Multi-center Study on New Cardiovascular Remodeling and Function Parameters in Hypertension
Conditions: Hypertension
Sponsor: Qilu Hospital of Shandong University

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Multi-center study on new cardiovascular remodeling 
and function parameters in hypertension 
（Observational study） 
 
 
 
 
 
 
Project undertaker: Qilu Hospital of Shandong University  
Date: 2022/08/14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Research Protocol 
Participant centers 
Qilu Hospital of Shandong University 
Qilu Hospital of Shandong University (Qingdao) 
Shenzhen People’s Hospital 
The Affiliated Sichuan Provincial People's Hospital 
West China Hospital, Sichuan University 
First Affiliated Hospital, School of Medicine, Shihezi University 
The First Affiliated Hospital of Xinjiang Medical University 
The First Affiliated Hospital of China Medical University 
Sun Yat-sen Memorial Hospital, Sun Yat-sen University 
China-Japan Union hospital of Jilin University 
The Second Affiliated Hospital of Harbin Medical University 
The First Affiliated Hospital of Guangxi Medical University 
Wuhan Asia Heart Hospital 
Zhongshan Hospital, Fudan University 
Henan Provincial People's Hospital 
Tangdu Hospital of Air Force Medical University of PLA 
Shengjing Hospital of China Medical University 
Beijing Anzhen Hospital, Capital Medical University 
The First Affiliated Hospital of Harbin Medical University 
The People’s Hospital of Liaoning Province 
 
 
 

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BACKGROUND  
Hypertension is the most important risk factor for the morbidity and mortality of 
cardiovascular and cerebrovascular diseases in China. Useful treatment of hypertension 
can reduce the incidence of cardiovascular and cerebrovascular diseases. 
Hemodynamic overload caused by hypertension can lead to left ventricular remodeling 
and functional changes, usually manifested as significant changes in the geometric 
configuration of the left ventricle, such as concentric hypertrophy (CH) and eccentric 
hypertrophy (EH). Left ventricular hypertrophy is an adaptive process after the increase 
of hemodynamic load, and also cause damages of target organs. Studies have shown 
that left ventricular hypertrophy (LVH) and left atrial enlargement caused by 
hypertension are independent risk factors for cardiovascular events. Epidemiological 
studies have confirmed that changes in the geometry of left ventricular remodeling may 
be harmful and increase the risk of incidence rate and mortality of cardiovascular 
disease. The different types of left ventricular remodeling are related to cardiovascular 
events and all-cause mortality. Different left ventricular geometric configurations had 
different prognosis. Studies show that CH has the larger left ventricular mass and worse 
prognosis, than EH, concentric remodeling (CR) and normal left ventricular geometry 
(NG). In patients with essential hypertension, ventricular remodeling and hypertrophy 
always occur, and myocardial diastolic and systolic function decline gradually, 
eventually leading to heart failure. Another study showed that the mortality of patients 
transferred from CR to NG significantly decreased, and the mortality of patients 
transferred from CR to LVH was significantly higher. Antihypertensive treatment could 
significantly reduce LVH and prevent or reverse the abnormal geometry of left ventricle. 
Therefore the type, distribution characteristics and configuration outcome of left 
ventricular hypertrophy remodeling, evaluate left ventricular systolic and diastolic 
function and left atrial size can improve the early prevention and attention of heart 
failure, and early intervention and treatment are of great significance for reducing the 
occurrence of cardiovascular events and evaluating the progress and prognosis of the 

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disease.  
Most researches on hypertension configuration adopt the Ganau classification, and 
evaluation of left ventricular hypertrophy ultrasonic technology in hypertension 
guidelines is also based on this classification standard. However, the reference values 
in this classification standard, including left ventricular mass index (LVMI) and relative 
wall thickness (RWT), are from European and American populations. It is not clear 
whether the criteria for defining the type of left ventricular remodeling is suitable for 
the Chinese population, and whether this classification method has an impact on the 
constituent ratio of left ventricular remodeling types. As we all know, the normal value 
of left ventricular mass (LVM) varies with gender, race, age, height and weight. Now 
body surface area (BSA) is usually used for index, but always over corrected. The 
international reference standard for left ventricular configuration recommended in the 
2015 ASE/EACVI guidelines for quantitative measurement of adult heart 
echocardiography, in which the left ventricular mass is indexed by BSA, and its 
abnormal threshold is LVMI>115g/m2 (male) or LVMI>95g/m ² (female). The newly 
issued hypertension management guidelines in 2018 mentioned that height2.7 should be 
used to calibrate LVM to define left ventricular hypertrophy, and its abnormal threshold 
is>50 g/m2.7 (male) or>47 g/m2.7 (female). The two different index methods affecting 
the configuration distribution characteristics remains to be determined. Recent studies 
have found that the normal reference values of the echocardiographic parameters from 
Chinese and Western people are different. With the normal reference values of 
echocardiographic parameters in the Study of Echocardiographic Measurements for 
Normal Chinese Han Adults (EMINCA Study), LVM was indexed by the two above 
indexed methods, to speculate that the range of normal reference values of LVMI and 
RWT, the indicators for Ganau classification, were different from those recommended 
in previous European and American guidelines, and the distribution of hypertension 
configurations was also different, as well as in WASE study. 
Persistent hemodynamic overload in patients with hypertension will not only lead 
to myocardial remodeling and ventricular and atrial remodeling, but also seriously 
damage the function of ventricle and atrium. The early cardiac damage in patients with 

