Medscimonit 25 5717

CLINICAL RESEARCH
e-ISSN 1643-3750
© Med Sci Monit, 2019; 25: 5717-5726
DOI: 10.12659/MSM.914482
Received: 2018.12.06
Accepted: 2019.03.21 Effect of Intensive Blood Pressure Control on
Published: 2019.08.01
Carotid Morphology and Hemodynamics in
Chinese Patients with Hyperhomocysteinemia-
Type Hypertension and High Risk of Stroke
Authors’ Contribution: ABCDEF 1 Wenjing Wu 1 Department of Cardiology, China-Japan Friendship Hospital, Beijing, P.R. China
Study Design A BCDE 2 Jian Liu 2 Department of Ultrasound Diagnosis, China-Japan Friendship Hospital, Beijing,
Data Collection B P.R. China
Analysis C
Statistical BCD 1 Aili Li

Data Interpretation D BCD 1 Jiahui Li
Manuscript Preparation E BCD 1 Yiyun Yang
Literature Search F
Collection G
Funds ACG 1 Xiaojun Ye
ACG 1 Jingang Zheng
Corresponding Authors: Xiaojun Ye, e-mail: [email protected], Jingang Zheng, e-mail: [email protected]
Source of support: This work was supported by grants from the National Natural Science Fund (91639110), the Beijing Natural Science Foundation
(7172195), and the China-Japan Friendship Hospital research topic within the hospital (2014-4-MS-23)
Background: Different blood pressure targets should be formulated for different groups of people. This study aimed to as-
sess the effectiveness of intensive blood control in improving the carotid morphology and hemodynamics in
Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke.
Material/Methods: Chinese hypertensive patients with high risk of stroke were randomized to intensive (n=187) and standard
(n=192; controls) blood pressure management groups. Systolic blood pressure (SBP) targets were 100< SBP
£120 and 120< SBP £140 mmHg, respectively. All patients received folic acid 0.8 mg/d and atorvastatin 20 mg/d.
Calcium antagonist was first used. If blood pressure was still uncontrolled, angiotensin-converting enzyme in-
hibitor or angiotensin receptor antagonist, b-receptor blocker, and diuretics were added successively. Follow-
up was 12 months. Carotid features, hemodynamics, and adverse events were examined.
Results: There were no differences in sex, age, body mass index, blood lipids, baseline carotid parameters, and histo-
ries of smoking, diabetes, statin use, and stroke between the 2 groups. Carotid plaques after 12 months of
treatment were 19.4±2.1 and 23.6±3.1 cm2 for the intensive and control groups, respectively (P=0.038). Plaque
scores were lower in the intensive group (1.75±0.52 vs. 2.45±0.47, P=0.023). Compared with controls, intensive
management resulted in relatively higher Vd and significantly lower Vs/Vd, PI, and RI (all P<0.05). Major ad-
verse events such as hypotension (n=5 (2.7%) vs. 3 (1.6%), P=0.020) and dizziness (n=20 (10.7%) vs. 16 (8.3%),
P=0.041) were more frequent in the intensive group.
Conclusions: Intensive blood pressure management could be beneficial for Chinese patients with hyperhomocysteinemia-
type hypertension and high risk of stroke.
MeSH Keywords: Hypertension • Risk • Stroke
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Wu W. et al.:
CLINICAL RESEARCH Blood pressure control and H-type hypertension
© Med Sci Monit, 2019; 25: 5717-5726
Background the morphologic features of the carotids and the hemody-

