Journal of the American Heart Association

ORIGINAL RESEARCH

Cardiovascular Risk in Patients With Treated

Isolated Diastolic Hypertension and Isolated
Low Diastolic Blood Pressure
Wei-­Lun Chang, PhD; Ying-­Fan Chen, MD; Yu-­Hsuan Lee , MBA; Ming-­Neng Shiu , MD, PhD;
Po-­Yin Chang, PhD; Chao-­Yu Guo , PhD; Chi-­Jung Huang , PhD; Chern-­En Chiang , MD, PhD;
Chen-­Huan Chen , MD; Shao-­Yuan Chuang , PhD; Hao-­Min Cheng , MD, PhD

BACKGROUND: The prognosis of high or markedly low diastolic blood pressure (DBP) with normalized on-­treatment systolic
blood pressure on major adverse cardiovascular events (MACEs) is uncertain. This study examined whether treated isolated
diastolic hypertension (IDH) and treated isolated low DBP (ILDBP) were associated with MACEs in patients with hypertension.

METHODS AND RESULTS: A total of 7582 patients with on-­treatment systolic blood pressure <130 mm Hg from SPRINT (Systolic
Blood Pressure Intervention Trial) were categorized on the basis of average DBP: <60 mm Hg (n=1031; treated ILDBP), 60 to
79 mm Hg (n=5432), ≥80 mm Hg (n=1119; treated IDH). MACE risk was estimated using Cox proportional-­hazards models.
Among the SPRINT participants, median age was 67.0 years and 64.9% were men. Over a median follow-­up of 3.4 years,
512 patients developed a MACE. The incidence of MACEs was 3.9 cases per 100 person-­years for treated ILDBP, 1.9 cases
for DBP 60 to 79 mm Hg, and 1.8 cases for treated IDH. Comparing with DBP 60 to 79 mm Hg, treated ILDBP was associ-
ated with an 1.32-­fold MACE risk (hazard ratio [HR], 1.32, 95% CI, 1.05–1.66), whereas treated IDH was not (HR, 1.18 [95%
CI, 0.87–1.59]). There was no effect modification by age, sex, atherosclerotic cardiovascular disease risk, or cardiovascular
disease history (all P values for interaction >0.05).
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CONCLUSIONS: In this secondary analysis of SPRINT, among treated patients with normalized systolic blood pressure, exces-
sively low DBP was associated with an increased MACE risk, while treated IDH was not. Further research is required for
treated ILDBP management.

Key Words: major adverse cardiovascular events ■ treated isolated diastolic hypertension ■ treated isolated low diastolic blood
pressure

H
ypertension affects around 30% of adults glob-
ally1 and is associated with an increased cardio-
vascular risk.2–4 SPRINT (Systolic Blood Pressure
Intervention Trial) revealed that intensive treatment
targeting systolic blood pressure (SBP) <120 mm Hg
was superior to standard treatment targeting SBP
<140 mm Hg in reducing cardiovascular events by 25%
and all-­cause death by 27%.5 Consequently, the 2017
American College of Cardiology (ACC)/American Heart
Association (AHA) guideline revised the blood pressure
(BP) treatment target to <130/80 mm Hg.6
For the patients on antihypertensive treatment, while
the association between high SBP and cardiovascular
risk is well established, the potential harms posed by
elevated diastolic BP (DBP) is still debated, especially
when SBP achieves the target. This condition is known

Correspondence to: Hao-­Min Cheng, MD, PhD, National Yang Ming Chiao Tung University, No. 201, Sec. 2, ShihPai Road, Beitou District, Taipei, Taiwan
11217, ROC. Email: hmcheng@vghtpe.gov.tw
This manuscript was sent to Tazeen H. Jafar, MD, MPH, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Preprint posted on MedRxiv August 16, 2023. doi: https://​doi.​org/​10.​1101/​2023.​08.​11.​23294003.
Supplemental Material is available at https://​www.​ahajo​urnals.​org/​doi/​suppl/​​10.​1161/​JAHA.​123.​032771
For Disclosures, see page 8.
Disclaimer: This article reflects the views of the authors and does not represent the views of U.S. Food and Drug Administration or the United States.
© 2024 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use
is non-commercial and no modifications or adaptations are made.
JAHA is available at: www.ahajournals.org/journal/jaha