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hypertension is mainly manifested as left ventricular hypertrophy, left atrial 
enlargement and other remodeling phenomena. With long-term high blood pressure, 
myocardial fibers will increase thickness, which will lead to reduction of myocardial 
compliance, increase of left ventricular filling pressure, and damage the diastolic 
function of the heart. When the left ventricular hypertrophy caused by long-term high 
blood pressure exceeds the compensatory threshold of the heart, it will inhibit the 
pumping function of the heart and reduce the contractility of the myocardium. When 
the disease continues to progress, it will even cause the continuous expansion of the 
heart cavity, increase of the tension of the ventricular wall and cause heart failure with 
reduced systolic function. Except for LVEF, the global longitudinal strain (GLS) of the 
left ventricle is more sensitive to the early damage of the left ventricular myocardium 
and has predictive value, which is widely concerned by people. LVGLS is affected by 
the wall shear stress, myocardial ischemia and myocardial fibrosis. Recently some 
studies have found that the increase of left ventricular afterload is significantly related 
to the decrease of GLS. Myocardial work (MW), a new indicator of the combination of 
GLS and cardiac afterload, can reflect the changes of the heart at the early stage of 
many diseases including assessing the systolic capacity of the heart and reflecting the 
remodeling of the left ventricle. With the construction and analysis of left ventricular 
pressure volume loop (PSL), we can get the global work index (GWI), global 
constructive work (GCW), global wasted work (GWW) and global work efficiency 
(GWE) of myocardium. Therefore, the index of myocardial work can provide us with 
more information about ventricular remodeling and afterload changes, which is helpful 
for us to evaluate the left ventricular remodeling caused by afterload changes. 
Echocardiography is a commonly used clinical examination method，with ease of 
operation, safety, non-invasive, real-time imaging, strong repeatability, low cost and so 
on, which is widely used to evaluate the structure and function of the heart and cardiac 
hemodynamics. Framingham et al. found that there is a strong correlation between LVM 
detected by echocardiography and the incidence rate and mortality of cardiovascular 
diseases, and LVM is also the most commonly used tool for clinical diagnosis of left 

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ventricular diastolic dysfunction (LVDD). 
The LVM and LAV derived from the normal value data of Chinese healthy adults 
have been reported to be different from the recommended reference values in guidelines, 
and the distribution characteristics of hypertension remodeling are also different. 
However, this difference still lacks of large multi-center research to further confirm it. 
Meanwhile, the characteristics and outcomes of cardiac remodeling in Chinese 
hypertensive population and whether this difference in configuration has an impact on 
the treatment, prognosis and cardiovascular events of hypertensive population are still 
needed to be explored. 
 
OBJECTIVES:  
This study was to observe the relationship between blood pressure and cardiovascular 
remodeling evaluated by different standards in hypertensive population; to compare 
the relationship between different cardiac configurations and cardiovascular events in 
Chinese hypertensive population. 
RESEARCH DESIGN  
Studies have shown that different configurations of left ventricle and left atrial 
enlargement in hypertensive patients can predict the occurrence of cardiovascular 
events. The standards of left ventricular remodeling and left atrial enlargement based 
on European and American populations may not be applicable to Chinese populations. 
This study was a multicenter study to verify different left ventricular remodeling in 
Chinese hypertensive population, and explore the influence of different left ventricular 
remodeling standards on the treatment options and prognosis. 
Participant:  
Participants with essential hypertension and healthy volunteers in the outpatient and 
hospital in research centers. 
Groups: 

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Healthy volunteers: volunteers without chronic disease history such as hypertension, 
diabetes, coronary heart disease, cerebrovascular disease, and transthoracic 
echocardiography showed normal cardiac structure and function.  
Hypertensions: grouped with ultrasonic cardiogram parameters (including LVMI, RWT 
and LAVI)  
(1) Left ventricle remodeling groups: 
2015 ASE/EACVI guideline standard: 
Normal left ventricular geometry, NG: LVMI≤115g/m2（male）or LVMI≤95g/m2（female）
and RWT≤0.42 
Concentric remodeling, CR: LVMI≤115g/m2（male）or LVMI≤95g/ m2（female）and 
RWT>0.42 
Eccentric hypertrophy, EH: LVMI>115g/ m2（male）or LVMI>95g/ m2（female）and 
RWT≤0.42 
Concentric hypertrophy, CH: LVMI>115g/ m2（male）or LVMI>95g/ m2（female）and 
RWT>0.42 
Reference Values for Chinese (EMINCA) and Configuration Analysis Based on 
Ganau Typing: 
Normal left ventricular geometry, NG: LVMI≤108g/ m2（male）and RWT≤0.51 or 
LVMI≤99g/ m2（female）and RWT>0.49 
Concentric remodeling, CR: LVMI≤108g/ m2（male）and RWT>0.51 or LVMI≤99g/ m2
（female）and RWT>0.49 
Eccentric hypertrophy, EH: LVMI>108g/ m2（male）and RWT≤0.51or LVMI>99g/ m2
（female）and RWT≤0.49 
Concentric hypertrophy, CH: LVMI>108g/ m2（male）and RWT>0.51 or LVMI>99g/ 
m2（female）and RWT>0.49 
(2) Left atrium remodeling groups: 
2015 ASE/EACVI guideline standard: 
Left atrium enlargement groups: LAVI>34ml/m2（male, female） 
Reference Values for Chinese (EMINCA) with BSA indexed: 
Left atrium enlargement groups: LAVI>34.3ml/m2 (male) or LAVI>35.5ml/m2 

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(female) 
Inclusion criteria for hypertension:  
(1) Age 30-75 years old; 
(2) No antihypertensive drugs were used and three blood pressure measurements 
were conducted on different days, with systolic blood pressure ≥ 140 mmHg (1 
mmHg=0.133 kPa) and/or diastolic blood pressure ≥ 90 mmHg; or have a history 
of hypertension and are using antihypertensive drugs, even if the blood pressure 
is lower than 140/90 mmHg; 
(3) Left ventricular ejection fraction was normal (LVEF ≥ 0.5). 
(4) All patients agreed to participate in the experiment and signed the informed 
consent form. 
Exclusion criteria for hypertension:  
(1) Secondary hypertension caused by renal parenchymal diseases, renal vascular 
diseases, coarctation of aorta and endocrine system diseases; 
(2) Severe cardiovascular and cerebrovascular diseases; heart valve disease; persistent 
atrial fibrillation and severe arrhythmia; previously undergone cardiovascular 
disease surgery; 
(3) Abnormal liver function; abnormal renal function and diabetes; 
(4) Pregnant or breastfeeding women; 
(5) Expected survival time due to non-cardiovascular disease<4 years; 
(6) Patients with poor echocardiographic image quality. 
 
EFFICACY ASSESSMENT   
Primary study endpoints: emerging atrial fibrillation, transient ischemic attack (TIA) or 
stroke, unstable angina, myocardial infarction, heart failure, coronary revascularization, 
cardiovascular death; 

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Secondary study endpoints: decreased cardiac function with preserved ejection fraction; 
new cardiac remodeling; aortic aneurysm or aortic dissection; ECG showed that QTc 
(QT interval corrected by heart rate) was more than 500ms or QTc was longer than the 
baseline level for more than 60ms, emerging torsade de pointes ventricular tachycardia 
and other serious arrhythmias; the relationship between the deviations of blood pressure 
within the same day and the difference of cardiac function indexes. 
 
RESEARCH PLAN 
Estimation of Sample Size 
Use PASS 11.0.7 software, bilateral inspections, α = 0.05, with the incidence rate of 
cardiovascular adverse events in the left ventricular hypertrophy group was 4.9%, and 
the incidence rate of cardiovascular adverse events in the left ventricular non-
hypertrophy group was 2.2%, at least 986 hypertensive patients were included in the 
left ventricular hypertrophy group and the left ventricular non hypertrophy group, 
respectively. Considering the 10% loss rate, at least 1085 patients were included. 
With 20 research centers, we planned to collect at least 110 patients with hypertension 
(including 55 patients in left ventricular hypertrophy group and 55 patients in left 
ventricular non hypertrophy group), 5-10 healthy volunteers (aged 30-60 years) in 
each center. Then 2200 patients with hypertension in total, and 100 healthy volunteers 
will be selected in this study. 
 
The main test indicators in the selection and follow-up period  
(1) Clinical data 
1) Demographic characteristics: name, hospitalization number/outpatient number, 
gender, age, nationality, occupation, address, postal code, telephone number; 
2) Baseline clinical data: blood pressure, body mass index, smoking history, drinking 
history, medication history, family history (smoking is defined as continuous or 

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cumulative smoking for 6 months or more in a lifetime); 
3) Routine physical examination; 
4) Medication history: antihypertensive drugs, statins, aspirin, etc. 
(2) Accessory examination 
1) ECG examination: use resting ECG to evaluate arrhythmia and ST-T changes, etc. 
2）Laboratory tests: 
 Fasting for more than 6 hours, blood routine, urine routine, fasting blood glucose, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, 
plasma total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density 
lipid Protein cholesterol, high-sensitivity C-reactive protein, prothrombin time, serum 
troponin, NT-proBNP. 
3）Transthoracic echocardiography: 
Two-dimensional dynamic images of left ventricular parasternal long axis, apical four-
chamber heart, apical two-chamber heart, apical long axis, left ventricular apex level, 
papillary muscle level, and mitral valve level short-axis view; measure left ventricular 
ejection fraction (LVEF); Pulse wave Doppler was used to obtain the diastolic mitral 
valve orifice blood flow spectrum, and tissue Doppler was used to obtain the mitral 
valve annulus motion spectrum, and E/e' was calculated; Using speckle tracking 
imaging (STI) ultrasound technology to measure global longitudinal strain (GLS)/strain 
rate, global circumferential strain, global radial strain, global area strain (3D-GAS), left 
ventricular torsion, left ventricular rotation/untwisting speed, systolic dissynchrony 
index (SDI) and right ventricular free wall systolic peak strain (RVFWS) and so on.  
4）Carotid ultrasound examination: the patient was the occipital supine position, with 
slightly raised jaw, the face was turned to one side, and the sternocleidomastoid muscle 
was fully exposed. The probe scans from the posterior edge of the sternocleidomastoid 
muscle to display the long axis and short axis images of the common carotid artery, 
internal and external carotid arteries, and bifurcation. The intima-media thickness, 
internal diameter and blood flow velocity were measured at 1-2 cm before the 

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bifurcation of the common carotid artery. 
(3) The main observation and detection indicators of the first follow-up  
Hypertensions will be followed up in the 12th, 24th, 36th and 48th months after being 
enrolled in this study. They can be followed up through outpatient service or telephone. 
Each follow-up shall not exceed two weeks before and after the specified follow-up 
time. Perform physical examination, ECG examination, laboratory examination, 
echocardiography, etc. Record the treatment and whether there are adverse 
cardiovascular clinical events (myocardial infarction, heart failure, cardiovascular 
death, unstable angina requiring hospitalization, aortic aneurysm or aortic dissection, 
stroke). Record the time when the adverse event occurred. 
 
Standard operation procedure of echocardiography and carotid ultrasound 
(1) Personnel requirements: 
The ultrasonic inspection personnel must be trained and have the qualification 
certificate to undertake the ultrasonic inspection of the research project. One or two 
ultrasonic examiners in the same research center will be fixed to participate in this study. 
All data shall be stored by DVD or hard disk in DICOM format. Each patient is a folder, 
including each image acquisition time and operator. The image information is sent by 
the person in charge of each center to the central laboratory via email for summary and 
storage, and then measured by two experienced ultrasound physicians through offline 
analysis software. Each data is measured three times and averaged data are stored. The 
data with poor image quality will be reviewed by professionals, analyzed repeatedly, 
and finally decided whether to use. 
(2) Application of cardiac and carotid ultrasound probe 
Probe models: S5-1, M5Sc, X5-1, 4D, PLI-2004BX; instrument models: Philips 
EPIQ7C, GE vivid E95 and Canon-Toshiba Ultrasound. The image display, storage and 
measurement modes will be uniformly preset by Philips, GE and Canon-Toshiba 's 
professional clinical doctors. 
(3) Echocardiographic and carotid examination process 

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1) Use the standardized section specified in the ASE/EACVI guidelines to perform 
routine echocardiography and save the image (in DICOM format); 
2) Connect ECG and record dynamic images (frame rate>40fps) of at least 5 cardiac 
cycles to ensure clear images (endocardium) and complete images (including 
epicardium); adjust the frame rate to 40% of the subject's heart rate; 
3) M-mode images: M-mode images were recorded at the level of the chordae tendineae 
of the parasternal left ventricle in the long axis section, and the systolic displacement 
of the tricuspid annulus plane at the lateral wall of the tricuspid annulus was recorded 
at the apical four chamber section (TAPSE); 
4) Two dimensional images: dynamic images were recorded and stored on the 
parasternal left ventricular long axis section, the parasternal left ventricular short axis 
section (mitral annulus level, papillary muscle level, apex level), the apical two 
chamber section, the apical three chamber section, the apical four chamber section, and 
the focused right ventricular four chamber section respectively; 
5) Pulse Doppler image: mitral diastolic blood flow spectrum, tricuspid diastolic blood 
flow spectrum, aortic systolic blood flow spectrum and pulmonary systolic blood flow 
spectrum were recorded respectively; 
6) Tissue Doppler images: TDI dynamic images were recorded in apical four chamber 
view; Pulsed tissue doppler images of mitral annular septum/lateral wall and tricuspid 
lateral wall were recorded on apical four chamber view; 
7) 3D image: full volume imaging mode of Philips system: use the transthoracic real-
time 3D probe X5-1 to collect images to ensure good connection of ECG signals. The 
four-chamber view of the left ventricular chamber fully displayed/the four-chamber 
view of the left atrium gathered/the four-chamber view of the right ventricle focused 
can be obtained on the apical view. Adjust the frame rate to more than 30 frames/second. 
Touch the Full Volume and rotate the 3D Opt key to the 4Beat position, Instruct the 
patient to hold his breath at the end of breath, press the Acquire button on the operation 
panel, and obtain the full volume information of the left ventricle (if EpiQ7c used, the 
Heart Model image will be retained after obtaining the ideal section). Four dimensional 
imaging mode of GE system: after entering the 4D mode, ensure that the ECG signal is 

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well connected, obtain four-chamber view images that fully display the left ventricular 
cavity/four-chamber view images that focus on the left atrium/four-chamber view 
images that focus on the right ventricle on the apical view, adjust the number of cardiac 
cycles (4-6 cardiac cycles), make the image frame rate meet the requirements (the 
image frame rate is required to be more than 40% of the subject's heart rate), instruct 
the patient to hold his breath after deep breath, Stabilize the probe and view the 
"splicing" artifacts in the volume reconstruction and front plane in the lower left 
window of the screen, or use Multi-Slice to evaluate the suture quality. If no artifacts 
are seen in several cardiac cycles, press Freeze. You can collect multiple cardiac cycles 
and then use the Cycle select control to select the best cycle. Press Img. on the operation 
panel Store saves the collected images. 
8) Carotid image: adjust the position of probe to adjust with the targeted vessel 
straightly, and start the VFM program to collect the original data. After the images are 
collected, the data are further analyzed and processed using the online software of the 
machine. Trace the blood flow and the vascular wall at the junction of the vascular wall 
on the frame image of the cardiac cycle which the blood flow was fullest, and then run 
the software to automatically track the trace points and calculate the shear force at the 
corresponding position. To check the range shown at the edge of the screen and the 
automatic calculation results, and calibrate the calculation deviation caused by aliasing 
frame. Then the shear stress values of each cardiac cycle of this segment of blood vessel 
can be obtained. 
 
 
Echocardiographic and carotid measurement parameters 
(1) M-mode and two-dimensional ultrasonic parameters: 
1) Left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic 
diameter, left ventricular long diameter at end-diastolic, left ventricular basal transverse 
diameter and left ventricular middle transverse diameter; 
2) End-diastolic ventricular septal thickness (IVSTd), end-diastolic left ventricular 
posterior wall thickness (LVPWTd); 

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3) Left atrial antero-posterior diameter, left atrial long diameter, left atrial transverse 
diameter, left atrial area and left atrial volume at end-systolic (Simpson method); 
4) The antero-posterior diameter of right ventricle, the transverse diameter of right 
ventricular basal segment, the transverse diameter of right ventricular middle segment 
and the long diameter of right ventricle at end-diastolic; 
5) The parasternal, proximal and distal diameters of the right ventricular outflow tract; 
6) Right atrial long diameter, right atrial transverse diameter, right atrial area and right 
atrial volume at end-systolic (Simpson method); 
7) The middle systolic aortic annulus diameter, the end-diastolic aortic sinus diameter, 
the end-diastolic aortic sinus tube junction diameter and the end-diastolic ascending 
aorta diameter; 
8) Left ventricular end diastolic volume, end-systolic volume and ejection fraction were 
measured by Simpson method in apical four-chamber view; 
9) TAPSE; 
10) RVFAC; 
(2) Doppler ultrasound parameters: 
1) Deceleration time EDT of mitral valve E peak, A peak, E/A peak and E peak; 
2) s', e 'and a' at the interventricular septum of mitral annulus; 
3) s', e 'and a' at the lateral wall of mitral annulus; 
4) E peak and A peak of tricuspid valve; 
5) s', e ', a' at the lateral wall of tricuspid annulus; 
6) Left ventricular Tei index: the ratio of the sum of left ventricular isovolumic systolic 
time (ICT) and isovolumic diastolic time (IRT) to ejection time (ET); 
7) Right ventricular Tei index: the ratio of the sum of right ventricular isovolumic 
systolic time (ICT) and isovolumic diastolic time (IRT) to ejection time (ET). 
(3) Relevant parameters of two-dimensional speckle tracking: 
1) Segmental longitudinal strain and strain rate of 17 segments of left ventricular 
myocardium, and global longitudinal strain and strain rate; 
2) Segmental circumferential strain and strain rate, global circumferential strain and 
strain rate of 17 segments of left ventricular myocardium; 

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3) Segmental radial strain and strain rate, global radial strain and strain rate of 17 
segments of left ventricular myocardium; 
4) Left ventricular bottom angular displacement, apex angular displacement, 
myocardial torsion torque; 
5) The longitudinal strain of the intima and adventitia of 17 segments of left ventricular 
myocardium, and global longitudinal strain of the intima and adventitia; 
6) The circumferential strain of the intima and adventitia of 17 segments of left 
ventricular myocardium, and the circumferential strain of global intima and adventitia; 
7) The radial strains of the intima and adventitia of 17 segments of left ventricular 
myocardium, and global radial strains of the intima and adventitia; 
(4) Myocardial work parameters: 
According to the patient's blood pressure, left ventricular outflow tract spectral Doppler 
image, apical four chamber heart, apical two chamber heart, and apical three chamber 
heart section dynamic images, the pressure strain loop (PSL) is obtained by offline 
analyzing and calculating with Echopac software. Then the global work index (GWI), 
global constructive work (GCW), global wasted work (GWW), global work efficiency 
(GWE) and other indicators are obtained. 
(5) The left ventricular remodeling parameters required in this study are 
calculated from the above obtained ultrasound parameters as follows: 
LVM=0.8×1.04×[(IVSTd+LVEDD+LVPWTd)3 -LVEDD3] +0.6 
RWT =(LVPWTd×2)/LVEDD 
(6) Cardiac morphological changes: 
Record whether there is pericardial effusion (small, medium and large) and pericarditis 
during follow-up, and whether there is mitral valve, tricuspid valve, aortic valve, 
pulmonary valve and other valve diseases, such as valve sclerosis, stenosis, etc. When 
each valve has regurgitation or stenosis, note the peak flow rate, peak pressure 
difference and average pressure difference, especially tricuspid regurgitation; 
(7) Three-dimensional ultrasound parameters:  
Echopac software and QLAB software were used to analyze the retained three-
dimensional images to obtain three-dimensional left ventricular volume parameters, 

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three-dimensional left ventricular ejection fraction, three-dimensional left ventricular 
strain, three-dimensional left atrial volume parameters, three-dimensional left atrial 
strain parameters, three-dimensional right ventricular volume parameters. 
(8) Carotid ultrasound parameters: 
Diameters, blood flow velocities and plaques and shear force strains of the common 
carotid artery, internal and external carotid arteries, and bifurcation. 
(9) Development of artificial intelligence analysis software: 
Using the images of hypertensive population collected by the project, we would 
measure, analyze and calculate to collect the two-dimensional, three-dimensional, 
Doppler, strain, work and remodeling parameters of hypertension. Combining with the 
artificial intelligence technology, we will establish an ultrasonic data bank of Chinese 
hypertensive population. Meanwhile, we will compare the data with the EMINCA 
database of Chinese healthy adults, and use machine learning methods to build an 
artificial intelligence measurement module. The combination of ultrasonic dynamic 
image and neural network algorithm can achieve the rapid, dynamic and real-time 
evaluation of the cardiac structure and function of hypertension, automatically measure 
and identify normal and abnormal thresholds, and help hypertensions get more accurate 
diagnosis, evaluation and treatment. 
 
 
 
 
 
 
 
 
 
 
 
DIAGRAM OF RESEARCH SCHEME 

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two echocardiographic 
examinations with an interval of 
more than 4 hours 
inclusion and exclusion criteria 
Sign the informed consent form 
Health volunteer 
medical history 
physical examination 
ECG and laboratory 
examination 
two echocardiographic 
examinations with an interval of 
more than 4 hours 
inclusion and exclusion criteria 
Sign the informed consent form 
Hypertension 
medical history 
physical examination 
ECG and laboratory 
examination 
follow-up in the 12th, 24th, 36th and 48th 
months, recording adverse events 
Data collected by each center 
Statistics Analysis 
publish research article 

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CHART OF RESEARCH SCHEME 
Follow-up time 
0 month 
12th month 24th month 36th month 48th month 
Information 
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Medical history 
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Inclusion Criteria 
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Informed consent 
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Electrocardiogram 
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Physical examination 
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● 
Laboratory examination 
● 
 
 
 
 
Echocardiography 
● 
 
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Arterial ultrasound 
● 
 
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Drugs treatments 
● 
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Adverse events 
 
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ETHICS 
(1) In the process of clinical research, the personal rights and interests of the subjects must 
be fully guaranteed, and the reliability of the research must be ensured. The rights, safety 
and health of subjects must be higher than the consideration of scientific and social interests. 
(2) The research scheme can only be implemented after being reviewed, agreed and signed 
by the Ethics Committee. During the study, any modification of the study protocol shall be 
approved by the Ethics Committee. 
(3) The investigator or its designated representative must explain the details of the clinical 
study to the subject, and obtain the informed consent after fully explained the study. 
(4) Informed consent of the subject (see the Informed Consent Form for details). 
Before each patient is enrolled in this study, the physician has the responsibility to 
completely and comprehensively introduce the purpose, procedure, possible benefits and 
risks of this study to him or his designated representative in written form. Patients should 
be made aware of their right to withdraw from the study at any time. Before enrollment, 
each patient must be given a written informed consent form (included in the protocol in the 
form of appendix) so that the subject can understand and agree. Only after signing the 
informed consent form voluntarily, they could be included in the clinical trial. The informed 
consent form will be kept as one of the original data of the clinical trial for future reference. 
 
ELECTRONIC DATA MANAGEMENT (eCDM) 
This test adopts the electronic data management system (DAS for eCDM). 
(1) Construction of electronic case report form (eCRF): the data administrator constructs 
eCRF according to the research scheme and research medical record. 
(2) Permission allocation: The data administrator creates accounts and grants different 
permissions to access eCDM according to different identities of main research center, 
supervisor, inspector, etc. If the researchers in each center can only see the contents of the 
center and have the right to modify the data, the main research centers are limited to 
browsing all cases; The monitors and auditors can read the case information of each center, 
but they have no authority to modify the data, but they can insert comments or questions. 
(3) Data entry: clinical investigators or data entry personnel designated by researchers 

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timely and accurately enter the data in the study medical records into eCRF. eCRF is not 
used as the original record, and its content is derived from the "study medical record". 
(4) Data questions and answers: The supervisor conducts the audit through eCDM, and 
raises questions online at any time when problems are found. The researcher will answer 
the questions online, correct the wrong data, and if necessary, the supervisor can repeat the 
questions. 
(5) Data locking and export: after each subject completes the test and is checked by the 
supervisor, the data administrator will lock the data until the last subject's data is locked. 
After all the data are locked, the data administrator will import them into the designated 
database and submit them to the statisticians for statistical analysis. 
6. After the study ends, eCRF was printed and archived as required. The data management 
center will keep the electronic data until 5 years. During this period, if SFDA needs to audit, 
the data management center can open the system at any time after making an appointment. 
 
STATISTICAL TREATMENT 
(1) Analysis data set 
Full analysis set (FAS): the patient enrolled according to the principle of Intention To Treat 
(ITT), and the data composed of all enrolled hypertensive patients. The patients who failed 
to observe adverse cardiovascular and cerebrovascular events were treated as deletion and 
carried outsides in the last follow-up date. 
PPS: refers to the cases that meet the inclusion criteria but do not meet the exclusion criteria, 
and the cases that meet the test protocol and complete the CRF requirements are analyzed 
(PP analysis). 
(2) Statistical methods 
Demographic Analysis 
1) Measurement data: mean, standard deviation, median, maximum, minimum and quartile 
are used for description; 
2) Counting data: described by frequency and composition ratio. 
(3) Group analysis: 
1) For the healthy volunteers and hypertensive patients enrolled in the group: between 9:00 

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a.m. and 17:00 p.m. on the day of enrollment, at an interval of more than 4 hours, the patients 
performed two echocardiographic examinations in a calm state, measured and recorded their 
blood pressure at the same time (three measurements at an interval of 1-2 minutes), and 
measured the indicators at the two baseline levels on the day of enrollment. The changes of 
left ventricular global longitudial strain (GLS) and myocardial work (MW) in hypertension 
and healthy volunteer were compared, and the correlation between them and the changes of 
blood pressure was analyzed; 
2) Analysis for hypertensive patients with different left ventricular configurations: 
configuration analysis was conducted based on the left ventricular remodeling standards 
recommended by ASE/EACVI 2015 guidelines and the EMINCA study combined with 
Ganau classification. Hypertensive patients were divided into normal left ventricular 
configuration group, left ventricular remodeling group, left ventricular eccentric 
hypertrophy group and left ventricular concentric hypertrophy group. Baseline, 12months, 
24months, 36months and 48months echocardiography images were recorded and analyzed, 
compared the cardiac structure and functional indicators, and recorded clinical adverse 
events; 
(2) Analysis for hypertensive patients with different left atrial configurations: according to 
the abnormal threshold of left atrial enlargement recommended by ASE/EACVI 2015 
guidelines and the standard of Chinese left atrial enlargement recommended by EMNICA 
study, hypertensive patients were divided into normal left atrial group and left atrial 
enlargement 
group. 
Baseline, 
12months, 
24months, 
36months 
and 
48months 
echocardiography images were recorded and analyzed, compared the cardiac structure and 
functional indicators, and recorded clinical adverse events. 
(4) Analysis of main endpoint events: 
1) Cox regression was used to analyze the predictive value of different types of left 
ventricular remodeling and left atrial enlargement on adverse cardiovascular events. ROC 
analysis was used to compare the incremental effect of left ventricular remodeling, left 
ventricular hypertrophy and left atrial enlargement on the predictive ability of hypertensive 
cardiovascular events; NRI [net corrected classification, i.e. (new sensitivity + new 
specificity) - (old sensitivity + old specificity)] was used to evaluate and compare the ability 

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of left ventricular remodeling, left ventricular hypertrophy and left atrial enlargement to re 
stratify and optimize the risk of cardiovascular events in hypertension. Multivariate 
regression analysis was used to analyze the factors affecting left ventricular remodeling and 
left atrial enlargement in hypertension. 
2) The incidence time of adverse cardiovascular events was stratified by left ventricular 
remodeling, left ventricular hypertrophy and left atrial enlargement. Cox regression analysis 
was used to calculate the hazard ratio and its bilateral 95% confidence interval of different 
influencing factors. 
(5) Statistical software: SAS 9.4 or SPSS software was used for analysis. Bilateral tests 
were used for statistical tests. P≤0.05 were considered statistically significant. 
(6) Interim analysis: No interim analysis will be conducted in this study. If special cases 
occur, the main research center, researchers and statistical experts will discuss and decide. 
 
QUALITY CONTROL 
(1) The main research centers and researchers perform their duties, strictly follow the 
clinical research scheme, adopt standard operating procedures, and verify all relevant 
observations and findings to ensure the implementation of the quality control and quality 
assurance system of the clinical research; 
(2) The investigator must provide necessary training for all personnel participating in the 
clinical study, explain relevant data, operation specifications and responsibilities, and ensure 
the data truthfully, accurately, completely, timely and legally recorded in the medical records 
and CRF. CRF must be kept by special person. Participants have project training certificates. 
(3) The supervisors dispatched by the main research centers follow the standard operating 
procedures, supervise the implementation of the research scheme, confirm that all data 
records and reports are correct and complete, and all CRF are correctly informed and 
consistent with the original data. 
(4) The results were uniformly verified by Qilu Hospital of Shandong University, and 
analyzed by two professionals. Each analyst repeated the measurements twice a week apart. 
(5) Major research centers can entrust auditors to systematically check the activities and 
documents related to clinical research to evaluate whether the research is conducted in 

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accordance with the protocol, standard operating procedures and relevant regulations. 
(6) All examination data in clinical research must be accurate, and the original or the copy 
of the report should be pasted on the case report form. 
(7) Medical statisticians should include the research data into the report quickly, completely 
and without error, and all the steps involved in data management should be recorded in order 
to check the data quality and research implementation. 
(8) The statistical analysis process of clinical research data and the expression of its results 
must adopt standardized statistical methods. Medical statisticians are required to participate 
in all stages of clinical research. The statistical report of the clinical study must be consistent 
with the clinical study summary report. 
(9) All parties conduct clinical research in accordance with the approved protocol, and any 
deviation from the protocol should be recorded. The modification of the research scheme 
should be described and reported to the Ethics Committee for approval before 
implementation. 
 
RESEARCH PLAN 
(1) Case entry stage: from May 2022 to May 2023—complete the entry of each group of 
cases. 
(2) Follow-up time: 48 months. For follow-up time points, please refer to the attached trial 
procedure.  
(3) Data analysis: May 2023 to December 2027—Data collection and analysis, writing 
papers. 
(4) Periodic analysis: summarize the periodic research results and submit them to relevant 
committees for evaluation. 
 
PAPER PUBLISHING PLAN 
After the collection and analysis of case follow-up data, articles will be published on clinical 
journals in the cardiovascular field in the form of research papers. 
The author of the paper is determined according to the researchers' contributions to scheme 
design, trial implementation and data analysis. The authors of this study are as follows: 

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Zhang Yun is the first person in charge of the author, other authors are listed in order 
according to their contributions (number of effective cases collected), and Zhang Yun is the 
corresponding author. Each participating center can provide 1-2 researchers to be included 
in the list of researchers. All authors are responsible for improving the scheme, writing the 
draft and verifying the paper before submitting. The names of the advisory committee, 
academic committee, data security and supervision committee, clinical event determination 
committee and other researchers who do not meet the author's qualification will be shown 
in the "Shandong Hypertension Prevention and Control Researchers" section of the paper 
attachment. The Data Security and Supervision Committee will review the papers before 
publication. After the study, each center will use the database for further analysis according 
to contribution. 
The source of funds has no influence on the data processing and analysis and the publication 
of papers.