namics in patients with H-type hypertension and high risk of
Hypertension with hyperhomocysteinemia, or ‘H-type hyper- stroke. The resulting findings could provide valuable evidence
tension’ (serum homocysteine, Hcy ³10 µmol/L), is an impor- for larger clinical trials focusing on hypertension management.
tant risk factor for cardiovascular events and stroke [1]. Its in-
cidence is significantly higher in China compared with other
countries, representing 75% of Chinese patients with hyper- Material and Methods
tension [2]. In addition, significantly elevated stroke incidence
and mortality are found in China compared with global aver- Study design and patients
ages, despite lower coronary heart disease incidence and mor-
tality [3]. Low rates of awareness, treatment, and control rates This was a randomized, open-label, controlled trial of con-
of hypertension in China can also be involved in the epidemi- secutive patients with H-type hypertension who visited the
ology of stroke [4]. Patients with H-type hypertension are ad- Department of Cardiology of China-Japan Friendship Hospital
vised to consume folate-rich foods as a general lifestyle inter- between January 2013 and October 2015. The study was ap-
vention for hypertension and to take supplemental folic acid in proved by the Ethics Committee of China-Japan Friendship
combination with blood pressure control [2,5]. A meta-analy- Hospital (ethics approval number: 2015-107). Signed written
sis in 2007 [6] indicated that folic acid supplementation could informed consent was obtained from all patients. This study
decrease the risk of stroke by 18% in patients with H-type hy- was registered (#ChiCTR-INR-16009437).
pertension and high-risk factors for stroke, corroborating an-
other meta-analysis [7]. A randomized, double-blind, controlled The inclusion criteria were according to those of the ACCORD
CSPPT clinical trial which assessed 20 702 adult hypertensive study [11]: 1) £75 years of age; 2) H-type primary hyperten-
patients in China (without stroke or myocardial infarction) com- sion (serum Hcy >10 µmol/L) [1]; and 3) at least 1 high-risk
prised 2 groups receiving enalapril maleate10 mg and folic acid factor for stroke among the following: a) ³40 years old with
0.8 mg vs. enalapril maleate only (10 mg); after 4.5 years of peripheral arterial disease or a history of TIA/ischemic stroke;
follow-up, blood pressure was similar in both groups, but the b) diabetes; c) TT genotype for the methylenetetrahydrofo-
risk of first stroke was decreased by 21% in patients receiving late reductase (MTHFR) gene; and d) ³55 years old and with
enalapril maleate and folic acid [8]. In addition, the compos- at least 2 confirmed factors among: atherosclerosis, protein-
ite cardiovascular event (cardiovascular death, myocardial in- uria, left ventricular hypertrophy, dyslipidemia, smoking, obe-
farction, and stroke) and ischemic stroke rates were reduced sity, fibrinogen >3 g/L, and C-reactive protein (CRP) >10 mg/L.
by 20% and 24%, respectively [8].
The exclusion criteria were: 1) severe hypertension (mean sit-
Nevertheless, the target for blood pressure control in H-type ting diastolic BP (msDBP) ³110 mmHg and/or mean sitting
hypertension remains unclear due to insufficient evidence from systolic BP (msSBP) ³180 mmHg); 2) secondary hypertension
large randomized trials. Current evidence-based guidelines with a history or evidence of renal parenchymal hypertension;
for the management of high blood pressure in adults, such as 3) renal vascular hypertension; 4) aortic constriction; 5) pri-
those released by the European Society of Cardiology (ESC) mary aldosterone; 6) Cushing’s syndrome; 7) pheochromo-
in 2013 [9] and the Eighth Joint National Committee (JNC 8) cytoma; 8) drug-induced hypertension; 9) treatment with >3
in 2014 [10], recommend a loose goal for blood pressure con- anti-hypertensive drugs; 10) confirmed postural hypotension;
trol. It was emphasized that individualized blood pressure tar- 11) isolated systolic hypertension; 12) acute stroke; 13) con-
gets should be considered for different cohorts and there is firmed myocardial infarction; 14) history of severe coronary ar-
a need for guideline updates in China [4]. In addition, previous tery disease; 15) carotid artery stenosis >50%; 16) severe liver
studies indicated that intensive blood pressure control could and kidney dysfunction; 17) life expectancy <5 years; 18) poor
benefit patients with certain types of hypertension [11–14]. treatment compliance; 19) substance abuse; or 20) any other
conditions considered by the investigators to be unsuitable
It is known that carotid atherosclerotic plaques, carotid in- for participation.
tima-media thickness (IMT), and hemodynamic features can
be used to evaluate the severity of atherosclerotic diseases, Randomization
and these indicators are of predictive value for cardiovascu-
lar events [15,16]. The patients were randomized 1: 1 to the intensive and rou-
tine management groups using sequential sealed envelopes
Because data regarding blood pressure targets in H-type hy- prepared by an independent statistician using a random num-
pertension are lacking, the present study aimed to assess ber table. The envelopes were opened sequentially once the
whether intensive blood pressure management could improve patients consented.
Wu W. et al.:
Blood pressure control and H-type hypertension
© Med Sci Monit, 2019; 25: 5717-5726
CLINICAL RESEARCH
A B
Intensive blood pressure control Standard blood pressure control
Intensive blood Standard blood
pressure control pressure control
Once-weekly follow-up Once bi-weekly follow-up
for first two months for first one month
Increase the dose of medicine or add Increase the dose of medicine or add
Yes another type of medicine, once-weekly Single follow-up SBP≥160 mmHg
SBP ≥120 mmHg or consecutive two follow-ups Yes another type of medicine, once-weekly
follow-up unitil the blood pressure in the follow-up unitil the blood pressure in the
range of 100 mmHg <SBP ≤120 mmHg SBP≥140 mmHg range of 120 mmHg <SBP ≤140 mmHg
No no
SBP <100 mmHg Yes Reduce the dose of medicine or reduce Single follow-up SBP<135 mmHg Yes Reduce the dose of medicine or reduce
the types of medicine, weekly follow-up the types of medicine, weekly follow-up
or consecutive two follow-ups until the blood pressure in the range of
until the blood pressure in the range of SBP≥130 mmHg
100 mmHg <SBP ≤120 mmHg 120 mmHg <SBP ≤140 mmHg
No
Once-monthly follow-up after No Once-monthly follow-up after
two months two months
Continue the Continue the
treatment treatment
C Demographic data of patient flow chart
Enrolled patients
n=400
Standard blood Intensive blood

