ORIGINAL RESEARCH

published: 17 March 2020

doi: 10.3389/fpsyt.2020.00069

Associations Between Child

Maltreatment, Autonomic Regulation,
and Adverse Cardiovascular
Outcome in an Urban Population: The
HELIUS Study
Maryse J. Bakema 1†, Mirjam van Zuiden 1†, Didier Collard 2, Jasper B. Zantvoord 1,
Susanne R. de Rooij 3, Leonie K. Elsenburg 4, Marieke B. Snijder 2,3, Karien Stronks 4,
Bert-Jan H. van den Born 2 and Anja Lok 1*
Edited by:
1Department of Psychiatry, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, Netherlands,
Andreas Menke,
2Department of Internal and Vascular Medicine, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam,
University Hospital Wuerzburg,
Germany Netherlands, 3 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC location AMC,
University of Amsterdam, Amsterdam, Netherlands, 4 Department of Public Health, Amsterdam UMC location AMC,
Reviewed by:
University of Amsterdam, Amsterdam, Netherlands
Yoshihiko Matsumoto,
Yamagata University, Japan
Seth Davin Norrholm, Introduction: A mounting body of literature emphasizes the potential negative effects of
Wayne State University,
United States adverse childhood experiences (ACEs) on both mental and physical health throughout life,
Ana Luiza Soares, including an increased risk for developing cardiovascular disease (CVD). Since CVD is one
University of Bristol,
United Kingdom
of the leading causes of mortality and morbidity worldwide, it is of great importance to
*Correspondence:
advance our understanding of the effects of on CVD. This holds both for the actual
Anja Lok incidence and for intermediate biological pathways that may convey CVD risk, such as
[email protected] imbalance in autonomic nervous system regulation, resulting in a chronically heightened
†
These authors share first authorship sympathetic activity and lowered reactivity. In a large urban, multi-ethnic population-
based cohort study we investigated whether there is an association between child
Specialty section:
This article was submitted to maltreatment, CVD incidence and autonomic regulation.
Molecular Psychiatry,
a section of the journal
Methods: Within the Health in an Urban Setting (HELIUS) study, a large, multi-ethnic
Frontiers in Psychiatry population cohort study including n = 22,165 Amsterdam residents, we used logistic
Received: 16 September 2019 regression analyses to investigate the association between the number of self-reported
Accepted: 27 January 2020
types of child maltreatment (range 0–4), and self-reported adverse cardiovascular
Published: 17 March 2020
outcome (aCVO). Self-reported child maltreatment included emotional neglect,
Citation:
Bakema MJ, van Zuiden M, emotional abuse, physical abuse, and sexual abuse. Furthermore, in a subsample (n =
Collard D, Zantvoord JB, de Rooij SR, 10,260), mean age 44.3, we investigated associations between child maltreatment,
Elsenburg LK, Snijder MB,
Stronks K, van den Born B-JH and
autonomic regulation, and aCVO using linear regression analyses. Both baroreflex
Lok A (2020) Associations Between sensitivity (BRS) and heart rate variability (HRV) were assessed as non-invasive indices
Child Maltreatment, Autonomic
of autonomic regulation.
Regulation, and Adverse
Cardiovascular Outcome in an Urban Results: The number of endorsed child maltreatment types was significantly associated
Population: The HELIUS Study.
Front. Psychiatry 11:69.
with a higher aCVO risk. The association remained significant after adjustment for
doi: 10.3389/fpsyt.2020.00069 demographic, socioeconomic, health-behavioral, and psychological covariates (p = 0.011,

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Bakema et al. Association Between ACEs and aCVO

odds ratio: 1.078, confidence interval: 1.018–1.142). The cumulative exposure to child
maltreatment was negatively associated with BRS and HRV, but the association was no
longer significant after correction for socioeconomic and demographic covariates.
Conclusion: In a large, multi-ethnic urban-population cohort study we observed a
positive association between number of endorsed child maltreatment types and self-
reported aCVO but not autonomic regulation, over and above the effect of relevant
demographic, health, and psychological factors. Future studies should examine the
potential role of the dynamics of autonomic dysregulation as potential underlying
biological pathways in the association between ACEs and CVD, as this could eventually
facilitate the development of preventive and therapeutic strategies for CVD.
Keywords: adverse childhood experience, cardiovascular disease, autonomic regulation, heart rate variability,
baroreflex sensitivity