J Am Heart Assoc. 2024;13:e032771. DOI: 10.1161/JAHA.123.0327711

 Chang et al
CLINICAL PERSPECTIVE
What Is New?
• Our secondary analysis of SPRINT (Systolic
Blood Pressure Intervention Trial) including pa-
tients with treated hypertension with normalized
systolic blood pressure showed that treated
isolated low diastolic blood pressure was inde-
pendently associated with an increased risk of
major adverse cardiovascular events.
• The association of treated isolated low diastolic
blood pressure and major adverse cardiovas-
cular events was consistent regardless of age,
sex, atherosclerotic cardiovascular disease risk,
and cardiovascular disease history.
What Are the Clinical Implications?
• Our study suggests the potential clinical sig-
nificance of treated isolated low diastolic
blood pressure in relation with major adverse
cardiovascular events among patients with
hypertension.
Nonstandard Abbreviations and Acronyms
IDACO International Database of Ambulatory
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Blood Pressure in Relation to
Cardiovascular Outcome
IDH isolated diastolic hypertension
ILDBP isolated low diastolic blood pressure
MACE major adverse cardiovascular event
SPRINT Systolic Blood Pressure Intervention
Trial
as treated isolated diastolic hypertension (IDH). Most
studies examining the ACC/AHA definition of IDH have
not found its correlation with cardiovascular disease,7–11
except in Asian populations and young adults.12–16 The
focus of these studies was primarily on treatment-­naive
individuals, leaving this correlation for antihypertensive
drug–treated patients uncertain. Additionally, concerns
also exist regarding the potential negative impact of ex-
cessive reduction of DBP, which could offset the car-
diovascular benefits of reducing SBP.
The 2018 European Society of Cardiology/European
Society of Hypertension guideline recommended a
DBP target range of 70 to 80 mm Hg for all risk lev-
els,17 while the ACC/AHA guideline did not specify a
lower limit of DBP for antihypertensive drug–treated
patients.6 However, these recommendations were
primarily based on expert opinion rather than empir-
ical evidence. It remains unknown whether high or
J Am Heart Assoc. 2024;13:e032771. DOI: 10.1161/JAHA.123.0327712
Cardiovascular Risk With Isolated High and Low DBP
extremely low DBP is associated with increased car-
diovascular risk in antihypertensive drug–treated pa-
tients with normalized SBP.
To answer this question, we conducted a second-
ary analysis of SPRINT to determine if treated IDH and
treated isolated low DBP (ILDBP) were associated with
major adverse cardiovascular events (MACEs) in pa-
tients with on-­treatment SBP <130 mm Hg.
METHODS
Study Design, Data Sources, and Study
Participants
We analyzed data from the SPRINT study. Anonymized
data and materials have been made publicly avail-
able at the National Heart, Lung, and Blood Institute’s
Biologic Specimen and Data Repository Information
Coordinating Center and can be accessed at https://​
bioli​ncc.​nhlbi.​nih.​gov/​studi​es/​sprint/​. The SPRINT pro-
tocol was approved by the institutional review boards
at the participating locations, and all participants gave
their informed permission. The procedure for the study
was approved by the Institutional Review Board of
Taipei Veterans General Hospital, and informed con-
sent was waived as the data used were deidentified.
This study adhered to Strengthening the Reporting of
Observational Studies in Epidemiology guidelines for
cohort studies (Data S1).18
SPRINT5 was an open-­label, randomized controlled
trial, which enrolled 9361 participants between 2010
and 2013 aged ≥50 years with SBP between 130 and
180 mm Hg, who had an increased cardiovascular
risk and no history of diabetes or stroke. The partici-
pants were randomly assigned to achieve an SBP goal
of <120 mm Hg (intensive treatment) or <140 mm Hg
(standard treatment). BP measurements and antihy-
pertensive drug adjustments were scheduled monthly
for the first 3 months, and every 3 months thereafter.
The trial intervention was terminated early in 2015 due
to a significantly lower rate of the primary composite
outcomes in the intensive treatment group than in the
standard treatment group.
Our study used SPRINT data from each partici-
pant’s initial visit to their final visit. During the inter-
vention and post-­intervention periods, comprehensive
participant information was meticulously recorded in
the SPRINT data. For instance, demographic informa-
tion was collected at the outset. During the follow-­up
period, clinical and laboratory data were collected at
baseline and every 3 months. At each study visit, BP
and antihypertensive drug use were recorded.
We selected participants from the SPRINT trial
whose SBP readings during treatment were consis-
tently <130 mm Hg. We identified eligible participants
by including those who had at least 2 consecutive
 Chang et al Cardiovascular Risk With Isolated High and Low DBP

