootstrapsamples (37). We examined the pre-specified hy-pothesized multiple mediator path (using PROCESSModel 6): SES to AmygA to bone marrow activity toarterial inflammation to MACE. Mediation analysesincorporated age, sex, and baseline coronary arterycalcium score (as a measure of pre-existing preclinicalatherosclerotic disease burden) as covariates. Statis-tical significance was determined as 2-tailed p < 0.05for all analyses.

RESULTS

BASELINE CHARACTERISTICS. A total of 509 in-dividuals had arterial imaging, SES, and clinicalevents data; brain imaging data were available in asubset of 289. Individuals who developed subsequentMACE had a higher prevalence of several atheroscle-rotic risk factors, a greater burden of coronary arterycalcium (indicative of pre-existing preclinical athero-sclerosis), and (as hypothesized) lower SES (Table 1).

SES INDEXES VERSUS AmygA ACTIVITY AND

ARTERIAL INFLAMMATION. Neighborhood medianincome negatively associated with stress-relatedneurobiological activity, measured as resting AmygA(standardized b: �0.156 [95% CI: �0.267 to �0.042];

Downloaded for Anonymous User (n/a) at Waikato DiFor personal use only. No other uses withou

p ¼ 0.007) after adjusting for age and sex, that is, forevery SD increase in neighborhood medianincome, there was a 0.156-SD decrease in AmygA.Similarly, income negatively associated with arterial

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FIGURE 2 Socioeconomic Status Versus Amygdalar Activity and Arterial Inflammation

0.5

A B

C D

β [95% CI]: –0.18 [–0.26, –0.06], p = 0.002

Median Income vs.Amygdalar Activity

Median Income vs.Arterial Inflammation

0.4

0.3

0.2

0.1

0.0

–0.1

–0.2

–0.3Q1 Q2 Q3 Q4

Amyg

dala

r Act

ivity

(z-s

core

)

Quartiles of Local Median Income

0.2β [95% CI]: –0.11 [–0.17, –0.02], p = 0.012

0.1

0.0

–0.1

–0.2

–0.3Q1 Q2 Q3 Q4

Arte

rial I

nfla

mm

atio

n (z

-sco

re)

Quartiles of Local Median Income

0.2

β [95% CI]: 0.15 [0.01, 0.21], p = 0.034

Crime Rate vs.Amygdalar Activity

Crime Rate vs.Arterial Inflammation

0.1

0.0

–0.1

–0.2

–0.5

–0.3

–0.4

Q1 Q2 Q3 Q4

Amyg

dala

r Act

ivity

(z-s

core

)

Quartiles of Local Crime

0.2

β [95% CI]: 0.05 [–0.05, 0.14], p = 0.308

0.1

0.0

–0.1

–0.2Q1 Q2 Q3 Q4

Arte

rial I

nfla

mm

atio

n (z

-sco

re)

Quartiles of Local Crime

Individuals were categorized according to quartiles of their neighborhood median income and neighborhood crime rates. Amygdalar activity (A) and arterial inflam-

mation (B) were lower as neighborhood median income increased. Conversely, amygdalar activity was higher (C) and arterial inflammation trended toward an increase

(D) as neighborhood crime rate increased. Amygdalar activity was adjusted for age and sex, and arterial inflammation was additionally adjusted for cardiovascular

disease risk factors. Error bars indicate standard error of the mean. CI ¼ confidence interval.



3248

D

inflammation after adjusting for CVD risk factors(standardized b: �0.098 [95% CI: �0.182 to �0.14];p ¼ 0.022). In sensitivity analyses, several additionalindexes of SES associated with AmygA (Table 2).


When neighborhood median income was catego-rized into quartiles (Figures 2A and 2B), we observedlower AmygA (standardized b: �0.18 [95% CI: �0.26to �0.06]; p ¼ 0.002) (Figure 2A) and lower arterial


FIGURE 3 Socioeconomic Status Versus MACE

00

N = 509P = 0.009, Q1 vs Q4

Surv

ival

Fre

e fr

om M

ACE

Years After Entry1 2 3 4 5

127Number at Risk

124 114 104 75 32127 117 114 98 62 31128 121 108 84 57 33127 118 109 91 70 37

Q4Q3Q2Q1

Q1

Q2Q3

Q4

0.85

0.90

0.95

1.00

Individuals in the lowest quartile of neighborhood median income experienced a nearly

4-fold higher risk of major adverse cardiovascular events (MACE) compared with those in

the highest quartile (hazard ratio: 3.91 [95% confidence interval: 1.30 to 11.77]; Cox

regression p ¼ 0.015; log rank p ¼ 0.009). Q ¼ quartile.