pressure control n=200 pressure control n=200
One patient not 2 patients not
meeting the meeting the
inclusion criteria inclusion criteria
Five patients excluded due to poor Five patients excluded due to poor
compliance compliance
Two patients excluded due to lack Three patients excluded due to lack
of carotid ultrasound data of carotid ultrasound data
One patients excluded to due One patients excluded to due
withdrwal of informed consent withdrwal of informed
Figure 1. (A) Management algorithm in the intensive group. (B) Management algorithm in the routine group. (C) Patient flowchart.
Intervention follow-ups prompted us to increase medication dose or to add

another anti-hypertension drug. When SBP was <130 mmHg at
Systolic blood pressure (SBP) targets were 100< SBP £120 and 1 follow-up or SBP was <135 mmHg at 2 consecutive follow-
120< SBP £140 mmHg in the intensive and routine manage- ups, the medication dose was decreased (Figure 1B). In the
ment groups, respectively, according to the ACCORD trial [11]. intensive group, SBP ³120 mmHg at any time prompted in-
All patients received folic acid at 0.8 mg daily and atorvas- creased medication dose or addition of other anti-hyperten-
tatin 20 mg daily [17]. Firstly, amlodipine 5 mg qd was used. sive drugs (Figure 1A).
If blood pressure (BP) did not meet the targets, it was increased
to 10 mg qd. Then, perindopril 4 mg qd was added if the BP The investigator made decisions regarding addition and re-
still could not meet the targets. The dose was increased to duction of doses, and whether or not to withdraw the pa-
8 mg qd if the BP could not meet the targets. Losartan 50 mg tient from the study according to the patient’s conditions.
qd was given and could be increased to 100 mg qd if the pa- Treatment was discontinued during the trial when any of the
tient experienced cough. If the BP still did not meet the tar- following occurred (intent-to-treat (ITT) analysis): 1) follow-up
gets, metoprolol or hydrochlorothiazide was used, according to DBP <60 mmHg at any time; 2) intolerable adverse effects such
heart rate conditions. The principles for dose reduction were as dizziness caused by hypotension in the intensive manage-
contrary to those of dosing escalation. ment group; 3) informed consent withdrawal; 4) poor compli-
ance; or 5) any other condition that the investigator consid-
For patients receiving routine management, SBP ³160 mmHg at ered as a termination point.
1 follow-up examination or SBP ³140 mmHg at 2 consecutive
Wu W. et al.:
© Med Sci Monit, 2019; 25: 5717-5726
Follow-up made in magnified longitudinal views of each plaque seen in

the right and left common, internal, and external carotid ar-
The intensive management group was evaluated for BP weekly teries. The plane in which the measurement of each plaque was
for the first 2 months, followed by monthly assessments af- made was chosen by panning around the artery until the view
terwards. Control patients were evaluated for BP weekly for showing the largest extent of plaque was obtained. The im-
the first month, and once a month afterwards. BP and the age was then frozen and magnified, and the plaque was mea-
endpoints were assessed. Anti-hypertensive drugs were ad- sured by tracing around the perimeter with a cursor on the
justed at each visit according to the BP readings. All patients screen. The built-in software in the scanner then displayed the
were instructed to perform self-blood pressure measurement cross-sectional area of the plaque. The operator then moved
(SBPM) at home. The last follow-up time was October 20th, on to the next plaque and repeated the process until all visible
2016. The rate of loss to follow-up was 4.3%. plaques were measured. The sum of the cross-sectional areas
of all plaques seen between the clavicle and the angle of the
Management of adverse events jaw was taken as the total plaque area (cm2) [20]. Regardless
of the actual plaque length, maximum thicknesses for plaques
The patients were trained for blood pressure monitoring at isolated from the same carotid were added to obtain the Crouse
home, and advised to contact their physician timely if SBP was score, as previously described [21]. All measurements and cal-
<100 mmHg or DBP was <60 mmHg, or if they experienced diz- culations were carried out by the same ultrasound physician
ziness. In this study, the main adverse effects included: hypo- (8 years of experience) using a Siemens digital color Doppler
tension, bradycardia, electrolyte imbalance, dizziness, and ab- ultrasound diagnostic instrument, with a probe frequency of
normal kidney function. 7.5 MHz. The patient was placed in the supine position, with
back to the examiner. The carotid was scanned sequentially
Endpoints from superior to inferior, and 3 measurements were obtained
beneath the lateral branch of the common carotid artery at
Carotid plaque area was assessed as the primary study end- about 1.0 cm. The IMT value was the average measurement
point. The secondary study endpoints included plaque score, of the 3 time points. The internal diameter (D) of the carotid
IMT, IMT/D, peak systolic velocity (Vs), end-diastolic velocity was measured to derive IMT/D.
(Vd), pulsatility index (PI), resistance index (RI), Vs/Vd, and
stroke occurrence. PI is the difference between maximum and For carotid hemodynamic measurement, the major intracranial
minimum blood velocity, and is calculated as PI=(Vs–Vd)/Vm, vessels were scanned using a pulsed Doppler probe at a fre-
where Vm=(Vs+Vd)/2 [18]. RI is a measure of pulsatile blood quency of 2.0 MHz through the temporal, ocular, and occipital
flow that reflects the resistance to blood flow caused by the windows. The carotid artery was examined using a probe at
vascular bed distal to the measurement site. RI is calculated a frequency of 4.0 MHz in combination with common carotid
as (Vs–Vd)/Vs [19]. artery compression. Blood flow rate, spectrum shape, and resis-
tance index of all arteries were recorded. The anterior cerebral
Blood pressure measurement circulation of the middle cerebral artery was recorded. The Vs,
Vd, PI [PI=(Vs–Vd)/Vm], RI [RI=Vs–Vd)/Vs], and Vs/Vd were ob-
Blood pressure was measured in the sitting position, 3 times, tained. The whole procedure was performed by the same cli-
at 5-min intervals, and by the same clinician. Two DBP read- nician before the treatment and 1 year after the treatment.
outs with a difference <4 mmHg were used. The patient rested
for at least 15 min before measurements, with no strong tea Sample size calculation
or coffee consumed within 30 min. A mercury sphygmoma-
nometer was used for blood pressure measurement. The read- This was a single-center, prospective, randomized trial with
outs at first and fifth sounds of the Korotkoff phase were con- a statistical power of 80% and bilateral significance level of
sidered systolic and DBP, respectively. When the pulse sound 0.05. Considering the main efficacy variable of 0.05 cm2, dif-
remained until the mercury sphygmomanometer showed ferences among treatments of 0.05 cm2 [20], and a loss rate
0 mmHg, the readout at the fourth sound of Korotkoff phase of 5%, the PASS software yielded a sample number of n=280.
was used as DBP.
Statistical analysis
Carotid plaque assessment
SPSS 17.0 (IBM, Armonk, NY, USA) was used for statistical
For carotid plaque assessment, plaque was defined as: 1) local analyses. All data were tested using the Shapiro-Wilk nor-
bulge protruding out of the arterial lumen by >0.5 mm or >50% mality test. If normally distributed, data were expressed as
of the surrounding IMT; or 2) IMT >1.5 mm. Measurements were means ± standard deviation (SD) and compared using the
Wu W. et al.:
© Med Sci Monit, 2019; 25: 5717-5726
CLINICAL RESEARCH
Table 1. Demographic and clinical data in the 2 treatment groups at enrollment.
Routine management Intensive management

P
(n=192) (n=188)
Male (n,%) 117 (60.9) 112 (59.9) 0.428
Age 54.7±11.2 53.9±10.9 0.232
Smoking (n,%) 65 (33.9) 67 (35.8) 0.183
History of diabetes (n,%) 63 (32.8) 58 (31.0) 0.216
History of ischemic stroke (n,%) 42 (21.9) 48 (25.7) 0.147
TT genotype of the MTHFR gene (n,%) 74 (38.5) 75 (40.1) 0.277
BMI (kg/m2) 24.57±4.93 24.71±4.86 0.241
TC (mmol/L) 4.92±1.02 4.94±1.06 0.563
TG (mmol/L) 2.53±0.82 2.36±1.47 0.608
HDL-C (mmol/L) 1.05±0.38 1.03±0.40 0.159
LDL-C (mmol/L) 2.29±0.73 2.31±0.80 0.328
FBG (mmol/L) 5.28±1.22 5.33±1.26 0.097
SBP (mmHg) 154.28±12.22 154.79±11.25 0.835
DBP (mmHg) 88.36±11.55 89.71±11.04 0.295
Hcy (µmol/l) 19.93±7.31 20.34±5.85 0.102
History of hyperlipidemia (n,%) 161 (83.9) 157 (83.5) 0.262
Number of patients using statins before inclusion (n,%) 161 (83.9) 157 (83.5) 0.262
MTHFR – methylenetetrahydrofolate reductase; BMI – body mass index; TC – total cholesterol; TG – triglycerides; HDL-C – high-
density lipoprotein cholesterol; LDL-C – low-density lipoprotein cholesterol; FBG – fasting blood glucose; SBP – systolic blood pressure;
DBP – diastolic blood pressure; Hcy – homocysteine.
independent-samples t test. If non-normally distributed, data groups were found regarding age, BMI, blood glucose, blood
were expressed as median (range) and analyzed using the cholesterol, baseline blood pressure, and serum Hcy (Table 1).
Mann-Whitney U test. Categorical data were presented as
frequencies and compared using the Fisher’s exact test. Two- Intensive blood pressure control results in reduced blood
tailed P-values <0.05 were considered statistically significant. pressure
The BP targets were achieved in both groups from the sec-

Results ond month of treatment initiation. As per management pro-
tocol, blood pressure in the intensive group was significantly
Demographic information lower than in the routine group. Blood pressure indexes in
both groups are summarized in Table 2 and Figure 2. By the
Four hundred patients were enrolled; 3 reported an age that end of follow-up, 11 patients in each group were lost to fol-
was incorrect after ID card validation, making them ineligi- low-up. There were no significant differences in blood lipids
ble, and 10, 5, and 2 were excluded because of poor com- from baseline to 12 months in the 2 groups.
pliance, lack of carotid plaque data, and informed consent
withdrawal, respectively. Finally, 380 patients were analyzed, Intensive blood pressure control improves the parameters
including 229 men and 151 women, aged between 40 and 75 of carotid atherosclerosis
years (54.68±11.28 years). There were 188 and 192 patients
assigned to the intensive and routine management groups, The carotid plaque areas and Crouse scores were significantly
respectively (Figure 1C). No significant differences between lower in the intensive management group compared with
Wu W. et al.:
© Med Sci Monit, 2019; 25: 5717-5726
Table 2. Blood pressure indexes in the 2 treatment groups.
Routine Intensive
P P P
management management
(vs. baseline) (vs. routine) (vs. baseline)
(n=192) (n=188)
n at 1 month 190 186
SBP at 1 month 124.72±9.27 <0.001 119.42±11.33 0.052 <0.001
n at 2 months 190 185
SBP at 2 months 128.64±8.71 <0.001 106.37±9.64 0.035 <0.001
SBP at 3 months 129.83±9.38 <0.001 108.59±11.38 0.041 <0.001
SBP at 6 months 128.85±7.35 <0.001 111.37±8.26 0.048 <0.001
SBP at 12 months 132.78±10.43 <0.001 108.93±10.11 0.026 <0.001
Number of anti-hypertensive
1.8±0.6 NA 2.3±0.7 0.045 NA
drugs at 12 months
BMI (kg/m2)* 23.67±4.89 0.054 23.55±4.83 0.195 0.056
TC (mmol/L)* 4.83±0.92 0.147 4.83±1.06 0.557 0.155
TG (mmol/L)* 2.54±0.77 0.327 2.33±1.62 0.598 0.361
HDL-C (mmol/L)* 1.05±0.42 0.589 1.05±0.36 0.221 0.432
LDL-C (mmol/L)* 2.34±0.86 0.386 2.29±0.92 0.297 0.377
FBG (mmol/L)* 5.22±1.38 0.418 5.34±1.31 0.164 0.387
Hcy (µmol/l)* 8.29±2.22 0.024 8.43±2.38 0.231 0.033
SBP – systolic blood pressure; BMI – body mass index; TC – total cholesterol; TG – triglycerides; HDL-C – high-density lipoprotein
cholesterol; LDL-C – low-density lipoprotein cholesterol; FBG – fasting blood glucose; Hcy – homocysteine. By the end of follow-up,
11 patients in each group were lost to follow-up. * At 12 months.
controls after 12 months of treatment (both P<0.05). There in plaque area was set as the dependent variable. Age, sex,
were no significant differences regarding IMT and IMT/D be- changes in blood pressure (12 months – baseline), blood lipids,
tween the 2 groups (all P>0.05). Furthermore, compared with glucose, and Hcy were set as independent variable. The results
the control group, intensive treatment resulted in significantly indicated that the changes in blood pressure (12 months – base-
lower Vs/Vd, PI, and RI (all P<0.05). Detailed data are provided line) (b=0.124, 95% confidence interval: 0.042–0.288, P=0.026),
in Table 3. No correlation could be found between changes and age (b=0.253, 95% confidence interval: 0.195–0.371,
in BP and changes in plaque score or hemodynamic indexes P=0.012) were independently associated with the changes in
(data not shown). plaque area (12 months – baseline) (R2=0.569).
Correlations Occurrence of cerebrovascular events and adverse effects
Blood pressure change (12 months – baseline) was positively Six (3.12%) and 5 (2.67%) patients had stroke after treatment
correlated with changes (12 months – baseline) in plaque area for 12 months in the intensive and standard treatment groups,
(r=0.702, P=0.041), plaque score (r=0.773, P=0.028), Vs/Vd respectively (P=0.246). The main adverse effects were hypo-
(r=0.751, P=0.039), PI (r=0.797, P=0.015), and RI (r=0.824, tension and dizziness, which were slightly higher in the inten-
P=0.011). To control for potential confounders, a multivariate sive group compared with controls (Table 4).
analysis was performed. The change (12 months – baseline)
Wu W. et al.:
© Med Sci Monit, 2019; 25: 5717-5726
CLINICAL RESEARCH
A B
Changes in systolic blood pressure Changes in diastolic blood pressure
180 n=192 120
160 n=192
n=190 n=190 n=189 n=188 n=181 100 n=189 n=188 n=188
140 n=190 n=190
120 80
n=188 n=186 n=188
100 n=188 n=188 n=188 n=188 n=188
n=185 n=185 n=183 n=177 60
80
60 40
40 Routine management 20
20 Intensive management
0 0
SBP at SBP at 1 SBP at 2 SBP at 3 SBP at 6 SBP at 12 DBP at DBP at 1 DBP at 2 DBP at 3 DBP at 6 DBP at 12
baseline month months months months months baseline month months months months months
Figure 2. Changes in systolic (SBP; A) and diastolic (DBP; B) blood pressure in the 2 groups during the 12-month treatment period.
Table 3. Carotid atherosclerosis parameters in the 2 groups.
Routine management (n=192) Intensive management (n=188)

P at baseline P at 12 months
Baseline 12 months Baseline 12 months
Plaque area (mm2) 26.03±3.48 24.56±3.14 26.17±3.51 18.41±2.13 0.482 0.038
Plaque score (mm) 3.31±0.64 2.45±0.47 3.28±0.63 1.75±0.52 0.217 0.023
IMT (mm) 1.13±0.10 0.99±0.14 1.14±0.13 0.92±0.19 0.231 0.062
IMT/D 16.71±3.96 15.53±4.87 16.88±4.05 11.47±2.30 0.362 0.089
Vd (cm/s) 76.38±6.42 92.31±9.72 79.74±6.94 107.53±8.42 0.225 0.056
Vs/Vd 2.06±0.25 1.88±0.18 2.01±0.18 1.68±0.11 0.126 0.031
PI 0.88±0.17 0.69±0.12 0.91±0.14 0.51±0.03 0.273 0.017
RI 0.79±0.06 0.52±0.01 0.74±0.05 0.30±0.03 0.328 0.008
IMT – intima-media thickness; D – carotid diameter; Vd – end-diastolic velocity; Vs – peak systolic velocity; PI – pulsatility index;
RI – resistance index.
Table 4. Occurrence of adverse events in the 2 groups.
Routine management (n=192) Intensive management (n=188) P
Adverse effects 19 (9.89%) 25 (13.36) 0.075
Withdrawn from trial 7/192 10/188 0.430
Hypotension 3 (1.56%) 5 (2.67%) 0.020
Bradycardia 4 (2.01%) 4 (2.13%) 0.281
Electrolyte disorder 4 (2.01%) 5 (2.67%) 0.094
Dizziness 16 (8.33%) 20 (10.69%) 0.041
Abnormal renal function 3 (1.56%) 2 (1.06%) 0.194
Wu W. et al.:
© Med Sci Monit, 2019; 25: 5717-5726
Discussion incidence could be significantly reduced by intensive blood