SBP readings <130 mm Hg. Figure Table S1 provides
details on the subject selection process. To establish
the starting point for follow-­up, we designated the date
of the first SBP reading <130 mm Hg as the index date.
Cardiovascular Outcomes and Follow-­Up
The primary outcome was composed of MACEs, in-
cluding coronary heart disease (myocardial infarction
and non–myocardial infarction acute coronary syn-
dromes), stroke, heart failure, or cardiovascular death,
occurring after the index date. Secondary outcomes
were each individual component of the primary com-
posite outcome.
Follow-­up for all study participants started from the
index date until the first occurrence of MACE, the date
of non-­cardiovascular death, or the last SPRINT visit.
Participant Classification Based on DBP
Levels
Each participant’s DBP levels were calculated from all
follow-­up visits. For each participant, we calculated an
average value by multiplying the DBP measured at each
follow-­up visit by the proportion of days between the
date of BP measurement and the next measurement.
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Using a multivariable adaptive regression spline
analysis for MACE, the lower limit for average DBP
during follow-­up visits was established at 60 mm Hg
(Figure 1). Participants were divided into 3 groups
on the basis of their on-­treatment DBP: <60 mm Hg
(treated ILDBP), 60 to 79 mm Hg, and ≥80 mm Hg
(treated IDH).
Statistical Analysis
Characteristics of study participants in each DBP
group were summarized as means and SDs (continu-
ous variables) or counts and percentages (categorical
variables). We examined differences in characteris-
tics between groups using analysis of variance tests
and χ2 tests. Time-­varying Cox proportional-­hazards
model was used to estimate the MACE risk, com-
paring treated IDH or treated ILDBP with DBP 60 to
79 mm Hg, with adjustment for time-­varying SBP over
the follow-­up, as well as time-­invariant demographic
characteristics, clinical and laboratory features, smok-
ing status, history of cardiovascular disease, number
of antihypertensive drugs, risk of atherosclerotic car-
diovascular disease (ASCVD), and assigned treatment.
In addition to the analysis of 3 DBP groups, the aver-
age DBP was analyzed using deciles as a categorical

Figure 1. Cubic-­ spline curve for the association between average diastolic blood
pressure and risk of major adverse cardiovascular events.
The solid line indicates the hazard ratio for major adverse cardiovascular events, and the
dotted line indicates the 95% CI. The hazard ratios were adjusted for age, sex, race, body mass
index, total cholesterol, high-­density lipoprotein cholesterol, plasma glucose, serum creatinine,
smoking status, history of cardiovascular disease, number of antihypertensive drugs, risk of
atherosclerotic cardiovascular disease, assigned treatment, and systolic blood pressure. The
mean of average diastolic blood pressure (70 mm Hg) was used as a reference.

