.

 (CHF)
=

CHF
proBNP, TnT

(AMI)
T, CK, CK- MB,
M, LDH, AST(GOT)

.
T T, hsCRP, , D-dimer,
AT-III, Protein C, Protein S, APC-resistance,sCD40L
, ,
(ROS, IL-6, IL-1b, TNF-a, MMP-9, NO)
,

, , , , ,
, , , ,
, ,
(, LDL, HDL, TG, Lp(a), Apo-A1, Apo-B, , HbA1c
, , , CRP)


CHD
M :

9
(INTERHEART study)

Psycho

social

?

Yusuf et al. Lancet. 2008;372:224-233.


Total Cholesterol

Apolipoproteins

LDL
HDL
TG
Lp(a)
ApoB
ApoAI

TC = TG/5 + HDL + LDL

,

.



.

Cholesterol Predicts CHD Mortality Rate in

Diabetic and Nondiabetic Men
Multiple Risk Factor Intervention Trial (MRFIT)
80

Diabetic

Nondiabetic

Rate/1000

60

40

20

2
3
4
Serum Cholesterol Quintile

Bierman EL, Arteriosder Thromb, June 1992

CM

VLDL

apoB

apoB

CM= chylomicron
VLDL= very low density lipoprotein
IDL= intermediate density lipoprotein
LDL= low density lipoprotein
HDL= high density lipoprotein
Apo = apolipoprotein

IDL
apoB

LDL
apoB

HDL
apoA-I

0.95

Chylomicron

VLDL
VLDL
Remnants

Density (g/ml)

1.006

IDL
Chylomicron
Remnants

1.02

LDL

1.06

Directly atherogenic
(found in plaque)

HDL2

Lp(a)

1.10

HDL3DL3

pre-2 HDL

1.20

pre-1 HDL
5

10

20

40

60

Particle Size (nm)

80

1000

LDL - cholesterol
= Low Density Lipoprotein
VLDL

M :
poB-100


.

 LDL-C

3.7
2.9

2.2

1.7

(log-linear) 1.3
1.0

40

70

100

130

160

190

LDL-Cholesterol, mg/dL

.
30-mg/dL LDL-C,
30%.
Grundy S, et al. Circulation. 2004;110:227-239

 :
LDL-C
Percentage with CHD event

10
9
8
7
6
5

AFCAPS-P

4
3
2

WOSCOPS-P

WOSCOPS-S

Primary prevention
Pravastatin

AFCAPS-S

Lovastatin

1
0
2.3 (90)

2.8 (110)

3.4 (130)

3.9 (150)

4.4 (170)

4.9 (190)

5.4 (210)

LDL-C, mmol/L (mg/dL)

S = statin treated; P = placebo treated

Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21




30

CHD Events (%)

y = 0.1629x 4.6776
R = 0.9029
p < 0.0001

25

4S-P

20

HPS-P
4S-S

15

LIPID-P

HPS-S
A2Z 20
CARE-P
A2Z 80
TNT 10 LIPID-S
IDEAL S20/40
PROVE-IT-AT TNT 80
CARE-S
IDEAL
A80
PROVE-IT-PR

10
5
0
30

50

70

90

110 130 150 170 190 210

LDL Cholesterol (mg/dl)

OKeefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

Patients Experiencing
Major CHD Events, %
N
LDL-C

28.0
19.4
15.9
12.3

13.2
10.2

11.8

10.9

8.7

7.9

5.5

6.8

4S1

LIPID2

CARE3

HPS4

4444
-35%

9014
-25%

4159
-28%

20 536
-29%

WOSCOPS5 AFCAPS/
TexCAPS6
6595
6605
-26%
-25%

High Risk

Primary

Secondary
1
2
3

4S Group. Lancet. 1994;344:1383-1389.

LIPID Study Group. N Engl J Med. 1998;339:1349-1357.
Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

4
5
6

HPS Collaborative Group. Lancet. 2002;360:7-22.

Shepherd J, et al. N Engl J Med. 1995;333:1301-1307
Downs JR, et al. JAMA. 1998;279:1615-1622.

 LDL-C:
LDL
Larger, More Buoyant LDL

Small, Dense LDL

LDL=130 mg/dL

LDL=130 mg/dL

More Apo-B100

Apo-100
Cholesterol
Ester

Less Atherogenic

More Atherogenic

LDL-C

Otvos JD, Jeyarajah EJ, Cromwell WC. Am J Cardiol. 2002;90:22i-29i.

