????????? - ??????????e

1
????????-?????? ??????????

• ????. ?-? ?. ?????????, ??
• ?? - ?????

2
????????? - ??????????e

• ?? ????? ??? ???? 1961 ?. ????? ?????,
  ?????? ???????????? ?? ?????????????? ?????????
  ???????? ????????? ?????? ?????? ??
  ????????-?????? ??????????.
• ???? 2001 ?. ??????? ????? ?? ????????????
  ??????? ???????? (NIH) ?????????????
  ????????????? ?? ????????? ???? ?????????, ?????
  ???? ?? ???? ????????? ??????? ? ? ????????? ??
  ?????????? ??????.
• ?? ?????? ??????????? ?? ???????????? ???????
  ?? ?? ??????? ???????????? ?????.

1. Biomarkers Definitions Working Group.
Biomarkers and surrogate endpointspreferred
definitions and conceptual framework. Clin
PharmacolTher. 20016989 95
3
??????????
4
??????? ??????? ?? ?????? ?????? ?????????
Womens Health Study
Lipoprotein(a) Homocysteine IL-6 TC LDL-C sIC
AM-1 SAA Apo B TCHDL-C hs-CRP hs-CRP
TCHDL-C
0
1.0
2.0
4.0
6.0
????????? ???? ?? ?????? ?????????
Ridker PM et al. N Engl J Med 2000342836-843.
5
????????????? ? ??????????

• ????? ?????? ?? ??????????? ? ????????????? ??
  ??????? ?????????????? ????????? ?? ?????? ??
  ???????????? ? ??????? ?? ???????? ??
  ???????????????.
• ??????? ?? ,?? ????????? ?????? ?? ?????? ???????
  ??? ???????????????? ????????? ?????? ??
  ???????????? ?? ????????? ??????????
  ????????????? ???????.

6
?????????????????? ?-????????? ???????

• ???????????? ?????????? ????????, ?? hsCRP ?
  ?????????? ?????? ?? ???????? ?????????? ? ?
  ????? ????????? ?? ????? ????????? ??????? ?
  ??????.
• CRP ???????? ??????????? ?????? ??? ????????? ??
  ?????????? ????????
• ?????????????? ?????????? ???????? 1 (ICAM-1)
  
• ??????-???????? ?????????? ???????? 1
  (VCAM-1),
• ?????????????? ???????? ?? CRP ?? ????????? ?
  ?????????
• 15 µg/mL.
• Yeh ET, Willerson JT. Coming of age of C-reactive
  protein using inflammation markers in
  cardiology. Circulation 2003 107(3)370-371.
• Venugopal SK, Devaraj S, Yuhanna I, Shaul P,
  Jialal I. Demonstration that C-reactive protein
  decreases eNOS expression and bioactivity in
  human aortic en- dothelial cells. Circulation
  2002 106(12)1439-1441.

7
????????? ?? ????????????? ?? ????????????? ????
?? ?????????? ? ??? ??? ST-???????? ??? ??????
?? ?????? ?? CRP
8
CRP

• ????????? ?? ???????????? ?? ???????? ??? ??
  ????.
• hs CRP ???? ?? ??????? ????????? ?????????????.
• ?????????? ??? ???????? ???? ??? ? ???????? ???
  ???????????, ?? hsCRP ???? ?? ?? ??????? ????
  ???????? ?? ??????? ??? ???????
• P. Ridker, 2013, ESC

9
?????????

• ???????? ???? ?? ??????????? ? ?????? ?????? ??
  ???????? ????????? ??? ??????? ? ??????????
  ??????2, 3 ??? ????????? ??????? ???
  ST-????????.4, 5
• ? ?????????? ? hsCRP ? ?????? ?? ??????????? ????
  ?? ??? ?????????? ????? ? ??????????? ??
  ????????-???????? ?????????.
• ???? ????? ?? ????????? WHIOS ?????????
• 72 242 ???? ? ????????? ??? ??? ?? ??????? 50-79
  ???. ??????????? ,?? ?????? ?? ??????????? ???
  6,7?10,9 ? ????????? ????????? ??
  ????????-????? ???????? ? ???? ?????????.
• . