JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
23, 2020
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VOL. 75, NO.
ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
Association of Age of Onset of
Hypertension With
Cardiovascular Diseases and Mortality
Chi Wang, MD,a,* Yu Yuan, MD, PHD,b,* Mengyi Zheng, MD,c An Pan, PHD,d Miao Wang, MD,a Maoxiang Zhao, MD,a
Yao Li, MD,a Siyu Yao, MD,a Shuohua Chen, MD,c Shouling Wu, MD,c Hao Xue, MDa
ABSTRACT
BACKGROUND The relations of hypertension onset age with cardiovascular diseases (CVD) and all-cause mortality
remain inconclusive.
OBJECTIVES This study sought to examine the associations of hypertension onset age with CVD and all-cause
mortality.
METHODS This prospective study included 71,245 participants free of hypertension and CVD in the first survey
(July 2006 to October 2007) of the Kailuan study, a prospective cohort study in Tangshan, China. All participants were
followed biennially until December 31, 2017. A total of 20,221 new-onset hypertension cases were identified during
follow-up. We randomly selected 1 control participant for each new-onset hypertensive participant, matching for age (
1
year) and sex, and included 19,887 case-control pairs. We used weighted Cox regression models to calculate the average
hazard ratios of incident CVD and all-cause mortality across the age groups.
RESULTS During an average follow-up of 6.5 years, we identified 1,672 incident CVD cases and 2,008 deaths. After
multivariate adjustment, with the increase in hypertension onset age, the hazards of outcomes were gradually attenu-
ated. The average hazard ratio (95% confidence interval) of CVD and all-cause mortality were 2.26 (1.19 to 4.30) and
2.59 (1.32 to 5.07) for the hypertension onset age <45 years old group, 1.62 (1.24 to 2.12) and 2.12 (1.55 to 2.90) for the
45- to 54-year age group, 1.42 (1.12 to 1.79) and 1.30 (1.03 to 1.62) for the 55- to 64-year age group, and 1.33 (1.04 to
1.69) and 1.29 (1.11 to 1.51) for the $65-year age group, respectively (p for interaction ¼ 0.38 for CVD and <0.01 for
death).
CONCLUSIONS Hypertension was associated with a higher risk for CVD and all-cause mortality, and the associations
were stronger with a younger age of onset. (J Am Coll Cardiol 2020;75:2921–30) © 2020 by the American College of
Cardiology Foundation.
E levated blood pressure (BP) has been well
recognized as a major risk factor for cardio-
vascular diseases (CVDs) (1) and mortality
(1,2). With the increasing trend of unhealthy lifestyles
in modern society, the prevalence of hypertension is
expected to continue to rise (3). A large national sur-
vey in China (2012 to 2015) suggested younger people
have a relatively low hypertension prevalence of
From the aDepartment of Cardiology, Chinese PLA General Hospital, Beijing, China; bDepartment of Occupational and Environ-
mental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental
Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,
China; cDepartment of Cardiology, Kailuan General Hospital, Tangshan, China; and the dDepartment of Epidemiology and
Biostatistics, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental
Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,
China. *Drs. Wang and Yuan contributed equally to this work. All authors have reported that they have no relationships relevant
to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ in-
stitutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit
the JACC author instructions page.
Manuscript received March 19, 2020; accepted April 14, 2020.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2020.04.038
2922 Wang et al.
Hypertension Onset Age With CVD and Mortality
ABBREVIATIONS 9.04% (4). Meanwhile, the same study also
AND ACRONYMS noted that young people tend to overlook
the health hazards of hypertension, with
AHR = average hazard ratio
much lower hypertension awareness, treat-
BP = blood pressure
ment, and control rates compared with the
CI = confidence interval
older generation (31.7%, 24.5%, and 9.9%,
CVD = cardiovascular disease respectively, for those 35 to 44 years of age
eGFR = estimated glomerular vs. 58.6%, 52.8%, and 18.4%, respectively,
filtration rate
for those 65 to 74 years of age) (4). CVD
FBG = fasting blood glucose
events generally occurred among adults
HS = hemorrhagic stroke older than 45 years of age (5); therefore,
IS = ischemic stroke more attention has been paid in middle-
MI = myocardial infarction aged and elderly populations to prevent
TC = total cholesterol CVD by the identification and intervention
of CVD risk factors, including hypertension.
Consequently, the impact of early-onset hyperten-
sion on later-life CVD risk was often overlooked.
Emerging evidence suggests that the rates of hy-