INTRODUCTION autonomic nervous dysregulation as one of the potential

underlying physiological mechanisms leading to CVD risk (7).
According to the World Health Organization (WHO), the widely Both baroreflex sensitivity (BRS) and heart rate variability
used umbrella term adverse childhood experiences (ACEs) refers (HRV) are non-invasive indices of autonomic regulation. HRV,
to some of the most intensive and frequently occurring sources of the beat-to-beat variation in the heartrate over time, is a reliable
stress that happens to someone before the age of 18 that the index of autonomic nervous regulation (18). Decreased HRV
person remembers as an adult (1), either directly (e.g., abuse and indicates an inability to reduce sympathetic activation of the
neglect), or indirectly through their living environments (e.g., heart (19). This makes the heart vulnerable to arrhythmia and
parental conflict, substance abuse, or mental illness). ACEs are sudden death and also accelerates development of atherosclerotic
common and affect a substantial part of our society. Estimations coronary artery disease (20, 21). Reduced HRV has been
from multiple studies on the prevalence of ACEs in large healthy established as a prognostic risk factor for CVD. For example,
adult populations in Western countries vary from 34 to 62% of lower HRV has been shown to be an independent predictor of
the population having experienced one or more ACEs (2–4). cardiac events and mortality in both healthy individuals and
ACEs, i.e. prolonged and/or severe (traumatic) stress patients with a history of myocardial infarction (19, 22).
experiences in childhood, can have lifelong consequences for a Additionally, BRS is the magnitude of change in heart rate
person's health and well-being (5, 6). Cross-sectional and interval in response to a change in systolic blood pressure
longitudinal studies have previously observed associations (SBP) (17). The baroreflex is important for hemodynamic
between ACEs and subsequent altered functioning of a myriad stability and for cardio protection. It has however repeatedly
of biological systems, including the nervous, endocrine, and been demonstrated that a decrease in BRS is a prognostic factor
immune system (7, 8). This may result in impaired emotional, for CVD and arrhythmic events post-myocardial infarction
cognitive, physical, and social functioning, and thereby affect [MI (19)].
mental and physical health. Additionally, ACEs have been Current models assume that ACEs increase CVD risk by
described to indirectly negatively impact mental and physical altering long-term patterns of autonomic regulation by
health through associations with increased maladaptive lifestyle disturbing the sympathetic and parasympathetic balance (7,
and behavior (such as smoking, alcohol use, physical inactivity, 23), characterized by enduring higher sympathetic activity and
and an unhealthy diet) (5, 9–14); decreased access to life lowered parasympathetic activity. Multiple studies have shown
opportunities; and lack of economic stability, although the associations between ACEs and HRV, generally finding lower
directionality of causality in these associations is difficult to HRV to be associated with ACEs, but not all findings in non-
establish (15). Thus, given the evidence of their negative long- clinical, depressed and adolescent samples have been consistent
term impact on public health, ACEs are of great concern. (24–28). The association between ACEs and BRS has not been
One of the unfavorable health outcomes associated with examined before.
ACEs is an increased risk for developing cardiovascular disease In this study, we aimed to investigate whether exposure to
(CVD), one of the leading causes of mortality and morbidity child maltreatment increases the risk for CVD, i.e. self-reported
worldwide (16). ACEs have been associated with a significantly adverse cardiovascular outcomes (aCVO), and autonomic
increased risk of both self-reported and objectively verified CVD regulation (as measured with HRV and BRS) in the general
in several studies, including general population cohorts and CVD adult population. The focus of the current study is on child
case–control studies [for systematic review see (17)]. maltreatment as this concerns a relatively common and directly
The pathophysiological pathway through which ACEs experienced type of ACE, which may occur in the form of
increase the risk of CVD is likely to be multifactorial, with physical, sexual, and psychological abuse, and emotional

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Bakema et al. Association Between ACEs and aCVO