3249

inflammation (standardized b: �0.11 [95% CI: �0.17to �0.02]; p ¼ 0.012) (Figure 2B) in subjects withhigher income. When neighborhood crime rate wascategorized into quartiles (Figures 2C and 2D), weobserved higher AmygA (standardized b: 0.15 [95% CI:0.01 to 0.21]; p ¼ 0.034) (Figure 2C), and nonsignifi-cantly higher arterial inflammation (standardized b:0.05 [95% CI: �0.05 to 0.14]; p ¼ 0.308) (Figure 2D), insubjects living in neighborhoods with higher crime rates.SES VERSUS SUBSEQUENT MACE. During a medianfollow-up period of 4.0 years (interquartile range: 3.0to 5.0 years), 40 individuals experienced 1 or moreMACE events (Online Table 1). As previously observedin larger cohorts (38–40), multiple indexes of neigh-borhood SES independently associated with MACE(Online Table 2). Neighborhood median incomenegatively associated with MACE (standardized haz-ard ratio [HR]: 0.673 [95% CI: 0.472 to 0.959];p ¼ 0.029), whereas neighborhood crime rate posi-tively associated with MACE (HR: 1.587 [95% CI: 1.135to 2.217]; p ¼ 0.007). Further, we observed a nearly 4-fold higher MACE risk in individuals in the lowestversus highest quartile of neighborhood median in-come (HR: 3.91 [95% CI: 1.30 to 11.77], Cox regressionp ¼ 0.015; log rank p ¼ 0.009) (Figure 3), remainingsignificant after adjusting for CVD risk factors (HR:3.59 [95% CI: 1.19 to 10.85]; p ¼ 0.024). Similar re-lationships between SES and MACE were seen whenindividuals were categorized by neighborhood crimerate (Online Figure 1).

We further evaluated the association between SESand MACE after considering important potentialconfounders: adverse health behaviors/risk factorsand decreased health care access. After adjusting forrisk factors associated with lower SES (i.e., smokingand obesity), we observed a w6-fold higher MACE(HR: 6.31; 95% CI: 1.41 to 1.83; p ¼ 0.016) risk in in-dividuals in the lowest (vs. highest) quartile ofneighborhood median income (HR: 6.31; 95% CI: 1.41to 1.83; p ¼ 0.016). Similarly, in stratified subgroupanalyses, wherein smokers and obese individualswere excluded, we observed persistent associationsbetween SES and MACE (Online Table 3). Addition-ally, when we adjusted for health care access (i.e.,insurance status and in-state vs. out-of-state resi-dence), we observed a w3.6-fold higher MACE risk inindividuals in the lowest (vs. highest) quartile ofneighborhood median income (HR: 3.57; 95% CI: 1.18to 10.83; p ¼ 0.036). Furthermore, in an analysiswherein individuals with limited health care accesswere excluded (i.e., uninsured individuals and in-dividuals living outside of Massachusetts, whichmandates health coverage), the association betweenSES and MACE remained significant (Online Table 3).


AmygA ACTIVITY VERSUS MACE AMONG THOSE

WITH LOWER SES. We observed that AmygAremained robustly predictive of MACE after adjustingfor SES (HR: 1.44 [95% CI: 1.14 to 1.83]; p ¼ 0.003). Toevaluate whether AmygA remained predictive ofMACE specifically among individuals living withinneighborhoods with high socioeconomic stress, weperformed subset analyses within the group of in-dividuals living in communities with: 1) lowerneighborhood median household income (lowesttertile); and 2) higher neighborhood total crime rate(highest tertile). AmygA continued robustly to predictMACE in both analyses: (HR: 1.63 [95% CI: 1.28 to2.07]; p < 0.001); and (HR: 1.59 [95% CI: 1.20 to 2.11];p ¼ 0.001), respectively (Table 3).

