Journal of Human Hypertension

https://doi.org/10.1038/s41371-019-0169-z

ARTICLE

Stage 1 hypertension, but not elevated blood pressure, predicts 10-

year fatal and non-fatal CVD events in healthy adults: the ATTICA
Study
Elena Critselis1 Christina Chrysohoou2 Natasa Kollia1 Ekavi N. Georgousopoulou1,3 Dimitrios Tousoulis2
● ● ● ● ●

Christos Pitsavos2 Demosthenes B. Panagiotakos 1,3 the ATTICA Study group

● ●

Received: 17 December 2018 / Revised: 9 January 2019 / Accepted: 10 January 2019

© Springer Nature Limited 2019

Abstract
The study evaluated the extent to which high normal blood pressure (HNBP), elevated BP, and Stage 1 hypertension predict
10-year incidence of cardiovascular disease (CVD). A population-based, prospective cohort study was conducted among
3042 randomly selected Greek adults, aged 18–89 years. Following 10-years follow-up (2002–2012), incidence of non-fatal
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and fatal CVD (ICD-10) was achieved in 2020 participants. The analytic sample (n = 1403) excluded hypertensive patients.
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At baseline, the prevalence rate of HNBP, elevated BP, and Stage 1 hypertension was 44.6% (n = 626), 29.0% (n = 408),
and 15.5% (n = 218), respectively. During follow-up, the 10-year combined (fatal or non-fatal) CVD incidence rates in
HNBP, elevated BP, and Stage 1 hypertensive individuals were 15.6% (n = 98), 12.0% (n = 49), and 22.5% (n = 49),
respectively, as compared to 6.3% (n = 49) in normotensives (all p’s < 0.0001). As compared to normotensives (and
following the adjustment for known demographic, lifestyle and clinical confounding factors), HNBP participants had a 1.5-
fold (Adjusted Hazard Ratio, Adj. HR: 1.49; 95% CI: 1.00–2.20) increased risk of 10-year CVD events. Similarly, Stage 1
hypertensive participants had an approximately twofold (Adj. HR: 1.90; 95% CI: 1.16–3.08) increased risk for 10-year
CVD, particularly among males (Adj. HR: 2.03; 95% CI: 1.08–3.83). However, individuals with elevated BP did not exhibit
a differential risk for developing 10-year CVD events (Adj. HR: 1.28; 95% CI: 0.82–2.02). Therefore, since HNBP and
Stage 1 hypertension individuals exhibit a notable increased risk of 10-year fatal and non-fatal CVD, the implementation of
targeted primary and secondary prevention interventions may deter both CVD and related adverse health outcomes.

Introduction AHA guidelines adopted further specified high normal BP

The most recent 2017 American College of Cardiology
(ACC)/American Heart Association (AHA) blood pressure
(BP) guideline highlights the emerging need for optimizing
blood pressure levels in relation to cardiovascular disease
(CVD) development. Within this context, the 2017 ACC/
* Demosthenes B. Panagiotakos
d.b.panagiotakos@usa.net
1 [5–7]. Nearly 26% of HNBP adults (including pre-
Department of Nutrition and Dietetics, School of Health Science
and Education, Harokopio University, 70 El. Venizelou Avenue,
176 71 Athens, Greece
2
First Cardiology Clinic, School of Medicine, University of Athens,
Athens, Greece
3
Faculty of Health, University of Canberra, Canberra, ACT,
Australia
(HNBP) as elevated BP (systolic BP (SBP) 120–129 mm
Hg and diastolic BP (DBP) <80 mm Hg) and Stage 1
hypertension (SBP 130–139 mm Hg or DBP 80–89 mm Hg)
[1, 2]. Controversy exists regarding the implications of
these most recently proposed BP categories upon the
implementation of preemptive therapeutic and public health
interventions for deterring CVD and related adverse health
outcomes [3].
HNBP afflicts 25–50% of adults worldwide [4], with
prevalence rates of elevated BP and Stage 1 hypertension in
young adults approximating 10% and 25%, respectively
dominantly Stage 1 hypertensive patients) progress to
hypertension [8], while meta-analytic findings reveal that
HNBP is associated with an elevated CVD risk (including
coronary heart disease and myocardial infarction, and stroke
[9, 10]) and a considerable proportion of attributable mor-
tality [11]. Furthermore, emerging evidence based on the