Small, Dense Low-Density Lipoprotein Particles as a Predictor

of the Risk of Ischemic Heart Disease in Men
Prospective Results From the Quebec Cardiovascular Study
Circulation 1997;95:69-75

6.2

6
4
3

2.1

2
1

1.0

1.0

Large

Small

LDL particle size

L
nu D L
m b pa
er rtic
(ap le
oB
)

Risk of IHD

High
Low

 ,
LDL (. , ),
apoB-100
,
LDL.
J Am Coll Cardiol. 2008;51:1512-1524

apoB

VLDL IDL
apoB.
Lancet. 2008;372:224-233.

HDL

()
HDL-C

HDL-C


HDL-C
?

The metabolic pathway of HDL particles:

Potential Novel Therapeutic Approaches.

Apo AI Prod

LxR agonists

Torcetrapib
Dalcetrapib (RO4607381/JTT-705)
Anacetrapib

The metabolic pathway of HDL particles:

Potential Novel Therapeutic Approaches.

:
LDL-C :
HDL-C
Apo AI Prod
LxR agonists

Torcetrapib
Dalcetrapib (RO4607381/JTT-705)
Anacetrapib




VLDL
, LDL-C
HDL-C

-

plasminogen activator inhibitor (PAI-1)

. VIIc

 ..

TG
500 mg/
dL
500
mg/dL
~2.5%
5
-6 M patients
5-6
TG 200
-499 mg/
dL*
200-499
mg/dL*
~13%
~28 M patients

US Adult Population
Total = 217 million


NCEP ATP III

TG (mg/dL)

500

200-499

150-199

<150

National Institutes of Health. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NIH Publication No. 02-5215. Bethesda,
Md: National Institutes of Health; 2002:VII-3-VII-5, Appendix III-A.

 TG :
*

Cumulative Probability of Death

20

20

HR: 1.41
(1.12-1.79)
P = 0.004

15

HR: 1.40
(1.10-1.78)
P = 0.006

15

TG 200 mg/dL

TG 200 mg/dL

10

10
TG <200 mg/dL
5

0
0

10

15

20

Years Since Randomization

25

30

TG <200 mg/dL

10

15

20

25

30

Years Since Randomization

* Based on 25-year follow-up data from MRFIT in 2809 men.

Multivariate adjusted for treatment group, age, LDL-C level, glucose level, SBP, cigarettes smoked per
day, alcohol use, BMI, and African American vs non-African American.
Eberly LE et al. Arch Intern Med. 2003/163:1077-1083.

 TG

The Framingham Heart Study (30-Year Follow-Up)

N = 5127 patients

2.5

2
1.5
1
0.5
0
50

100

150

200

250

300

350

400

TG , mg/dL
Univariate analysis of data from the Framingham Heart Study, including 5127 patients aged 30
to 60 years without CHD, to determine the relationship between TGs and CHD.
Castelli WP. Am J Cardiol. 1992;70:3H-9H




HDL

AIDS

Lipoprotein (a)
H Lp(a)
apo B-100 (
LDL, )
10
LDL!
(0-100 mg/dL) Lp(a)
,
.
, , ,
,

Lp(a): ?

Lp(a)

ATPIII,

NCEP ATPIII, AHA, and ADA:

Recommended Lipid Goals
Parameter

ATP III1

AHA Women2 ADA Position3

(for adults
with
diabetes)

LDL-C
- Very high risk

<100 mg/dL
<70 mg/dL4

<100 mg/dL

<100 mg/dL

Non-HDL-C*

<130 mg/dL

<130 mg/dL

--

>40 mg/dL

>50 mg/dL

>40 mg/dL men;

>50 mg/dL
women

<150 mg/dL

<150 mg/dL

<150 mg/dL

HDL-C

TGs

* Non-HDL-C = Total cholesterol HDL-C.

1. National Cholesterol Education Program. NIH Publication No. 02-5215; September 2002.
2. Mosca L et al. Circulation. 2007. 3. American Diabetes Association. Diabetes Care. 2008;30:S4-S41.
4. Grundy SM et al. Circulation. 2004;110:227-239.

 -
LDL-C
,
non-HDL-C.
LDL-C, (
)

,
B-100 (apoB)
LDL
,
.
Lp(a)
/

J Am Coll Cardiol. 2008;51:1512-1524.

Lp-PLA2
Lp-PLA2





.


.

Lp-PLA2
LDL-C.


LDL-C, (lysoPC) NEFA.
Lp- PLA2




.

Role of Lp-PLA2 in Atherosclerosis

Zalewski. Arterioscler Thromb Vasc Biol 2005;25:923

Lp-PLA2 and Risk

(ARIC study)

Plasma sPLA2
concentration vs activity
sPLA2



sPLA2 .