AMYGDALAR-HEMATOPOIETIC-ARTERIAL INFLAMMATORY

ACTIVITY AND MACE. Prior work showed that AmygAassociates with hematopoietic tissue (i.e., bonemarrow) activity and arterial inflammation (20),which in turn predict MACE (20). In the present







TABLE 3 Amygdalar Activity Versus MACE in Individuals From Neighborhoods With Lower SES

SES Subgroup

Amygdalar Activity Association With MACE

UnadjustedAdjusted for CVDRisk Factors*

Adjusted for SubclinicalAtherosclerosis†

General Description Subgroup Detail HR (95% CI) p Value HR (95% CI) p Value HR (95% CI) p Value

All neighborhoods All individuals from all neighborhoods 1.509 (1.198–1.900) <0.0001 1.423 (1.088–1.860) 0.010 1.431 (1.097–1.867) 0.008

Neighborhoods with lowerincome

Individuals from neighborhoods withmedian income <33rd percentile

1.626 (1.276–2.072) <0.001 1.877 (1.312–2.684) 0.001 1.606 (1.232–2.092) <0.001

Neighborhoods with highercrime

Individuals from neighborhoods withcrime rate >66th percentile

1.593 (1.203–2.112) 0.001 1.688 (1.224–2.330) 0.001 1.557 (1.131–2.143) 0.007

Neighborhoods with lowerincome OR high crime

Individuals from neighborhoods withcrime rate >66th percentile ORmedian income <33rd percentile

1.642 (1.280–2.107) <0.001 1.738 (1.286–2.350) 0.001 1.636 (1.242–2.154) <0.001

Neighborhoods with lowerincome AND high crime

Individuals from neighborhoods withcrime rate >66th percentile ANDmedian income <33rd percentile

1.560 (1.136–2.140) 0.006 1.736 (1.165–2.585) 0.007 1.571 (1.086–2.273) 0.016

Standardized hazard ratios are shown. Bold p values are significant. *CVD risk factors entered into these models were age, sex, smoking, hypertension, diabetes, and hyperlipidemia. †Baseline preclinicalatherosclerosis determined as coronary artery calcium score at index scanning.

CVD ¼ cardiovascular disease; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.



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analysis, after adjusting for CVD risk factors andneighborhood median income, AmygA associatedwith both hematopoietic tissue activity (b: 0.190[95% CI: 0.077 to 0.306]; p ¼ 0.001) and arterialinflammation (b: 0.202 [95% CI: 0.100 to 0.346],p<0.001) (Online Table 4A). Similarly, AmygA, (HR:1.423 [95% CI: 1.088 to 1.860]; p ¼ 0.010), hemato-poietic tissue activity (HR: 2.196 [95% CI: 1.400 to3.445]; p ¼ 0.001), and arterial inflammation (HR:1.819 [95% CI: 1.399 to 2.366]; p < 0.001) each pre-dicted MACE after adjusting for CVD risk factors andincome (Online Table 4B).

MEDIATION ANALYSIS. We performed mediationanalysis to examine the pre-specified pathway of: Y

SES to [ AmygA to [ hematopoietic tissue activity to[ arterial inflammation to [MACE. SES was estimatedhere by quartiles of neighborhood median income(Figure 4, Online Table 5). We observed that this pathsignificantly mediated the association of SES withMACE (standardized log odds ratio: �0.0137;95% CI: �0.0570 to �0.0003; p < 0.05). Additionally,the path of: Y SES to [ AmygA to [ arterial inflam-mation to [ MACE was also significant (�0.0137;95% CI: �0.0546 to �0.0001; p < 0.05). Together, the2 paths accounted for 28% of the total effect of SES onrisk of MACE.

DISCUSSION

Results of the current study indicate that lower SESassociates with heightened: 1) amygdalar activity;2) arterial inflammation; and 3) risk of subsequentMACE. Further, path analysis supports the pre-specified hypothesis that lower SES links to MACE


through a serial multitissue pathway involving theamygdala, hematopoietic tissues, and arterialinflammation. Thus, the current study provides sup-portive evidence for the existence of a neuro-immune pathway linking lower SES to CVD in adulthumans.