2017 ACC/AHA guidelines reveal that particularly young
adults with either elevated BP or Stage 1 hypertension
exhibit 1.67-fold (95% confidence interval, CI, 1.01–2.77)
and 1.75-fold (95% CI, 1.22–2.53) increased risk for
developing CVD events, respectively [7]. However, to date,
similar elevated risk rates have not been confirmed in older
individuals aged ≥60 years old [5], while evidence regarding
potential gender discrepancies in risk rates remain lacking.
Several lifestyle, dietary, and clinical factors (including
metabolic syndrome components such as (central) obesity,
type 2 diabetes mellitus, and dyslipidemia) [12, 13], as well
as bioclinical factors, are suggested to be pivotal in deterring
CVD and associated mortality in individuals with HNBP
[14]. Additionally, in Stage 1 hypertension individuals, with
concomitant overweight or obesity, reduced kidney function
is associated with a higher risk of atherosclerotic disease and
subsequent CVD events [15]. In particular, in HNBP
patients the activation of biochemical markers entailed in
inflammatory pathways (including C-reactive protein (CRP)
and TNF-a) are implicated in the onset of atherosclerotic
processes [16], including early vascular damage [17], sub-
sequent hypertension [18], and target organ damage [17],
while endothelial progenitor cell colony-forming capacity is
also apparently impaired particularly among Stage 1
hypertension adults [19]. Furthermore, metabolic abnorm-
alities (including metabolic syndrome components such as
(central) obesity, diabetes, and dysplidemia) are hypothe-
sized to be implicated in CVD risk through positive feed-
back mechanisms of the dysregulated renin-angiotensin-
aldosterone-system leading to the activation of the afore-
mentioned inflammatory cascade and lipid dysregulation
[20]. However, the underlying pathophysiological links
between such elevated BP levels and the onset of CVD,
ultimately encompassing the complex interplay between
underlying mechanistic, sociodemographic, and lifestyle
factors, remains to be elucidated. It is anticipated that such
findings would provide essential insights for developing
optimal comprehensive primary and secondary strategies for
preventing CVD in high risk individuals [16]. Hence, the
aim of this study was to determine to which extent HNBP,
elevated BP and Stage 1 hypertension may predict 10-year
incidence of CVD, as well as to evaluate their respective
associations with sociodemographic, lifestyle, and bioclini-
cal factors, among apparently healthy individuals partici-
pating in the ATTICA study [21].
Materials and methods
Study design
The methodological design and selection criteria of the
ATTICA Study have been previously detailed [21]. In brief,
E. Critselis et al.
this population-based, prospective cohort study was
implemented in the capital province of Attica (including
78% urban municipalities), Greece. Random, multistage
sampling was employed based on the age and gender dis-
tribution of the population, according to the 2001 National
Census Survey. One participant per household was enrolled,
while institutionalized individuals were excluded from
study participation. Of the initially invited 4056 individuals,
3042 agreed to participate (75% participation rate); 1514 of
the participants were male (aged 46 ± 13 years; range 18–87
years) and 1528 were female (aged 45 ± 13 years; range:
18–89 years). The study sample did not significantly differ
from the general population with respect to distributions of
age and gender. All participants were interviewed by trained
personnel (including cardiologists, nutritionists, and nurse
practitioners) who used standard questionnaires. Each par-
ticipant gave informed written consent and the protocol was
approved by the Medical Research Ethics Committee of the
University of Athens Medical School.
Baseline measurements
Participants’ characteristics, dietary, and lifestyle habits
The questionnaire used in the face-to-face interviews
encompassed demographic characteristics (e.g., age, gender,
income level, and highest attained educational level),
detailed medical history, dietary and lifestyle habits,
including smoking status, and habitual/leisure-time physical
activity. In particular, based on the years of education
completed and income, participants were categorized into
the following socioeconomic status (SES) categories: (i)
Low SES (i.e., <10-years education and low/medium mean
annual income (≤10,000 €) or <14 years education and low
mean annual income (≤8000 €), (ii) Moderate SES (i.e.,
including (a) <10-years education and high/very high mean
annual income (>10,000 €), (b) 10–14 years education and
medium/high mean annual income (8000–20,000 €), or ≥15
years education and low/medium mean annual income
(≤10,000 €); (iii) High SES (i.e., 10–14 years education and
very high mean annual income (>20,000 €), or ≥15 years
education and high/very high mean annual income
(>10,001 €).
Dietary habits were assessed based on a validated semi-
quantitative food-frequency questionnaire [22], according to
which participants reported average weekly or daily intakes
of food items during the past year. Subsequently, the
approximate monthly frequency of food item consumption
was calculated. Composite scores were employed to
describe overall dietary patterns. The Mediterranean diet
score was used (range 0–55) to depict adherence to dietary
patterns most proximal to those of the Mediterranean diet