J Am Heart Assoc. 2024;13:e032771. DOI: 10.1161/JAHA.123.0327713

 Chang et al
variable. Due to the nonlinear relationship between av-
erage DBP and cardiovascular disease, we used the
deviation from the mean coding to estimate the risk
in the deciles of average DBP.19 SBP, age, clinical and
laboratory characteristics, number of antihyperten-
sive drugs, and ASCVD risk were treated as continu-
ous variables, whereas the remaining variables were
treated as categorical variables. To reduce potential
bias due to missing data, missing values on covariates
were estimated using multiple imputations. Results of
Cox proportional-­hazards models were presented as
hazard ratios (HRs) and 95% CIs.
Subgroup analyses were performed to explore
whether the HR for MACEs in relation to the DBP groups
differed between age (50–64 years and ≥65 years), sex
(male and female), ASCVD risk (<10% and ≥10%), and
history of cardiovascular disease (yes and no).
Sensitivity analyses were performed to assess the
robustness of results. In the initial analysis, the Cox
proportional-­hazards models were repeated after ad-
ditional adjustment for duration between the start of
SPRINT follow-­up and index date. In the second analy-
sis, we used 85 mm Hg or 90 mm Hg as a cutoff deter-
mining the treated IDH group to examine if the risk for
treated IDH would vary with different thresholds. In the
third analysis, given the high degree of correlation be-
tween SBP and DBP, we decorrelated the 2 BP indices
by regressing SBP on DBP and using the SBP residual
to estimate the HRs. Following this, a heat map was
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created to illustrate the contribution of the DBP and
SBP in their associations with MACEs.
A 2-­tailed P value of <0.05 was considered to indi-
cate statistical significance. Data processing and sta-
tistical analyses were performed using SAS version 9.4
(SAS Institute, Cary, NC).
RESULTS
Characteristics of Study Participants
A total of 7582 SPRINT participants aged ≥50 years with
at least 2 consecutive readings of SBP <130 mm Hg
were identified for analysis (Figure S1). These partici-
pants’ median age was 67.0 years, and 64.9% were
men. The participants were divided into 3 groups
according to their average DBP levels: <60 mm Hg
(n=1031), 60 to 79 mm Hg (n=5432), and ≥80 mm Hg
(n=1119). Compared with the other 2 DBP groups,
treated ILDBP participants were more likely to be older
and never smokers, have a lower body mass index and
total cholesterol, and have greater risk of ASCVD. The
participants with treated IDH, who were more likely to
be younger and active smokers, had a greater body
mass index and total cholesterol but a decreased risk
of ASCVD (Table 1).
J Am Heart Assoc. 2024;13:e032771. DOI: 10.1161/JAHA.123.0327714
Cardiovascular Risk With Isolated High and Low DBP
Overall Analyses
During a median (interquartile range) follow-­up of 3.4
(2.7–4.0) years, 512 participants developed MACEs.
Figure S2 illustrates the HRs and 95% CIs for MACEs
according to deciles of average DBP, with adjustment
for covariates. Only in the lowest decile group (average
DBP <58 mm Hg) was the risk significantly higher than
the population average risk (adjusted HR [aHR]: 1.40
[95% CI, 1.10–1.77]).
When participants were divided into 3 DBP groups,
the incidence of MACEs per 100 person-­years were 3.9
for treated ILDBP, 1.9 for DBP 60 to 79 mm Hg, and 1.8
for treated IDH. Compared with DBP 60 to 79 mm Hg,
treated ILDBP was associated with an 1.32-­fold risk
of MACEs (aHR, 1.32 [95% CI, 1.05–1.66]), whereas
treated IDH was not (aHR, 1.18 [95% CI, 0.87–1.59];
Table 2). Treated ILDBP was associated with an in-
creased risk for all MACE types, with coronary heart
disease having the highest risk (aHR, 1.37 [95% CI,
1.28–1.46]; Table 2).
Subgroup Analyses
There was no effect modification by age group, sex,
ASCVD risk, or cardiovascular disease history. The
aHR for MACEs in treated ILDBP was similar between
participants aged 50 to 64 years and those aged
≥65 years (P value for interaction=0.7994). The same
was observed for treated IDH (P value for interac-
tion=0.0550; Figure 2). The aHR of MACEs in treated
ILDBP and treated IDH were comparable in male and
female participants (P value for interaction for treated
ILDBP=0.5491; for treated IDH=0.4952), as well as in
participants with low and high ASCVD risk (P value
for interaction for treated ILDBP=0.9785; for treated
IDH=0.1381; Figure 2). The correlation between
treated ILDBP or treated IDH and MACEs remained
consistent for both patients with and without a car-
diovascular disease history (P value for interaction
for treated ILDBP=0.8214; for treated IDH=0.4322;
Figure 2).
Sensitivity Analyses
The results of the first sensitivity analysis, with fur-
ther adjustment for the length of time between the
start of the SPRINT follow-­ up and the index date,
were comparable to those found in the primary analy-
sis (Table 2). The second sensitivity analysis applying
other treated IDH cutoffs gave comparable results to
the initial analysis (Table S1). The third sensitivity analy-
sis using the residual method revealed an association
between treated ILDBP (aHR, 1.34 [95% CI, 1.07–1.69])
or treated IDH (aHR, 1.15 [95% CI, 0.75–1.56]) and
MACEs comparable to the primary analysis. The heat
map revealed that along the vertical axis, the 3-­year
 Chang et al Cardiovascular Risk With Isolated High and Low DBP

