Atherosclerosis 383 (2023) 117330

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Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Association of physical activity with endothelial dysfunction among adults

with and without chronic kidney disease: The Maastricht Study
Ioannis Bellos a, b, *, Smaragdi Marinaki b, Pagona Lagiou a, Ioannis N. Boletis b,
Coen D.A. Stehouwer c, d, Marleen M.J. van Greevenbroek f, g, Simone J.P.M. Eussen c, i, g,
Bastiaan E. de Galan e, f, g, Hans H.C.M. Savelberg h, Annemarie Koster g, h, Anke Wesselius i, j, 1,
Vassiliki Benetou a, 1
a
Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Greece
b
Department of Nephrology and Renal Transplantation, Laiko General Hospital, National and Kapodistrian University of Athens, Greece
c
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, 6229ER, Netherlands
d
Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, 6229HX, Netherlands
e
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands
f
Department of Human Biology and Movement Science, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical
Centre+, PO Box 616, 6200, MD, Maastricht, the Netherlands
g
CAPRHI Care and Public Health Research Institute, Maastricht University, Netherlands
h
Department of Social Medicine, Maastricht University, Netherlands
i
Department of Epidemiology, Maastricht University, Maastricht, 6229ER, Netherlands
j
School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229ER, Netherlands

A R T I C L E I N F O A B S T R A C T

Keywords: Background and aims: Physical activity (PA) constitutes an established protective factor while sedentary behavior
Physical activity (SB) an emerging independent risk factor for cardiovascular diseases. This study evaluated the association of PA
Sedentary and SB with endothelial dysfunction (ED) depending on kidney function status.
Chronic kidney disease
Methods: Cross-sectional data from the prospective, population-based Maastricht Study were used. PA and SB
Endothelial dysfunction
were measured using the ActivPAL3 accelerometer 24h/day for eight consecutive days. ED was evaluated by
plasma levels of soluble vascular cell adhesion protein-1, intercellular adhesion molecule-1, E-selectin and von
Willebrand factor, which were combined into an ED score with higher values depicting higher ED.
Results: Overall, 2,668 participants, 323 with chronic kidney disease, were included. In normal kidney function
individuals, the ED score presented a significant negative association with total, lower-intensity and moderate-to-
vigorous PA duration and a positive association with total sedentary time, sedentary breaks and sedentary bout
duration. In participants with chronic kidney disease, a significant negative association of ED score with total [β:
-4.42, 95% confidence intervals (95% CI): -7.98; − 0.87] and lower-intensity (β: -7.08, 95% CI: -13.41; − 0.74) PA
duration, as well as a positive association of ED score with sedentary bout duration (β: 43.72, 95% CI: 9.85;
77.59) were noted. The strength of associations did not significantly differ across kidney function subgroups (p >
0.05).
Conclusions: This analysis showed that PA duration is inversely associated with ED both among patients with
normal kidney function and chronic kidney disease. In chronic kidney disease, longer sedentary bouts were
associated with greater endothelial dysfunction.

1. Introduction characterized by progressive and non-reversible changes in kidney

structure and function. Its prevalence is estimated to range from 7 to
Chronic kidney disease represents a rising global health concern, 12%, showing a steady increase due to the aging of the population and

* Corresponding author. 75, Mikras Asias str., 11527, Athens, Greece.