[23, 24]. In addition, “current smokers” included those who
Stage 1 hypertension, but not elevated blood pressure, predicts 10-year fatal and non-fatal CVD events. . .
smoked at least one cigarette per day, “never smokers”
those who have never smoked, and “former smokers” those
who had ceased smoking at least 1 year prior to examina-
tion. For the evaluation of physical activity status, the
International Physical Activity Questionnaire (IPAQ) [25]
was used as an index of weekly energy expenditure. Phy-
sical activity was defined as >1 day/week leisure-time
activity during the past year, of specific intensity and
duration. Alternatively, subjects were categorized as phy-
sically inactive.
Anthropometric measurements and clinical assessment
Weight (in kilograms) and standing height (in meters
squared) were used to calculate body mass index (BMI),
and those with >29.9 kg/m2 were defined as obese. Waist
and hip circumferences (in cm) were used to calculate
waist-to-hip ratio, based on standard procedures. At the end
of the physical examination, following >30 min at rest and
while in a sitting position, subjects’ arterial blood pressure
was measured three times by a trained cardiologist (in a
blinded fashion) on participants’ right arm, which was
relaxed and well supported by a table, at 45° from the trunk
(ELKA aneroid manometric sphygmometer, Von Schlieben
Co, West Germany). The systolic and diastolic blood
pressure levels were determined by the first perception of
sound (of tapping quality) and phase V (fully muffed
repetitive sounds), respectively. Participants were classified
into the following groups based on mean systolic/diastolic
blood pressure and the most recent 2017 ACC/AHA
guidelines [26]: (a) HNBP: SBP 120–139 mm Hg and DBP
80–89 mm Hg and no prior history of high blood pressure
[27], (b) Elevated BP: SBP 120–129 mm Hg and DBP<80
mm Hg, and (c) Stage 1 hypertension (SBP 130–139 mm
Hg or DBP 80–89 mm Hg [2].
Laboratory assessment
Following 12 h of fasting and alcohol abstinence, blood
samples were collected between 8 to 10 a.m. from partici-
pants’ antecubital vein. Blood lipid examinations (serum
total cholesterol, oxidized low-density lipoprotein, high-
density lipoprotein and triglycerides) were measured using
chromatographic enzymic method in a RA-1000 Technicon
automatic analyzer (Dade-Behring, Marburg, Germany).
Hypercholesterolemia was defined as >220 mg/dl total
cholesterol levels or use of hypolipidemic medication.
Blood glucose levels (in mg/dl) were measured with a
Beckman Glucose Analyzer (Beckman Instruments, Full-
erton, CA, USA). Fasting blood sugar levels >125 mg/dl, or
the use of antidiabetic medication, were indicative of dia-
betes mellitus. High sensitivity C-reactive protein was
measured by particle-enhanced immunonephelometry
(range: 0.175–1100 mg/dl, N Latex, Dade-Behring Marburg
GmbH, Marburg, Germany).
Follow-up assessment
Follow-up assessments were conducted for 10 years fol-
lowing initial recruitment (i.e., in 2012). Of the initially
enrolled 3042 participants at baseline, 10-year follow-up
was achieved in 2583 participants (85% participation rate; of
those lost to follow-up, n = 224 could not be contacted due
to missing or erroneous contact information and n = 235
denied to participate). Complete CVD assessment was
achieved in 2020 participants. Individuals with hypertension
(SBP ≥ 140 or DBP >90 mm Hg, or under antihypertensive
medication) were excluded from further analysis. Hence, the
analytic sample of the present investigation consists of 1403
individuals. Follow-up examination included the retrieval of
detailed information from participants’ medical records.
Participants without accurate records were evaluated by
face-to-face interview by trained study investigators. The re-
examination included: (a) vital status (death from any cause
or due to cardiovascular disease), or (b) development of
coronary heart disease (including myocardial infarction,
angina pectoris, other identified forms of ischemia (WHO-
ICD coding 410–414.9, 427.2, 427.6-) heart failure of dif-
ferent types, and chronic arrhythmias (WHO-ICD coding
400.0–404.9, 427.0 –427.5, 427.9-), or development of
stroke (WHO-ICD coding 430–438).
Statistical analysis
Assuming study powr of 90%, two-sided significance level
of 5%, and 5% occurrence rate of 10-year CVD events
among normotensive individuals, a sample size of
1384 subjects was considered adequate for estimating
relative risks of 2.0 or higher between comparison groups.
Continuous variables are presented as mean ± standard
deviation (M ± SD) and categorical variables as absolute
and relative frequencies (n, %). The normality of distribu-
tions was assessed with P–P plots. For the comparison of
baseline characteristics between CVD-free and CVD event
groups, stratified according to the presence of normoten-
sion, high normal blood pressure, elevated BP, and Stage 1
hypertension at baseline, the Student’s t-test and Pearson’s
Chi-squared test were was applied to compare means of
normally distributed continuous variables and the fre-
quencies of categorical variables, respectively. Cox pro-
portional hazard models were used to explore the effect of
baseline blood pressure status (vs. normotensive) on 10-
year CVD incidence. Unadjusted and adjusted hazard ratios
(Unadj. and Adj. HR, respectively) and corresponding 95%
confidence intervals (95% CI) were computed separately for
high normal blood pressure, elevated BP, and Stage 1
 E. Critselis et al.

