Luận án nghiên cứu nồng độ apolipoprotein huyết tương ở bệnh nhân nhồi máu não do xơ vữa động mạch ta

MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES NGUYEN CAM THACH STUDY ON PLASMA APOLIPOPROTEIN CONCENTRATION IN PATIENTS WITH ATHE[.]

108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES

NGUYEN CAM THACH

STUDY ON PLASMA APOLIPOPROTEIN

CONCENTRATION IN PATIENTS WITH

ATHEROSCLEROTIC ISCHEMIC STROKE

Speciality: NeurologyCode: 62720147

ABSTRACT OF MEDICAL PHD THESIS

HaNoi - 2021

PHARMACEUTICAL SCIENCES

Supervisor:

1 PhD Nguyen Van Tuyen

2 Assoc Prof PhD Nguyen Hoang Ngoc

Day Month Year

The thesis can be found at:

National Library of Vietnam Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences

INTRODUCTION

Stroke is a global health problem, the third leading cause of death after cardiovascular disease and cancer, but the leading cause of disability in humans, ischemic stroke (IS) accounts for 80% to 85% of all strokes Patients with ischemic stroke have a high rate of recurrence

or death

The main cause of IS is atherosclerosis Therefore, the prevention

of atherosclerosis will reduce the rate of new cases as well as the mortality and disability rates for patients with IS One of the important measures in the prevention and treatment of atherosclerotic disease is the control of lipoproteins (cholesterol, HDL, LDL ) However, sometimes these indicators do not fully reflect disease risk due to changes in cholesterol between close tests Recent studies have shown the role of apolipoproteins such as apolipoprotein A-I (apoA-I), apolipoprotein B (apoB) and the apoB/apoA-I ratio that can be used as predictors and assessment of the risk of IS with other lipid indices; These indicators reflect the balance between atherogenic lipoproteins and antiatherogenic lipoproteins; Reflecting Intracranial atherosclerosis (ICAS), even plasma apoA1 UP concentration is considered as a biomarker in early prediction

of IS Besides, testing for apolipoproitein has some advantages over lipoproteins such as accuracy, convenience and efficiency

Studies have also shown that atherosclerosis can occur in the intracranial and extracranial arteries and that intracranial atherosclerosis

is more likely in blacks and Asians than in whites Therefore, it is very important to study and apply apolipoproteins to predict cerebral atherosclerosis and intracranial atherosclerosis in Vietnamese people However, until now, the research and application of the apolipoprotein test to monitor, predict and prevent ischemic stroke have received little attention and only focused on cardiovascular diseases

From the above reasons, we study the thesis “Study on plasma apolipoprotein concentration in patients with atherosclerotic ischemic stroke” has been conducted with two following purposes:

1 Describe clinical characteristics, imaging characteristics and changes in plasma apolipoprotein concentration in patients with atherosclerotic ischemic stroke

2 Evaluation of the relationship between the concentration of some apolipoproteins in plasma and the state of cerebral atherosclerosis

Thesis layout:

The thesis is presented on 133 pages, including: introduction 02 pages, overview 38 pages, subjects and methods 26 pages, research results 30 pages, discussion 34 pages, conclusion 02 pages, recommendations 01 page

The thesis has 36 tables, 15 charts, 22 figures, 133 references (23 Vietnamese documents and 110 English documents)

Chapter 1

OVERVIEW

1.1 The concept of stroke

The World Health Organization definition of stroke in 1989

1.2 Classification of ischemic stroke

Classification of ischemic stroke according to TOAST

1.3 Anatomy of cerebral arteries

1.3.1 Carotid arteries

1.3.2 Vertebral artery, basilar artery

1.4 Clinical and imaging of ischemic stroke

1.4.1 Clinical of ischemic stroke

1.4.2 Imaging of ischemic stroke

1.5 Cerebral atherosclerosis

1.5.1 Mechanism of atherosclerosis

Atherosclerosis is the result of hyperlipidemia and lipid oxidation The atherosclerosis process follows 3 stages: Fatty streaks formation, atheroma formation, atherosclerotic plaques formation 1.5.2 Epidemiology of cerebral atherosclerosis

1.5.3 Some characteristics of cerebral atherosclerosis

- Some characteristics of atherosclerosis according to cerebral artery location: Overall, intracranial atherosclerosis develops ≈20 years later in life compared with atherosclerosis in extracranial arterial beds Intracranial atherosclerotic stenoses were described as dynamic lesions showing progression and regression

- Difference between ICAS and ECAS: Two major characteristics that distinguish intracranial and extracranial atherosclerosis are the later onset and the more stable plaque phenotype in intracranial arteries, which may be explained by the distinct characteristics of the intracranial Arteries It can be explained because the wall structure of the intracranial arteries has its own characteristics compared with the extracranial arteries Intracranial arteries are less sensitive to hypercholesterolemia

In intracranial arteries, LDL, Ox-LDL, macrophages are less infiltrated and antioxidant enzymes are more active than in extracranial arteries

1.5.4 Differences in the location of cerebral atherosclerosis between races

Studies have shown that ICAS is more common in Asians, blacks than whites However, due to the recent availability of non-invasive vascular imaging techniques that can assess intracranial cerebral arteries, there are a growing number of studies on risk factors for ICAS to explain this difference

1.6 The role of apolipoproteins in atherosclerosis

1.6.1 General knowledge of apolipoproteins

1.6.2 The role of apolipoprotein A-I in atherosclerosis

ApoA-I has anti-atherosclerotic effects In peripheral tissues (including atheroma), HDL picks up excess cholesterol and transports it back to the liver The reverse transport mechanism of HDL is the only way for cells to remove excess cholesterol and helps protect arteries, eliminating the accumulation and deposition of lipoproteins that cause atherosclerosis ApoA-I activates enzymes that transport cholesterol from tissues into HDL and allows HDL to recognize and bind to receptors in the liver at the end of transport

1.6.3 The role of apolipoprotein B in atherosclerosis

ApoB has a central role in the development of atherosclerosis In apoB, there are 2 binding sites for proteoglycan, so atherogenic lipoproteins will penetrate and stay in the arterial wall This is an important factor in the formation of atheroma

1.6.4 The role of the apoB/apoA-I ratio in the assessment of atherosclerosis

The apoB/apoA-I ratio represents a balance between the rich cholesterol particles and the anti-atherogenic apoA-I-rich cholesterol particles When this balance is disrupted, it will lead to an increase or decrease in the risk of atherosclerosis, for example, an increase in the apoB/apoA-I ratio will increase the risk of atherosclerosis

apoB-1.7 Studies on apolipoprotein in atherosclerotic ischemic stroke

1.7.1 Overseas studies

A study by Koren-Morag et al: the hazard ratios (HR) for incident ischemic cerebrovascular events associated with the top versus bottom quartile of Apo B was 1.68, of Apo A-I 0.71, and of Apo A-I/Apo B ratio 0.51 These indicators have a role in predicting atherosclerotic ischemic stroke

In 2009 Michael S Kostapanos, et al studied 163 patients with ischemic stroke The concentration of apoA-I in the group of patients

was lower than that of the control group The apoB concentration and apoB/apoA-I ratio of the disease group were higher than that of the control group The ratio apoB/apoA-I is a predictor of ischemic stroke

in the elderly

A study in Korea by Jong-Ho Park et al in 2011 showed that the apoB/apoA-I ratio is a biomarker for intracranial atherosclerosis in Asian patients with ischemic stroke

According to a study by Shilpasree A.S et al (2013): a group of patients with ischemic stroke had decreased apoA-I concentrations, increased apoB concentrations, and increased apoB/apoA-I ratios compared with the control group The apoB concentration, apoA-I concentration and apoB/apoA-I ratio are significant in predicting the risk

of ischemic stroke

Hongli Dong analyzed studies of apolipoproteins from 1991 to

2015, and found that decreased apoA-I concentration, increased apoB concentration, and increased apoB/apoA-I ratios were risk factors for ischemic stroke

A retrospective study by Yu-Ching Chou showed that apoB and apoB/apoA-I ratio were both better predictors of ischemic stroke than total cholesterol, LDL, and cholesterol/HDL ratio

In 2020, Yang et al studied on 658 patients with ischemic stroke and TIA, the results: the ratio apoB/apoA-I was associated with ICAS more than other lipid indices (TC/HDL, LDL/ HDL, nonHDL/HDL)

< 1.2 is 9.8 times if compared with normal people

Truong Thanh Son et al (2017): Triglyceride is the only plasma lipid index associated with the risk of ischemic stroke TC/HDL index is

an important atherogenic index for patients with ischemic heart disease According to Nguyen Cong Hoan (2018): there is a relationship between a decrease in HDL alone and degrees of carotid stenosis due to

atherosclerosis (p < 0.05)

Chapter 2 SUBJECTS AND METHODS 2.1 Studying subjects

2.1.1 Patient group

Including 248 ischemic stroke patients who were hospitalized

treated at the Stroke Center - 108 Military Central Hospital from October

2017 to December 2019 and these patients were divided into 2 groups:

- The ischemic stroke group due to large artery atherosclerosis (LAA) has 146 patients and is divided into subgroups: + Intracranial atherosclerotic ischemic stroke subgroup, n = 88 patients

+ Subgroup of extracranial atherosclerotic ischemic stroke, n = 31 patients

+ Subgroup of intracranial and extracranial atherosclerotic ischemic stroke, n = 27 patients

- The ischemic stroke group due to small artery occlusion (SAO):

102 patients

* Selection criteria for study patients

- Clinical criteria: according to the definition of stroke by the World Health Organization (1989)

- Paraclinical criteria: all patients were scanned with one or more methods: CT, CTA, MRI, MRA to determine the location, number, and size of infarcts and cerebral artery stenosis and occlusion

* Criteria to divide the ischemic stroke group due to large artery atherosclerosis and the small artery occlusion group according to TOAST

- Ischemic stroke group due to LAA: patients with impaired cortical function or brain stem dysfunction or cerebellar dysfunction CT and MRI: cortical or cerebellar and brainstem lesions or bilateral cerebral infarction > 1.5cm There is stenosis of more than 50% of the affected artery Exclude cardiovascular causes

- Ischemic stroke group due to small artery occlusion: have typical lacunar infarct syndrome The image of the MRI film shows an infarction of the brain stem or cerebral hemisphere less than 1.5cm in diameter There was no evidence of embolism from the heart and

atherosclerosis of the great vessels

* Exclusive criterial

- Patients with ischemic stroke have heart valve disease, arrhythmia, complete arrhythmic atrial fibrillation on electrocardiogram, arterial disease or a history of the above diseases Patients with ischemic stroke who have a pacemaker or have factors that cannot be computed tomography, magnetic resonance imaging

- Patients with ischemic stroke due to rare causes: hypercoagulable disorder, sickle cell disease, systemic lupus erythematosus, arteritis, AIDS

- Patients with diseases: heart failure, kidney failure, cirrhosis of the liver, thyroid cancer

- Patients are taking drugs that affect the test such as carbamazepine, estrogen, ethanol, lovastatin, simvastatin

2.1.2 Control group

Including 40 people selected at random during the health examination at 108 Central Military Hospital, they all had MRI and MRA scans Selected at the same time as the patient group, adjusted for age, gender, underlying medical condition, race, genetics, and epidemiology compared with the patient group

* Selection criteria for the control group

- No stroke, no history of stroke or transient ischemic attack at the time of the study

- No diseases such as heart failure, cirrhosis of the liver, kidney failure, cancer

- No symptoms of stroke (clinical and CT, MRI)

- Voluntary participation in the research program

Formula for calculating sample size for case-control studies:

n is the minimum sample size for each group; Z is the value from the normal distribution; Ϭ is the common standard deviation of the two groups; d is the acceptable error level Substitute the data into the formula to calculate sample size = 40

2.2.3 Study devices

Automated biochemical analyzer AU5800 of Beckman Coulter;

32 slice CT computed tomography scan - Siemens; Philips EPIQ 5 Dupplex ultrasound; 3Tesla Achieva, Philips, The Netherlands The testing and diagnostic imaging equipment belonged to the Center Lab, the Diagnostic Imaging Center - 108 Central Military Hospital

2.3 Research content

2.3.1 Data collection

- Collect personal information, history, risk factors, medical history

- Clinical examination, test orders

+ Hematological and Biochemical tests: blood count, routine biochemical tests and apo indexes (apolipoprotein A-I, apolipoprotein B and apoB/apoA-I)

+ Echocardiography, electrocardiogram

+ Duplex extracranial carotid ultrasound: evaluate atherosclerotic stenosis of the common carotid artery and the extracranial internal carotid artery

+ All patients were taken CT, CTA to determine the location, number and size of infarcts and narrowed or blocked cerebral blood vessels For patients who do not have a CTA (drug allergy ) or CTA does not detect lesions or the results are inconsistent with clinical symptoms, the patient will be taken for an MRA

+ 100% of the control group received MRI, MRA to exclude IS

2.3.2 Variables

 Clinical research

- Risk factors: smoking, alcohol abuse, overweight and obesity (body mass index), high blood pressure (JNC VII 2014), type 2 diabetes (American Diabetes Association - ADA 2019), lipid metabolism disorders (ATP III 2001), metabolic syndrome (World Diabetes Association)

- Disorders of consciousness (Glasgow scale), muscle strength (British Medical Research Council), clinical status (National Institutes

of Health's stroke scale - NIHSS)