E-mail address: bellosg@windowslive.com (I. Bellos).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.atherosclerosis.2023.117330
Received 13 May 2023; Received in revised form 10 September 2023; Accepted 3 October 2023
Available online 5 October 2023
0021-9150/© 2023 Elsevier B.V. All rights reserved.
I. Bellos et al.
the growing incidence of important risk factors, especially hypertension
and type 2 diabetes mellitus [1]. Among chronic kidney disease patients,
cardiovascular disease constitutes a major source of morbidity and
mortality, since the risk of major adverse cardiac event occurrence in­
creases linearly as glomerular filtration rate declines and exceeds the
probability of reaching the stage of kidney failure requiring renal
replacement therapy [2]. Apart from the effects of the traditional car­
diovascular risk factors, a combination of several non-traditional fac­
tors, such as vascular calcification, inflammation and metabolic
acidosis, contributes to the progression of atherosclerotic disease among
chronic kidney disease patients [3].
The endothelium plays a central role in the pathophysiology of
atherogenesis since endothelial dysfunction promotes the upregulation
of adhesion molecules, the increase of chemokine secretion and cell
permeability, as well as platelet activation, low-density lipoprotein
oxidation and vascular smooth muscle cell migration [4]. Therefore,
endothelial dysfunction has been proposed as a surrogate marker of
cardiovascular disease, while it can be used to predict coronary artery
disease and major cardiovascular events [5,6]. More specifically,
inflammation and oxidized low-density lipoprotein trigger the
up-regulation of intercellular adhesion molecule-1 (ICAM-1) and
vascular cell adhesion protein-1 (VCAM-1), in order to enable the
adhesion of leukocytes to the endothelium; hence, the concentration of
their soluble forms have been shown to be predictive of cardiovascular
events, such as acute coronary syndromes and arrhythmias [7,8].
Moreover, E-selectin is a specific marker of endothelial activation and its
circulating levels have been proposed to reflect early stages of the
atherosclerosis process [9,10]. Interestingly, the hepatic expression of
E-selectin, as well as its plasma levels have been associated with markers
of non-alcoholic fatty liver disease [11]. In this context, soluble
E-selectin has been shown to be linked to intrahepatic lipid content,
suggesting the potential role of liver sinusoidal endothelial cells in the
pathogenetic process of non-alcoholic fatty liver disease [12]. Von
Willebrand factor (vWF) is excreted from endothelial Weibel–Palade
bodies in response to cellular injury, serving as a ligand for platelet
glycoproteins, while its plasma levels have been proposed as predictive
of cerebrovascular accidents and ischemic heart disease [13].
Physical activity represents a major cardiovascular disease protec­
tive factor, presenting a dose-response relationship with reduced risk of
cardiovascular events [14]. Its preventive effects rely, among others, on
its beneficial impact on blood lipids, insulin sensitivity, fatty acid oxi­
dization and nitric oxide availability [15]. Limited physical activity is
common among chronic kidney disease patients [16], although exercise
has been shown to reduce inflammation [17], as well as to improve
physical function and quality of life in this population [18]. However, its
exact effects on endothelial function remain less clear.
Growing evidence has emerged indicating that sedentary behavior
may constitute a novel independent risk factor for cardiovascular dis­
ease [19]. Specifically, greater sedentary time has been associated with
significantly increased risk of diabetes mellitus, as well as with higher
cardiovascular disease incidence and mortality [20]. A dose-response
meta-analysis has demonstrated that total sitting time is associated
with greater cardiovascular disease mortality even after adjusting for
physical activity, especially when exceeding a threshold of 6–8 h per day
[21]. In addition to greater total sedentary time, findings of the Objec­
tive Physical Activity and Cardiovascular Health (OPACH) study have
pointed towards a significant link of cardiovascular risk not only with
greater total sedentary time but also with longer sedentary bouts [22]. It
has been assumed that a highly sedentary state may reduce insulin
sensitivity, promote inflammation and affect muscle cell gene expres­
sion through blood flow changes [23]; nonetheless, its exact impact on
vascular health remains to be elucidated.
The present study aims to shed more light on the association of
physical activity and sedentary behavior with markers of endothelial
dysfunction among individuals with and without chronic kidney disease,
taking advantage of objective physical activity measurement tools, such
2
Atherosclerosis 383 (2023) 117330
as accelerometry data, elucidating further whether physical activity and
sedentary behavior exert differential effects on the cardiovascular health
of individuals with and without kidney impairment.
2. Patients and methods
2.1. Study population and design
Cross-sectional data were used from the Maastricht Study, which is a
prospective, population-based, cohort study, conducted in the southern
part of the Netherlands. The full methodology has been previously
described in detail [24]. Briefly, the rationale of the Maastricht Study
focuses on the etiology, pathogenesis and complication of type 2 dia­
betes mellitus, following an extensive phenotyping approach. In­
dividuals aged between 40 and 75 years were potentially eligible.
Recruitment, which was stratified according to known type 2 diabetes
mellitus status, with an oversampling of individuals with type 2 diabetes
mellitus, was performed via mass media campaigns, as well as from
municipal registries and the regional Diabetes Patient Registry via
mailings. The present report is based on participants with available
kidney function, physical activity and endothelial dysfunction data, who
completed the baseline survey between November 2010 and September
2013. All participants were fully informed about the study procedures
and provided written informed consent. The study procedures were
ethically approved by the institutional medical ethical committee
(NL31329.068.10) and the Netherlands Health Council (Permit
131088-105234-PG).
2.2. Physical activity and sedentary behavior
Daily physical activity and sedentary behavior were measured with
the ActivPAL3™ physical activity monitor (PAL Technologies, Glasgow,
UK), a small (53 x 35 × 7 mm) and light-weight triaxial accelerometer,
as described in more detail elsewhere [25]. Acceleration data were
exploited to capture movements in the vertical, anteroposterior and
mediolateral axes and to recognize posture as sitting/lying, standing or
stepping. Specifically, the device was firstly rendered waterproof using a
nitrile sleeve and then it was attached to the front right thigh and
secured with a transparent 3 M Tegaderm™ tape. Individuals wore the
monitor for eight days consecutively and were asked not to remove it at
any time. The accelerometer was not replaced in case of removal. Data
from the first wear day were excluded. Similarly, data from the final day
providing less than 14 h of measurement were also not used in the
analysis. Measurements were considered valid if they provided more
than 10 h of out-of-bed data. The ActivPAL3™ software was used for
data uploading and processing was performed using customized soft­
ware built in MATLAB® R2013b (MathWorks. Natick, MA, USA) [26].
Daily total physical activity was calculated as the mean time (in
minutes) spent stepping during waking time. Lower-intensity physical
activity was defined as the time spent standing or stepping with a fre­
quency below 100 steps/minute, while moderate-to-vigorous intensity
physical activity time referred to the walking time with a stepping fre­
quency over 100 steps/minute.
The daily amount of sedentary time was estimated as the time spent
in a sedentary position (sitting or lying) during waking time. Sedentary
brakes represented the transitions from the sitting/lying position to the
standing/stepping one with a minimum duration of 1 min, while pro­
longed sedentary bouts were defined as periods over 30 min in contin­
uous sedentary time. To identify the waking time of each individual, an
automated algorithm was applied, which takes into account the duration
and number of active and sedentary periods to recognize out-of-bed and
in-bed times. The algorithm has been validated, showing a high degree
of agreement with self-report [26].
I. Bellos et al.
2.3. Endothelial dysfunction
Endothelial dysfunction was evaluated by the plasma levels of the
following biomarkers: soluble VCAM-1 (sVCAM-1), soluble ICAM-1
(sICAM-1), soluble E-selectin (sE-selectin) and vWF. The concentration
of sVCAM-1, sICAM-1 and sE-selectin was measured in EDTA plasma
samples using 4-plex sandwich immunoassay kits (Meso Scale Discov­
ery, Rockville, MD, US). The lower limit of detection was 6, 1.94 and 45
pg/ml for sVCAM, sICAM sE-selectin, respectively. The intra- and inter-
assay coefficients of variation were 10.3 and 8.4% for sICAM-1, 5.0 and
4.7% for sVCAM-1 and 2.9 and 7.4% for sE-selectin. Biomarker data
from multi-array Meso Scale Discovery platforms have been shown to be
comparable to single-biomarker methods after proper re-alignment of
absolute concentrations, presenting equal associations with cardiovas­
cular risk factors [27]. For the measurement of vWF levels, citrated
samples were collected and analyzed with sandwich ELISA (Dako,
Glostrup, Denmark), expressing vWF concentration as a percentage of
vWF measured in pooled citrated plasma of healthy volunteers. The
intra- and inter-assay coefficients of variation for vWF were 3.0 and
4.3%, respectively. To combine all endothelial dysfunction biomarkers
in one measure, a composite endothelial dysfunction score was devel­
oped by combining the four biomarkers, with higher values of the
composite score indicating a greater degree of endothelial dysfunction
[28].
2.4. Kidney function
The estimated glomerular filtration rate was determined using the
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equa­
tion, which is based on the combination of serum creatinine and serum
cystatin-C values (eGFRCr-Cys) [29]. In case cystatin-C measurements