neglect, and has been previously observed to have pervasive aCVO

consequences for subsequent health and well-being of affected History of CVD, i.e. aCVO, was based on three self-report items
individuals throughout life. We used data from the Health in an in the HELIUS questionnaire: 1) Have you ever had a heart
Urban Setting (HELIUS) study, which is a large representative attack (MI)? 2) Have you ever had a stroke? 3) Have you ever had
urban cohort study, N = 22,615, among several ethnic groups a dotter procedure (angioplasty) or a bypass operation on your
living in Amsterdam, the Netherlands. The design of the heart or legs? The scale was dichotomized to 0 (no reported
HELIUS study guarantees a heterogeneous cross-section of the CVD) and 1 (at least one item endorsed). Three hundred
general Western population, generalizable on demographic seventeen participants were excluded due to missing data on
factors such as socioeconomic status (SES), educational level, self-reported CVD.
and ethnicity (29, 30).
Autonomic Regulation
Electrocardiogram (ECG) measurements were performed in all
METHODS participants (MAC 1600 System, GE Healthcare). Due to logistic
constraints, only a subset of n = 13,726 participants was
The HELIUS study is a large cohort study carried out in subjected to continuous blood pressure (BP) measurement by
Amsterdam, the Netherlands. The HELIUS study mainly finger plethysmography using the Nexfin device (BMEYE,
focuses on three disease categories: CVD, mental health, and Amsterdam). BP measurements were obtained for 3–5 min in
infectious diseases. Between 2011 and 2015, baseline HELIUS the supine position after 10-min rest. Automated analysis of the
data were collected among Amsterdam residents of South-Asian hemodynamic data was performed using custom-written
Surinamese, African Surinamese, Turkish, Moroccan, Ghanaian, software in Matlab (R2018b, The MathWorks, Inc. Natick) as
and Dutch origin. Persons were randomly sampled, by ethnic described elsewhere (32). In brief, to remove noise and possible
origin, via the municipality register of Amsterdam and received ectopic beats, the beat-to-beat dataset was filtered using a local
an invitation to take part in the study. Contact could be made moving median filter with a length of nine beats. Beats which
with 55% of selected invitees, of which approximately 50% duration diverted more than 25% of the mean interbeat interval
responded and agreed to participate, leading to a total response (IBI), the duration between successive heartbeats, from the local
rate of 28%. Previous non-response analyses revealed only minor median IBI were removed. Participants with no detected sinus
differences in socioeconomic characteristics between invited rhythm on the ECG or more than 20% removed beats were
individuals agreeing to participate, invited individuals not excluded (32). This yielded n = 10,260 participants with available
participating, and non-invited eligible individuals, indicating HRV and BRS data. We observed several small but statistically
that the HELIUS cohort is representative for the investigated significant differences between included and non-included
ethnic groups living in Amsterdam [for details see (29, 30). Data participants (see Supplementary Table 1). Compared to non-
were collected through an extensive questionnaire and a physical included participants, those included were more commonly
examination that included the collection of biological samples. males (45.8% versus 39.1%) and on average 5 months younger.
The Institutional Review Board of the Amsterdam UMC location Also, included participants had a somewhat higher BMI, but
AMC approved the study's protocols and all participants gave reported a lower number of maltreatment types experienced and
written informed consent. For the current analyses, we used data lower prevalence of CVD.
of n = 22,165 participants for whom data from the questionnaire
regarding child maltreatment and aCVO as well as the physical HRV
examination were available. HRV was determined by calculation of the mean IBI, the square
root of the mean squared successive differences between adjacent
Measures normal-to-normal (NN) intervals (RMSSD) and the standard
Child Maltreatment deviation of NN intervals (SDNN), following international
The occurrence of child maltreatment was assessed using a guidelines (33). For the analyses, both RMSSD and SDNN (in
questionnaire based on the NEMESIS Trauma questionnaire ms) were included, as they both measure different aspects of
(31). It contains four items, reflecting specific types of HRV (34, 35). RMSSD mostly reflects the parasympathetic
maltreatment experienced before the age of 16: emotional system, while SDNN reflects all the cyclic components
neglect (ignored or unsupported), physical abuse (kicked, hit, responsible for HRV in the period of recording with the
bitten, or hurt), emotional abuse (yelled at, insulted, or influence of the sympathetic system and all other influential
threatened), and sexual abuse (any unwanted sexual systems on the heart rate included (33, 35, 36).
experience). A Likert scale was used to answer these questions
(never–once–sometimes–often–would rather not say). BRS
Maltreatment types were scored as endorsed when experienced Estimates of BRS were obtained from beat-to-beat changes in
sometimes or often, except for sexual abuse which was scored as SBP and heart rate, using the xBRS method. First, the change in
endorsed when experienced at least once. Finally, the total heart rate in response to change in BP was assessed, using a
number of maltreatment types endorsed was calculated (range: cross-correlation method over a sliding 10-s window with
0–4) (see below for details on imputation strategy in case of various delay compensations (37, 38). Second, for each
missing data). segment with a significant positive cross-correlation, xBRS was

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Bakema et al. Association Between ACEs and aCVO