Koenig et al., Eur Heart J (2009) 30, 27422748

Circulation 108: 250-252



..( CRP, )
(L-1b, IL-6, TNF-a)

(sVCAM-1, sICAM-1, E-selectin, P-selectin)

(
sCD40L)

CRP vs hs-CRP
CRP

(IL-6, IL-1, tumor necrosis factor)
,
CRP
1000

CRP
High-sensitivity CRP (hs-CRP)
CRP ,
.


CRP

Szmitko et al. Circulation 2003;108;1917-1923

 hs-CRP
TC:HDL

Relative Risk
P
R
-C
s
h

Total Cholesterol:HDL Ratio

Ridker et al, Circulation. 1998;97:20072011.

 hs-CRP

Kuller MRFIT 1996
Death
Ridker PHS
1997
Ridker PHS 1997

CHD
MI

Stroke

Tracy CHS/RHPP 1997

CHD

Ridker PHS 1998,2001

PAD

Ridker WHS 1998,2000,2002

CVD

Koenig MONICA 1999CHD

Roivainen HELSINKI 2000

CHD

Mendall CAERPHILLY 2000

CHD

Danesh BRHS 2000

CHD

Gussekloo LEIDEN 2001

Fatal Stroke

Lowe SPEEDWELL 2001

CHD

Packard WOSCOPS 2001

CV Events*

Ridker AFCAPS 2001

CV Events*

Rost FHS 2001

Stroke

Pradhan WHI 2002

MI,CVD death

Albert PHS 2002

Sudden Death

Sakkinen HHS 2002

MI

0
Ridker PM. Circulation 2003;107:363-9

1.0

2.0

3.0

4.0

5.0

Relative Risk (upper vs lower quartile)

6.0

 hs-CRP

1 mg/L

3 mg/L

Low Moderate
Risk Risk

Ridker PM. Circulation 2003;107:363-9

10 mg/L

High
Risk

>100 mg/L

Acute Phase Response

Ignore Value, Repeat Test in
3 weeks

 hs-CRP

1.00

CVD Event-Free
Survival Probability

0.99
0.98
CRP <1 mg/L
0.97
CRP 1-3 mg/L

0.96
0.95

CRP >3 mg/L

0

Years of Follow-Up
Ridker et al, Circulation 2003;107:391-7


hs-CRP LDL-C
Probability of Event-free Survival

Median LDL 124 mg/dl

Median CRP 1.5mg/l

1.00

Low CRP-low LDL

0.99

Low CRP-high LDL

0.98
High CRP-low LDL
0.97

0.96

High CRP-high LDL

0.00
0

Years of Follow-up
Ridker et al, N Engl J Med. 2002;347:1157-1165.

:


cy >16 mol/l
:
(16-30 mol/l)
(31-100 mol/l)
(>101 mol/l)

N Engl J Med 1995;332:328-329

Dietary intake

Methionine

THF
MTHFR

B12

MS
BHMT

MTH
F

Homocysteine
CBS
B6

Cystathionine
B6

CBS: --
S:
MTHFR: --
BHMT: ---

Cysteine

RCH3



ROS

(NF-kB)

F
V, X XII
C
Antoniades C, Antonopoulos AS et al. Eur Heart J. 2009 Jan;30(1):6-15

H Hcy

Antoniades C, Antonopoulos AS et al. Eur Heart J. 2009 Jan;30(1):6-15

Improvement in Stroke Mortality in U.S. after folate fortification

Yang et al. Circulation. 2006;113:1335-1343

HCY . 6 12

. 6 & 12,
.
Antoniades C, Antonopoulos AS et al. Eur Heart J. 2009 Jan;30(1):6-15

AHA (American Heart Association)

CDC (Centers of Disease Control and Prevention)

(,
, , ,
).

,

6 12 .






(>100mol/L)
(30-100 mol/L)

Glomerular Filtration Rate

( )

GFR = o
(mL/min)


GFR ,

. Cockcroft-Gault equation,
MDRD (Modified Diet in Renal Disease)
equation

GFR

GFR :

Go AS et al. N Engl J Med. 2004 Sep 23;351(13):1296-305

Glomerular Filtration Rate

1.120.295

Go AS et al. N Engl J Med. 2004 Sep 23;351(13):1296-305

(UACR)

UACR
urine albumin : creatinine ratio
1.
.
1. , .
1. 24
.
1. dipstick
,
.

Urine albumin : creatinine ratio (UACR)

Follow-up (years)
Amlov J et al. Circulation. 2005 Aug 16;112(7):969-75.