pertension treatment and control differ with age (4).
Meanwhile, there is a graded relation between hy-
pertension and cardiovascular risks across age groups
(6,7). Early hypertension onset age is associated with
increased risks of cardiovascular mortality (8) and
hypertension end-organ damage (9). However, these
existing studies (6,7) mostly evaluated the health
consequences of prevalent hypertension age rather
than hypertension new-onset age. There is a lack of
studies evaluating the association of hypertension
new-onset age with incident CVD and all-cause mor-
tality. Therefore, we investigated the associations of
new-onset hypertension with the risks of incident
CVD and all-cause mortality across different age
groups in a large community-based Chinese cohort.
SEE PAGE 2931
METHODS
STUDY DESIGN AND PARTICIPANTS. The Kailuan
study is a prospective cohort study in the Kailuan
community in Tangshan, China. The detailed study
design and procedures have been described previ-
ously (10,11). During July 2006 to October 2007, a
total of 101,510 adult participants from the Kailuan
community were enrolled in the first survey and have
completed questionnaires and health assessments
every 2 years since 2006. The questionnaires
collected information on demographic characteris-
tics, medical comorbidities, medication history, and
lifestyle factors (including smoking status and alcohol
consumption). All participants were followed up until
their death or December 31, 2017. We excluded par-
ticipants who had hypertension at the baseline survey
in 2006 (BP $140/90 mm Hg or the use of an antihy-
pertensive medication based on the Seventh Report
JACC VOL. 75, NO. 23, 2020
JUNE 16, 2020:2921–30
of the Joint National Committee recommendation
[12]), those with a history of CVD before the diagnosis
of hypertension, and individuals with missing
important covariates (e.g., age, sex, smoking status,
and drinking status) at the time of hypertension
diagnosis that could not be replaced by previous
surveys (Supplemental Figure 1). Of the 71,245 par-
ticipants who were normotensive in the first survey
(2006 to 2007), 20,221 had been diagnosed with hy-
pertension until December 31, 2015 (the fifth survey).
The date of hypertension onset was defined as the
median date between the examination date when
hypertension was first reported and the last exami-
nation date when the participant was normotensive
(8). The control participants were randomly selected
from the normotensive participants who attended the
examination of the same year as the case was iden-
tified and were matched for age (
1 year) and sex. The
follow-up for the incident case started at the time the
new-onset hypertension was identified, and the
follow-up of the age- and-sex matched controls star-
ted the same year the incident case was identified.
For instance, a new-onset hypertension case 52 years
of age was identified in 2008. Meanwhile, the
matched control was randomly selected from the
normotensive participants 51 to 53 years of age when
they attended the resurvey in 2008 (both initiated the
follow-up at 2008).
Ultimately, a total of 19,887 normotensive
participants and 19,887 patients with new-onset
hypertension were included in the study
(Supplemental Figure 1). The study protocol was
approved by the ethics committee of Kailuan General
Hospital. All participants signed written informed
consent forms.
DEFINITION OF NEW-ONSET HYPERTENSION. In
line with the Seventh Report of the Joint National
Committee recommendation (12), we defined hyper-
tension as a BP measurement $140/90 mm Hg or the
self-reported use of an antihypertensive medication.
The BP measurements and questionnaires were
administered by trained physicians and nurses. BP
was measured in the left upper arm using a calibrated
mercury sphygmomanometer with the participant in
a sitting position. At least 2 BP measurements were
taken after 5 min of rest. BP was then measured again
if the difference between the 2 measurements
was $5 mm Hg. We used the average value of the BP
measurements for the diagnosis of hypertension.
New-onset hypertension was defined as a previously
normotensive participant who had hypertension
(either blood pressures $140/90 mm Hg or the use of
an antihypertensive medication) on 2 or more
JACC VOL. 75, NO. 23, 2020
JUNE 16, 2020:2921–30
consecutively attended examinations (8,9). This
approach aimed to reflect a long-time hypertension
status and reduce misclassifications because of vari-
ations in BP measurements (8,9).
OUTCOME VARIABLES: INCIDENT CVD AND
ALL-CAUSE MORTALITY. The outcomes in the pre-
sent study were the first occurrence of CVD or
all-cause mortality. The types of CVD included
myocardial infarction (MI), ischemic stroke (IS), and
hemorrhagic stroke (HS). We used ICD-10th revision