were not available, the creatinine-based CKD-EPI equation was imple­
mented [30]. Urinary albumin excretion was quantified by two 24-h
urine collections. Valid collections were considered those with collec­
tion times between 20 and 28 h. Extrapolation to the 24-h excretion was
performed in case the collection time was not exactly 24 h. Chronic
kidney disease was defined as an estimated glomerular filtration rate
<60 ml/min/1.73 m2 and/or as the presence of albuminuria, defined as
urinary albumin excretion ≥30 mg/24 h. Staging was performed
following the KDIGO (Kidney Disease Improving Global Outcomes)
2012 criteria [31].
2.5. Covariates
Questionnaires were used to collect self-reported information about
sex, age, ethnicity, educational level, total alcohol consumption (g/day)
and smoking habits. Diabetes status was evaluated by performing a 7-
point 75 gr oral glucose tolerance test, classifying glucose metabolism
as normal, prediabetes or type 2 diabetes following the World Health
Organization 2006 criteria [32]. Participants without type 1 diabetes
using anti-diabetic medications were classified as having type 2 dia­
betes. Body mass index (BMI) was calculated by dividing weight by the
square of height in meters. A validated food frequency questionnaire
was used to capture daily dietary habits and energy intake [33], while
the Dutch Health Diet index (without the alcohol component) was
estimated to assess the degree of adherence to the Dutch Guidelines for a
Healthy Diet [34]. The 36-Item Short Form Health Survey questionnaire
[35] was used to extract data regarding mobility limitation, defining it
as any difficulty in climbing one flight of stairs or walking 500 m. The
lipid profile of participants was determined by collecting fasting blood
samples. The measurement of office blood pressure was performed on
the right arm, three times following a 10-min rest in a sitting position
and the average blood pressure values were recorded. Hypertension was
defined by the presence of one of the following: average systolic blood
pressure ≥140 mmHg, average diastolic blood pressure ≥90 mmHg or
the use of anti-hypertensive medications.
3
Atherosclerosis 383 (2023) 117330
2.6. Statistical analysis
Statistical analysis was conducted in R-4.0.5. The distribution of
continuous variables was evaluated by the visual inspection of histo­
grams. For the presentation of baseline characteristics, continuous data
were described by their median and 25th – 75th percentiles, using the
Kruskal-Wallis test for comparisons. Categorical variables were pre­
sented as proportions and were statistically compared with the chi-
square test or the Fischer’s exact test when the assumptions of the
former were not satisfied.
For the calculation of the composite endothelial dysfunction score, Z-
scores were calculated for each marker as follows: (individual value-
population mean value)/(population standard deviation). Then, the
composite endothelial dysfunction score was estimated as (Z-score
sVCAM-1+ Z-score sICAM-1 + Z-score sE-Selectin + Z-score vWF)/4
[28]. Linear regression analysis was performed to evaluate the associ­
ation of physical activity and sedentary behavior with the composite
endothelial dysfunction Z-score and with individual markers (sVCAM-1,
sICAM-1, sE-Selectin, vWF).
Multivariable models were constructed, including potential con­
founders. All covariates were pre-specified in the study protocol based
on factors assumed to be associated with physical activity and endo­
thelial dysfunction. Specifically, model 1 included the basic de­
mographic data (i.e., sex, age and educational level and ethnicity), as
well as the presence of diabetes mellitus status to account for over­
sampling. Subsequently, model 2 also included important covariates
that could impact physical activity, such as body mass index, smoking
and mobility limitation. Model 3 additionally included alcohol con­
sumption and the Dutch Healthy Diet score. A directed acyclic graph was
constructed to schematically depict confounding paths and possible
causal effects (Supplementary Fig. 1). For the regression analyses, mean
endothelial dysfunction scores were multiplied by 1000. Stratified an­
alyses were conducted based on the presence of chronic kidney disease
and the potential interactions were statistically tested. Additionally, the
possible interactions with sex and diabetes mellitus status were also
tested. Subgroup analysis was performed, depending on whether
chronic kidney disease was defined by criteria of kidney function (eGFR
<60 ml/min/m2) or albuminuria (urinary albumin excretion ≥30 mg/
24h). Sensitivity analyses were conducted to test the robustness of
outcomes in patients without hypertension and those without dyslipi­
demia requiring lipid-modifying medications. Statistical significance
was defined by a two-sided p ≤ 0.05.
Compositional data analysis (CoDA) was also performed to evaluate
the association between the movement composition (physical activity)
and its components with endothelial dysfunction. CoDA is useful for
data (i.e., movement behavior) that sum up to a certain whole (i.e., wake
time), considering the effects of codependence and allocation of time
from one behavior to another one. The isometric log-ratio data trans­
formation was applied, adjusting the models for the time spent in other
movement behaviors [36]. Geometric means for the time destined to
each behavior were estimated, adding collectively to 100% of wake time
[37]. The endpoint was the mean endothelial dysfunction score, while
all models adjusted for all the aforementioned covariates. CoDA was
performed using the R packages compositions [38] and robcompositions
[39].
3. Results
3.1. Study population
The process of participant selection is schematically depicted in
Fig. 1. A total of 5,021 individuals were excluded due to missing in­
formation regarding physical activity (n = 1,232), kidney function (n =
58), baseline covariates (n = 477) and endothelial dysfunction bio­
markers (n = 3,254). As a result, 2,668 participants were included in the
analysis, of whom, 323 fulfilled the diagnostic criteria of chronic kidney
I. Bellos et al.
Fig. 1. Flowchart of participant inclusion.
disease and 2,345 presented normal kidney function. The demographic
and clinical characteristics of included and excluded individuals are
compared in Supplementary Table 1.
Table 1 presents the general characteristics of participants, stratified
by total physical activity tertiles. The median age of participants was 61
years and 51.2% of them were males. In addition, eGFR below 60 ml/
min/1.73 m2 was observed in 127 individuals and urinary albumin
excretion over 30 mg/24 h in 241 individuals. Specifically, 78 in­
dividuals had stage 1, 118 had stage 2, 125 had stage 3 and 2 had stage 4
chronic kidney disease. In addition, 219 participants presented micro­
albuminuria and 22 had 24-h albumin excretion over 300 mg/24 h.
Participants with a higher degree of total physical activity were younger,
had a slight female predominance, reported healthier behaviors in terms
of nutrition, smoking and alcohol consumption, presenting favorable
lipid profiles and lower rates of obesity, hypertension and diabetes
mellitus. Chronic kidney disease individuals presented significantly
higher plasma sVCAM-1 (454.4 vs. 412.3 ng/ml, p < 0.001), sICAM-1
(367.8 vs. 334.4 ng/ml, p < 0.001), sE-selectin (126.77 vs. 104.23 ng/
ml, p < 0.001), vWF (150.52 vs. 123.04%, p < 0.001) and endothelial
dysfunction score (3.21 vs. 2.63, p < 0.001).
3.2. Physical activity and endothelial dysfunction
The relationship between physical activity duration (total, lower-
intensity, moderate-to-vigorous physical activity) and each of the
endothelial dysfunction biomarker as well as with the endothelial
dysfunction score among participants with normal kidney function and
among participants with chronic kidney disease is presented in Table 2.
Details about the results of the 3 regression models are provided in
Supplementary Table 2. After adjustment for clinicodemographic
covariates, higher total physical activity was associated with a signifi­
cantly lower endothelial dysfunction score both among participants
4
Atherosclerosis 383 (2023) 117330
with normal (model 3, β: -2.68, 95% confidence intervals: -4.07 to
− 1.30) and impaired (model 3, β: -4.42, 95% CI: -7.98 to − 0.87) kidney
function; hence, no significant interaction with chronic kidney disease
was noted (pinteraction: 0.359) (Fig. 2). In particular, in individuals with
normal kidney function, total physical activity was negatively associated
with sVCAM-1, sICAM-1, sE-selectin and vWF in all models. Among
those with chronic kidney disease, this association was observed for
sVCAM-1, sICAM-1 and vWF, while significance was lost for sE-selectin
in the fully-adjusted models. No significant interaction with chronic
kidney disease was detected in any of the models with individual
biomarkers.
A greater duration of lower-intensity physical activity was associated
with a significantly lower endothelial dysfunction score in participants
with (model 3, β: -7.08, 95% CI: -13.41 to − 0.74) and without (model 3,
β: -4.10, 95% CI: -6.57 to − 1.63) chronic kidney disease (pinteraction:
0.387). Specifically, after covariate adjustment, lower-intensity physical
activity was significantly associated with sVCAM-1, sICAM-1 and vWF in
normal kidney function participants, as well as with sVCAM-1 and
sICAM-1 in those with chronic kidney disease. No significant interaction
with kidney function was observed in any lower-intensity physical ac­
tivity statistical model.
In fully-adjusted models, moderate-to-vigorous physical activity was
associated with a significantly lower endothelial dysfunction score in
normal kidney function individuals (β: -3.28, 95% CI: -5.43 to − 1.13)
but not in those with chronic kidney disease (β: -5.63, 95% CI: -11.49 to
0.23); however, no significant interaction was noted (p-value: 0.449).
Among those without chronic kidney disease, moderate-to-vigorous
physical activity showed a significant association with sVCAM-1,
sICAM-1 and vWF, while among participants with kidney dysfunction,
moderate-to-vigorous physical activity was negatively associated with
sICAM and vWF. In patients with chronic kidney disease, moderate-to-
vigorous physical activity was linked to significantly lower levels of
I. Bellos et al. Atherosclerosis 383 (2023) 117330