obtained by dividing the standard deviation of the IBI by the categorical predictors) and predictive mean matching. All
standard deviation of the SBP. The overall xBRS (in ms/mm Hg) variables used for our final analysis were included as auxiliary
is the geometric mean of all obtained xBRS values per segment variables (40). Eventually 30 imputations were needed to obtain
with a significant positive cross-correlation. adequate imputation efficiency. All reported findings concern the
pooled results from these 30 imputed datasets.
Covariates We first investigated whether child maltreatment were
Socioeconomic and demographic variables included were age, significantly associated with aCVO, using binomial logistic
sex, ethnicity, and educational level. Ethnicity was divided into regression analyses. Secondly, we investigated whether child
seven groups: Dutch, South-Asian Surinamese, African maltreatment were significantly associated with the three
Surinamese, Ghanaian, Turkish, Moroccan, and “other.” This autonomic measures: RMSSD, SDNN, and BRS, using three
latter group consists of participants with a Javanese-Surinamese separate sets of linear regression analyses. Third, we
origin, other/unknown Surinamese origin, or other/unknown investigated whether the three autonomic measures were
ethnic origin, which were combined due to relatively small associated with aCVO, using three separate sets of binomial
sample size (2.5% of total sample size). In all analyses, ethnic logistic regression analyses. Prior to each regression analysis, it
minority groups were compared to the Dutch ethnicity. was confirmed that relevant statistical assumptions were met.
Educational level was divided into two categories: 1) no or In each regression analysis, adjustment for covariates was
lower education (no schooling, elementary schooling only, performed in a stepwise manner. First, we assessed a model
lower vocational schooling, or lower secondary schooling) and without any covariates added. Second, we added a block of
2) intermediate or higher education (intermediate vocational covariates regarding demographic and socioeconomic variables
schooling, intermediate/higher secondary schooling, higher that may potentially confound the association between child
vocational schooling, or university) (30). maltreatment and CVD. Third, a block of covariates regarding
Furthermore, the following health behaviors and health-behavioral characteristics and chronic stress was added.
anthropometric measurements were taken into account: This latter block represents potential mediating factors in the
current smoking (yes/no), alcohol intake in past 12 months child maltreatment–aCVO association. It was included in the
(yes/no), physical activity (reaching the international goal of 30 regression models as we aimed to examine whether there was an
min per day on at least 5 days per week: yes/no), and body mass additional effect of child maltreatment on CVD over and above
index (BMI) (measured during physical examination, kg/m2), as these previously described mediating pathways. Additionally, for
well as current stress (negative life events in the last 12 months: the models containing autonomic measures only,
yes or no). A broad range of studies have consistently shown antihypertensive medication use added as additional covariate
associations between ACEs and higher risk of adult smoking in a separate block, before adding the other covariate blocks.
(12), obesity (15), physical inactivity (39) and heavy alcohol use Furthermore, a sensitivity analysis was performed to adjust for
(5), and increased experienced stressors in adulthood, as well as the potential influential effect of already experienced aCVO on
associations between these variables and aCVO risk, and thus the relationship between child maltreatment and autonomic
these factors represent potential mediating pathways in the child regulation, excluding all participants reporting aCVO.
maltreatment–aCVO association. To assess whether moderation effects between ACEs and age
Because of the expected influence of use of antihypertensive or gender should be considered in addition to their main effects,
medication on both HRV and BRS, use of antihypertensives regression analyses on associations between child maltreatment
(dichotomous) was also corrected for in analyses including and aCVO, HRV, and BRS were additionally performed
autonomic measures. including the interaction effects between number of endorsed
child maltreatment types and gender or age group respectively.
Statistical Analysis For this purpose, the age variable was categorized into four
For the data analyses in this study, IBM SPSS statistics version categories containing equal percentages of participants (i.e.
25.0 was used. A two-sided p-value of <0.05 was considered quartiles): 18–32, 33–45, 46–53, and 54–70. The first three
significant. Because of the high percentage of missing values in categories were compared to the eldest category, because
child maltreatment data (range: 4.4% for Dutch participants, up aCVO was expected to be highest within that group. Sex and
to 12% for Ghanaian participants), multiple imputation was age did not significantly moderate the effect of child
performed to avoid underestimation of the prevalence of child maltreatment on BRS or HRV, nor the effect of child
maltreatment and thereby biased results on the probable maltreatment on aCVO (Supplementary Tables 5A, B), and
association between child maltreatment and our outcomes. therefore we considered only main effects of age and gender in
Multiple imputation is an effective method for dealing with the results.
missing data (40), and is becoming increasingly common, also
specifically for studies on ACEs (41, 42). As missingness (item
either left blank or scored “would rather not say”) correlated with RESULTS
the large majority of variables, the missing data for the four child
maltreatment items were imputed in SPSS using Markov Chain Sample characteristics per ethnic group are shown in Table 1.
Monte Carlo imputation with fully conditional specification with The average age of all participants was 44.3 (SD = 13.2) years,
auxiliary variables (main effects and two-way interactions among with 57.8% women. Overall, 7676 participants (34.6%)

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Bakema et al. Association Between ACEs and aCVO

experienced any type of child maltreatment, and 1135 Association Between Child Maltreatment
participants (5.2%) reported a history of aCVO. and Autonomic Regulation
In the models without covariates, the number of endorsed ACE
Association Between Child Maltreatment types was significantly associated with RMSSD and BRS, but not
and aCVO SDNN (Table 3). An increasing number of child maltreatment
A higher number of endorsed ACE types was significantly types endorsed was significantly associated with lower BRS and
associated with a 1.1 times higher risk for aCVO, as shown in lower RMSSD. These associations were not affected by
Table 2. After correction for all covariates, this association additionally adjusting for antihypertensive medication use but
remained significant, with each additional child maltreatment were no longer present after adding the sociodemographic
type endorsed increasing the odds of aCVO by 7.8% [95% covariates to the model (see Supplementary Tables 3A, B).
confidence interval (CI): 1.05–1.17, p = 0.011]. The This was not affected by the final step of adding the covariates
corresponding table is shown in Supplementary Table 2. concerning health-behavioral characteristics and current stress

TABLE 1 | Baseline characteristics of the study population.

Total Dutch South-Asian African Ghanaian Turkish Maroccan Other

(N = 22,165) (N = 4564) Surinamese Surinamese (N = 2339) (N = 3614) (N = 3906) (N = 548)
(N = 3043) (N = 4151)