codes to identify CVD cases (I21 for MI, I63 for IS, and
I60 to I61 for HS) (13,14). The database of CVD di-
agnoses was obtained from the Municipal Social In-
surance Institution and Hospital Discharge Register
and was updated annually during the follow-up
period. An expert panel collected and reviewed
annual discharge records from 11 local hospitals to
identify patients who were suspected of CVD. The
diagnosis of MI was determined by the patient’s
clinical symptoms, electrocardiogram, and dynamic
changes of myocardial enzyme following the World
Health Organization’s Multinational Monitoring of
Trends and Determinants in Cardiovascular Disease
criteria (15). Stroke was diagnosed based on neuro-
logical signs, clinical symptoms, and neuroimaging
tests, including computed tomographic or magnetic
resonance imaging, in line with the World Health
Organization criteria (16). All-cause mortality data
were gathered from provincial vital statistics offices
and reviewed by physicians.
ASSESSMENT OF OTHER VARIABLES. Data on other
related variables were collected through question-
naires, basic anthropometric measurements, and
blood tests. Body mass index was calculated by
dividing body weight (kg) by the square of height (m).
Participants who had a history of smoking or who
currently smoked were defined as ever-smokers, and
those who had a history of drinking or who currently
drank were defined as ever-drinkers. All participants
underwent blood tests after overnight fasting at
each physical examination. The blood samples were
analyzed using an auto-analyzer (Hitachi 747, Hitachi,
Tokyo, Japan) on the day of the blood draw. The
biochemical indicators tested included fasting blood
glucose (FBG), triglycerides, total cholesterol (TC), and
serum creatinine. We used the Chronic Kidney Disease
Epidemiology Collaboration creatinine equation to
calculate the estimated glomerular filtration rate
(eGFR) (17). FBG $6.1 mmol/l was defined as hyper-
glycemia (18), whereas TC $5.17 mmol/l (200 mg/dl)
was defined as hyperlipidemia (19,20).
Wang et al. 2923
Hypertension Onset Age With CVD and Mortality
STATISTICAL ANALYSIS. The new-onset hyperten-
sive participants and the corresponding controls
were categorized according to their age of onset
as <45 years of age, 45 to 54 years of age, 55 to 64
years of age, and $65 years of age to be consistent
with the relevant literature (6,8,9,21,22). Continuous
variables were compared using analysis of variance
or the Kruskal-Wallis test according to distribution,
and categoric variables were compared with the chi-
square test. We used weighted Cox regression (23)
to calculate the average hazard ratios (AHRs) and
95% confidence intervals (CIs) of CVD and all-cause
mortality for new-onset hypertensive participants
compared with normotensive participants. The
multivariable adjusted model was further adjusted
for body mass index, heart rate, FBG, triglycerides,
TC, eGFR, smoking status (never- or ever-smoker),
drinking status (never- or ever-drinker), and anti-
hypertensive medication use. The covariates were
collected from the examination when the new-onset
hypertension was identified, and missing values
were replaced by the last observation carried
forward method from the previous survey cycles.
Furthermore, we also calculated the AHRs for
subtypes of CVD, including MI, stroke, IS, and HS.
We further conducted stratified analyses among the
participants with or without antihypertensive treat-
ment. To test the robustness of our findings, we further
conducted several sensitivity analyses. We excluded
the outcome events that occurred within the first year
of the follow-up period to minimize potential reverse
causation (24–28). We excluded control subjects with
episodic hypertension (with only a one-time hyper-
tensive status). Similar to a previous publication (29),
new-onset hypertension was identified at the first
follow-up examination (the 2008 survey) when the
participants either had blood pressures $140/
90 mm Hg or used antihypertensive medication,
regardless of the hypertension status later on. New-
onset hypertensive patients with missing BP mea-
sures in the examination cycle immediately before the
diagnosis of hypertension were excluded in a sensi-
tivity analysis. We further tested the results with the
propensity score matching method (matching all
covariates except antihypertensive medication use).
Moreover, we examined the associations of new-onset
hypertension with the study outcomes among pre-
specified subgroups based on smoking status, hyper-
glycemia, and hyperlipidemia.
All analyses were performed using SAS version 9.4
(SAS Institute, Cary, North Carolina) and R software
version 3.6.0 (R Core Team, Vienna, Austria). All
2924 Wang et al. JACC VOL. 75, NO. 23, 2020