Table 1
Clinicodemographic, accelerometry and endothelial function patients’ characteristics.
Variable Overall (n = 2,668) Total physical activity p

1st tertile (n = 890) 2nd tertile (n = 888) 3rd tertile (n = 890)

Age (years) 61 [55–66] 63 [56–68] 61 [55–66.25] 60 [54.25–65] <0.001

Male sex 1,366 (51.2%) 526 (59.1%) 393 (44.3%) 447 (50.2%) <0.001
Caucasian ethnicity 2,637 (98.8%) 876 (98.4%) 881 (99.2%) 880 (98.9%) 0.301
Educational level
Low 911 (34.1%) 353 (39.7%) 283 (31.9%) 275 (30.9%) <0.001
Medium 727 (27.2%) 229 (25.7%) 262 (29.5%) 236 (26.5%)
High 1,030 (38.6%) 308 (34.6%) 343 (38.9%) 379 (42.6%)
Alcohol consumption (g/day) 8.70 [1.65–18.94] 7.08 [0.84–17.06] 8.69 [1.85–18.69] 9.96 [2.85–19.64] <0.001
Smoking status
Former 1,389 (52.1%) 475 (53.4%) 464 (52.3%) 450 (50.6%) <0.001
Current 337 (12.6%) 167 (18.8%) 100 (11.3%) 70 (7.9%)
Lifetime smoking (packyears) 2.1 [0–18] 7.65 [0–25.27] 1.5 [0–16] 0.2 [0–12.25] <0.001
BMI (kg/m2) 26.3 [23.9–29.4] 27.9 [24.9–31.6] 26.2 [23.7–28.8] 25.3 [23.2–27.8] <0.001
Waist circumference (cm) 94.6 [85.97–103.72] 100 [91.35–111] 93 [85–101.85] 91.25 [83.3–98.92] <0.001
Waist-to-hip ratio 0.9 [0.9–1] 1 [0.9–1] 0.9 [0.9–1] 0.9 [0.9–1] <0.001
Limited mobility 554 (20.8%) 290 (32.6%) 169 (19.0%) 95 (10.7%) <0.001
Energy intake (kcal/day) 2087.7 [1723–2510.4] 2029.7 [1663.3–2444.8] 2075.1 [1735.6–2458.8] 2175.3 [1780.6–2607.3] <0.001
Dutch Healthy Diet score 76.79 [66.97–86.36] 73.4 [63.37–82.82] 78.16 [68.11–87.67] 78.99 [70.10–88.33] <0.001
Office SBP (mmHg) 134 [122–146] 135 [123–149] 135 [123–146] 132 [121–144] <0.001
Hypertension 1556 (58.3%) 290 (32.6%) 169 (19.0%) 95 (10.7%) <0.001
Diabetes mellitus status
Prediabetes 401 (15.0%) 130 (14.6%) 146 (16.4%) 125 (14.0%) <0.001
Type 2 diabetes 756 (28.3%) 387 (43.5%) 204 (23.0%) 165 (18.5%)
Other diabetes 29 (1.1%) 13 (1.5%) 11 (1.2%) 3 (0.3%)
Serum LDL-C (mmol/l) 3 [2.3–3.7] 2.7 [2–3.6] 3 [2.4–3.8] 3.1 [2.5–3.7] <0.001
Serum HDL-C (mmol/l) 1.5 [1.2–1.8] 1.35 [1.10–1.70] 1.50 [1.20–1.80] 1.60 [1.30–2.0] <0.001
Serum triglycerides (mmol/l) 1.23 [0.9–1.72] 1.41 [1.03–1.98] 1.21 [0.87–1.69] 1.10 [0.83–1.48] <0.001
Use of lipid-modifying drugs 998 (37.4%) 447 (50.2%) 296 (33.3%) 255 (28.7%) <0.001
eGFR (ml/min/1.73 m2) 88.05 [77.94–97.80] 85.49 [73.47–94.88] 87.97 [79.01–97.38] 90.86 [81.07–99.73] <0.001
Albuminuria (mg/24h) 6.47 [3.85–12.27] 7.47 [4.23–16.52] 6.31 [3.79–11.06] 5.97 [3.76–10.50] <0.001
Chronic kidney disease 323 (12.1%) 163 (18.3%) 89 (10.0%) 71 (8.0%) <0.001
Accelerometry
Total physical activity (min/day) 116.7 [89.17–145.42] 78.41 [64.73–89.17] 116.7 [107.1–124.85] 158.1 [145.4–176.5] <0.001
Moderate-vigorous activity (min/day) 50.34 [34.7–68.73] 29.64 [20.75–38.59] 51.07 [42.88–60.06] 77.21 [63.65–92.42] <0.001
Lower-intensity activity (min/day) 62.94 [49.21–77.78] 45.4 [37.68–52.85] 64.13 [55.82–72.37] 83.42 [71.2–96.62] <0.001
Sedentary time (h/day) 9.40 [8.27–10.58] 10.63 [9.67–11.52] 9.30 [8.39–10.25] 8.38 [7.50–9.30] <0.001
Sedentary breaks (/day) 36.5 [31.43–42.17] 33.38 [29.14–38.29] 37.07 [32.14–42.86] 38.86 [33.71–42.28] <0.001
Average sedentary bout (min) 10.71 [8.78–13.22] 13.14 [10.83–15.66] 10.43 [8.75–12.37] 9.10 [7.55–10.92] <0.001
Sedentary bouts ≥30 min (/day) 4.86 [3.71–5.86] 13.14 [10.83–15.66] 10.43 [8.75–12.37] 9.10 [7.55–10.92] <0.001
Endothelial function
sVCAM (ng/ml) 415.8 [363.9–478.1] 437.2 [377.6–504.9] 412.5 [359.5–471.2] 405.2 [358.9–457.4] <0.001
sICAM (ng/ml) 338.4 [291.7–398.3] 357.1 [305.6–425.7] 336.5 [291.7–393.7] 323.5 [278–376.7] <0.001
sE-selectin (ng/ml) 106.6 [73.74–142.8] 117.4 [83.39–156.1] 106.7 [73.19–141.8] 98.56 [69.53–129.9] <0.001
vWF (%) 125.3 [99.29–158.7] 135.8 [107.4–172.6] 124 [98.88–153.7] 118.5 [93.9–151.3] <0.001

