Significance of Small Dense Low-Density Lipoprotein as a Risk Factor for Coronary Artery Disease

and Acute Coronary Syndrome

Sung Woo Kwon

Department of Medicine

The Graduate School, Yonsei University

Significance of Small Dense

Low-Density Lipoprotein as a Risk

Factor for Coronary Artery Disease

and Acute Coronary Syndrome

Directed by Professor Hyuck Moon Kwon

The Master's Thesis submitted to the Department of Medicine, the Graduate School of Yonsei

University in partial fulfillment of the requirements for the degree of Master of Medical Science

Sung Woo Kwon

June 2005

This certifies that the Master's Thesisof Sung Woo Kwon is approved.

------------------------------------------------------Thesis Supervisor : Hyuck Moon Kwon

------------------------------------------------------Thesis Committee Member Hyun-Seung Kim

------------------------------------------------------Thesis Committee Member Jeong-Ho Kim

The Graduate School Yonsei University

June 2005

감감감사사사의의의 글글글

이 논문의 시작부터 끝마무리까지 격려와 가르침 그리고 충고를 베풀어 주신 권혁문 교수님께 먼저진심으로 감사를 올립니다.

그리고 이 논문이 완성되기까지 지도하여 주신심장내과 김현승 교수님과 진단검사의학과 김정호 교수님께도 깊은 감사를 올립니다.

연구진행에 물심양면으로 도와준 영동세브란스병원 내과의국 동기인 성주,종관,진혁,근만,민수,지현,혜진에게도 진심으로 감사드립니다.

끝으로 오늘날까지 끊임없는 사랑과 격려를 주신 아버지와 어머니 그리고 장인어른과 장모님,사랑하는 아내 세라와 논문 완성의 기쁨을 함께 하고 싶습니다.

저 자 씀

<TABLE OF CONTENTS>

I. INTRODUCTION..............................................................................................................2

II. MATERIALS AND METHODS....................................................................................5

1. Subjects..........................................................................................................................5

2. Estimation of extent of CAD.....................................................................................6

3. Global risk assessment scoring...................................................................................7

4. Lipoprotein and metabolic parameter analysis..........................................................8

5. Statistical analysis.......................................................................................................10

III. RESULTS.......................................................................................................................11

1. Comparison between CAD and controls................................................................11

2. Multivariate analysis of risk factor for CAD.......................................................15

3. Correlation between CAD severity and mean LDL particle size......................16

4. Correlation between mean LDL particle size and Framingham risk score......18

5. Analysis between ACS and non-ACS groups......................................................19

6. Multivariate analysis of risk factor for ACS.......................................................21

IV. DISCUSSION...............................................................................................................22

V. CONCLUSION..............................................................................................................25

REFERENCES.....................................................................................................................26

LIST OF FIGURES

Figure 1. Estimation of extent of coronary artery disease

by Gensini score.......................................................6

Figure 2. Framingham scoring system for calculating the

10-year risk of major coronary events..................7

Figure 3. Densitometric scans of LDL subfraction................9

Figure 4. Comparison of mean LDL particle size between

CAD and control group.........................................13

Figure 5. Comparison of mean Gensini score between LDL

pattern A and B...............................................16

Figure 6. Correlation between mean LDL particle size and

Gensini score...........................................................17

Figure 7. Correlation between mean LDL particle size and

Framingham risk score...........................................18

Figure 8. Comparison of mean LDL particle size between

ACS and non-ACS group in CAD......................20

LIST OF TABLES

Table 1. Comparison of the general and metabolic

characteristics between CAD and controls.............12

Table 2. Univariate tests for correlation with mean LDL

particle size................................................................14

Table 3. Multiple logistic regression analysis for CAD......15

Table 4. Comparison of the general and metabolic

characteristics between ACS and non-ACS

group in CAD...........................................................19

Table 5. Multiple logistic regression analysis for ACS......21

A BSTRA CT

Significance of Small Dense Low-Density Lipoprotein as a Risk Factor

for Coronary Artery Disease and Acute Coronary Syndrome

Sung Woo Kwon

Department of Medicine

The Graduate School, Yonsei University

(Directed by Professor Hyuck Moon Kwon)

Low-density lipoprotein(LDL) cholesterol is a proven risk factor for

coronary artery disease (CAD). Recently, small dense LDL is now emerging as

an important risk factor for CAD. However, data regarding the relationship of

LDL particle size and extent of coronary artery disease are limited in Korean

population. This study was performed to investigate the relationship between

mean LDL particle size and extent of CAD as well as acute coronary syndrome.