hypertension at baseline (independent factors) vs. normo-
tension in relation to 10-year incidence of CVD incidence
(outcome) based on Cox proportional hazard models [28].
Stratified analyses were conducted according to gender. All
models were adjusted for patient age, and additionally for
adherence to the Mediterranean diet, physical activity, and
hypercholesterolemia at baseline. The proportionality
assumption for the Cox models was assessed graphically.
Kaplan–Meier curves were constructed to depict the prob-
ability of time to CVD fatal or non-fatal events, and the
Log-rank test was used to compare CVD survival rates
between groups, overall and stratified according to gender.
All reported p-values were based on two-sided tests.
STATA 15 software was used for all analyses (M Psarros
and Assoc., Sparti, Greece/Stata Corp LLC, Texas, USA).
Results
High normal blood pressure (HNBP), elevated BP,
and Stage 1 hypertension in relation to 10-year
incidence of fatal and non-fatal CVD
At baseline examination, among the study population (n =
1403) the prevalence rate of HNBP was 44.6% (n = 626),
including 29.0% (n = 408) elevated BP and 15.5% (n =
218) Stage 1 hypertension individuals. The 10-year com-
bined (fatal or non-fatal) CVD incidence was 10.5% (n =
147 cases), which occurred approximately twice as often in
males as compared to females (10-year CVD events in
males vs. females: 14.2% (n = 89/626) vs. 7.5% (n = 58/
777), p < 0.0001). Of the total number of combined 10-year
CVD events, 25.2% (n = 37) were fatal, with similar rates
being documented among males and females with CVD
events (fatal events among males vs. females with 10-year
CVD events: 28.1% (n = 25/89) vs. 20.7% (n = 12/58);
p = 0.198).
As shown in Table 1, among HNBP individuals the 10-
year CVD incidence rate was 15.6% (n = 98) as compared
to 6.3% (n = 777) among normotensive individuals (p <
0.001). As compared to their CVD-event free counterparts,
HNBP individuals with 10-year CVD events were of older
mean age, of lower socioeconomic status, with lower mean
MedDietScore, and more frequently had abnormal waist-to-
hip ratio and hypercholesterolemia. Additionally, they had
higher mean levels of inflammatory biochemical markers,
including CRP and Il-6.
Furthermore, as shown in Table 2, among individuals
with elevated BP (n = 408), 12.0% (n = 49) developed 10-
year fatal or non-fatal CVD events. As compared to their