Sociodemographics
Age 44.3 ± 13.2 46.2 ± 14.1 45.5 ± 13.4 47.9 ± 12.5 44.7 ± 11.2 40.4 ± 12.2 40.5 ± 12.9 47.5 ± 12.5
Female 12,810 (57.8%) 2475 1672 (54.9%) 2535 (61.1%) 1434 (61.3%) 1980 (54.8%) 2392 (61.2%) 322 (58.8%)
(54.2%)
Educational level
No–lower 9679 (44.1%) 796 (17.5%) 1447 (47.8%) 1708 (41.5%) 1577 (68.7%) 2024 (56.6%) 1899 (49.1%) 228 (42.5%)
intermediate–higher 12,279 (55.9%) 3743 1580 (52.2%) 2407 (58.5%) 720 (31.3%) 1552 (43.4%) 1969 (50.9%) 308 (57.5%)
(82.5%)
Health behavior
Smoking 5302 (24.0%) 1129 861 (28.4%) 1309 (31.7%) 104 (4.5%) 1240 (34.6%) 525 (13.5%) 134 (24.8%)
(24.8%)
Drinking alcohol 11,221 (50.9%) 4151 1708 (56.4%) 2826 (68.6%) 1101 (47.6%) 813 (22.7%) 286 (7.4%) 336 (62.6%)
(91.1%)
BMI 27.1 ± 5.3 24.8 ± 4.2 26.3 ± 4.8 27.8 ± 5.5 28.4 ± 5.0 28.6 ± 5.7 27.6 ± 5.2 26.7 ± 5.0
Child maltreatment
Any type 7676 (34.6%) 1689 1132 (37.2%) 1645 (39.6%) 688 (29.4%) 1231 (34.1%) 1066 (27.3%) 225 (41.1%)
(37.0%)
Emotional neglect 5542 (25.0%) 1287 828 (27.2%) 1070 (25.8%) 412 (17.6%) 1017 (28.1%) 763 (19.5%) 165 (30.1%)
(28.2%)
Emotional abuse 3615 (16.3%) 734 (16.1%) 609 (20.0%) 820 (19.8%) 278 (11.9%) 514 (14.2%) 538 (13.8%) 122 (22.3%)
Physical abuse 3640 (16.4%) 443 (9.7%) 626 (20.6%) 969 (23.3%) 427 (18.3%) 505 (14.0%) 556 (14.2%) 114 (20.8%)
Sexual abuse 1871 (8.4%) 531 (11.6%) 232 (7.6%) 585 (14.1%) 156 (6.7%) 116 (3.2%) 181 (4.6%) 70 (12.8%)
Number of types
experienced
0 14,489 (65.4%) 2875 1911 (62.8%) 2506 (60.4%) 1651 (70.6%) 2383 (65.9%) 2840 (72.7%) 323 (58.9%)
(63.0%)
1 3464 (15.6%) 856 (18.8%) 455 (15.0%) 644 (15.5%) 333 (14.3%) 628 (17.4%) 461 (11.8%) 87 (15.9%)
2 2000 (9%) 455 (9.9%) 279 (9.2%) 408 (9.8%) 169 (7.2%) 327 (9.0%) 304 (7.8%) 58 (10.6%)
3 1640 (7.4%) 282 (6.2%) 307 (10.1%) 389 (9.4%) 141 (6.0%) 233 (6.5%) 236 (6.0%) 52 (9.5%)
4 572 (2.6%) 96 (2.1%) 90 (2.9%) 204 (4.9%) 45 (1.9%) 43 (1.2%) 65 (1.7%) 28 (5.1%)
CVD 1135 (5.2%) 167 (3.7%) 271 (9%) 216 (5.3%) 101 (4.5%) 233 (6.6%) 126 (3.3%) 21 (3.9%)
Autonomic
regulation
N 10,260 2045 1341 2079 1251 1729 1815 0
BRS 13.43 ± 9.07 14.98 ± 12.51 ± 8.31 12.96 ± 8.44 12.63 ± 8.82 12.69 ± 8.39 14.16 ± 9.61 –
10.55
RMSSD 46.73 ± 29.46 49.70 ± 43.63 ± 30.09 46.68 ± 29.60 47.35 ± 26.97 44.13 ± 27.26 47.77 ± 28.7 –
32.43
SDNN 52.41 ± 27.82 58.50 ± 51.43 ± 28.97 50.73 ± 26.84 49.63 ± 26.75 50.71 ± 26.10 51.72 ± 25.31 –
31.16

Baseline characteristics per ethnic group, described as means and standard deviations for continuous variables, and frequency and percentage for categorical variables. CVD, cardiovascular
disease; BRS, baroreflex sensitivity; RMSSD, a parameter reflecting heart rate variability calculated as the square root of the mean squared successive differences between adjacent normal-to-
normal interbeat intervals; SDNN, a parameter reflecting heart rate variability calculated as the standard deviation of normal-to-normal interbeat intervals; BMI, body mass index.

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Bakema et al. Association Between ACEs and aCVO

TABLE 2 | Logistic regression analyses on the association between child maltreatment and adverse cardiovascular outcome (aCVO).

R2 b Odds ratio 95% Confidence interval p

Model 1 0.002 0.101 1.106 [1.049, 1.167] <0.001

Model 2* 0.150 0.108 1.114 [1.054, 1.178] <0.001
Model 3*† 0.159 0.096 1.100 [1.039, 1.165] 0.001
Model 0.164 0.075 1.078 [1.018, 1.142] 0.011
4*†‡

Each model shows the regression results of child maltreatment–number of types endorsed.
*Adjusted for sociodemographic covariates (sex, age, education, and ethnicity).
†
Adjusted for health-behavioral covariates (smoking, alcohol, body mass index, physical activity).
‡
Adjusted for psychological covariate (current stress).

TABLE 3 | Multiple linear regression analyses on association between child maltreatment and xBRS and heart rate variability.