Hypertension Onset Age With CVD and Mortality JUNE 16, 2020:2921–30

(14.1%), respectively, in the hypertensive cases and

T A B L E 1 Basic Characteristics for Participants With New-Onset Hypertension
and Their Normotension Controls
210 (25.4%), 46 (5.6%), 207 (25.0%), and 111 (13.4%),
respectively, among the control subjects.
New-Onset
Normotension Hypertension
After multivariate adjustment, the risks of CVD and
(n ¼ 19,887) (n ¼ 19,887) p Value all-cause mortality were generally significantly higher
Age, yrs 56.42
10.83 56.42
10.83 — in the new-onset hypertensive population than in the
Male 16,412 (82.53) 16,412 (82.53) — normotensive population across the age range.
Body mass index, kg/m2 24.51
3.17 25.27
3.00 <0.01
Interestingly, the risk estimates gradually declined
Heart rate, beats/min 72.71
9.92 74.05
9.27 <0.01
with each decade increase in the age at hypertension
FBG, mmol/l 5.56
1.56 5.83
1.67 <0.01
onset. Participants whose hypertension onset age was
Triglycerides, mmol/l 1.20 (0.86–1.75) 1.36 (0.99–2.00) <0.01
TC, mmol/l 4.99
1.03 5.13
0.93 <0.01 younger than 45 years had the highest risk for all
eGFR, ml/min/1.73 m2 85.78
18.11 87.11
16.75 <0.01 study outcomes with AHRs (95% CI) of 2.26 (1.19 to
Ever-smoker 7,763 (39.04) 10,542 (53.01) <0.01 4.30) for CVD and 2.59 (1.32 to 5.07) for all-cause
Ever-drinker 7,030 (35.35) 11,054 (55.58) <0.01 mortality. For the age groups of 45 to 54 years, 55 to
Antihypertensive medication use 0 (0.00) 7,623 (38.33) <0.01 64 years, and $65 years, the AHRs (95% CI) for CVD
were 1.62 (1.24 to 2.12), 1.42 (1.12 to 1.79), and 1.33
Values are mean
SD, n (%), or median (interquartile range). The characteristics were collected
from the examination cycle when the new-onset hypertension was first identified. (1.04 to 1.69), respectively, whereas the AHRs
eGFR ¼ estimated glomerular filtration rate; FBG ¼ fasting blood glucose; TC ¼ total
(95% CI) for all-cause mortality were 2.12 (1.55 to
cholesterol.
2.90), 1.30 (1.03 to 1.62), and 1.29 (1.11 to 1.51),
respectively (Central Illustration).
In the subtype analyses of CVD, similar results
statistical tests were 2-sided, and p < 0.05 was
were yielded for stroke, IS, and HS, with AHRs
considered statistically significant.
attenuated across increasing age groups (Figure 1).
RESULTS However, most of the AHRs in MI and HS were not
statistically significant (Figure 1), which could be
The sample sizes of normotensive and new-onset limited by the relatively small sample size of cases.
hypertensive participants by age group were as fol- The results were not materially changed among both
lows: 5,424 at <45 years of age, 12,040 at 45 to 54 the untreated and treated hypertensive participants
years of age, 14,210 at 55 to 64 years of age, and (Figure 2). The associations between hypertension
8,100 at $65 years of age. The characteristics of study and risks of CVD and mortality seemed to be stronger
participants are shown in Tables 1 and 2. Compared at each age group among the treated participants
with the normotensive group, the hypertensive group compared with the corresponding untreated partici-
is more likely to be ever-smokers and ever-drinkers, pants. Further analysis showed that the median sys-
with a higher body mass index, heart rate, FBG, tri- tolic blood pressure level of the untreated group was
glycerides, TC, and eGFR (Table 1). With the increase significantly lower (141 mm Hg [IQR: 137 to
of hypertension onset age, the proportions of ever- 150 mm Hg]) than the treated group (147 mm Hg [IQR:
smokers and ever-drinkers as well as body mass in- 140 to 155 mm Hg], p < 0.01). The sensitivity analyses
dex, triglycerides, and eGFR gradually decreased. In excluding the events within the first year (n ¼ 39,590)
contrast, the proportion of participants taking anti- (Supplemental Table 1), excluding normotensive
hypertensive medication and FBG levels gradually participants with episodic hypertension (n ¼ 37,432)
increased along with hypertension onset age (Supplemental Table 2), defining hypertension with
(Table 2). the first follow-up examination regardless of the hy-
During the average follow-up period of 6.5 years, pertension status later on (n ¼ 20,784) (Supplemental
we identified 1,672 cases of CVD (including 387 cases Table 3), excluding new-onset hypertensive patients
of MI, 1,166 cases of IS, and 182 cases of HS) and 2,008 with missing BP measures in the examination cycle
cases of all-cause mortality. The detailed number of immediately before the diagnosis of hypertension
CVD and all-cause mortality of participants is shown (n ¼ 33,060) (Supplemental Table 4), and using pro-
in the Central Illustration. The distribution of the pensity score matching (n ¼ 38,852) (Supplemental
cause-specific mortality is shown in Supplemental Table 5) all generated similar findings with the pri-
Figure 2. The numbers and proportions of CVD, can- mary analysis. In the joint analyses of hypertension
cer, respiratory diseases, and other causes of deaths and smoking status, hyperglycemia, and hyperlipid-
were 272 (23.1%), 62 (5.3%), 255 (21.6%), and 166 emia, we still observed a progressive attenuation in
JACC VOL. 75, NO. 23, 2020 Wang et al. 2925
JUNE 16, 2020:2921–30 Hypertension Onset Age With CVD and Mortality