Blood samples were collected from 504 patients who underwent

coronary angiography to evaluate chest pain, and the particle size of LDL was

measured. LDL particle size correlates significantly with age, total cholesterol,

triglyceride, HDL cholesterol and LDL cholesterol (P<0.05). Mean LDL

particle size was smaller in patients with angiographically proven CAD than in

controls (26.41±0.95 vs 26.73±0.64nm, p<0.001),and had a negative correlation

with Framingham risk score (r=-0.121, p=0.007). LDL particle size was smaller

in patients who had more extensive CAD. LDL particle size in patients with

acute coronary syndrome was also smaller than the size in non-ACS patients

(26.09±1.42 vs 26.54±0.63nm, p=0.011). This study suggests that small dense

LDL was independently associated with the incidence and extent of CAD in

Korean population.

Key Words: small dense low-density lipoprotein, coronary artery disease, acute

coronary syndrome

Significance of Small Dense Low-Density Lipoprotein as a Risk Factor of Coronary Artery Disease and Acute Coronary Syndrome

Sung Woo Kwon

Department of Medicine The Graduate School, Yonsei University

(Directed by Professor Hyuck Moon Kwon)

I. IN TROD U CTION

Epidemiologic studies have shown a positive relationship between

total cholesterol concentrations and mortality from coronary artery disease

(CAD).1 However, total cholesterol does not accurately predict the risk of CAD

in many patients, because it is the sum of all cholesterol carried not only by

atherogenic lipoproteins such as very-low-density lipoprotein(VLDL),

low-density lipoprotein(LDL), intermediate-density lipoprotein(IDL), but also

by antiatherogenic lipoproteins like high-density lipoprotein(HDL). Therefore,

the decision to treat is based on LDL cholesterol values. The importance of

LDL cholesterol in the development of atherosclerosis has long been

recognized, and LDL cholesterol remains the primary target of therapy for the

prevention of CAD. Lowering the LDL cholesterol level in order to reduce or

prevent CAD progression and cardiovascular events in hypercholesterolemic

patients is now widely accepted.2 Nevertheless, increasing research attention

over the past decade has been devoted to the heterogeneity of LDL particles and

the atherogenicity of lipids and lipoproteins other than LDL. LDL heterogeneity

is now well recognized as an important factor that reflects differences in

lipoprotein composition, size, and metabolism, as well as dietary and genetic

influences.3,4,5 For these reasons, among the lipoprotein heterogeneity, small,

dense low-density lipoprotein(sd-LDL) is emerging as an important risk factor

for CAD.3,6,7

There are several proposed biochemical and cellular mechanisms

related to atherogenicity of sd-LDL. First, on the aspects of biochemical

mechanisms, sd-LDL has a longer residence time in plasma,8,9,10,11,12 binds less

well to the LDL receptor but more avidly to the scavenger receptor,13,14,15,16 is

more susceptible to oxidation,17,18,19 has a decreased content of antioxidants in

their core,20,21 enters the arterial wall more easily,22,23 and binds more readily to

the glycosaminoglycans in the arterial wall.24,25 Next, on the aspects of cellular

mechanisms, sd-LDL promotes endothelial cell dysfunction,26 induces greater

production of PAI-1(plasminogen activator inhibitor-1) in endothelial cells,27

increases the secretion of thromboxane in endothelial cells,28 increases

intracellular calcium in arterial smooth muscle cells.29

Gradient gel electrophoresis using nondenaturing conditions is

commonly used to characterize the distribution of LDL particle by size.30

Densitometric scans of LDL subfraction shows a bimodal distribution. LDL

subclass pattern A is characterized by a predominance of large, buoyant LDL

particles which consists of a major peak of LDL greater than 25.5nm, whereas

LDL subclass pattern B is characterized by a predominance of sd-LDL particles

which consists of a major peak less than 25.5nm.31,32,33 Sd-LDL is often

accompanied by increased triglyceride, increased apo B and low HDL levels.

and this change is also related to the increased risk of development of CAD.

However, it is not clear whether the influence of development of CAD by small,

dense LDL is related with changes in lipoproteins and lipid parameters or

independent.