R2 b 95% Confidence Interval p

xBRS
Model 1 0.001 −0.016 [−0.028, −0.005] 0.006
Model 2* 0.068 −0.017 [−0.028, −0.006] 0.003
Model 3*† 0.370 −0.002 [−0.009, 0.010] 0.907
Model 4*†‡ 0.395 −0.001 [−0.007, 0.008] 0.981
RMSSD
Model 1 0.001 −0.015 [−0.025, −0.004] 0.007
Model 2* 0.031 −0.015 [−0.026, −0.005] 0.004
Model 3*† 0.220 −0.003 [−0.013, 0.006] 0.530
Model 4*†‡ 0.233 −0.007 [−0.016, 0.003] 0.169
SDNN
Model 1 0.000 −0.006 [−0.014,0.003] 0.196
Model 2* 0.041 −0.006 [−0.015,0.002] 0.148
Model 3† 0.184 −0.003 [−0.005,−0.011] 0.760
Model 4*†‡ 0.196 0.001 [−0.007, 0.009] 0.747

N = 10,260. Each model shows the regression results of child maltreatment-number of types endorsed on xBRS/RMSSD and SDNN.
*Adjusted for antihypertensive medication.
†
Adjusted for sociodemographic covariates (sex, age, education, and ethnicity).
‡
Adjusted for health-behavioral and psychological covariates (smoking, alcohol, body mass index, physical activity, current stress).
xBRS, baroreflex sensitivity; RMSSD, a parameter reflecting heart rate variability calculated as the square root of the mean squared successive differences between adjacent normal-to-
normal interbeat intervals; SDNN, a parameter reflecting heart rate variability calculated as the standard deviation of normal-to-normal interbeat intervals.

to the model. Results remained unchanged after excluding form of direct ACEs is associated with higher risk of self-reported
participants reporting previous aCVO (Supplementary history of CVD and autonomic regulation as CVD risk factor.
Table 3C). This is to our knowledge, the first study on the association
between child maltreatment and CVD risk in a representative
Associations Between Autonomic urban population: heterogeneous and generalizable on
Regulation and aCVO demographic factors such as SES, educational level, and
The main effects of BRS, RMSSD, SDNN, on aCVO were all ethnicity (29, 30).
significant, also after adjustment for antihypertensive medication Our study confirmed that child maltreatment is significantly
use. Lower BRS, RMSSD, and SDNN were associated with associated with higher risk for CVD later in life. This association
increased odds for aCVO (Table 4). For both HRV remained significant after adjusting for potentially relevant
parameters, the association was no longer significant after covariates. With every additional child maltreatment type
adding socioeconomic covariates to the model (see reported, the odds for reporting aCVO was 7.8% (95% CI:
Supplementary Table 4B). For BRS, the association remained 1.018–1.142) higher. Thus, child maltreatment was associated
significant after adjusting for sociodemographic covariates, but with an increased risk for adult aCVO over and above the effects
was no longer significant after adding the additional covariates of a range of sociodemographic, health-behavioral, and current
concerning health-behavioral characteristics and current stress stress factors, which were previously found to be associated with
(see Supplementary Table 4A). both increased self-reported ACEs and risk for CVD (3, 43, 44).
Our finding is in concordance with existing literature that ACEs
are important determinants of health problems in adulthood and
DISCUSSION more specifically consistent with the results of previous studies
examining the association between childhood maltreatment and
In this large, population-based, multi-ethnic urban cohort study, CVD (39). These previous studies also reported a linear association
we tested whether exposure to child maltreatment as a specific between cumulative exposure and increased risk for self-reported

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Bakema et al. Association Between ACEs and aCVO

TABLE 4 | Logistic regression analyses on the association between adverse cardiovascular outcome (aCVO) and xBRS and heart rate variability.

R2 b Odds Ratio 95% Confidence Interval p

xBRS
Model 1 0.041 −0.882 0.414 [0.356, 0.470] <0.001
Model 2* 0.118 −0.534 0.586 [0.499, 0.689] <0.001
Model 3*† 0.135 −0.209 0.811 [0.673, 0.978] 0.028
Model 4*†‡ 0.192 −0.071 0.932 [0.769, 1.129] 0.470
RMSSD
Model 1 0.018 −0.652 0.521 [0.441, 0.616] <0.001
Model 2* 0.110 −0.360 0.698 [0.588, 0.828] <0.001
Model 3*† 0.179 0.015 1.015 [0.844, 1.220] 0.877
Model 4*†‡ 0.197 0.011 1.011 [0.838, 1.220] 0.909
SDNN
Model 1 0.022 −0.868 0.420 [0.344, 0.513] <0.001
Model 2* 0.111 −0.442 0.643 [0.524, 0.789] <0.001
Model 3*† 0.179 −0.117 0.890 [0.717, 1.103] 0.286
Model 4*†‡ 0.197 −0.080 0.923 [0.741, 1.150] 0.476

Each model shows the regression results of xBRS, RMSSD, and SDNN.
*Adjusted for antihypertensive medication.
†
Adjusted for sociodemographic covariates (sex, age, education, and ethnicity).
‡
Adjusted for health-behavioral and psychosocial covariates (smoking, alcohol, body mass index, physical activity, current stress).
xBRS, baroreflex sensitivity; RMSSD, a parameter reflecting heart rate variability calculated as the square root of the mean squared successive differences between adjacent normal-to-
normal interbeat intervals; SDNN, a parameter reflecting heart rate variability calculated as the standard deviation of normal-to-normal interbeat intervals.