Continuous data are presented as median [interquartile range] and categorical data as number (column percentage).
The 1st tertile corresponds to the lowest level of total physical activity. BMI: body mass index; SBP: systolic blood pressure; LDL-C: low-density lipoprotein cholesterol;
HDL-C: high-density lipoprotein cholesterol; eGFR: estimated glomerular filtration rate; sVCAM: soluble vascular cell adhesion molecule-1; sICAM: soluble inter­
cellular adhesion molecule; vWF: von Willebrand factor.

sVCAM-1 in models 1 and 2, although the association marginally lost its
significance in the fully-adjusted model. No significant interactions with
chronic kidney disease were observed in any moderate-to-vigorous
physical activity model with individual endothelial dysfunction
markers.
3.3. Sedentary behavior and endothelial dysfunction
The association between sedentary behavior and endothelial
dysfunction biomarkers among participants with normal kidney func­
tion and participants with chronic kidney disease is described in Table 2,
while details about the full results of the 3 regression models are pro­
vided in Supplementary Table 3. In fully-adjusted models, total seden­
tary time was significantly associated with higher endothelial
dysfunction score only in individuals with normal kidney function (β:
55.25, 95% CI: 20.13 to 90.38) and not in those with chronic kidney
disease (β: 76.7, 95% CI: -6.43 to 159.89), although no significant
interaction with chronic kidney disease was observed (p-value: 0.634). In
particular, among participants with normal renal function, more daily
sedentary time was linked to significantly higher sVCAM-1, sICAM and
vWF, while no significant associations were noted among those with
impaired kidney function after taking into account all covariates. The
number of daily sedentary breaks was negatively associated with the
mean endothelial dysfunction score in individuals with normal kidney
function (β: -6.79, 95% CI: -13.23 to − 0.35), but not among chronic
kidney disease patients (β: -4.38, 95% CI: -21.91 to 13.15) (pinteraction:
0.799). More sedentary breaks were associated with lower vWF levels
both in individuals with (β: -0.75, 95% CI: -1.36 to − 0.14) and without
(β: -0.54, 95% CI: -0.77 to − 0.32) renal dysfunction. No significant
interaction with chronic kidney disease was noted in any model of
sedentary breaks.
After adjusting for covariates, greater average sedentary bout dura­
tion was associated with significantly higher mean endothelial
dysfunction score in participants with (β: 23.13, 95% CI: 6.65 to 39.61)
and without (β: 43.72, 95% CI: 9.85 to 77.59) chronic kidney disease
(pinteraction: 0.274). This association was observed especially for sVCAM-
1 and vWF but not for sICAM and sE-selectin levels. The number of daily
prolonged sedentary bouts was associated with significantly higher

5
I. Bellos et al. Atherosclerosis 383 (2023) 117330

Table 2
Multivariable linear regression analysis of the relationship between physical activity, sedentary behavior and endothelial function markers among participants with
normal and chronic kidney disease.
Total physical Lower-intensity Moderate-to-vigorous Sedentary time Sedentary breaks Average sedentary Sedentary bouts
activity physical activity physical activity bout duration ≥30 min