Several large prospective studies have examined the relationship

between small, dense LDL and CAD, using gradient gel electrophoresis to

determine peak particle size. In each study, the odds ratio of CAD increased

significantly when small, dense LDL was the predominant LDL subclass

present.34,35,36 Evidence from several angiographic clinical trials indicates that

treatment benefit was related to a decrease in small, dense LDL

particles.2,37,38,39,40

However, data regarding the relationship of LDL particle size and

coronary artery disease are limited in Korean population. Moreover, the

relationship of LDL particle size and extent of coronary artery disease and acute

coronary syndrome are limited worldwide. Therefore, this study was performed

to investigate the relationship between mean LDL particle size and extent of

CAD as well as the development of acute coronary syndrome. Also, by using

Framingham risk score, this study investigated the relationship between LDL

particle size and Global risk assessment score(GRAS) whether small, dense

LDL can be a predictor of cardiovascular event.

II. MA TERIA LS A N D METHOD S

1. Subjects

This study enrolled consecutive 504 patients who underwent coronary

angiography at Yongdong Severance Hospital, Yonsei University from October

2003 to June 2004, excluding patients who underwent previous coronary

angiography, previous myocardial infarction history, patients with chronic renal

failure or end stage renal disease, hepatic failure or liver cirrhosis, infectious

disease, or malignancy. Data from repeated coronary angiography for the same

patient were excluded.

The diagnosis of hypertension was based on the known history of

hypertension and the systolic blood pressure over 140 mmHg systolic or

diastolic blood pressure over 90 mmHg. Diabetes mellitus was diagnosed as

fasting serum glucose value over 126 mg/dL or treatment with either oral

hypoglycemic agents or insulin. Height and weight were recorded in all subjects

and body mass index(BMI) was calculated by the formula, weight(kg) ⁄

height2(m2).11,53

Control group was defined as normal or minimal CAD on coronary

angiogram and CAD group was divided into ACS and non-ACS group. The

diagnosis of myocardial infarction and angina pectoris was based on clinical

symptoms, EKG changes, biochemical markers. Significant CAD on coronary

angiography was defined as stenosis of ≥50% luminal narrowing of the

diameter in ≥1 branch of the coronary arteries.11

2. Estimation of extent of CAD

The extent of CAD was calculated by the measure of Gensini score

(Figure 1).41 The Gensini score, a measure of the extent of myocardial ischemia

was computed by assigning the severity score to each coronary artery stenosis,

according to the degree of luminal narrowing and its geographic importance.

Figure 1. Estimation of extent of coronary artery disease by Gensini score.

3. Global risk assessment scoring

10-year risk of major coronary events was calculated by using Framingham

scoring system based on Framingham Heart Study.1,43

Figure 2. Framingham scoring system for calculating the 10-year risk of major

coronary events in adults without diabetes. All age ranges are given in years.

Abbreviations; HDL:high-density lipoprotein, BP:blood pressure.

4. Lipoprotein and metabolic parameter analysis

Fasting blood samples were obtained by venipuncture on the day of

coronary angiography before cardiac catheterization was performed. Total

cholesterol, triglyceride, HDL cholesterol, LDL cholesterol were measured by

direct enzymatic method. LDL subfraction was analysed by polyacrylamide

tube gel electrophoresis (Quantimetrix LipoprintTM LDL system, Redondo

Beach, CA, USA).42 It was categorized as pattern A and B according to the

mean LDL particle size, and the fraction of the sd-LDL ( subtype 3~7 of LDL)

was measured (Figure 2,3).

LDL subtype 1~2 was large, buoyant LDL and subtype 3~7 was small,

dense LDL. It was defined that the pattern of mean LDL particle size over

26.5nm was large, buoyant dominant 'pattern A'. In contrast, the particle size

below 26.5mm was small, dense LDL dominant 'pattern B'.

sd-LDL fraction(%) = LDL3+LDL4+LDL5+LDL6+LDL7

* 100(%)LDL1+LDL2+LDL3+LDL4+LDL5+LDL6+LDL7

(a)

(b)

Figure 3. Densitometric scans of LDL subfraction. LDL subtype 1, 2

represents large, buoyant LDL, and LDL subtype 3~7 represents small, dense

LDL. Areas under the curve for each fraction were measured, and the fraction

of small, dense LDL was calculated.(a) Large, buoyant LDL dominant pattern

A which has mean LDL particle size greater than 26.5nm (b) Small, dense LDL

dominant pattern B which has mean LDL particle size smaller than 26.5nm.