CVD after adjustment for relevant covariates. However, this is the reported CVD and both HRV indices was no longer
first study establishing this relationship in a heterogeneous, multi- significant. Initially, we hypothesized that the absence of a
ethnic, and thus Western urban population representative cohort as stable association between HRV and CVD, which seems to be
the HELIUS cohort. contradictory to the existing literature (19, 22), could be
In addition to self-reported history of CVD, we also examined influenced by the composition of our cohort. First of all, as our
the association between child maltreatment and autonomic cohort is relatively young and correspondingly aCVO prevalence
regulation as CVD risk factor. We did find, as we expected, is relatively low (5.2%), we may have had limited signal to detect
that the cumulative exposure to child maltreatment was these associations in the whole sample. However, we found that
negatively associated with autonomic regulation within models age was not a significant moderator in any of the associations.
without any covariates added. However, this association Secondly, the HELIUS study includes both individuals without
disappeared after adding the sociodemographic covariates to prior CVD and individuals who have already experienced one or
the models, which in themselves were previously found to be more CVD events, and thereby departs from the existing
associated with increased risk for ACEs and CVD (5, 12–16, 39). literature which investigated the association between
In agreement with our findings, some previous studies also did autonomic regulation and future CVD events in either healthy
not find a significant direct association between HRV and ACEs. populations or specific populations of CVD patients (19, 22, 45–
The study by van Ockenburg et al. (25), based on a randomly 53). However, a sensitivity analysis revealed that our results
selected large cohort of people with albuminuria, found remained unchanged after excluding participants who reported
significantly lower HRV in individuals reporting ACEs, but as CVD. The association between BRS and CVD remained
in the current study this association also disappeared after significant upon adding the sociodemographic covariates, but
correcting for sociodemographic and health behavioral was no longer significant upon additionally adding the health-
covariates (25). Winzeler et al. (24) found an association behavioral and current stress factors, indicating that these factors
between ACEs and HRV in young healthy women when the may be mediating pathways influencing the formerly observed
HRV was measured during performance of a stress task and not association between BRS and CVD (19).
during baseline measurements (24), which is in concordance Thus we did not observe an association between child
with the null findings in our study, with HRV also measured maltreatment and autonomic regulation, nor an association
during resting conditions. between autonomic regulation and CVD after inclusion of
Interestingly, to verify the assumed association between covariates, although we cannot exclude that measuring these
autonomic (dys) regulation and aCVO in our cohort, we also indices during specific physical or psychological challenges
investigated associations between HRV, BRS, and aCVO. would reflect another pattern. Alternatively, ACEs including
Contrary to our expectations, we observed that the initially child maltreatment may trigger, besides ANS, a cascade of
observed negative associations between self-reported CVD and molecular alterations in other systems that regulate stress
the objective measures of autonomic regulation were no longer responses and may be involved in CVD development, such as
present in the corrected models. Upon adding the potential neuroendocrine, immune systems, endothelial damage or
sociodemographic confounders, the association between self- accelerated atherosclerosis (54).

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Bakema et al. Association Between ACEs and aCVO