Table 1. Characteristics of the Study Participants by DBP Group

DBP <60 mm Hg DBP 60–79 mm Hg DBP ≥80 mm Hg

Characteristics (n=1031) (n=5432) (n=1119) P value

Age, y 76.6±7.4 68.0±8.9 61.5±7.0 <0.0001

Age group, n (%) <0.0001
50–64 y 79 (7.7) 2112 (38.9) 791 (70.7)
≥65 y 952 (92.3) 3320 (61.1) 328 (29.3)
Male, n (%) 673 (65.3) 3494 (64.3) 751 (67.1) 0.1959
Race or ethnicity, n (%) <0.0001
White 730 (70.8) 3237 (59.6) 502 (44.9)
Black 186 (18.0) 1535 (28.3) 515 (46.0)
Hispanic 90 (8.7) 553 (10.2) 90 (8.0)
Other 25 (2.4) 107 (2.0) 12 (1.1)
SBP at the index date, mm Hg 119.6±7.6 119.2±7.6 120.4±7.5 <0.0001
DBP at the index date, mm Hg 56.0±7.0 68.7±8.0 78.1±7.1 <0.0001
PP at the index date, mm Hg 63.7±8.3 50.6±8.3 42.2±6.6 <0.0001
2
Body mass index, kg/m 28.0±5.4 30.1±5.7 31.5±6.0 <0.0001
Total cholesterol, mg/dL 178.0±37.7 188.4±41.4 196.5±41.5 <0.0001
HDL cholesterol, mg/dL 54.1±14.4 52.4±14.0 51.4±13.7 0.0015
Plasma glucose, mg/dL 98.6±11.3 99.1±14.9 98.4±17.2 0.5338
Serum creatinine, mg/dL 1.2±0.5 1.1±0.4 1.1±0.4 <0.0001
Smoking status, n (%) <0.0001
Current 65 (6.3) 644 (11.9) 217 (19.4)
Noncurrent 965 (93.6) 4785 (88.1) 900 (80.4)
Missing data 1 (0.1) 3 (0.1) 2 (0.2)
Diabetes history, n (%) 0 (0.0) 10 (0.2) 0 (0.0) 0.2113
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CVD history, n (%) 313 (30.4) 1127 (20.8) 150 (13.4) <0.0001
No. of antihypertensive drugs 2.8±1.2 2.3±1.1 2.0±1.1 <0.0001
ASCVD risk, % 26.9±12.8 17.1±10.3 12.5±6.0 <0.0001
ASCVD risk group, n (%) <0.0001
<10% 38 (3.7) 929 (17.1) 242 (21.6)
≥10% 607 (58.9) 2761 (50.8) 462 (41.3)
Missing data 386 (37.4) 1742 (32.1) 415 (37.1)
Intensive treatment, n (%) 810 (78.6) 3398 (62.6) 208 (18.6) <0.0001
Duration between the start of SPRINT 179.8±287.4 166.6±278.1 208.9±308.2 <0.0001
follow-­up and index date, days

Data are expressed as mean±SD or n (%). ASCVD indicates atherosclerotic cardiovascular disease; CVD, cardiovascular disease; DBP, diastolic blood
pressure; HDL, high-­density lipoprotein; PP, pulse pressure; SBP, systolic blood pressure; and SPRINT, Systolic Blood Pressure Intervention Trial.

risk of MACEs was significantly associated with DBP
levels (P value=0.0068; Figure S3).
DISCUSSION
This study investigated the association between
treated IDH and treated ILDBP with MACEs in
antihypertensive-­treated patients with normalized SBP.
The analysis of SPRINT indicated that individuals with
treated ILDBP had a higher risk of MACEs compared
with those with normalized SBP and DBP between 60
and 79 mm Hg, while treated IDH did not. These find-
ings were consistent across different age groups, sex,
atherosclerotic cardiovascular disease risk, and car-
diovascular disease history. This study is the first to
observe and establish an association between isolated
high and low DBP and MACEs in patients who have
been treated with antihypertensive drugs.
In our analysis, patients classified as having treated
IDH according to the 2017 ACC/AHA guidelines
showed similar risk of MACEs compared with those
with DBP between 60 and 79 mm Hg. However, pre-
vious studies examining the cardiovascular risk of IDH
have produced conflicting results, which may be due to
variations in study comparators or the low prevalence
of IDH among older individuals. For example, Yano et al

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 Chang et al Cardiovascular Risk With Isolated High and Low DBP

Table 2. Event Rates and HRs of MACEs by DBP Group

Event rate Unadjusted Adjusted* Adjusted†

per 100
No. of person-­
Outcome events (%) years HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value