T A B L E 2 Basic Characteristics for New-Onset Hypertensive Participants Across Age Groups

<45 Years of Age 45–54 Years of Age 55–64 Years of Age $65 Years of Age
(n ¼ 2,712) (n ¼ 6,020) (n ¼ 7,105) (n ¼ 4,050) p Value

Age, yrs 38.71
5.19 50.58
2.76 59.45
2.81 71.62
5.03 <0.01
Male 2,410 (88.86) 4,856 (80.66) 5,687 (80.04) 3,459 (85.41) <0.01
Body mass index, kg/m2 26.17
3.24 25.35
2.93 25.23
2.88 24.61
2.99 <0.01
Heart rate, beats/min 75.75
9.10 74.90
9.07 73.06
9.13 73.39
9.63 <0.01
FBG, mmol/l 5.46
1.29 5.80
1.70 5.93
1.74 5.94
1.69 <0.01
Triglycerides, mmol/l 1.66 (1.17–2.61) 1.46 (1.06–2.20) 1.31 (0.97–1.89) 1.18 (0.88–1.62) <0.01
TC, mmol/l 5.08
0.96 5.13
0.90 5.19
0.94 5.08
0.92 <0.01
eGFR, ml/min/1.73 m2 99.11
17.19 90.88
15.87 85.34
14.36 76.58
14.49 <0.01
Ever-smoker 1,729 (63.75) 3,631 (60.32) 3,603 (50.71) 1,579 (38.99) <0.01
Ever-drinker 2,101 (77.47) 3,837 (63.74) 3,494 (49.18) 1,622 (40.05) <0.01
Antihypertensive medication use 884 (32.60) 2,101 (34.90) 2,933 (41.28) 1,705 (42.10) <0.01

Values are mean
SD, n (%), or median (interquartile range). The characteristics were collected from the examination cycle when the new-onset hypertension was first
identified.
Abbreviations as in Table 1.

the risks of outcome events caused by new-onset
hypertension combined with other risk factors with
increasing age (Supplemental Figures 3 to 5).
DISCUSSION
In this cohort study, we found that the highest risks
of CVD and all-cause mortality were observed among
participants with hypertension onset younger than 45
years of age. Notably, the risks of these outcomes
gradually declined with each decade increase in hy-
pertension onset age. Similar patterns were observed
for stroke. The trend remained robust among the
stratified analyses and multiple sensitivity analyses.
These findings suggest that patients with younger age
of hypertension onset had an increased risk of inci-
dent CVD and all-cause mortality.
Several studies have sought to investigate the as-
sociation between age and the prognosis of hyper-
tension. Findings from international databases on
ambulatory and home BP showed that the relative
risk for 20–mm Hg higher systolic BP on cardiovas-
cular outcomes attenuated with increasing age among
hypertensive individuals (6), whereas analysis in the
Framingham Heart Study did not observe a relative
risk decline in cardiovascular events with advancing
age among hypertensive individuals
studies (6,7) mainly focused on the prevalent hyper-
tension cases, whereas we identified incident hyper-
tension cases that occurred during the follow-up.
Therefore, we were able to reduce the influence of
the potential prevalence-incidence bias (30) that
was present when using prevalent cases. Addition-
ally, some studies have compared
consequences of early-onset hypertension with late-
onset hypertension. A multicenter cohort analysis
(N ¼ 10,313) in 1987 (21) showed that compared with
normotensive individuals of the same age group, pa-
tients with hypertension onset at 40 to 49 years of
age have significantly higher CVD risk than patients
with hypertension onset at 60 to 65 years of age.
However, this early study was based on an outdated
definition of hypertension (diastolic BP $90 mm Hg)
and lacked further adjustment for confounding fac-
tors. More recently, analyses from the Framingham
Heart Study (8) and the CARDIA (Coronary Artery Risk
Development in Young Adults) study (9) found that
compared with the normotensive population, in-
dividuals with early-onset hypertension have higher
odds of cardiovascular death (8) and target organ
damage (9) than individuals with late-onset hyper-
tension. However, these studies did not examine
nonfatal CVD and all-cause mortality. As mentioned
previously, there is a lack of prospective studies
comprehensively evaluating the relation of hyper-
tension new-onset age with incident CVD and all-
cause mortality, which have important clinical and
public health implications. There is a need for
bridging the disconnect between policies that address
hypertension treatment among older adults while
(7). These overlooking the remarkable cardiometabolic risks of
early-onset hypertension among young adulthood.
Our study suggested a novel perspective that hyper-
tension was associated with a higher risk for CVD and
all-cause mortality in Chinese adults, and the asso-
ciations were stronger with a younger age of onset.
The mechanisms underlying the associations of
the health higher CVD and all-cause mortality risks among
2926 Wang et al. JACC VOL. 75, NO. 23, 2020