 Subclinical research

- Imaging studies: CT, CTA, MRI, MRA Method to determine %

of arterial stenosis according to WASID and NASCET

- Test some hematological and biochemical indicators

- Quantification of apolipoprotein A-I, apolipoprotein B in plasma: immunoassay for turbidity

Chapter 3 RESEARCH RESULTS 3.1 Patient’s general characteristics

3.1.1 Gender and age characteristics

Table 3.1 Gender characteristics of the groups

Gender

IS group due to

LAA (n = 146)

IS group due SAO (n = 102 )

Control group (n = 40)

IS group due to SAO (n = 102 )

Control group (n = 40)

Comment: the mean age and proportion of patients in each age

group between the 3 groups were not different with p > 0.05

3.1.2 BMI characteristics

There was no difference in mean BMI, as well as in the proportion

of thin, normal, overweight and obese patients between the 3 groups (control, IS due to LAA, IS due to SAO)

3.1.3 Characteristics of some diseases and blood biochemical indexes

Results: the proportion of patients according to diseases (hypertension, type 2 diabetes, lipid metabolism disorders, metabolic syndrome, overweight-obesity) did not differ between the 3 groups (p> 0.05) The control group had lower concentrations of glucose, triglycerides, and higher HDL concentrations than IS due to LAA and

IS due to SAO (p < 0.01)

3.2 Clinical characteristics and imaging characteristics of patients with atherosclerotic ischemic stroke

3.2.1 Clinical characteristics

Table 3.3 Time from onset to hospital admission of patients with IS

Time IS group due to LAA (n = 146) IS group due to SAO (n = 102 )

Comment: the percentage of patients admitted to the hospital

between 3 and under 6 hours was the highest in each group

Table 3.4 Consciousness status of the patient with IS on admission

Comment: the highest percentage of patients with glasgow score

13-15 in both groups The average Glasgow score in the IS group due to

LAA was 12.98 ± 2.54; the IS group due to SAO was 14.80 ± 0.65

Table 3.5 Upper and lower extremity motor strength

Strength

IS group due

to LAA (n = 146)

IS group due SAO (n = 102 )

IS group due to LAA (n = 146)

IS group due SAO (n = 102 )

Comment: upper extremity motor strength (or lower extremity motor strength) of IS group due to LAA was lower than that of IS group due to SAO with p < 0.05 and p < 0.01

Table 3.6 Assessment of stroke severity of patients based on NIHSS

on admission

Comment: Patients with NIHSS ≤ 6 of ischemic stroke group due

to SAO had the highest rate

Table 3.7 The recovery rate of patients with ischemic stroke

Time

NIHSS (Mean ± SD) Group of IS due to LAA

Comment: The mean NIHSS of the 2 groups at hospital discharge

decreased compared to hospital admission

3.2.2 Imaging characteristics

Table 3.8 Percentage of patients with ischemic stroke by the position

of arterial stenosis, arterial occlusion

Statistics Group of IS due to LAA

Comment: In the atherosclerotic ischemic stroke group, patients

in the ICAS group had the highest rate, followed by ECAS group, the

lowest was in the ICAS + ECAS group

Table 3.9 Prevalence by the position of artery stenosis and occlusion

of the ischemic stroke group due to LAA

Extracranial

arteries

Intracranial arteries Carotid artery Vertebral artery,

basilar artery Arteries CCA ICA VA ICA MCA ACA PCA BA VA

M1 M2 M3 A1 A2 P1 P2

n 2 52 15 8 64 14 3 3 1 8 3 28 13

% 0.9 24.3 7 3.7 29.9 6.6 1.4 1.4 0.5 3.7 1.4 13.1 6.1

Comment: Atherosclerosis in the M1 segment of the middle

cerebral artery had the highest rate (29.9%), the lowest was in the

anterior cerebral artery A2 (0.5%)

Table 3.10 Prevalence by the degree of artery stenosis and occlusion

of the ischemic stroke group due to LAA

Degree Ischemic stroke subtypes due to LAA Total

(n,%) ICAS

Comment: The percentage of patients with arterial occlusion was

the highest in each subgroup

Table 3.11 Prevalence by number of artery stenosis and occlusion of

the ischemic stroke group due to LAA

Number of

positions

Ischemic stroke subtypes due to LAA Total

(n,%) ICAS

Comment: the rate of patients with stenosis, occlusion at one site

in the ICAS subgroup was 76.1%; ECAS subgroup is 71.0%; for the

whole group is 60.96%