Primary outcome
MACEs
DBP 60–79 mm Hg 328 (6.0) 1.9 Reference Reference Reference
DBP ≥80 mm Hg 61 (5.5) 1.8 0.95 (0.84–1.07) 0.4137 1.18 (0.87–1.59) 0.2986 1.19 (0.88–1.61) 0.2616
DBP <60 mm Hg 123 (11.9) 3.9 2.12 (1.93–2.32) <0.0001 1.32 (1.05–1.66) 0.0188 1.32 (1.05–1.67) 0.0186
Secondary outcome
Coronary heart disease
DBP 60–79 mm Hg 159 (2.9) 0.9 Reference Reference Reference
DBP ≥80 mm Hg 29 (2.6) 0.8 0.93 (0.78–1.11) 0.4305 1.06 (0.97–1.16) 0.1919 1.04 (0.95–1.14) 0.3712
DBP <60 mm Hg 58 (5.6) 1.8 2.07 (1.81–2.36) <0.0001 1.37 (1.28–1.46) <0.0001 1.38 (1.29–1.49) <0.0001
Stroke
DBP 60–79 mm Hg 62 (1.1) 0.3 Reference Reference Reference
DBP ≥80 mm Hg 8 (0.7) 0.2 0.66 (0.48–0.92) 0.0134 1.09 (1.00–1.18) 0.0443 1.06 (0.97–1.14) 0.1958
DBP <60 mm Hg 24 (2.3) 0.7 2.14 (1.73–2.64) <0.0001 1.33 (1.26–1.42) <0.0001 1.35 (1.27–1.44) <0.0001
Heart failure
DBP 60–79 mm Hg 90 (1.7) 0.5 Reference Reference Reference
DBP ≥80 mm Hg 15 (1.3) 0.4 0.90 (0.70–1.14) 0.3749 1.01 (0.93–1.10) 0.8287 0.99 (0.91–1.08) 0.8055
DBP <60 mm Hg 45 (4.4) 1.4 3.10 (2.65–3.63) <0.0001 1.30 (1.22–1.38) <0.0001 1.31 (1.23–1.40) <0.0001
Cardiovascular death
DBP 60–79 mm Hg 54 (1.0) 0.3 Reference Reference Reference
DBP ≥80 mm Hg 13 (1.2) 0.4 1.28 (0.98–1.68) 0.0744 1.04 (0.96–1.12) 0.3682 1.02 (0.94–1.10) 0.6991
DBP <60 mm Hg 26 (2.5) 0.8 2.85 (2.31–3.50) <0.0001 1.31 (1.23–1.39) <0.0001 1.32 (1.25–1.41) <0.0001
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DBP indicates diastolic blood pressure; HR, hazard ratio; MACEs, major adverse cardiovascular events; and SPRINT, Systolic Blood Pressure Intervention
Trial.
*Adjusted for age, sex, race, body mass index, total cholesterol, high-­density lipoprotein cholesterol, plasma glucose, serum creatinine, smoking status,
history of cardiovascular disease, number of antihypertensive drugs, risk of atherosclerotic cardiovascular disease, assigned treatment, and systolic blood
pressure.
†
Adjusted for age, sex, race, body mass index, total cholesterol, high-­density lipoprotein cholesterol, plasma glucose, serum creatinine, smoking status,
history of cardiovascular disease, number of antihypertensive drugs, risk of atherosclerotic cardiovascular disease, assigned treatment, systolic blood pressure,
and duration between the start of SPRINT follow-­up and index date.