5. Statistical Analysis

Statistical analyses were performed using a SPSS 11.0 for Windows

(SPSS Inc., IL, USA). Comparison between control and CAD groups was

performed using Student's t-test. All values are described as mean ± standard

deviation. Statistical significance was accepted at P <0.05.

The extent of CAD was evaluated by reviewing the coronary

angiography and measured by Gensini score. The extent of CAD, acute

coronary syndrome and mean LDL particle size were investigated by

multivariate analysis.

III. RESU LTS

1. Comparison between CAD and controls

The general and metabolic characteristics of all the patients studied

are shown in Table 1. There was no difference between CAD and controls in

BMI, total cholesterol, and triglyceride levels. Significant difference was found

in age, hypertension, diabetes mellitus, LDL cholesterol, HDL cholesterol,

mean LDL size, and sd-LDL fraction. Mean LDL particle size was smaller in

patients with angiographically proven CAD than in controls (26.41±0.95 vs

26.73±0.64nm, p<0.001)(Figure 4a). The mean LDL particle still had

significance between CAD and controls in both male and female group

(26.35±1.10 vs 26.67±0.74nm, p=0.009) and in female (26.50±0.68 vs

26.78±0.54nm, p=0.001)(Figure 4b).

Table 1. Comparison of the general and metabolic characteristics between

CAD and controls

Data are expressed as mean ± SD.

Abbreviations; control: normal control group, CAD: coronary artery disease

group, DM: diabetes mellitus, BMI: body mass index, T.chol: total cholesterol,

LDL chol: low-density lipoprotein, HDL: high-density lipoprotein, TG:

triglyceride, A: pattern A, B: pattern B, NS: not significant.

Control(n=242) CAD(n=262) p-value

Age(yr) 57.4 ±±±± 11.6 63.1 ±±±± 11.0 <0.001BMI(kg/m2) 25.1 ±±±± 3.5 24.4 ±±±± 3.3 0.037

Hypertension(%) 40.9 57.3 <0.001Current smoker(%) 27.3 39.4 0.005

DM(%) 11.6 32.4 <0.001T.chol(mg/dL) 172.9 ±±±± 34.1 178.5 ±±±± 38.3 NS

TG(mg/dL) 132.0 ±±±± 73.6 144.5 ±±±± 76.3 NSHDL chol(mg/dL) 44.9 ±±±± 11.9 41.1 ±±±± 10.1 <0.001LDL chol(mg/dL) 102.1 ±±±± 29.4 109.2 ±±±± 35.7 0.015

Mean LDL size(nm) 26.73 ±±±± 0.64 26.41 ±±±± 0.95 <0.001LDL class(A/B)(%) 74.4/25.6 51.1/48.9 <0.001

Fraction % of sd-LDL 12.2 ±±±± 13.9 18.2 ±±±± 18.0 <0.001Framingham score 11.0 ±±±± 4.9 13.9 ±±±± 3.1 <0.001

(a)p<0.001p<0.001p<0.001p<0.001

26.7 26.7 26.7 26.7 ±±±± 0.60.60.60.6 26.4 26.4 26.4 26.4 ±±±± 0.90.90.90.9

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Figure 4. Comparison of mean LDL particle size between CAD and control

group. (a) The mean LDL particle size was significantly smaller in CAD group

than in controls (26.41±0.95 vs 26.73±0.64nm, p<0.001). (b) The mean LDL

particle size was significantly smaller in CAD than in controls, both in male

(26.35±1.10 vs 26.67±0.74nm, p=0.009) and in female (26.50±0.68 vs

26.78±0.54nm, p<0.001).

Mean LDL particle size showed significant correlation with age, total

cholesterol, HDL cholesterol, LDL cholesterol and Framingham risk score

(Table 2).

Table 2. Univariate tests for correlation with mean LDL particle size

Abbreviations; r: correlation coefficient, BMI: body mass index, HDL:

high-density lipoprotein, LDL: low-density lipoprotein.