Table 1 Baseline characteristics of the ATTICA study’s participants (n = 1403) according to the presence of high normal blood pressure (including
elevated BP and Stage 1 hypertension) in relation to the 10-year fatal or non-fatal incidence of cardiovascular disease (CVD)
Normotensive individuals High normal blood pressure individuals
(n = 777) (n = 626)
CVD-free events CVD events p CVD-free events CVD events p
(n = 728) (n = 49) (n = 528) (n = 98)

Age (years, M ± SD) 37.6 ± 11.5 50.1 ± 11.1 <0.0001 44.4 ± 12.0 56.9 ± 13.9 <0.0001
Gender (men, n(%)) 248 (34.1%) 26 (53.1%) 0.009 289 (54.7%) 63 (64.3%) 0.096
Socioeconomic status (n(%)) 0.096 0.002
Low 34 (7.5%) 5 (19.2%) 60 (18.1%) 19 (40.4%)
Moderate 245 (53.7%) 13 (50.0%) 155 (46.8%) 18 (38.3%)
High 177 (38.8%) 8 (30.8%) 116 (35.0%) 10 (21.3%)
Abnormal waist-to-hip ratio (n(%)) 171 (25.0%) 13 (28.9%) 0.596 200 (39.0%) 59 (62.8%) <0.0001
MedDietScore (0–55, M ± SD) 28.3 ± 6.4 25.6 ± 6.0 0.004 25.9 ± 5.3 22.3 ± 5.7 <0.0001
Physically active (n(%)) 296 (40.7%) 21 (42.9%) 0.766 216 (40.9%) 47 (48.0%) 0.220
Current smokers (n(%)) 338 (46.6%) 24 (49.0%) 0.769 211 (40.0%) 39 (39.8%) 0.975
Systolic blood pressure (mm Hg, M ± SD) 104.7 ± 7.1 106 ± 5.4 0.238 124.0 ± 4.9 124.5 ± 4.9 0.282
Diastolic blood pressure (mm Hg, M ± SD) 69.8 ± 7.7 70.1 ± 8.4 0.826 78.2 ± 5.7 77.0 ± 5.7 0.064
Pulse pressure (mm Hg, M ± SD) 34.9 ± 7.4 35.8 ± 7.4 0.378 45.8 ± 7.3 47.5 ± 7.4 0.031
Hypercholesterolemia (n(%)) 203 (28.0%) 26 (53.1%) 0.001 239 (45.3%) 51 (52.0%) 0.227
C-reactive protein (mg/l, M ± SD) 1.6 ± 2.2 1.8 ± 2.6 0.624 2.0 ± 2.4 2.7 ± 3.0 0.014
Interleukin-6 (pg/ml, M ± SD) 1.4 ± 0.6 1.5 ± 0.4 0.039 1.4 ± 0.5 1.6 ± 0.5 0.001
Continuous variables are presented as mean ± standard deviation (M ± SD), and categorical variables as absolute and relative frequencies (n(%))
p-values referring to differences between CVD-events and CVD-free events during the 10-year follow-up, derived using either the Student’s t-test
or the Pearson chi-square test for continuous and categorical characteristics, respectively
Stage 1 hypertension, but not elevated blood pressure, predicts 10-year fatal and non-fatal CVD events. . .

Table 2 Baseline characteristics among ATTICA study participants with elevated BP or Stage 1 hypertension in relation to the 10-year fatal or
non-fatal incidence of cardiovascular disease (CVD)
Individuals with Elevated BP Individuals with Stage 1 hypertension
(n = 408) (n = 218)
CVD-free events CVD events p CVD-free events CVD events p
(n = 359) (n = 49) (n = 169) (n = 49)