Hypertension Onset Age With CVD and Mortality JUNE 16, 2020:2921–30

C E NT R AL IL L U STR AT IO N The Average Hazard Ratios (95% Confidence Interval) of Incident Cardiovascular
Disease and All-Cause Mortality of New-Onset Hypertensive Participants Across Age Groups

New-Onset
Hypertension Normotension Average Hazard Ratio Average Hazard Ratio
Hypertension
Onset Age Case/Total (95% CI) (95% CI)
Case/Total

Cardiovascular Disease (p for interaction = 0.38)

<45 yrs 26/2,712 66/2,712 2.26 (1.19-4.30)

45-54 yrs 157/6,020 266/6,020 1.62 (1.24-2.12)

55-64 yrs 249/7,105 348/7,105 1.42 (1.12-1.79)

≥65 yrs 245/4,050 315/4,050 1.33 (1.04-1.69)

All-cause mortality (p for interaction < 0.01)

<45 yrs 21/2,712 50/2,712 2.59 (1.32-5.07)

45-54 yrs 101/6,020 206/6,020 2.12 (1.55-2.90)

55-64 yrs 232/7,105 322/7,105 1.30 (1.03-1.62)

≥65 yrs 474/4,050 602/4,050 1.29 (1.11-1.51)

0.7 1 2 3 4 5 6
Wang, C. et al. J Am Coll Cardiol. 2020;75(23):2921–30.

This study of 39,774 Chinese adults suggested that the risks of cardiovascular disease and all-cause mortality gradually declined with increasing hypertension onset
age. The models were adjusted for body mass index, heart rate, fasting blood glucose, triglycerides, total cholesterol, estimated glomerular filtration rate, smoking
status, drinking status, and antihypertensive medication use. CI ¼ confidence interval.

younger hypertensive participants remain unclear.
Some potential explanations are as follows. First,
hypertension is generally recognized as a complex
disease that arises from both genetic predisposition
(31) and exposure to environmental factors (32,33).
Existing evidence suggested that early-onset hyper-
tension has been found to be more affected by he-
reditary susceptibility (8,34,35). Based
multigenerational analysis of the Framingham Heart
Study, researchers found that early-onset hyperten-
sion in grandparents raises the risk for hypertension
in grandchildren, even after adjusting for early-
onset hypertension in parents and lifestyle factors
(33). Previous studies have identified numerous ge-
netic loci and gene variants that are associated with
early-onset hypertension (35–38). Among
several genetic variants, including TMOD4, COL6A3,
CXCL8, MARCH1, PLCB2, and VPS33B have been
found to be associated with both early-onset
hypertension and early-onset MI (37). In addition,
findings from the International Consortium for
Blood Pressure Genome-Wide Association Studies
(39) and the CARDIoGRAM (Coronary Artery Disease
Genome-Wide Replication and Meta-Analysis) study
(40) also suggested that the genetic risk scores
based on hypertension-related single-nucleotide
on a polymorphisms are associated with left ventricular
hypertrophy, stroke, and coronary artery disease.
Based on this evidence, we infer that early-onset
hypertensive participants are very likely to be
genetically susceptible to hypertension. They may
carry some hypertension-related genetic variants
that would contribute to CVD and result in the
higher excess risk of cardiovascular events in this
them, group. On the other hand, younger-onset hyperten-
sion patients have the increased risk of left ven-
tricular hypertrophy, coronary calcification, and
multiple target organ damage including proteinuria
JACC VOL. 75, NO. 23, 2020 Wang et al. 2927
JUNE 16, 2020:2921–30 Hypertension Onset Age With CVD and Mortality