Mean LDL particle size(nm)r p-value

Age 0.110 0.013BMI -0.084 0.065

Total cholesterol -0.278 0.001Triglyceride -0.536 0.001

HDL cholesterol 0.273 0.001LDL cholesterol -0.159 0.001

Framingham score -0.121 0.007

2. Multivariate analysis of risk factor for CAD

Multiple logistic regression analysis showed that small, dense LDL fraction is

independent risk factor for CAD(odds ratio [OR] 2.312, 95% CI 1.512-3.537,

p<0.001)(Table 3).

Table 3. Multiple logistic regression analysis for CAD

Abbreviations; O.R.: odds ratio, C.I.: confidence interval, HDL: high-density

lipoprotein, LDL: low-density lipoprotein, chol: cholesterol, sd-LDL: small,

dense LDL.

O.R. 95% C.I. p-valueAge(yr) 3.763 2.085~6.791 <0.001Obesity 0.811 0.537~1.224 NS

Smoking 1.835 1.186~2.838 0.006Hypertension 1.521 1.009~2.293 0.045

Diabetes Mellitus 3.291 1.957~5.537 <0.001Low HDL chol 1.208 0.714~2.044 NSHigh LDL chol 2.220 0.754~6.538 NS

sd-LDL(Pattern B) 2.312 1.512~3.537 <0.001

3. Correlation between CAD severity and mean LDL particle size

Mean Gensini score showed significant difference between pattern A

and pattern B (14.4±22.9 vs 24.1±28.9, p<0.001)(Figure 5). Univariate linear

analysis between mean LDL particle size and Gensini score showed significant

negative correlation (Correlation coefficient=-0.188, p<0.001)(Figure 6).

0000

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Pattern APattern APattern APattern A Pattern BPattern BPattern BPattern B

Mean Mean Mean Mean GensiniGensiniGensiniGensiniscorescorescorescore

14.4 14.4 14.4 14.4

24.1 24.1 24.1 24.1

p<0.001p<0.001p<0.001p<0.001

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Pattern APattern APattern APattern A Pattern BPattern BPattern BPattern B

Mean Mean Mean Mean GensiniGensiniGensiniGensiniscorescorescorescore

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Pattern APattern APattern APattern A Pattern BPattern BPattern BPattern B

Mean Mean Mean Mean GensiniGensiniGensiniGensiniscorescorescorescore

14.4 14.4 14.4 14.4

24.1 24.1 24.1 24.1

p<0.001p<0.001p<0.001p<0.001

Figure 5. Comparison of mean Gensini score between pattern A and B. Mean

Gensini score showed significant difference between pattern A and pattern B

(14.4±22.9 vs 24.1±28.9, p<0.001). Pattern A represents large, buoyant

dominant LDL, which has mean LDL particle size bigger than 26.5nm, and

pattern B represents small, dense dominant LDL, which has mean LDL particle

size smaller than 26.5nm.

Figure 6. Correlation between mean LDL particle size and Gensini score. The

mean LDL particle size had significant negative correlation with Gensini score

(r=-0.188, p<0.001). Abbreviation; r: correlation coefficient.

4. Correlation between mean LDL particle size and Framingham risk

score

Mean LDL particle size showed significant negative correlation with

Framingham risk score(correlation coefficient=-0.121, p=0.007)(Figure 7).

GRASGRASGRASGRAS

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r=r=r=r=----0.1210.1210.1210.121p= 0.007p= 0.007p= 0.007p= 0.007

GRASGRASGRASGRAS

3020100-10

Mean L

DL p

artic

le

Mean L

DL p

artic

le

Mean L

DL p

artic

le

Mean L

DL p

artic

le s

ize(n

msiz

e(n

msiz

e(n

msiz

e(n

m)) ))

28

27

26

25

24

r=r=r=r=----0.1210.1210.1210.121p= 0.007p= 0.007p= 0.007p= 0.007

Figure 7. Correlation between mean LDL particle size and Framingham risk

score. The mean LDL particle size had a negative correlation with GRAS

(r=-0.121, p=0.007). Abbreviations; GRAS: global risk assessment score by

using Framingham risk scoring, LDL: low-density lipoprotein, r: correlation

coefficient.

5. Analysis between ACS and non-ACS groups in CAD

The general and metabolic characteristics of ACS and non-ACS

groups studied are shown in Table 4. There was no difference between ACS

and non-ACS in age, diabetes mellitus, BMI, total cholesterol, LDL

cholesterol, HDL cholesterol, triglyceride levels. Significant difference was

noted in smoking, hypertension, mean LDL particle size, and sd-LDL fraction.