Age (years, M ± SD) 42.7 ± 10.8 55.6 ± 13.7 <0.0001 47.8 ± 13.6 58.2 ± 14.0 <0.0001
Gender (men, n(%)) 197 (54.9%) 28 (57.1%) 0.878 92 (54.4%) 35 (71.4%) 0.048
Socioeconomic status (n(%)) 0.107 0.027
Low 43 (17.8%) 8 (34.8%) 17 (19.1%) 11 (45.8%)
Moderate 111 (45.9%) 10 (43.5%) 44 (49.4%) 8 (33.3%)
High 88 (36.4%) 5 (21.7%) 28 (31.5%) 5 (20.8%)
Abnormal waist-to-hip ratio (n(%)) 131 (37.6%) 24 (51.1%) 0.082 69 (41.8%) 35 (74.5%) <0.0001
MedDietScore (0–55, M ± SD) 26.2 ± 5.6 23.3 ± 4.9 0.001 25.3 ± 4.5 21.4 ± 6.3 <0.0001
Physically active (n(%)) 139 (38.7%) 22 (44.9%) 0.438 77 (45.6%) 25 (51.0%) 0.519
Current smokers (n(%)) 152 (42.3 %) 25 (51.0%) 0.283 59 (34.9%) 14 (28.6%) 0.493
Systolic blood pressure (mm Hg, M ± SD) 120.8 ± 1.9 120.0 ± 0.1 0.003 130.6 ± 1.6 129.1 ± 2.6 <0.0001
Diastolic blood pressure (mm Hg, M ± SD) 78.1 ± 5.4 76.6 ± 5.3 0.078 78.4 ± 6.1 77.4 ± 6.0 0.340
Pulse pressure (mm Hg, M ± SD) 42.7 ± 5.6 43.4 ± 5.3 0.446 52.3 ± 6.3 51.7 ± 6.8 0.567
Hypercholesterolemia (n(%)) 154 (42.9%) 29 (59.2%) 0.033 85 (50.3%) 22 (44.9%) 0.521
C-reactive protein (mg/l, M ± SD) 1.9 ± 2.5 2.8 ± 2.9 0.037 2.0 ± 2.3 2.6 ± 3.1 0.203
Interleukin-6 (pg/ml, M ± SD) 1.4 ± 0.5 1.6 ± 0.4 0.014 1.5 ± 0.5 1.7 ± 0.6 0.082
Continuous variables are presented as mean ± standard deviation (M ± SD), and categorical variables as absolute and relative frequencies (n(%)). p-
values referring to differences between CVD-events and CVD-free events during the 10-year follow-up, derived using either the Student’s t-test or
the Pearson chi-square test for continuous and categorical characteristics, respectively

CVD-event free counterparts, individuals with elevated BP
at baseline and who subsequently developed 10-year CVD
events were of older mean age and lower mean MedDiet-
Score. They also more frequently had hypercholesterolemia,
as well as elevated levels CRP and Il-6. Similarly, among
individuals with Stage 1 hypertension (n = 218), 22.5%
(n = 49) manifested 10-year CVD events. In contrast to
their counterparts who did not develop CVD, Stage 1
hypertension individuals with 10-year CVD events were of
older mean age, more often male, and of lower socio-
economic status. Additionally, they had lower mean Med-
DietScore and more often had an abnormal waist-to-hip
ratio at baseline.
Time to fatal and non-fatal CVD events according to
baseline high normal blood pressure (HNBP),
elevated BP, and Stage 1 hypertension
Figure 1 illustrates the Kaplan–Meier curves for differences
in the probability and time to developing combined (fatal or
non-fatal) CVD events, according to the presence of base-
line HNBP. Individuals with HNBP at baseline were sig-
nificantly more likely to subsequently develop CVD events
(Log-rank test p < 0.001). Moreover, following stratified
analysis according to gender, HNBP at baseline was
inversely associated with the probability of 10-year CVD
events in both males (Log-rank p = 0.002) and females
(Log-rank p < 0.0001). Similarly, as shown in Fig. 2, both
elevated BP and Stage 1 hypertension at baseline were
adversely associated with combined 10-year CVD events in
both genders (all Log-rank test p-values <0.0001).
Risk of 10-year fatal and non-fatal CVD events
according to high normal blood pressure (HNBP),
elevated BP, and Stage 1 hypertension
As shown in Table 3, as compared to normotensives, HNBP
participants had approximately a 1.5-fold (Adjusted hazard
ratio, Adj. HR: 1.49; 95% CI: 1.00–2.20) increased risk of
developing 10-year CVD events, following the adjustment
for known confounding factors including age, adherence to
the Mediterranean dietary pattern, physical activity, and
hypercholesterolemia. It is of interest that, following
adjustment for the aforementioned demographic, lifestyle
and clinical confounding factors, individuals with elevated
BP at baseline did not exhibit a differential risk for devel-
oping 10-year CVD events (Adj. HR: 1.28; 95% CI:
0.82–2.02). In contrast, participants with Stage 1 hyper-
tension at baseline had an approximately twofold (Adj. HR:
1.90; 95% CI: 1.16–3.08) increased risk for developing
10-year CVD, even following adjustment for all afore-
mentioned factors. Furthermore, it is noteworthy that in the