Solomon SD et al. Circulation 2007;116;2687-2693;

Cystatin - C

Cystatin C
Cystatin C GFR
HbA1c
(Perkins, Curr Diab Rep, 05)
Cystatin C


(Shlipak, NEJM, 06)

Cystatin C (CysC)
o
,
.
(13.3 kDa)

.

o.

,
.

Cystatin C (CysC)
H

Cystatin C.


.
,
,
.

.

Cystatin C:
Better Estimate of GFR
than current equations

Perkins, NEJM, 2005

Cystatin C and the Risk of Death and Cardiovascular

Events among Elderly Persons

Shlipak et al. N Engl J Med 2005;352:2049-60

Cystatin C and the Risk of Death and Cardiovascular

Events 1 year post-AMI

the SIESTA Investigators Atherosclerosis 2009

 /

: von Willebrand
factor(vWF),
(PAI-1), V VII,
, C S,
(), ..

:
(tPA), ..

Atherosclerosis 1996;121:185-191

fVII
(ARIC
study)
Circulation 1997;96:1102-1108

t-PA PAI-1

Atherosclerosis 1995;11535-43


Fibrinogen Studies Collaboration

-
154 211
31

JAMA. 2005;294:1799-1809

The CD40/CD40 Ligand System

Linking Inflammation With Atherothrombosis
CD40: type I transmembrane receptor
CD40L: rapidly expressed in stimulated platelets
sCD40L: circulating CD40L (cleaved from platelets surface)

Antoniades C, Bakogiannis C et al. JACC 2009;54:66977

The CD40/CD40 Ligand System

Linking Inflammation With Atherothrombosis

Antoniades C, Bakogiannis C et al. JACC 2009;54:66977

Antoniades C, Bakogiannis C et al. JACC 2009;54:66977


sCD40L


sCD40L sCD40L
in
vitro .


. (3 h)
sCD40L

sCD40L
(
).

Antoniades C, Bakogiannis C et al. JACC 2009;54:66977



multiples of reference range

Myoglobin
CK total
CK-MB
Troponin I

80
70
60
50

Troponin T

40
30
20
10
0

hours
8 12 18 24 32 48 after AMI



CPK-MB: 6-8 , 24 ,
2-3 (
3 36 )
SGOT: 6-8 , 48 ,
4
LDH (1, 2): <24 , 72
, >10
TnT, TnI: <2 , 8 ,
7

:




Lothar Thomas, Clinical Laboratory Diagnostics, 1998, p.106



2-4

Myo 6-10

,
,
.

, ,


Lothar Thomas, Clinical Laboratory Diagnostics, 1998, p.106-107

European Society for Cardiology (ESC)

American Heart Association (AHA)
American College of Cardiology (ACC)

WHO

> 10 min

CK-MB golden standard
HA Katus, Symposium Neue Entwicklungen in der Kardiologie, Heidelberg, 25. Nov. 2000.


(TnC, TnI
TnT)

,
..

C
I

Ca++

-

cTn :

( LDH)

cTn :



(
)

, ,
, , ,
, , ,
,

, (>30%) Jaffe et al,
JACC 2006

 ;
TnT
TnI EM .
4-12 ,
12-48 .

.

Newby LK et al, J Am Coll Cardiol 2003;41:31S36S

 TnT-TnI
- 4,000
,
:
* 2.7 (95%C: 2.1-3.4, p 0.001) TnT(+)
* 4.2 (95%CI: 2.7-6.4,p=0.001) nI(+)
.

Ilatidoye AG et al, Am J Cardiol 1998;81:140510


,
CPK-MB
J Am Coll Cardiol 2000;36:95969

nI <99

N Engl J Med 2009;361:868-77

 TnI

N Engl J Med 2009;361:868-77.

Diagnosis of Acute Myocardial Infarction with the Use of

Sensitive Troponin I Assay

N Engl J Med 2009;361:868-77.

Correct Diagnosis of Acute Myocardial Infarction, According

to the Time of a Single Sensitive Troponin I Assay*

The diagnostic criteria for acute myocardial infarction were a troponin I

level (as measured by sensitive assay) above the 99th percentile of 0.04 ng
per milliliter in at least one measurement and a rise or fall in the level of at least 30%.

N Engl J Med 2009;361:868-77.