Mean LDL particle size was smaller in patients with ACS group than non-ACS

group (26.09±1.42 vs 26.54±0.63nm, p=0.011)(Figure 8).

Table 4. Comparison of the general and metabolic characteristics between ACS

and non-ACS group

Data are expressed as mean ± SD.

Abbreviations; ACS: acute coronary syndrome group, DM: diabetes mellitus,

BMI: body mass index, hs-CRP: high-sensitivity c-reactive protein, T.chol:

total cholesterol, LDL chol: low-density lipoprotein, HDL: high-density

lipoprotein, TG: triglyceride, A: pattern A, B: pattern B, NS: not significant.

Non-ACS

(n=188)

ACS

(n=74)p-value

Age(yr) 63.6 ± 10.06 61.8 ± 13.2 NSBMI(kg/m2) 24.6 ± 3.4 23.9 ± 3.1 NS

Hypertension(%) 62.2 44.6 0.012Current smoker(%) 35.6 49.3 0.048

DM(%) 33.0 31.1 NShs-CRP(mg/dL) 7.2 ± 23.7 18.4 ± 36.7 0.019T.chol(mg/dL) 178.9 ± 36.5 177.4 ± 42.5 NS

TG(mg/dL) 145.1 ± 74.8 142.9 ± 80.3 NSHDL chol(mg/dL) 41.1 ± 10.0 41.0 ± 10.4 NSLDL chol(mg/dL) 109.2 ± 33.5 109.4 ± 40.9 NS

Mean LDL size(nm) 26.54 ± 0.63 26.09 ± 1.42 0.011LDL class(A/B)(%) 53.2/46.8 45.9/54.1 NS

Fraction % of

sd-LDL16.5 ± 15.0 22.9 ± 23.6 0.034

Framingham score 14.0 ± 2.8 13.6 ± 3.6 NS

74747474188188188188N =N =N =N =

ACSACSACSACSnon ACSnon ACSnon ACSnon ACS

Mean L

DL

Mean L

DL

Mean L

DL

Mean L

DL

partic

le

partic

le

partic

le

partic

le s

ize(n

msiz

e(n

msiz

e(n

msiz

e(n

m)) ))

28282828

26262626

24242424

26.54 26.54 26.54 26.54 ±±±± 0.630.630.630.63

26.09 26.09 26.09 26.09 ±±±± 1.421.421.421.42

p=0.011p=0.011p=0.011p=0.011

74747474188188188188N =N =N =N =

ACSACSACSACSnon ACSnon ACSnon ACSnon ACS

Mean L

DL

Mean L

DL

Mean L

DL

Mean L

DL

partic

le

partic

le

partic

le

partic

le s

ize(n

msiz

e(n

msiz

e(n

msiz

e(n

m)) ))

28282828

26262626

2424242474747474188188188188N =N =N =N =

ACSACSACSACSnon ACSnon ACSnon ACSnon ACS

Mean L

DL

Mean L

DL

Mean L

DL

Mean L

DL

partic

le

partic

le

partic

le

partic

le s

ize(n

msiz

e(n

msiz

e(n

msiz

e(n

m)) ))

28282828

26262626

24242424

26.54 26.54 26.54 26.54 ±±±± 0.630.630.630.63

26.09 26.09 26.09 26.09 ±±±± 1.421.421.421.42

p=0.011p=0.011p=0.011p=0.011

Figure 8. Comparison of mean LDL particle size between ACS and non-ACS

group. The mean LDL particle size was significantly smaller in ACS group

than in non-ACS group (26.09±1.42 vs 26.54±0.63nm, p=0.011).

6. Multivariate analysis of risk factor for ACS

Multiple logistic regression analysis showed that small dense LDL is

not independent risk factor for ACS(odds ratio[OR] 1.394, 95% CI,

0.765-2.540, p=NS)(Table 5).

Table 5. Multiple logistic regression analysis for ACS

Abbreviations; O.R.: odds ratio, C.I.: confidence interval, HDL: high-density

lipoprotein, LDL: low-density lipoprotein, chol: cholesterol, sd-LDL: small,

dense LDL.