pressure control (0.32% vs. 0.53%; risk ratio of 0.59, 95%CI
The results of the present study strongly suggest that inten- 0.39-0.89) [11]. A 2012 meta-analysis by McBrien et al. [12],
sive hypertension management resulted in significantly lower assessing 7312 hypertensive patients with type II diabetes,
carotid plaque areas and scores compared with routine man- compared stroke incidences with targeted blood pressures of
agement in patients with H-type hypertension and high risk of £130/80 mmHg and £140–160/85–100 mmHg, and found that
stroke. Vs/Vd, PI, and RI were significantly lower after inten- intensive blood pressure control could significantly reduce the
sive management compared with the control group. No signif- risk of stroke by 35%. The effect of intensive blood pressure
icant difference between the 2 groups was found in terms of control on cerebrovascular blood flow velocity in type II dia-
cerebrovascular events. The major adverse effects were hypo- betes patients was evaluated by Kim et al. [13]; after inten-
tension and dizziness, with incidence rates relatively higher in sive blood pressure control, a transient decrease of cerebral
the intensive treatment group. No significant differences were blood flow velocity was only found in patients without mi-
observed between the 2 groups regarding bradycardia, elec- crovascular complications, suggesting that for type II diabe-
trolyte disturbance, renal dysfunction, and medication with- tes patients, intensive blood pressure control should be initi-
drawal occurrences. Nevertheless, the patients in the inten- ated at the early stage of hypertension when the automatic
sive group received a more anti-hypertension drugs compared regulatory function of the brain is still sufficient to counteract
with the control group because the BP targets were lower for the effect of decreased perfusion [13]. The recently released
the intensive management scheme than for the standard man- SPRINT study indicated that intensive blood pressure control
agement scheme. reduces cardiovascular risk by 25% [14]. Together, these find-
ings suggest that intensive blood pressure control could ben-
H-type hypertension refers to hypertension with hyperhomo- efit patients with specific types of hypertension. In this study,
cysteinemia (Hcy ³10 μmol/L) and is in itself an important the carotid plaque area and score were significantly lower in
risk factor for cardiovascular events and stroke [22]. Given patients receiving intensive management compared with those
the particularly high rate of the MTHFR C677T mutation in Hcy receiving routine management, as supported by the previous
metabolism in the Chinese population and in relation to the study described above, suggesting that H-type hypertension
Chinese diet, the incidence of H-type hypertension is signifi- patients with high risk of stroke could benefit from intensive
cantly higher in China compared with other counties [3,23,24]. blood pressure control.
Previous studies showed that awareness, treatment, and con-
trol rates of hypertension in China were low [4]. This results in It was reported that carotid atherosclerosis plays an impor-
significantly higher stroke incidence and mortality compared tant role in cerebral infarction, with extracranial atheroscle-
with global averages, although coronary disease incidence rotic plaque representing the major cause of stroke [16,27–29].
and related mortality are lower compared with other coun- Indeed, increased vascular intima-media thickness was revealed
tries [3,23,24]. The Third National Survey on Death Causes in- as a phenotype of atherosclerosis at an early stage; therefore,
dicated that cerebrovascular diseases have become the pri- this parameter was used in the present study for the early di-
mary cause of death in China [25]. Meanwhile, the incidence agnosis of stroke [30]. Though IMT is broadly used in clinical
of ischemic stroke steadily increases by 8.7% annually [14]. practice, it has many limitations. First of all, atherosclerosis is
Therefore, the key point in the prevention and treatment of an endothelial disease, and acute cerebral infarction is caused
cerebrovascular disease is stroke prevention. In other words, by rupture of an unstable plaque [27–29], but ultrasound scan-
it is very important to provide primary stroke prevention in ning for IMT poorly differentiates intima-media from endothe-
H-type hypertension in China, and physicians must thus ef- lial thicknesses, and stable from unstable plaques; alteration
fectively control blood pressure for patients. in IMT could be due to medial hypertrophy or atherosclerosis.
Secondly, IMT and plaque response are different aspects and
Currently, the target blood pressure for H-type hypertension stages of atherosclerotic disease [31]. Accumulating evidence
remains unclear due to the lack of evidence from large ran- indicates that the properties and amount of carotid plaques
domized trials. Nevertheless, blood pressure control in these are associated with cerebral infarction and severity; in addi-
patients is essential since H-type hypertension has been tion, plaque area and score are more associated with cerebro-
shown to be an independent factor for asymptomatic extra- vascular events than with IMT [32–35]. In the present study,
cranial artery stenosis and primary and recurrent ischemic although no significant improvement of IMT was found after
strokes [1,23,26]. Recent evidence-based guidelines for the intensive management vs. routine management, plaque score
management of high blood pressure in adults [9,10] recommend and area were both significantly improved, indicating that in-
a loose goal for blood pressure control, while emphasizing the tensive blood pressure control could benefit patients with cer-
need for individualized blood pressure targets in different co- tain types of hypertension. Surprisingly, LDL-C did not change,
horts. The ACCORD study demonstrated that the annual stroke in spite of treatment with atorvastatin 20 mg/d for 12 months.
Wu W. et al.:
© Med Sci Monit, 2019; 25: 5717-5726
CLINICAL RESEARCH
In fact, many patients were already taking a statin before the potential long-term benefits, which will have to be confirmed.
study, and the patients were all given the same dose of atorv- We cannot exclude that folic acid and atorvastatin had stron-
astatin in order to minimize this bias during the study. Hence, ger effects on stroke incidence than blood pressure manage-
in the present study, the major effect on carotid morphology ment. This study only examined Chinese patients with H-type
was probably related to the larger BP drop in the intensive care hypertension; therefore, its generalizability is limited. Finally,
group compared with the control group, rather than to improve- and most importantly, despite predefined management algo-
ment in other parameters that may affect the arterial wall. rithms, anti-hypertensive treatment was achieved by arbitrary
selection of various drug classes without a controlled regimen,
Cerebral blood supply disorder is the main cause and an impor- and this may have affected the overall results. Additional stud-
tant pathogenesis factor of cerebral arteriosclerosis. The mid- ies with different treatment strategies could provide some
dle cerebral artery is a straight blood vessel with rare congen- more definitive results.
ital variation and could be used to predict the risk of cerebral
vascular disease induced by atherosclerosis. PI is an index re-
flecting cerebral vascular compliance and elasticity, while RI Conclusions
describes cerebral vascular resistance, both of which could be
used as sensitive indexes for the diagnosis and prognosis of Intensive blood pressure management can benefit patients
ischemic cerebrovascular disease [36]. In this study, Vs/Vd, PI, with H-type hypertension and high risk of stroke. Although the
and RI in the intensive management group were significantly subjects of this study were patients with H-type hypertension,
lower compared with the control group, indicating that inten- the results of this study are similar to those of previous reports
sive treatment can alleviate cerebrovascular disease. in patients with hypertension without hyperhomocysteinemia.
Nevertheless, well-designed clinical trials with a larger study
A limitation of this study was its small sample size. In addition, population are required to confirm these findings.
there was no significant difference between the 2 groups re-
garding the occurrence of stroke, but the follow-up was short Conflict of interest
and stroke pathogenesis is an ongoing process over many
years. Nevertheless, carotid plaque index improvements were None.
better with intensive than routine management, suggesting
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CLINICAL RESEARCH