F I G U R E 1 The Average Hazard Ratios (95% Confidence Interval) of the Subtypes of Cardiovascular Disease of New-Onset Hypertension Participants
Across Age Groups

New-Onset
Hypertension Normotension Average Hazard Ratio Average Hazard Ratio
Hypertension
Onset Age Case/Total (95% CI) (95% CI)
Case/Total
MI (p for interaction = 0.56)

<45 yrs 8/2,712 11/2,712 1.53 (0.44-5.26)

45-54 yrs 44/6,020 51/6,020 0.98 (0.56-1.72)

55-64 yrs 69/7,105 78/7,105 0.89 (0.50-1.58)

≥65 yrs 70/4,050 56/4,050 1.04 (0.62-1.72)

0.5 1 2 3 4 5
Stroke (p for interaction = 0.56)

<45 yrs 18/2,712 55/2,712 2.59 (1.22-5.52)

45-54 yrs 118/6,020 220/6,020 1.85 (1.36-2.51)

55-64 yrs 183/7,105 278/7,105 1.62 (1.25-2.09)

≥65 yrs 181/4,050 266/4,050 1.39 (1.06-1.83)

0.5 1 2 3 4 5
IS (p for interaction = 0.75)

<45 yrs 15/2,712 46/2,712 2.42 (1.06-5.50)

45-54 yrs 102/6,020 194/6,020 1.73 (1.26-2.38)

55-64 yrs 168/7,105 252/7,105 1.59 (1.22-2.08)

≥65 yrs 155/4,050 234/4,050 1.40 (1.04-1.89)

0.5 1 2 3 4 5
HS (p for interaction = 0.14)

<45 yrs 3/2,712 9/2,712 5.85 (1.26-27.20)

45-54 yrs 18/6,020 32/6,020 2.83 (1.06-7.54)

55-64 yrs 20/7,105 31/7,105 1.87 (0.92-3.80)

≥65 yrs 28/4,050 41/4,050 1.65 (0.84-3.26)

0.2 0.5 1 10 30

The risks of cardiovascular disease subtypes of stroke also attenuated with the increasing hypertension onset age. The model adjustment was the same as
in the Central Illustration. CI ¼ confidence interval; HS ¼ hemorrhagic stroke; IS ¼ ischemic stroke; MI ¼ myocardial infarction.
2928 Wang et al. JACC VOL. 75, NO. 23, 2020

Hypertension Onset Age With CVD and Mortality JUNE 16, 2020:2921–30

F I G U R E 2 The Average Hazard Ratios (95% Confidence Interval) of Events Among Untreated and Treated New-Onset Hypertensive Participants Across Age
Groups

Hypertension Untreated New-Onset Hypertension Treated New-Onset Hypertension

Onset Age (N = 24,528) (N = 15,248)

CVD

<45 yrs 2.32 (1.26-4.27) 3.83 (1.01-14.53)

45-54 yrs 1.61 (1.23-2.11) 2.17 (1.26-3.73)

55-64 yrs 1.39 (1.09-1.78) 1.84 (1.09-3.12)

≥65 yrs 1.38 (1.08-1.77) 1.48 (0.81-2.70)

0.7 1 2 3 4 5 0.5 1 5 10 15
p for interaction < 0.01 p for interaction = 0.10

All-Cause Mortality

<45 yrs 2.14 (1.13-4.06) 3.07 (0.74-12.74)

45-54 yrs 1.95 (1.42-2.66) 2.81 (1.41-5.60)

55-64 yrs 1.37 (1.09-1.73) 1.69 (0.93-3.08)

≥65 yrs 1.33 (1.13-1.57) 1.30 (0.88-1.90)

0.7 1 2 3 4 5 0.5 1 5 10 15
p for interaction < 0.01 p for interaction = 0.17

The risks of cardiovascular disease (CVD) and all-cause mortality declined with the increasing age of hypertension onset in both untreated and treated patients. The
model adjustment was the same as in the Central Illustration, except antihypertensive medication use.