A causal interpretation of the present findings issupported by prior observations in animal models. Inmacaques, experimentally-induced social subordina-tion alters immune function, even in the absence ofvariation in resource access, and leads to alterationsin immune cell proportions, cell type-specific geneexpression, and response to an immune challenge(41). Increased stress is the likely stimulus for suchimmune changes that are triggered by experimentallyaltered social status. Similarly, in mice, chronicexperimental stress increases sympathetically medi-ated leukopoietic progenitor cell proliferation andaccelerates innate immune cell output and cytokineproduction (22,42,43). This pro-inflammatory im-mune activity in turn potentiates arterial inflamma-tion (22), a critical driver of atherosclerotic events(24,44). The present results also build upon priorstudies that have demonstrated a link between hu-man childhood SES and amygdalar activity inresponse to threats in adulthood, the first steps in thehypothesized pathway tested in this study (45–51). Byextending these observations to demonstrate thatlower SES links to MACE in adults through multiorganpathways driven by amygdalar activity, these resultssuggest new approaches to reducing the risk of MACEamong low SES adults (Central Illustration).

The hypothesized biological pathways betweenSES and MACE presented here should not be





FIGURE 4 A Hypothesized Pathway Linking Lower SES to MACE

Bone MarrowActivity

ArterialInflammation

MACESocioeconomicStatus

AmygdalarActivity

0.023P = 0.616

0.256P = 0.905

0.796P = 0.028

0.0110P = 0.039

0.199P = 0.014

0.554P < 0.001

–0.425P < 0.001

c’= –0.305P = 0.301

Indirect Paths1) ↓SES→ ↑AmygA → ↑Bone Marrow → ↑art inflam → ↑MACE: –0.0137 (–0.0570, –0.0003), p < 0.052) ↓SES→ ↑AmygA → ↑art inflam → ↑MACE: = –0.0137 (–0.0546, –0.0001), p < 0.05

A serial 3-mediator analysis testing the hypothesized indirect path of: Y SES to [ amygdalar activity to [ bone marrow activity to [ arterial

inflammation to [ MACE (red arrows) was significant (standardized log odds ratio: �0.0137 [95% confidence interval: �0.0570 to

�0.0003]; p < 0.05). Additionally, the path of: Y SES to [ amygdalar activity to [ arterial inflammation to [ MACE was also significant

(�0.0137 [95% confidence interval: �0.0546 to �0.0001]; p < 0.05). Exact p values are not available for a dichotomous outcome measure,

but in the bootstrap model used, confidence intervals that do not cross zero indicate p < 0.05. AmygA ¼metabolic activity in the amygdala;

c’ ¼ residual direct effect of SES on MACE (independent of mediated effects); other abbreviations as in Figure 1.


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interpreted as encompassing all possible pathologicalinfluences. For example, a reciprocal limb of thepresented model likely exists, wherein heightenedsystemic inflammation reciprocally impacts brainfunction and exacerbates stress as a manifestation ofa neuro-immune circuit (43,51–53). Additionally, it isimportant to note that statistically significant medi-ation analyses, as observed here, do not provecausation. Future studies, especially ones containinginterventions that target the nodes of the postulatedmechanism, will be needed to confirm a causal rolefor the hypothesized pathway.

The proposed model linking SES to MACE providesa potentially important construct within which toconsider future interventions. Although adverse so-cioeconomic factors (e.g., lower income and highercrime) have proven notoriously difficult to remedy, abiological pathway may be amenable to direct in-terventions to prevent MACE. Specifically, severalcomponents of the amygdalar-leukopoietic-arterialaxis reported herein could be therapeutically tar-geted with the goal of lessening the burden of SES-related disease. Potential approaches include theuse of drugs that reduce arterial inflammation (e.g.,


anti-inflammatory drugs or statins) or drugs thatinhibit the release of pro-inflammatory cells from thebone marrow in response to stress (e.g., beta-adrenoreceptor antagonists) (22). The brain, themost proximal component of the biological pathway,may represent the most attractive target. Ameliora-tion of the neural response to low SES could poten-tially be accomplished through stress reductiontechniques, exercise (which has well-describedstress-relieving benefits), or novel drugs targetingthe amygdala or other stress-related brain regions.Furthermore, it is particularly notable that AmygAremains significantly predictive of MACE even amongindividuals with the lowest levels of SES. This raisesthe possibility that reducing AmygA (or its down-stream biological consequences) may reduce MACE,particularly in socioeconomically disadvantagedindividuals.