O.R. 95% C.I. p-valueAge 0.961 0.336~2.746 NS

Obesity 0.464 0.248~0.867 0.016Smoking 2.135 1.163~3.922 0.014

Hypertension 0.600 0.334~1.077 NSDiabetes Mellitus 0.891 0.477~1.665 NSLow HDL chol 0.980 0.498~1.930 NSHigh LDL chol 1.026 0.299~3.519 NS

sd-LDL(Pattern B) 1.394 0.765~2.540 NS

IV . D ISCU SSION

In this study, sd-LDL fraction was significantly associated with CAD.

This association is still applied in both male and female group. Even after

adjusting for traditional risk factors such as age, obesity, smoking, diabetes

mellitus, HDL cholesterol level, and LDL cholesterol level, by using multiple

logistic regression analysis, sd-LDL and CAD still showed significant

correlation. This suggests that sd-LDL can be an independent risk factor for the

development of CAD besides traditional risk factors.

Moreover, by using Gensini score, this study investigated the

correlation between mean LDL particle size and extent of CAD. Several reports

suggested that sd-LDL is an independent risk factor of CAD and might

contribute to the severity of CAD. However, they simply used the number of

diseased coronary arteries as to compute the severity of CAD.7,44 In a previous

report, the prevalence of sd-LDL was strongly associated with various types of

CAD, which was both independent of traditional and nontraditional coronary

risk factors, but unrelated to the severity and extent of coronary artery lesions

by using Gensini score.33 On the contrary, this study was investigated by using

the Gensini score to compute the extent of CAD, which is a measure of the

extent of coronary artery disease, by computing the severity score to each

coronary stenosis, according to the degree of luminal narrowing and its

geographic importance. Therefore, this is the first study which has significant

correlation between mean LDL particle size and extent of CAD by using the

Gensini score, which can be a more objective approach than the diseased

coronary artery number.

There were many reports of the relation between triglyceride, LDL

cholesterol, LDL particle size and prevalence of CAD including acute

myocardial infarction, and a strong negative correlation between high

triglyceride concentrations and LDL particle size is well documented.45,46,47,48

Several reports suggested negative correlation of LDL particle size and risk of

acute myocardial infarction.35,49 Furthermore, negative association between

LDL particle size and development of CAD was also reported.50,51 But, after

adjustment for triglyceride level, these reports failed to prove LDL particle size

as an independent risk factor of CAD. Whereas, some studies demonstrated that

CAD is associated with sd-LDL independently of triglyceride level.44,52 This

present study revealed that LDL particle size had significant correlation with

total cholesterol, triglyceride, HDL cholesterol, and LDL cholesterol. But, by

using Student's t-test, triglyceride level had no significance between CAD group

and control group. This result is probably due to the relatively large variation in

triglyceride level.

We also studied the correlation between mean LDL particle size and

global risk assessment score(GRAS). There were significant negative

correlation between LDL particle size and GRAS. This result suggests that

further studies will be required to determine sd-LDL as a predictor of 10-year

coronary event risk, and the significance of sd-LDL will be elucidated.

Sd-LDL is associated with increased triglyceride and decreased HDL

levels.53 The size and density of LDL are partly determined by the exchange of

triglycerides at the expense of cholesteryl esters from LDL, possibly mediated

by cholesteryl ester transfer protein. Through this mechanism, LDL becomes

enriched in triglycerides at the expense of cholesteryl esters. The presence of an

excess amount of triglycerides in the LDL particle then allows continued

particle size reduction through hepatic triglyceride lipase action, which may

finally result in lipid-poor and, thus, protein-rich LDL particles of relatively

high density.54 In addition to triglycerides, it has been suggested that genetic

factors and increased hepatic lipase and lipid transfer activities also contribute

to LDL heterogenicity. Also, carbohydrate rich diet is associated with increased

level of small, dense LDL. Increased carbohydrate intake causes the synthesis

of free fatty acid in the liver, which in turn potentially stimulates the production

of large triglyceride rich VLDL.55

LDL particle size is more stable, and has less variation on meal,

comparing with triglyceride. Therfore, LDL particle size has more importance

on prediction for coronary artery disease than triglyceride. LDL subfraction had

difficulty in measurement compared with triglyceride. Conventional methods

for measuring LDL subfraction, such as density gradient ultracentrifugation,

nondenaturing gradient gel electrophoresis, and nuclear magnetic resonance

spectroscopy are not suitable for clinical laboratory because it is labor intensive,