Brain natriuretic peptide

(BNP)

Natriuretic peptides
RI G

D
A
M
Q
R
S
G
G
L
G
F
G
C C
N
S
S
S
F
R
R

RI S

V
M
K

D
S
M
S
K
S
R
G
L
G
F
G
C C
K
G
V
S
L
G
R
Q
R

RI G

S
L
M
K
S
L
G
L
G
F
G
C C
G
K
S

ANP

BNP

CNP

28aa peptide

32aa peptide

22aa peptide



ANP

(
)

CNP

BNP

,


ANP (30
min)

Urodilatin

Mechanisms of ProBNP Expression

Ventricular
dysfunction

Myocyte
Stretch

Reduced coronary
blood flow

Myocardial
Hypoxia

BNP mRNA
transcription
Rapid ventricular

ProBNP

Circulating BNP &

NT-ProBNP
Goetze JP Scand J Clin Lab Invest 2004; 64: 497-510

 proBNP

 proBNP BNP

NT- proBNP
120
100
%

- 10%

80

- 25%

60
40
20
0

NT- proBNP
BNP
0h

24 h

48 h

72 h

[h]

, 72 h



,
.


BNP

Maron J, Circulation 2004; 109:984-989


-

(
)



-

McCullough, Rev Cardiovasc Med. 2004;5(1):16-25

 BNP/T-proBNP
:
1) BNP/T-proBNP
(
)
2) /

3)
.

 proBNP BNP

(, , )



(5-35.000 pg/ml,
70.000 pg/ml )
FDA approved
( BNP
)

BNP & NT-ProBNP

McCullough el al Reviews in Cardiovascular Medicine 2003 4 (2) 72-80

- .

Maron J, Circulation 2004; 109:984-989


/proBNO
;


100pg/ml BNP
300pg/ml NT-proBNP
(>75)
.

ESC guidelines for treatment of AHF (2005)

BNP vs NT-proBNP
BNP
AUC = 0.916 (95% CI: 0.874, 0.947)
NT-proBNP AUC = 0.903 (95% CI: 0.859, 0.939)

BNP

>80pg/mL
,
( ),

.

Morrow DA et al, J Am Coll Cardiol 2003;41:1264 72

multimarker approach





;

For all markers,

associations were substantially attenuated and
with the exception of C-reactive protein
no longer significant after adjustment for
cardiovascular risk factors, particularly bodymass index and the presence or absence of
diabetes and hypertension.

Multiple Biomarkers for the Prediction of

First CVD Events and Death (Wang TJ et al.,
NEJM 2006; 355: 2631-9)
10 biomarkers examined in 3209 pts of the Framingham
Heart Study
CRP, BNP, N-T pro-ANP, aldosterone, renin, fibrinogen, ddimer, PAI-1, homocysteine, and urine albumin/creatinine
ratio.
7.4 years medial follow-up
Adjusted HRs per SD: BNP 1.4, CRP 1.4,
albumin/creatinine 1.2, homocysteine 1.2, renin 1.5 for
death, and BNP 1.25, albumin/creatinine 1.2 for CVD
events
Multimarker scores in highest quintile vs. lowest two
quintiles had adjusted HR for death of 4.1, p<0.001 and
CVD events of 1.8, p=0.02
Only moderate increases in C-statistic seen from
biomarkers over standard risk factors

Use of Multiple Biomarkers to Improve

Prediction of CVD Death (Zethelius B et al.,
NEJM 2008; 358: 2107-16)
1135 elderly men from the Uppsala Longitudinal Study
of Adult Men, mean age 71 years at baseline, 10 years
median follow-up
Examined role of multiple markers reflecting myocardial
cell damagetroponin I, LV dysfunction N-T pro BNP,
renal failurecystatin C, and inflammation CRP
C-statistic increased significantly when the four
biomarkers were put in a model with established risk
factors (0.77 vs. 0.66, p<0.0001) in the whole cohort
and in those without CVD at baseline (0.748 vs. 0.688,
p=0.03).
Among elderly men, multiple biomarkers may
significantly improve risk for death from CVD causes
beyond standard risk factors.




)

)

Lipoprotein(a)
Homocysteine
IL-6
TC
LDLC
sICAM-1
SAA
Apo B
TC: HDLC
hs-CRP
hs-CRP + TC: HDLC
0

1.0

2.0

4.0

6.0

Relative Risk of Future Cardiovascular Events

Ridker et al, N Engl J Med. 2000;342:836-43

TnT, TnI, CK-MB, SGOT SGPT, BNP etc

CRP, IL-6, IL-1b, TNF-a, ICAM-1, VCAM-1, MMP-9,
Fbg, sCD40L, PAI-1, ox-LDL, Cystatin-C, Lp-PLA2
Cholesterol, LDL, HDL, ApoB100,
Homocysteine, Glucose

DISEASE