(9), which would consequently increase the risk of
CVD and all-cause mortality (41–43).
Although young adults <45 years of age have a
relatively low incidence of hypertension (4), most of
these young hypertensive patients are unaware of
their heightened cardiometabolic and mortality risk,
which would still translate into a great disease
burden. Our study suggests that the consideration of
hypertension onset age would provide novel and
preventive information beyond traditional cardio-
vascular risk assessment systems. Self-awareness of
the condition is the first step to modify behavior and
lifestyle changes. Our study also provides valuable
information in clinical treatment that early-onset
hypertensive patients need more stringent antihy-
pertensive therapy as early as possible to reduce the
burden of CVD and loss of life. More intensive life-
style interventions should also be actively encour-
aged, including weight loss, limiting salt intake,
smoking and alcohol cessation, and regular physical
exercise. It also highlights the need to include age at
hypertension diagnosis in cardioprotective guidelines
and policies. The 2018 European Society of Cardiol-
ogy/European Society of Hypertension guidelines for
the management of arterial hypertension suggest that
office BP should be reduced to 130/80 mm Hg for
hypertensive patients under 50 years of age (44).
However, this recommendation is based on observa-
tional research and lacks support from stronger evi-
dence. Large-scale randomized controlled trials are
still warranted to determine the ideal target BP levels
among young hypertensive patients.
STUDY STRENGTHS AND LIMITATIONS. Our study
has several strengths. We conducted this study in a
large prospective community cohort and put great
emphasis on data quality. The entire study popula-
tion was covered by biennial medical examinations
and medical information enquiries, which enabled us
JACC VOL. 75, NO. 23, 2020 Wang et al. 2929
JUNE 16, 2020:2921–30 Hypertension Onset Age With CVD and Mortality

to collect precise data on the occurrence time of new-
onset hypertension and track the outcome events in
all participants. We followed standard protocols
during the BP measurement process and the ascer-
tainment of the events, which avoided bias in self-
reported data. Additionally, we matched new-onset
hypertensive participants and normotensive partici-
pants on age and sex to consider and reduce the
confounding of these factors. Furthermore, previous
studies (8,9,21) on the differential effects of hyper-
tension onset ages were mostly conducted among
Caucasian populations. However, the total preva-
lence, age-specific prevalence (45), and genetic sus-
ceptibility (39) of hypertension vary greatly for
populations of different origins. By presenting find-
ings for the Asian population, our study fills a gap in
this research field.
The present study also has several potential limi-
tations. First, we determined whether the partici-
pants had hypertension by measuring their BP
multiple times and inquiring about their antihyper-
tensive medication history. We did not further screen
for the diagnosis of essential or secondary hyperten-
sion. However, a previous study suggested that only
5% to 10% of hypertension patients have secondary
hypertension (46), which had a minimal influence on
our results. Second, the present study is also limited
by the relatively short follow-up period and low
number of re-examinations over a short period of
time. Further studies with larger sample sizes and
long follow-up are still warranted.
with a younger age of onset. Currently, young hy-
pertensive patients tend to overlook potential health
hazards, which translates into high disease burden of
CVD in the coming decades. Our data suggest a need
to better target cardiovascular and mortality risk
among those with early-onset hypertension. There
are readily effective and available approaches to
mitigate the risk, notably early antihypertensive
treatment, dietary intervention, modification of un-
healthy lifestyles, and long-term BP management for
this population.
ACKNOWLEDGMENTS The authors thank all the
survey teams of the Kailuan study group for their
contribution and the study participants who contrib-
uted their information.
ADDRESS FOR CORRESPONDENCE: Dr. Hao Xue,
Department of Cardiology, Chinese PLA General
Hospital, 28 Fuxing Road, Beijing 100853, China.
E-mail: xuehaoxh301@163.com. OR Dr. Shouling Wu,
Department of Cardiology, Kailuan General Hospital,
57 Xinhua East Road, Tangshan 063000, China.
E-mail: drwusl@163.com.
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: Onset of hy-
pertension early in life is associated with a greater risk of adverse
outcomes than late-onset hypertension.

TRANSLATIONAL OUTLOOK: More aggressive efforts are

CONCLUSIONS
needed to identify hypertension earlier in life and develop
management strategies that sustain long-term blood pressure
Our study suggests that hypertension was associated
control.
with a higher risk for CVD and all-cause mortality in
Chinese adults, and the associations were stronger

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KEY WORDS cardiovascular disease risk,
early-onset hypertension, mortality risk
A PPE NDI X For supplemental tables and fig-
ures, please see the online version of this paper.