It is additionally important to note that the rela-tionship between income and AmygA does not remainlinear at higher incomes. A closer evaluation ofAmygA as it relates to neighborhood median income(in deciles) (Online Figure 2) suggests no further im-provements in AmygA beyond household income



CENTRAL ILLUSTRATION A Model of Lower Socioeconomic Status Leading to Major Adverse Coronary Events

Tawakol, A. et al. J Am Coll Cardiol. 2019;73(25):3243–55.

Prior data have demonstrated a link between low socioeconomic status and higher rate of cardiovascular disease. This study suggests that a biological pathway

contributes to this link, involving, in series, higher amygdalar activation, increased activation of the bone marrow (with release of inflammatory cells), which in turn

leads to increased atherosclerotic inflammation and its atherothrombotic manifestations. Nonbiological (and likely other biological) paths also exist. Although the

social variables involved in this pathway are notoriously difficult to change, the biological factors are potentially more modifiable. BM ¼ bone marrow.



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PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Low SES is

linked to stress and a greater risk of MACE through up-regulation

of neural activity, activation of the immune system, and arterial

inflammation.

TRANSLATIONAL OUTLOOK: Future research should target

the neuro-immunological mechanisms mediating socioeconomi-

cally driven health disparities.


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levels above approximately the sixth decile. Thisthreshold effect is consistent with prior findings byKahneman et al. (54), who observed no furtherimprovement in reported perceived stress beyondhousehold income levels above the second incometertile.

STUDY LIMITATIONS. First, the subjects were iden-tified from a clinical database of patients who hadundergone imaging for clinical indications (mostlycancer surveillance), thus possibly limiting general-izability of the findings. However, there is littlereason to believe that any of these clinical indicationsshould have changed the relationships among SES,amygdalar activity, and MACE. In fact, it is possiblethat the effects would be even stronger among pa-tients not connected to ongoing care in a health caresystem. Second, neighborhood SES variables werebased upon 2015 census data (because it was closestto the time of follow-up of the cohort) rather than theindividual subjects’ year of imaging. Although thisapproach may have led to some misclassification ofSES measures, multiple studies have demonstratedthat there is little reclassification of neighborhoodSES between census time periods (55). Furthermore,any misclassification is likely to have been non-differential, thereby making it harder to find an as-sociation. Third, in the absence of individual SESdata, we necessarily used neighborhood SES mea-sures as a surrogate for individual SES. NeighborhoodSES measures have an effect on individual stressbeyond individual SES measures (3), and haverepeatedly been shown to associate with adversehealth outcomes (2–5). However, future studiesshould examine whether individual-level SES mea-sures yield further insights into the observed associ-ations. Fourth, it is possible that the context of cancerscreening, within which the 18F-FDG-PET/CT imagingwas conducted, may have affected amygdalar activityin our participants (e.g., being evaluated for cancermay increase anxiety). However, we do not neces-sarily see this as a disadvantage. Individuals who are


more likely to have a negative emotional reaction tobeing screened for cancer may also be likely to have amore negative reaction to adverse socioeconomiccircumstances. Overall, we believe these limitationsare substantially counterbalanced by several impor-tant innovations, including the unique use of socio-economic-, neuro-, and somatic imaging, andcardiovascular data to study hypothesized biologicalmechanisms linking SES disparities to CVD events.

CONCLUSIONS

The current findings identify a potentially modifiablebiological pathway driving the increased burden ofCVD that encumbers the socioeconomically disad-vantaged. These pathways originate in the brain,which provides a bridge between external factors andextra-neural diseases. By illuminating a multi-organsystem linking SES to CVD, this study sets the stagefor testing new interventions that may forestallfuture heart attacks and strokes and reduce SES-driven health disparities.

ADDRESS FOR CORRESPONDENCE: Dr. AhmedTawakol, Cardiology Division, Massachusetts GeneralHospital and Harvard Medical School, 55 Fruit Street,Yawkey 5050, Boston, Massachusetts 02114-2750.E-mail: [email protected]. Twitter:@ATawakolMD.

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KEY WORDS cardiovascular disease,neurobiology, positron emissiontomography, socioeconomic disparities,stress

APPENDIX For an expanded Methods sectionas well as supplemental figures and tables,please see the online version of this paper.

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