Fig. 1 Kaplan–Meier curves for depicting the probability and time to
occurrence of combined (fatal or non-fatal) cardiovascular (CVD)
events according to the presence of high normal blood pressure
(including elevated BP or Stage 1 hypertension) at baseline in the
ATTICA study population (n = 1403). Individuals with high normal
Fig. 2 Kaplan–Meier curves for depicting the probability and time to
occurrence of combined (fatal or non-fatal) cardiovascular (CVD)
events according to the presence of elevated BP or Stage 1 hyper-
tension at baseline in the ATTICA study population (n = 1403).
Individuals with elevated BP or Stage 1 hypertension were
stratified analysis conducted by gender, the observed asso-
ciation was sustained only among males who exhibited in
excess of a twofold risk (Adj. HR: 2.03; 95% CI:
1.08–3.83) for 10-year combined fatal and non-fatal CVD
events.
Discussion
The most recent 2017 ACC/AHA High Blood Pressure
Clinical Practice Guidelines underlined novel aspects
regarding the definition of both elevated BP and Stage 1
hypertension, blood pressure management and, consequently,
E. Critselis et al.
blood pressure were significantly more likely to develop 10-year CVD
events (a Log-rank test p < 0.0001). The association between baseline
high normal blood pressure and 10-year CVD events was sustained in
both males (b Log-rank test p = 0.002) and females (c Log-rank test
p < 0.0001)
significantly more likely to develop 10-year CVD events in the overall
study population (a Log-rank test p < 0.0001), as well as among both
males (b Log-rank test p < 0.0001), and females (c Log-rank test p <
0.0001)
CVD prevention. The present study evaluated to which extent
HNBP, and particularly elevated BP and Stage 1 hyperten-
sion, predict 10-year incidence of CVD, as well as its asso-
ciation with sociodemographic, lifestyle, and biochemical
factors among apparently healthy individuals. The main study
findings revealed that, as compared to normotensives, HNBP
individuals were at approximately a 1.5-fold increased risk of
developing fatal and non-fatal CVD events. Furthermore,
Stage 1 hypertension individuals, and particularly males,
experienced an approximately twofold excess risk of devel-
oping 10-year fatal and non-fatal CVD events. It is note-
worthy that such an association was not detected among
individuals with elevated BP. Thus, targeted primary and
Stage 1 hypertension, but not elevated blood pressure, predicts 10-year fatal and non-fatal CVD events. . .

Table 3 Unadjusted and adjusted hazard ratios (95% CI) of high normal including older individuals. Even so, similarly to previous
blood pressure, as well as elevated BP and Stage 1 hypertension, vs.
normotension in relation to 10-year incidence of cardiovascular disease
reports [30, 31], our study demonstrated that CVD events
(CVD) incidence (outcome), as derived from univariate Cox Proportional occurred most often in individuals with elevated BP levels.
Hazards models among ATTICA study participants Specifically, the incidence rate of combined (fatal and non-
Unadjusted HR Age-adjusted HR Adjusted HRa fatal) 10-year CVD events was amplified according to
(95% CI) (95% CI) (95% CI) escalating BP level, since adults with normotension, ele-
vated BP, and Stage 1 hypertension were observed to have
Individuals with high normal blood pressure (including elevated BP
respective incidence rates of 6.3%, 12.0%, and 22.5%,
and Stage 1 hypertension)
respectively.
Overall 2.76 (1.92–4.00) 1.55 (1.05–2.29) 1.49 (1.00–2.20)
Previous studies have documented the characteristics of
Males 2.08 (1.28–3.39) 1.42 (0.84–2.40) 1.40 (0.83–2.38)
adults with varying high normal levels of blood pressure
Females 3.06 (1.77–5.29) 1.38 (0.76–2.54) 1.40 (0.76–2.59)
(e.g., 120–129/<80 mm Hg and 130–139/80–89 mm Hg)
Individuals with elevated BP
[32], as well as related bioclinical factors [33]. However, the
Overall 2.03 (1.34–3.07) 1.32 (0.84–2.07) 1.28 (0.82–2.02)
majority of these findings arise from randomized clinical
Males 1.36 (0.77–2.39) 1.07 (0.59–2.00) 1.07 (0.58–1.96) trials [34, 35] that, secondary to the study design and patient
Females 2.70 (1.46–5.02) 1.46 (0.74–2.85) 1.46 (0.74–2.87) selection procedures entailed, have limited external validity
Individuals with Stage 1 hypertension and generalizability of findings. Additionally, evidence
Overall 4.31 (2.80–6.62) 1.97 (1.21–3.21) 1.90 (1.16–3.08) arising from population-based longitudinal cohorts are
Males 3.63 (2.07–6.36) 2.03 (1.09–3.80) 2.03 (1.08–3.83) limited to non-Mediterranean countries, such as the USA or
Females 3.79 (1.87–7.69) 1.36 (0.60–3.09) 1.40 (0.61–3.23) Japan [32, 33], as well as among very young (18–26-years-
HR hazard ratios, 95% CI 95% confidence interval old) adults [33]. Hence, cumulatively the aforementioned
a
Adjusted HR (95% CI): Adjusted hazard ratios for age, MedDiet findings are apparently insufficient for providing the
Score, physical activity, and hypercholesterolemia necessary evidence base for informing and guiding the
development of related public health strategies, particularly
in Mediterranean populations.
secondary prevention interventions, particularly among Stage The present population-based prospective cohort study,
I hypertensive individuals, may deter the manifestation of entailing an inception cohort from a Mediterranean country,
CVD and related adverse health outcomes. Since the study displayed that HNBP participants had approximately a 1.5-
shares all the limitations associated with investigations fold increased risk of 10-year CVD, following adjustment
encompassing a single set of blood pressure measurements, for several known CVD risk factors, including age, physical
following the recommendations of the most recent European activity, adherence to the Mediterranean dietary pattern, and
Society of Cardiology/European Society of Hypertension hypercholesterolemia. Furthermore, these findings were
guidelines [28], investigations incorporating repeated office amplified in Stage 1 hypertension patients who exhibited a
blood pressure measurements or out of office measurements twofold greater risk for 10-year CVD incidence as com-
are necessary for confirming acute haemodynamic load. Even pared to their normotensive counterparts. However, fol-
so, the main study findings support the necessity for further lowing adjustment for several known CVD risk factors,
investigating potential beneficial effects of targeted preven- individuals with elevated BP did not exhibit an increased
tion strategies in Stage I hypertensive individuals, but do not risk for 10-year CVD. Our findings regarding CVD risk in
provide insights and/or support for the initiation of pre- HNBP individuals are higher to those reported in previous
emptive drug therapy in this high risk population group. meta-analyses (HR: 1.44 (95% CI: 1.35 to 1.53), likely as a
In the present cohort, 44.6% of participants had HNBP at result of differences in population characteristics, pre-
baseline, a rate within the range of previously reported valence of underlying risk factors, and extent of follow-up
global prevalence rates approximating 25–50% [29]. duration [9]. Moreover, according to the ACC/AHA 2017
Moreover, the prevalence rate of elevated BP and Stage 1 Evidence Writing Committee, adults with Stage 1 hyper-
hypertension in the present cohort was 29.0% and 15.5%, tension have a twofold increased CVD risk and, based on
respectively. Previous investigations suggest that the pre- clinical trial findings, apparently benefit from SBP lowering
valence rates of elevated BP and Stage 1 hypertension in to levels below 130 mm Hg [2, 34–37]. Our findings reveal
young adults residing in China, Korea, and the USA a comparable CVD risk in Stage 1 hypertension adults,
approximate 10% and 25%, respectively [5–7]. The dis- albeit greater than that reported in investigations conducted
crepancies in the reported prevalence rates may be poten- in young adults aged <40-years-old [7]. Furthermore, in
tially attributed to the fact that the present cohort was not contrast to previous studies, which show that young adults
limited to the enrollment of young adults, but rather with elevated BP have a 1.67-fold (95% Confidence Inter-
recruited a representative population-based sample val, CI, 1.01–2.77) increased risk for developing CVD