Soluble vascular cell adhesion molecule-1

Normal kidney − 0.19 (− 0.29; − 0.30 (− 0.47; − 0.24 (− 0.39; − 0.08) 3.98 (1.45; 6.52) − 0.49 (− 0.95; 1.67 (0.48; 2.86) 4.39 (1.71; 7.06)
function − 0.09) − 0.12) − 0.03)
Chronic kidney − 0.32 (− 0.58; − 0.51 (− 0.97; − 0.41 (− 0.83; 0.02) 5.53 (− 0.46; − 0.32 (− 1.58; 3.15 (0.71; 5.59) 4.75 (− 1.35;
disease − 0.06) − 0.05) 11.53) 0.95) 10.85)
p for interaction 0.359 0.387 0.449 0.634 0.799 0.274 0.913
Soluble intercellular adhesion molecule-1
Normal kidney − 0.18 (− 0.27; − 0.21 (− 0.39; − 0.26 (− 0.41; − 0.11) 3.72 (1.26; 6.18) − 0.05 (− 0.50; 0.44 (− 0.72; 1.59) 2.16 (− 0.45;
function − 0.08) − 0.04) 0.40) 4.76)
Chronic kidney − 0.27 (− 0.52; − 0.35 (− 0.79; 0.10) − 0.43 (− 0.84; − 0.02) 2.23 (− 3.60; 0.02 (− 1.21; 0.51 (− 1.87; 2.89) − 0.67 (− 6.61;
disease − 0.02) 8.06) 1.25) 5.26)
p for interaction 0.475 0.578 0.450 0.638 0.923 0.957 0.384
E-selectin
Normal kidney − 0.07 (− 0.14; − 0.10 (− 0.22; 0.01) 0.10 (− 0.20; 0.00) 1.33 (− 0.34; 0.21 (− 0.09; − 0.21 (− 0.99; 0.57) − 0.01 (− 1.77;
function − 0.01) 2.99 0.52) 1.75)
Chronic kidney − 0.15 (− 0.32; − 0.17 (− 0.47; 0.13) − 0.26 (− 0.54; 0.02) − 1.04 (− 4.98; 0.18 (− 0.65; − 0.95 (− 2.55; 0.66) − 4.22 (− 8.22;
disease 0.02) 2.99) 1.00) − 0.23)
p for interaction 0.380 0.682 0.267 0.268 0.935 0.411 0.055
von Willebrand factor
Normal kidney − 0.09 (− 0.13; − 0.14 (− 0.22; − 0.10 (− 0.18; − 0.03) 1.25 (0.02; 2.47) − 0.54 (− 0.77; 1.50 (0.92; 2.07) 1.79 (0.49; 3.09)
function − 0.04) − 0.05) − 0.32)
Chronic kidney − 0.18 (− 0.30; − 0.29 (− 0.51; − 0.23 (− 0.43; − 0.03) 1.38 (− 1.53; − 0.75 (− 1.36; 1.58 (0.40; 2.76) 3.19 (0.23; 6.14)
disease − 0.06) − 0.07) 4.28) − 0.14)
p for interaction 0.159 0.210 0.231 0.934 0.536 0.895 0.388
Endothelial dysfunction score ( × 103)
Normal kidney − 2.68 (− 4.07; − 4.10 (− 6.57; − 3.28 (− 5.43; − 1.13) 55.25 (20.13; − 6.79 (− 13.23; 23.13 (6.65; 39.61) 60.85 (23.72;
function − 1.30) − 1.63) 90.38) − 0.35) 97.98)
Chronic kidney − 4.42 (− 7.98; − 7.08 (− 13.41; − 5.63 (− 11.49; 0.23) 76.73 (− 6.43; − 4.38 (− 21.91; 43.72 (9.85; 77.59) 65.92 (− 18.67;
disease − 0.87) − 0.74) 159.89) 13.15) 150.5)
p for interaction 0.359 0.387 0.449 0.634 0.799 0.274 0.913

Data presented as β coefficient (95% confidence intervals). Bold text indicates statistical significance.Models adjusts for age, sex, ethnicity, educational levels, diabetes
mellitus, body mass index, smoking, mobility limitation, alcohol consumption and Dutch Healthy Diet score.

Fig. 2. Association of total physical activity and sedentary behavior with the composite endothelial dysfunction score in participants with and without chronic
kidney disease.
No significant heterogeneity was observed across the two subgroups.

endothelial dysfunction scores among individuals with normal kidney
function (β: 60.85, 95% CI: 23.72 to 97.980), but not among those with
renal impairment (β: 65.92, 95% CI: -18.67 to 150.5) (pinteraction: 0.913).
In particular, in participants without kidney dysfunction, prolonged
sedentary bouts were linked to significantly higher sVCAM-1 and vWF,
while among chronic kidney disease patients prolonged sedentary bouts
were associated with significantly higher sE-selectin and vWF. No sig­
nificant interaction with chronic kidney disease was noted in any
sedentary bout model.
3.4. Compositional data analysis
The ternary plots of compositional data analysis in individuals with
and without chronic kidney disease are illustrated in Fig. 3. In patients
with chronic kidney disease, the normalized geometric means for the
total of wake time showed that an average of 31% of the wake time is
spent in lower-intensity physical activity, 4% in moderate-to-vigorous
physical activity, and 65% in sedentary behavior. The time spent in
sedentary behavior relative to other movement behaviors was associ­
ated with significantly higher mean endothelial dysfunction score (β:

6
I. Bellos et al.
Fig. 3. Ternary plots illustrating endothelial dysfunction score as a function of movement behavior components in patients with and without chronic kidney disease.
SB: sedentary behavior; LIPA: lower-intensity physical activity; MVPA: moderate-to-vigorous physical activity.
0.61, 95% CI: 0.17 to 1.05). The relative time spent in moderate-to-
vigorous physical activity was associated with significantly reduced
mean endothelial dysfunction score (β: -0.54, 95% CI: -0.91 to − 0.17). In
addition, the time spent in lower-intensity physical activity relative to
that spent in moderate-to-vigorous physical activity was linked to higher
mean endothelial dysfunction score (β: 0.54, 95% CI: 0.10 to 0.99).
Among participants without chronic kidney disease, the normalized
geometric means for the total of wake time demonstrated that an
average of 35% of the wake time is spent in lower-intensity physical
activity, 5% in moderate-to-vigorous physical activity, and 60% in
sedentary behavior. The relative time spent in sedentary behavior was
associated with higher mean endothelial dysfunction score (β: 0.31, 95%
CI: 0.17 to 0.45). The time spent in moderate-to-vigorous physical ac­
tivity relative to other movement behaviors was linked to significantly
lower endothelial dysfunction score values (β: -0.26, 95% CI: -0.38 to
− 0.13). The time spent in lower-intensity physical activity relative to
that spent in moderate-to-vigorous physical activity was associated
greater higher mean endothelial dysfunction score (β: 0.21, 95% CI: 0.06
to 0.35).
3.5. Subgroup analysis
The results of the subgroup analysis are presented in Supplementary
Table 4. The association of endothelial dysfunction score with physical
activity and sedentary behavior did not vary by chronic kidney status,
independently by whether it was defined by eGFR or albuminuria
criteria (pinteraction >0.05). Among participants with eGFR <60 ml/min/
1.73 m2, endothelial dysfunction score showed a significant association
with total and moderate-to-vigorous physical activity. Among those
with urinary albumin excretion ≥30 mg/24h, a significant association
was noted between endothelial dysfunction score on one hand and total
physical activity, lower-intensity physical activity, sedentary time,
average sedentary bout duration and prolonged sedentary bouts on the
other hand. Additionally, total physical activity and moderate-to-
vigorous physical activity presented a stronger association with sE-
selectin levels among individuals with urinary albumin excretion >30
mg/24h, compared to those without albuminuria (pinteraction: 0.039 and
0.035, respectively). No significant interactions were noted in the
models of sVCAM-1, sICAM-1 and vWF.
3.6. Sensitivity analysis
The outcomes of the sensitivity analyses are exhibited in Supple­
mentary Table 5. Among normotensive participants, no significant
interaction of chronic kidney disease was observed in any statistical
model of physical activity or sedentary behavior. On the other hand,
when participants without a history of dyslipidemia were separately
7
Atherosclerosis 383 (2023) 117330
examined, average sedentary bout duration presented a stronger asso­
ciation with endothelial dysfunction score in chronic kidney disease
patients compared to those with normal kidney function (pinteraction:
0.023). A similar effect was noted when the association of sedentary
bout duration with sVCAM-1 (pinteraction: 0.023) and sICAM (pinteraction
<0.001) was investigated. In addition, a stronger association in partic­
ipants with chronic kidney disease was observed between sICAM and
total physical activity (pinteraction: 0.014), lower-intensity physical ac­
tivity (pinteraction: 0.018) and sedentary time (pinteraction: 0.002)
compared to associations observed among those with normal kidney
function.
3.7. Additional analyses
The results of analyses stratified by diabetes mellitus status are
shown in Supplementary Table 6. The association of endothelial
dysfunction score with total, lower-intensity and moderate-to-vigorous
physical activity, as well as sedentary time, sedentary bout duration
and prolonged sedentary bouts was statistically significant in partici­
pants with prediabetes and type 2 diabetes mellitus and was signifi­
cantly stronger compared to those with normal glucose metabolism
(pinteraction <0.05, Supplementary Table 7). The analysis stratified by sex
is exhibited in Supplementary Table 8. Among males, endothelial
dysfunction score showed an inverse association with total, lower-
intensity and moderate-to-vigorous physical activity and a positive
one with sedentary time, average sedentary bout duration and pro­
longed sedentary bouts, while among female participants, endothelial
dysfunction score was significantly associated with sedentary time and
prolonged sedentary bouts. No significant interactions with sex were
noted in the association of endothelial dysfunction score with physical
activity or sedentary behavior parameters (pinteraction >0.05).
4. Discussion
4.1. Summary of findings
The present cross-sectional, population-based study evaluated the
associations of physical activity and sedentary behavior with biomarkers
of endothelial dysfunction among participants with and without chronic
kidney disease. Among individuals without evidence of kidney
dysfunction, total, lower-intensity and moderate-to-vigorous physical
activity were inversely associated with endothelial dysfunction. Simi­
larly, greater sedentary time and prolonged sedentary bouts were posi­
tively associated with endothelial dysfunction markers. Overall, chronic
kidney disease did not modify the association of physical activity and
sedentary behavior with endothelial dysfunction. For participants with
chronic kidney disease, a significant association with endothelial
I. Bellos et al. Atherosclerosis 383 (2023) 117330

dysfunction could be ascertained for average sedentary bout duration, beneficial effects, improving cardiometabolic health and physical
total and lower-intensity physical activity (Fig. 4). The association of function status [50]. In particular, aerobic exercise programs have been
endothelial dysfunction with physical activity and sedentary behavior shown to prevent obesity, ameliorate blood pressure and increase ex­
was significantly stronger among participants with prediabetes and type ercise capacity [51]. On the other hand, conflicting outcomes have been
2 diabetes mellitus than in those with normal glucose metabolism, derived regarding the effects of exercise interventions on endothelial
confirming the findings of previous research in the field [40]. function. Specifically, a systematic review based on a small number of
studies has suggested that exercise is not significantly linked to sono­
graphic markers of endothelial function in chronic kidney disease pa­
4.2. Relevance to existing literature
tients [52]. Nonetheless, a recent study of stage 3–4 chronic kidney
disease individuals concluded that aerobic training may improve
The link between physical activity and endothelial dysfunction is in
endothelial function as measured by the reactive hyperemia index [53],
line with the findings of previous research in the general population [41,
although such a finding was not confirmed by a study in obese patients
42]. Physical exercise has been proposed to improve endothelial func­
[54]. In addition, short-term aerobic exercise has been shown to
tion by increasing vascular laminar shear stress, promoting nitric
ameliorate microvascular function, reduce endothelin-1 and asymmetric
oxide-mediated vasodilation and ameliorating the oxidative balance
dimethylarginine levels, as well as to augment brachial artery
[43], as reflected by its favorable effects on brachial artery
flow-mediated dilatation [55]. Notably, an intradialytic cycling pro­
flow-mediated dilatation and carotid intima-media thickness [44].
gram was able to increase circulating endothelial progenitor cells, which
Chronic kidney disease represents a state of altered endothelial function,
may enable the endothelial regeneration of damaged vessels, leading
as reflected by the presence of impaired flow-mediated dilatation and
possibly to reduced cardiovascular risk [56].
increased levels of asymmetric dimethylarginine, adhesion molecules
Greater sedentary time and longer sedentary bouts have been linked
and circulating vWF [45]. In this study, chronic kidney disease patients
with higher all-cause mortality, indicating the value of both decreasing
presented higher levels of sVCAM-1, sICAM-1, sE-selectin and vWF,
and interrupting sedentary time with physical activity [57,58]. Experi­
while a significant association was observed between vWF levels and all
mental evidence has pointed out an association of physical inactivity
levels of physical activity intensity. Previous research has provided
with increased oxidative stress, impaired endothelium-dependent vas­
mixed evidence regarding the link between exercise intensity and
orelaxation and progression of atherosclerosis [59]. Prolonged sitting
endothelial adhesion molecules, with high-intensity physical activity
has been suggested to exert a negative impact on traditional cardio­
being suggested to produce an acute, short-lived change in their levels
vascular disease risk factors, such as blood pressure and glucose meta­
[46]. Interestingly, higher-intensity resistance training has been pro­
bolism, as well as to promote vascular dysfunction by reducing shear
posed to decrease sICAM-1 but not sVCAM-1 concentration [47]. In this
stress and inducing the release of endothelin-1 [60]. However, data
study, fully-adjusted models of participants with chronic kidney disease
regarding the effects of sedentary behavior in states of renal dysfunction
suggested that lower-intensity physical activity was associated with
remain scant. Previous cross-sectional data have indicated that the
sVCAM-1, while moderate-to-vigorous physical activity was inversely
amount of sedentary time is inversely associated with renal function
associated only with sICAM-1.
[61]. In the present cohort of chronic kidney disease patients, longer
A mendelian randomization study has suggested that physical ac­
sedentary bouts were significantly associated with endothelial
tivity may causally affect the risk of chronic kidney disease [48]. Lower
dysfunction, as manifested by the higher levels of sVCAM-1 and vWF.
physical activity levels have been also linked to higher mortality among
Interestingly, when a history of dyslipidemia was absent, the link be­
patients with kidney failure, although reverse causality cannot be
tween sedentary bout duration and endothelial dysfunction was signif­
excluded due to the observational nature of evidence [49]. A recent
icantly stronger among participants with chronic kidney disease
umbrella review including 31 systematic reviews and meta-analyses on
compared to those with normal kidney function. These findings rein­
the therapeutic effects of exercise interventions for patients with chronic
force the current recommendations, suggesting that non-dialysis chronic
kidney disease, has pointed out that exercise interventions may exert

Fig. 4. Association of physical activity with endothelial dysfunction in individuals with and without chronic kidney disease.

8
I. Bellos et al.
kidney disease patients should minimize prolonged sedentary periods by
interrupting them with light-intensity physical activity and aim for 150
min of moderate-to-vigorous aerobic physical activity weekly [62].
4.3. Strengths and limitations
The present study has several strengths. Physical activity and
sedentary behavior were assessed by thigh worn accelerometry data
providing objective evaluations of the primary exposures and over­
coming the limitations associated with self-reported data, such as recall
and information bias. Furthermore, the activPAL accelerometer used for
this study, apart from acceleration, collected additional information on
posture and thus estimates on sedentary time are considered to be more
accurate compared to those based exclusively on acceleration [63,64].
Multiple endothelial markers were measured, achieving a comprehen­
sive assessment of the degree of endothelial dysfunction. A variety of
clinical and demographical covariates were also taken into account,
constructing different multivariate models to test the robustness of
outcomes and limit the effects of potential confounding. Compositional
data analysis has been also conducted, which supported the outcomes of
the primary regression analysis, straightening thus the reliability of the
results. On the other hand, the study followed a cross-sectional design,
precluding the drawing of conclusive causal associations. It is also
important to state that the ActivPAL3™ monitor is incapable of
capturing information about the type of physical exercise and thus no
data were available concerning the possible differential effects of
endurance and strength exercise. The lack of adequate statistical power
may have limited the possibility of demonstrating significant associa­
tions in fully-adjusted models of chronic kidney disease patients, espe­
cially regarding the association of endothelial dysfunction with
moderate-to-vigorous physical activity, total sedentary time and pro­
longed sedentary bouts. It should be noted that the vast majority of
participants had an eGFR >30 ml/min/1.73 m2; hence, no conclusions
can be drawn about stages 4 and 5 of chronic kidney disease.
4.4. Conclusions
The findings of this study support an inverse association of total,
lower-intensity, and moderate-to-vigorous physical activity duration
with endothelial dysfunction, which is not significantly affected by the
presence of chronic kidney disease. A link between sedentary behavior
and endothelial damage was not only observed in participants with
normal kidney function but also in individuals with chronic kidney
disease, with longer sedentary bouts being associated with higher levels
of endothelial dysfunction biomarkers, especially sVCAM-1 and vWF.
These outcomes warrant the conduct of further prospective studies to
confirm whether interventions aiming to more frequent physical activ­
ity, as well as to the interruption of sedentary time, may reduce endo­
thelial dysfunction, evaluating both serum biomarkers and sonographic
indices. Future randomized trials are needed to elucidate the pattern and
type of physical activity that may effectively ameliorate endothelial
function and reduce cardiovascular risk across different stages of
chronic kidney disease.
Financial support
The Maastricht Study was supported by the European Regional
Development Fund via OP-Zuid, the Province of Limburg, the Dutch
Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst
(Maastricht, the Netherlands), the Pearl String Initiative Diabetes
(Amsterdam, the Netherlands), School for Cardiovascular Diseases
(CARIM, Maastricht, the Netherlands), School for Public Health and
Primary Care (CAPHRI, Maastricht, the Netherlands), School for Nutri­
tion and Translational Research in Metabolism (NUTRIM, Maastricht,
the Netherlands), Stichting Annadal (Maastricht, the Netherlands),
Health Foundation Limburg (Maastricht, the Netherlands), and by
9
Atherosclerosis 383 (2023) 117330
unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands),
Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands),
Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands), and Med­
tronic (Tolochenaz, Switzerland). The study sponsors/funders were not
involved in the design of the study; the collection, analysis and inter­
pretation of data; writing the report; and did not impose any restrictions
regarding the publication of the report.
CRediT authorship contribution statement
Ioannis Bellos: Conception and design, Analysis and interpretation
of the data, Drafting of the article, Final approval of the article, Statis­
tical expertise. Smaragdi Marinaki: Drafting of the article, Final
approval of the article. Pagona Lagiou: Critical revision for important
intellectual content, Final approval of the article. Ioannis N. Boletis:
Critical revision for important intellectual content, Final approval of the
article. Coen D.A. Stehouwer: Conception and design, Critical revision
for important intellectual content, Final approval of the article. Marleen
M.J. van Greevenbroek: Critical revision for important intellectual
content, Final approval of the article, Collection and assembly of dat.
Simone J.P.M. Eussen: Critical revision for important intellectual
content, Final approval of the article, Collection and assembly of data.
Bastiaan E. de Galan: Critical revision for important intellectual con­
tent, Final approval of the article, Collection and assembly of data. Hans
H.C.M. Savelberg: Critical revision for important intellectual content,
Final approval of the article, Collection and assembly of data. Anne­
marie Koster: Critical revision for important intellectual content, Final
approval of the article, Collection and assembly of data. Anke Wesse­
lius: Conception and design, Analysis and interpretation of the data,
Critical revision for important intellectual content, Final approval of the
article, Statistical expertise, Collection and assembly of data. Vassiliki
Benetou: Conception and design, Analysis and interpretation of the
data, Drafting of the article, Final approval of the article, Statistical
expertise.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The authors thank all participants from The Maastricht Study for
their willingness to participate in the study, as well as all the funders.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.atherosclerosis.2023.117330.
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