found discrepant outcomes in different age groups,
suggesting the heterogeneity of patients with IDH and
the need for extensive phenotyping to identify those at
higher cardiovascular risk.19 This highlights the need for
extensive phenotyping to identify patients with IDH at
higher risk for cardiovascular disease, as they are likely
a heterogeneous group. Jacobsen et al also noted that
individuals with stage 1 IDH did not consistently exhibit
elevated cardiovascular disease risk compared with
those with normal BP.20 Therefore, these patients do
not require drug treatment and should instead undergo
lifestyle changes, interval BP checks, and only con-
sidered for drug treatment if systolic hypertension or
stage 2 IDH develops. Some meta-­analyses and the
IDACO (International Database of Ambulatory Blood
Pressure in Relation to Cardiovascular Outcome) trial
have found increased cardiovascular risk in young
patients with IDH but not overall mortality rate,19,21,22
which contrasts with previous studies. The physiolog-
ical explanation for this discrepancy remains unclear.
Additionally, a study using a DBP threshold of
90 mm Hg did not show a significant increase in the
risk of MACEs in IDH on the basis of European Society
of Cardiology/European Society of Hypertension crite-
ria.17 Several post hoc studies that found a linear as-
sociation between DBP level and cardiovascular risk
seem to challenge this finding.23 The heightened sus-
ceptibility to high DBP observed in the post hoc stud-
ies can be attributed to the strong correlation between
high DBP and elevated SBP, which is known to be as-
sociated with cardiovascular risk. Per the definition, IDH
studies excluded patients with high SBP. Therefore,
we can observe the independent correlation between
DBP and cardiovascular risk. Furthermore, our study
revealed an elevated risk in the treated ILDBP group
when using a cutoff of 130/80 mm Hg, indicating that
the ACC/AHA classification for hypertension accurately
assesses this unique phenotype. Notably, our research
demonstrated that lower DBP levels were associated
with worse clinical outcomes, with treated ILDBP

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 Chang et al Cardiovascular Risk With Isolated High and Low DBP
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Figure 2. Subgroup analyses of hazard ratios of major adverse cardiovascular events

according to age, sex, risk of atherosclerotic cardiovascular disease, and history of
cardiovascular disease.
*Adjusted for age, sex, race, body mass index, total cholesterol, high-­ density lipoprotein
cholesterol, plasma glucose, serum creatinine, smoking status, history of cardiovascular
disease, number of antihypertensive drugs, risk of atherosclerotic cardiovascular disease,
assigned treatment, and systolic blood pressure. †Adjusted for age, race, body mass index,
total cholesterol, high-­
density lipoprotein cholesterol, plasma glucose, serum creatinine,
smoking status, history of cardiovascular disease, number of antihypertensive drugs, risk
of atherosclerotic cardiovascular disease, assigned treatment, and systolic blood pressure.
‡
Adjusted for age, sex, race, body mass index, total cholesterol, high-­ density lipoprotein
cholesterol, plasma glucose, serum creatinine, smoking status, number of antihypertensive
drugs, risk of atherosclerotic cardiovascular disease, assigned treatment, and systolic blood
pressure. ASCVD indicates atherosclerotic cardiovascular disease; CVD, cardiovascular
disease; DBP, diastolic blood pressure; and HR, hazard ratio.

posing a higher risk compared with DBP in the range
of 60 to 79 mm Hg. This J-­curve pattern has been ob-
served in previous studies, including Khan et al.24 Their
analysis of SPRINT data revealed that DBP <55 mm Hg
was associated with 25% higher risk compared with
70 mm Hg. This may be due to intensive treatment
affecting coronary artery blood flow autoregulation and
increasing the risk of ischemia. Lee et al found a higher
risk of adverse outcomes in SPRINT participants ex-
periencing diastolic hypotension with a baseline DBP
≥65 mm Hg.25 Further randomized controlled trials are
needed to clarify this issue.