events [7], the present study findings demonstrated that such
an association is not sustained in older adults, particularly
following the adjustment for potential confounding effects
from several known CVD risk factors. Preliminary previous
reports have also indicated that elevated risk rates based on
BP are not detected in older individuals aged ≥60 years old
[5]. To the best of our knowledge, the present cohort is the
first of its kind arising from a prospective population-based
Mediterranean cohort, which demonstrates that among
adults aged 18–90-years-old, HNBP and, in particular,
Stage 1 hypertension are associated with an approximate
twofold increase risk of 10-year fatal and non-fatal CVD
risk.
In addition, the present cohort additionally demonstrated
that gender disparities regarding particularly Stage 1
hypertension and 10-year CVD risk may exist. Specifically,
particularly men with Stage 1 hypertension were observed
to exhibit in excess of a twofold increased risk of devel-
oping combined CVD within a decade, while a corre-
sponding differential risk based on BP levels was not
detected in women. In fact, it is notable that following
adjustment for known confounding variables, women were
not found to exhibit an excess 10-year CVD risk for any of
the BP levels evaluated. The largest similar study conducted
to date among middle-aged adults and the elderly demon-
strated that HNBP increased the risk of 10-year CVD by
2.5- and 1.6-fold in women and men, respectively [31]. To
the best of our knowledge, findings regarding potential
related gender disparities in risk rates according to the 2017
ACC/AHA guidelines among comparable populations have
not been documented to date.
Among other known confounding factors, the present
investigation evaluated the risk of 10-year CVD following
adjustment for adherence to the Mediterranean diet and
physical activity, which when concomitantly lacking ulti-
mately lead to overweight/obesity and ultimately CVD.
Overweight and obesity [38], as well as waist circumference
and central obesity [39], have been previously documented
as risk factors for CVD in HNBP subjects. Particularly in
such individuals, obesity may trigger dysregulation of the
renin-angiotensin-aldosterone-system (RAAS), and adipo-
kine- and leptin-mediated adrenergic tone increases [20].
Central obesity and non-adherence to the Mediterranean
diet have been associated with a chronic inflammation [26]
and CVD related inflammatory markers [40], respectively.
Given the positive impact of physical activity on CVD
incidence diminishment [41], cumulatively these findings
emphasize the importance of employing comprehensive
lifestyle interventions for deterring the onset of 10-year
CVD in HNBP individuals. Based on the cumulative pre-
sent study findings, it is hypothesized that high BP, and
particularly Stage 1 hypertension, may pose an additional
CVD risk especially when combined with either an
E. Critselis et al.
underlying metabolic syndrome and/or several of its com-
ponents [20].
While the underlying pathophysiological mechanisms
remain to be elucidated, it is hypothesized that an associa-
tion between high BP and inflammatory markers exists [40].
Our findings indicate that at baseline HNBP, and particu-
larly elevated BP, individuals who develop CVD have
higher mean levels of both C-reactive protein and IL-6. As
reviewed in ref. [16], there exists increasing consensus that
high BP is characterized by a pro-inflammatory state,
potentially as part of a advancing continuum in the pro-
gression to CVD. Established risk factors of hypertension
and CVD (including tobacco smoking, hypercholester-
olemia, and/or hyperinsulinemia) have been shown to sti-
mulate the secretion of leukocyte soluble adhesion
molecules and hemostatic factors, propagating both the
atherosclerotic process and increased inflammatory marker
levels [40]. Hence, such inflammatory markers may be used
as part of a biomarker panel for identifying individuals
particularly with elevated BP and at highest risk for 10-year
CVD.
Currently, while notable progress has been achieved in
Greece regarding the diagnosis and treatment of hyperten-
sion, only 65% of patients are aware of having hypertension
[42], whereas there is a complete lack of respective data
regarding HNBP awareness rates. Collectively, the present
study findings reveal that targeted primary and secondary
prevention strategies for deterring CVD are hence likely
necessary in HNBP and particularly Stage 1 hypertension
individuals. Such strategies would likely benefit most if a
comprehensive approach, encompassing both lifestyle and
clinical modifications, were employed. Ultimately, such
preemptive interventions particularly in Stage 1 hyperten-
sion individuals may diminish the disease burden and
associated healthcare costs of subsequent CVD events.
Strengths and limitations
The study strengths include that a prospective cohort study
design was applied in a representative randomly selected,
population-based sample residing in the most densely
populated urban district of Greece. In addition, follow-up
duration extended one decade, allowing for sufficient eva-
luation of the outcomes of interest, while concomitantly
deterring a misclassification bias due to disease latency.
Even so, the study limitations include that the evaluation of
blood pressure may be prone to measurement error resulting
from the “white coat effect.” Specifically, although three
consecutive measurements were taken, average blood
pressure measurement may remain higher upon first visit.
However, in the event that such a measurement error was
introduced, it is upheld that such an error would only lead to
an underestimation of true BP rates during follow-up.
Stage 1 hypertension, but not elevated blood pressure, predicts 10-year fatal and non-fatal CVD events. . .
Moreover, since the study shares all the limitations asso-
ciated with observational investigations encompassing a
single set of blood pressure measurements, additional
investigations with repeated office or out of office blood
pressure measurements are needed for accurately measuring
acute haemodynamic load. Additionally, while adherence to
the Mediterranean Diet (MedDietScore) was measured,
complete dietary analysis for nutrient components was not
evaluated within the context of the current investigation.
Even so, due to the extended follow-up period entailed, it is
upheld that dietary patterns more accurately predict CVD
risk as they provide a more comprehensive understanding of
how dietary factors cumulatively affect the risk of disease.
Also, risk trajectories of BP measurements based on 24-h
blood pressure monitoring could provide valuable insights
into imminent CVD risk, however, such frequency of
measurements entailed was not encompassed in the original
study design and would have likely led to unfavorable loss
rates of loss to follow-up among study participants. Finally,
initiation of pharmaceutical treatment was not evaluated
within the context of the present analysis. The potential
confounding effects of pharmacological treatment were
indirectly evaluated as the classification of hypertension
status included prior use of high blood pressure treatment.
Moreover, it is upheld that such treatment effects would
only bias towards the null hypothesis, and as of such our
findings are an underestimation of true effect sizes. As of
such, the main study findings support the necessity for
further investigating potential beneficial effects of targeted
prevention strategies in Stage I hypertensive individuals,
but do not provide insights and/or support for the initiation
of preemptive drug therapy in this high risk population
group.
Conclusions
Since HNBP and Stage 1 hypertension individuals exhibit a
notable increased risk of 10-year fatal and non-fatal CVD,
the implementation of targeted prevention interventions
may deter both CVD and related adverse health outcomes.
Future investigations may provide insights regarding the
potential beneficial effects of targeted prevention strategies
and or preemptive therapeutic interventions for preventing
CVD in Stage I hypertensive individuals.
Summary
What is already known about this topic?
● The most recent 2017 American College of Cardiology
(ACC)/American Heart Association (AHA) blood pres-
sure (BP) guideline highlights the emerging need for
optimizing blood pressure levels in relation to cardio-
vascular disease (CVD) development.
● While the prevalence rates of elevated BP and Stage 1
hypertension approximate 10 and 25%, evidence is
limited regarding their association with CVD and
consequent necessity for preemptive primary and
secondary interventions.
What this study adds?
● This study determined to which extent HNBP, elevated
BP, and Stage 1 hypertension predicts 10-year incidence
of CVD among otherwise healthy ATTICA study
participants.
● As compared to normotensives (and following the
adjustment for known demographic, lifestyle, and
clinical confounding factors), HNBP participants had a
49% increased risk of 10-year CVD events.
● Similarly, Stage 1 hypertensive participants had an
approximately 90% increased risk for 10-year CVD,
particularly among males (Adj. HR: 2.03; 95% CI:
1.08–3.83).
● However, individuals with elevated BP did not exhibit a
differential risk for developing 10-year CVD events
(Adj. HR: 1.28; 95% CI: 0.82–2.02).
● Therefore, targeted primary and secondary prevention
interventions are necessary particularly among HNBP
and Stage 1 hypertension individuals so as to deter CVD
and related adverse health outcomes.
Acknowledgements We would like to thank the field investigators of
the study: M. Toutouza (biochemical evaluation), I. Papaioannou
(physical examination), E. Tsetsekou (physical examination), A.
Zeimbekis (physical examination), K. Masoura (physical examina-
tion), A. Katinioti (physical examination), S. Vellas (physical exam-
ination), E. Kambaxis (nutritional evaluation), K. Paliou (nutritional
evaluation), C. Tselika (technical support), S. Poulopoulou (technical
support), M. Koukoura (technical support), K. Vassiliadou (genetic
evaluation) and M. Toutouza (data management).
Funding The Hellenic Cardiology Society, the Hellenic Athero-
sclerosis Society, the Graduate Program in Applied Nutrition and
Dietetics of Harokopio University and the Coca-Cola SA funded this
study by research grants (KE252/ELKE/HUA). The ATTICA Study is
funded by research grants from the Hellenic Society of Cardiology
(grant–1, 2002).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

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