In addition, there may be psychological mechanisms that may maltreatment were assessed, not the overall severity, frequency of
also play a role in the association between ACEs, including child distinct types of maltreatment, or perceived impact of these
maltreatment, and increased CVD risk, such as maladaptive experiences. We also did not examine the developmental timing
cognitive models, impaired attachment, dysfunctional coping and chronicity of maltreatment, which may also have an influence on
behaviors, and unhealthy peer associations (55). Moreover, the associations we investigated. Recent evidence indicates a
studies suggest that ACEs and especially child maltreatment distinctive impact of childhood adversity type and timing on
could induce emotional problems, including depression, physical and mental health and neurobiological correlates in
anxiety, and affective lability, and this could be associated with adulthood, supporting the notion of stress-sensitive periods in
CVD risk in adulthood (26). Thus, poor mental health could (organ) development in childhood (62).
either moderate or mediate associations between ACEs and In addition, since the assessment of child maltreatment was
health outcomes (56). Additionally, use of psychotropic based on retrospective self-report, effects of memory biases
medication may additionally influence these associations. cannot be excluded. Moreover, child maltreatment may also
Furthermore, adversity is only one part of the equation occur before children have the cognitive ability to remember
regarding childhood environmental influences on future health. such events. Evaluating retrospective self-report to assess
One could argue that in the face of adversity, neither disease nor childhood maltreatment, a study performed on retrospective
resilience is a certain outcome. The presence of protective recalls of sexual and physical abuse, as well as physical and
factors, particularly safe, stable, and nurturing relationships, emotional neglect, ascertained retrospective surveys to be
can often mitigate the consequences of ACEs (57, 58). Also sufficiently valid (63). In contrast, a recent meta-analysis and
neighborhood greenness for example might buffer against the systematic review performed on the extent of agreement between
detrimental effects of stress by specifically promoting activity of retrospective and prospective measures of child maltreatment
the parasympathetic nervous system in restoring the body to a concluded that prospective and retrospective measures cannot be
calm state after stress reactivity (59). However, these factors were used interchangeably to study risk mechanisms and associations
not considered in the current study. with health outcomes (64). They mention that “caution should
be used in assuming that retrospective reports accurately
represent experiences, rather than perceptions, interpretations
Strengths and Limitations or existential recollections.” Thus, ideally our study should be
There are several strengths and weaknesses of this study that replicated in a prospective design.
need to be considered when interpreting our results. The first Moreover, missing data in the child maltreatment
major strength of this study is that the study was conducted in a questionnaire were significantly more frequent in every
large cohort, which provides notable statistical power. A random ethnicity compared to the Dutch ethnicity, which may be
sampling technique was used through the municipality register related to two factors. First, there could be a larger component
of Amsterdam, which guarantees a non-selective, community of shame and taboo within some ethnicities to report these
recruited general population study sample. It is unlikely that the adverse experiences (65). Second, the ethnic differences may
relatively low response rate of 28% has led to selection bias, as have resulted from the formulation of our items on child
analysis of non-responders within our cohort established that maltreatment: it is possible that some participants would have
there was no difference in socioeconomic characteristics between endorsed the objective explanation (e.g. being beaten during
participants and non-participants (30). childhood), but did not agree on the following interpretation of
Second, with the prevalence rate of any type of child that behavior as representative of maltreatment (e.g. having
maltreatment (around 30%) being in line with that of a large experienced physical abuse). However, we applied multiple
Dutch study on its prevalence in the general population (31), the imputation with auxiliary variables to deal with the impact of
experiences of participants in this study are representative for the non-randomly missing data, which presumably resulted in a
Dutch general adult population, and results of our study are thus more accurate estimation of the relationship between
likely generalizable. maltreatment and our outcome variables (40).
Potential limitations and weaknesses of our study also require Finally, although our analyses concerning BRS and HRV
consideration. First, the HELIUS data are cross-sectional, this included over 10,000 participants, these analyses only included
poses constraints on the directionally in the investigated 46.3% of the sample. Due to logistic constraints concerning
associations, especially in the association between autonomic availability of equipment, continuous BP measurements were
regulation and CVD. Furthermore, the measurement of CVD by not performed for 28.1%. An additional 15.6% of participants
self-report may have led to under-reporting or over-reporting were excluded from analyses upon data preprocessing. We
when compared to direct assessment of CVD events, although observed several statistically albeit small significant differences
previous studies have shown a high degree of specificity for self- between included and non-included participants, and therefore
reported CVD and stroke (60, 61). cannot exclude results were impacted by this selective subset.
Moreover, we measured four types of child maltreatment: Also, BRS and HRV were only assessed once. As these
emotional neglect, psychological abuse, physical abuse, and sexual measurements are highly dynamic within an individual (66),
abuse, which certainly does not cover the full spectrum of ACEs. the assessment could be more valuable after repeated
Furthermore, only the number of endorsed types of child measurements. Moreover, HRV and BRS were only assessed in

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Bakema et al. Association Between ACEs and aCVO

resting conditions. We can therefore not exclude that associations AUTHOR CONTRIBUTIONS
between child maltreatment and the sympathovagal balance
would be present under stressful conditions, such as in the MB, MZ, and AL contributed to the conception and design of the
study by Winzeler et al. (24). current study. MS and DC organized the database. MB and MZ
performed the statistical analysis. MB wrote the first draft of the
manuscript. MZ and AL wrote sections of the manuscript. All
Conclusion, Implications, and Future authors contributed to manuscript revision, and read and
Directions approved the submitted version.
The use of this large, population urban population representative
sample provides insight into the long-term correlates of child
maltreatment. A positive association was established between FUNDING
cumulative ACEs in the form of child maltreatment and risk on
aCVO, over and above the effect of relevant demographic, health, The Amsterdam UMC, location Academic Medical Center (AMC)
and psychological factors. The association between child of Amsterdam and the Public Health Service of Amsterdam (GGD
maltreatment and autonomic regulation indices was no longer Amsterdam) provided core financial support for HELIUS. The
present after correcting for sociodemographic factors. The HELIUS study is also funded by research grants of the Dutch
quality of research on this topic will be strengthened with Heart Foundation (Hartstichting; grant no. 2010T084), the
prospective longitudinal studies starting in early age and Netherlands Organization for Health Research and
continuing into old age, more expansive measurement of child Development (ZonMw; grant no. 200500003), the European
maltreatment, and other ACE types as well as potential resiliency Integration Fund (EIF; grant no. 2013EIF013) and the European
factors and direct and objective assessments of CVD events and Union (Seventh Framework Programme, FP-7; grant no. 278901).
assessment of dynamic autonomic regulation.

ACKNOWLEDGMENTS
DATA AVAILABILITY STATEMENT
We gratefully acknowledge the participants of the HELIUS study
The datasets generated for this study are available on request to and the management team, research nurses, interviewers,
the corresponding author. research assistants, and other staff who have taken part in
gathering the data of this study.

ETHICS STATEMENT
SUPPLEMENTARY MATERIAL
The HELIUS study has been approved by the Ethical Review
Board of the Academic Medical Center Amsterdam. The The Supplementary Material for this article can be found online
patients/participants provided their written informed consent at: https://www.frontiersin.org/articles/10.3389/fpsyt.2020.
to participate in this study. 00069/full#supplementary-material

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Int J Environ Res Public Health (2015) 12:15860–74. doi: 10.3390/
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