J Am Heart Assoc. 2024;13:e032771. DOI: 10.1161/JAHA.123.0327717

 Chang et al
The results of our study showed a clear indication
of vascular aging in the form of treated ILDBP, which
closely resembles isolated systolic hypertension.
Vascular aging is characterized by increased arterial
stiffness and pulse pressure,26 which significantly in-
creases the risk of hypertension in middle-­aged and
elderly individuals. This process results in heightened
arterial rigidity and wave reflection, which raises cen-
tral BP. Previous longitudinal studies corroborate this
viewpoint.27–29 Our research confirmed the signifi-
cance of identifying treated ILDBP in the context of
vascular aging, similar to isolated systolic hyperten-
sion. Our study is one of the first to introduce a new
phenotype of hypertension related to arterial stiffness,
particularly in the context of intensive BP control.
Given the well-­established role of SBP as a major car-
diovascular risk factor requiring intensive treatment, it
is crucial for patients with treated ILDBP to maintain
SBP levels within the target range. Further research
is needed to develop effective treatment strategies for
treated ILDBP.
In Figure S3, we generated a heat map to illustrate
the impact of DBP and SBP on their associations with
MACEs. The heat map indicated that patients with
an SBP ranging from 100 to 110 mm Hg and a DBP
of ≥80 mm Hg had an increased risk of MACEs. To
thoroughly investigate the risk of MACEs in this par-
ticular group, we specifically chose patients with SBP
levels ranging from 100 to 110 mm Hg. Our objective
Downloaded from http://ahajournals.org by on April 14, 2024
was to evaluate the MACE risk for individuals with
DBP levels <60 mm Hg, as well as those with DBP
levels ≥80 mm Hg. The risk of MACEs was not signifi-
cantly higher in patients with DBP <60 mm Hg (aHR,
1.22 [95% CI, 0.57–2.59]) and ≥80 mm Hg (aHR, 2.58
[95% CI, 0.85–7.84]) compared with those with DBP
between 60 and 79 mm Hg. However, it is important to
note that these findings are based on a relatively small
sample size of 684 and 368 patients, respectively, in
these populations. Additional research is required to
examine the cardiovascular risk in patients with very
low SBP and varying DBP levels.
Our study has notable merits. First, we included a
significant number of treated patients with hyperten-
sion by selecting participants from SPRINT. Moreover,
in the secondary analysis of the SPRINT study, we used
the average of multiple BP measurements to classify
DBP, thus reducing the likelihood of misclassification
bias when determining DBP status. Additionally, we
considered repeated SBP readings as a time-­varying
variable to account for their contribution to cardiovas-
cular events.
Our study has several limitations. First, since we
assessed secondary data from a randomized con-
trolled trial, unmeasured confounding cannot be ruled
out completely. Second, the absence of biomarkers
of vascular aging hinders our understanding of the
J Am Heart Assoc. 2024;13:e032771. DOI: 10.1161/JAHA.123.0327718
Cardiovascular Risk With Isolated High and Low DBP
underlying mechanism between treated low DBP and
cardiovascular risk. Although our findings suggest the
existence of a new hypertension phenotype, treated
ILDBP, confirming the causal relationship between
on-­treatment low DBP and increased risk requires
randomized controlled trials. Third, the participants
of SPRINT were 50 years of age or older and without
diabetes or a history of stroke, which limits generaliz-
ability to younger adults or populations with diabetes
and stroke.
In conclusion, in antihypertensive-­treated patients
with SBP of <130 mm Hg, excessively low DBP was
associated an increased MACE risk, and there is no
evidence of higher MACE risk for treated IDH. Further
study is needed to develop appropriate treatments for
treated ILDBP.
ARTICLE INFORMATION
Received September 21, 2023; accepted March 8, 2024.
Affiliations
Division of Faculty Development (W-L.C., Y-H.L., H-M.C.) and Department
of Internal Medicine (Y-F.C.), Taipei Veterans General Hospital, Taipei,
Taiwan, Department of Pharmacy, College of Pharmaceutical Sciences,
National Yang Ming Chiao Tung University, Taipei, Taiwan (M-N.S.); Office
of Surveillance and Epidemiology, Center for Drug Evaluation and Research,
US Food and Drug Administration, Silver Spring, MD (P-Y.C.); Division of
Biostatistics and Data science, Institute of Public Health, College of Medicine,
National Yang Ming Chiao Tung University, Taipei, Taiwan (C-Y.G.); Center
for Evidence-­ based Medicine, Taipei Veterans General Hospital, Taipei,
Taiwan (C-J.H., H-M.C.); School of Medicine, College of Medicine, National
Yang Ming Chiao Tung University, Taipei, Taiwan (C-E.C., C-H.C.); Division
of Cardiology, Department of Medicine, Taipei Veterans General Hospital,
Taipei, Taiwan (C-E.C., C-H.C.); ReShining Clinic, Taipei, Taiwan (C-H.C.);
Institute of Population Health Science, National Health Research Institutes,
Miaoli County, Taiwan (S-Y.C.); Ph.D. Program of Interdisciplinary Medicine
(PIM) (H-M.C.), Institute of Public Health (H-M.C.) and Institute of Health and
Welfare Policy (H-M.C.), National Yang Ming Chiao Tung University College of
Medicine, Taipei, Taiwan.
Acknowledgments
The authors gratefully acknowledge the participants involved in SPRINT. The
authors also express gratitude to the investigators who took part in data col-
lection and management.
Disclosures
None.
Source of Funding
This work was supported by the Health Promotion Administration, Ministry of
Health and Welfare, Taiwan (MOHW112-­HPA-­H-­113-­0 00102).
Supplemental Material
Table S1
Figures S1–S3
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