need skillful and experienced technician, it has low reproducibility and it needs

a lot of time for analysis. But recently, Quantimetrix LipoprintTM LDL system

using polyacrylamide tube gel electrophoresis has benefit than previous

methods, and LDL subfraction can be easily analyzed and time-saving.56

This study also investigated about the correlation between sd-LDL and

ACS. CAD group was divided into ACS and non-ACS group. Mean LDL

particle size was smaller in ACS group compared with non-ACS group, and

fractional percentage of sd-LDL was higher in ACS group than non-ACS

group. However, on multivariate analysis, we could not conclude that LDL

particle size was independent risk factor for development of acute coronary

syndrome. In comparing lipid profile between ACS and non-ACS group by

using Student's t-test, there were no significant difference between two groups.

The blood samples were obtained on the day of coronary angiography, and this

might affect the values of LDL or HDL cholesterol. Several studies reported

that there were significance decrease in lipid profiles on acute phase of acute

coronary events.57,58,59,60

Recent study reported an increase in LDL size was noted with

intensive lipid-lowering therapy, and its decrease was strongly associated with

CAD regression.2 Further studies will be required to determine the correlations

between LDL particle size, and progression or regression of coronary artery

disease and acute coronary syndrome. And after intensive lipid-lowering

therapy, further investigation is needed whether LDL particle size or LDL

cholesterol level is more differentiator for development of CAD and ACS.

Furthermore, among CAD patients who underwent percutaneous coronary

intervention, evaluating the relationship between restenosis after percutaneous

coronary intervention and LDL particle size might be interesting for

investigation.

V . CON CLU SION

LDL particle size was smaller among patients with CAD, and

associated with extent of coronary artery disease and moreover in acute

coronary syndrome patients. This study demonstrates that the prevalence of

small, dense LDL is strongly associated with CAD, which is both independent

of traditional and nontraditional coronary risk factors and related to the extent

of coronary lesions. These results suggest that small, dense LDL plays an

important role not only in the onset of CAD, but also in the progression of this

disease.

This study suggests that small dense LDL was independently

associated with the incidence and extent of CAD and can be a risk factor for

CAD in Korean population and development of ACS.

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관상동맥폐쇄성질환과 급성관동맥증후군에서 위험인자로서의smalldenseLDL의 중요성

<지도교수 권 혁 문>

연세대학교 대학원 의학과

권 성 우

저밀도지단백은 관상동맥폐쇄성질환의 입증된 위험인자로 잘 알려져있으며,그 중요성이 커지고 있다.그러나,국내에서는 아직 LDL입자 크기와 관상동맥폐쇄성질환의 발생 및 정도와의 연관성에 대해서는 잘 알려지지 않았다.본 연구는 관상동맥폐쇄성질환의 발생 및 정도와 급성관동맥증후군의 발생과 LDL입자 크기와의 연관성에 대해알아보고자 하였다.흉통을 주소로 내원한 504명의 환자들을 대상으로 하여 채혈이 이루어졌으며,LDL입자 크기를 측정하였다.LDL입자 크기는 연령,총 콜레스테롤,중성지방,고밀도 콜레스테롤,저밀도콜레스테롤 수치와 유의한 상관 관계가 있었다 (p<0.05).평균적인LDL입자 크기는 관상동맥혈관조영술로 입증된 관상동맥폐쇄성질환환자군에서 대조군에 비해 더 작게 나타났으며(26.41±0.95 vs26.73±0.64nm,p<0.001),Framingham riskscore와 음의 상관관계를나타냈다.LDL입자 크기는 관상동맥폐쇄성질환의 정도가 심할수록더 작음을 알 수 있었다.또한,평균적인 LDL입자 크기는 급성관동맥증후군 환자군에서 대조군에 비해 작게 나타났다 (26.09±1.42vs26.54±0.63nm,p=0.011).본 연구는 한국인에서 smalldenseLDL이관상동맥폐쇄성질환의 발생 및 중증도,그리고 급성관동맥증후군과연관이 있으며,나아가 관상동맥폐쇄성질환의 발생을 예측할 수 있는독립적인 위험인자임을 시사한다고 하겠다.

핵심되는 말 :smalldenseLDL,관상동맥폐쇄성질환,급성관동맥증후군