MeSH Keywords: Hypertension • Risk • Stroke

Full-text PDF: https://www.medscimonit.com/abstract/index/idArt/914482

3621 4 2 36

Background the morphologic features of the carotids and the hemody-

C Demographic data of patient flow chart

Standard blood Intensive blood

Intervention follow-ups prompted us to increase medication dose or to add

Follow-up made in magnified longitudinal views of each plaque seen in

Table 1. Demographic and clinical data in the 2 treatment groups at enrollment.

Routine management Intensive management

Male (n,%) 117 (60.9) 112 (59.9) 0.428

Age 54.7±11.2 53.9±10.9 0.232

Smoking (n,%) 65 (33.9) 67 (35.8) 0.183

History of diabetes (n,%) 63 (32.8) 58 (31.0) 0.216

History of ischemic stroke (n,%) 42 (21.9) 48 (25.7) 0.147

TT genotype of the MTHFR gene (n,%) 74 (38.5) 75 (40.1) 0.277

BMI (kg/m2) 24.57±4.93 24.71±4.86 0.241

TC (mmol/L) 4.92±1.02 4.94±1.06 0.563

TG (mmol/L) 2.53±0.82 2.36±1.47 0.608

HDL-C (mmol/L) 1.05±0.38 1.03±0.40 0.159

LDL-C (mmol/L) 2.29±0.73 2.31±0.80 0.328

FBG (mmol/L) 5.28±1.22 5.33±1.26 0.097

SBP (mmHg) 154.28±12.22 154.79±11.25 0.835

DBP (mmHg) 88.36±11.55 89.71±11.04 0.295

Hcy (µmol/l) 19.93±7.31 20.34±5.85 0.102

History of hyperlipidemia (n,%) 161 (83.9) 157 (83.5) 0.262

The BP targets were achieved in both groups from the sec-

Table 2. Blood pressure indexes in the 2 treatment groups.

n at 1 month 190 186

SBP at 1 month 124.72±9.27 <0.001 119.42±11.33 0.052 <0.001

n at 2 months 190 185

SBP at 2 months 128.64±8.71 <0.001 106.37±9.64 0.035 <0.001

n at 3 months 189 185

SBP at 3 months 129.83±9.38 <0.001 108.59±11.38 0.041 <0.001

n at 6 months 188 183

SBP at 6 months 128.85±7.35 <0.001 111.37±8.26 0.048 <0.001

n at 12 months 181 177

SBP at 12 months 132.78±10.43 <0.001 108.93±10.11 0.026 <0.001

BMI (kg/m2)* 23.67±4.89 0.054 23.55±4.83 0.195 0.056

TC (mmol/L)* 4.83±0.92 0.147 4.83±1.06 0.557 0.155

TG (mmol/L)* 2.54±0.77 0.327 2.33±1.62 0.598 0.361

HDL-C (mmol/L)* 1.05±0.42 0.589 1.05±0.36 0.221 0.432

LDL-C (mmol/L)* 2.34±0.86 0.386 2.29±0.92 0.297 0.377

FBG (mmol/L)* 5.22±1.38 0.418 5.34±1.31 0.164 0.387

Hcy (µmol/l)* 8.29±2.22 0.024 8.43±2.38 0.231 0.033

Correlations Occurrence of cerebrovascular events and adverse effects

Table 3. Carotid atherosclerosis parameters in the 2 groups.

Routine management (n=192) Intensive management (n=188)

Plaque area (mm2) 26.03±3.48 24.56±3.14 26.17±3.51 18.41±2.13 0.482 0.038

Plaque score (mm) 3.31±0.64 2.45±0.47 3.28±0.63 1.75±0.52 0.217 0.023

IMT (mm) 1.13±0.10 0.99±0.14 1.14±0.13 0.92±0.19 0.231 0.062

IMT/D 16.71±3.96 15.53±4.87 16.88±4.05 11.47±2.30 0.362 0.089

Vd (cm/s) 76.38±6.42 92.31±9.72 79.74±6.94 107.53±8.42 0.225 0.056

Vs/Vd 2.06±0.25 1.88±0.18 2.01±0.18 1.68±0.11 0.126 0.031

PI 0.88±0.17 0.69±0.12 0.91±0.14 0.51±0.03 0.273 0.017

RI 0.79±0.06 0.52±0.01 0.74±0.05 0.30±0.03 0.328 0.008

Table 4. Occurrence of adverse events in the 2 groups.

Routine management (n=192) Intensive management (n=188) P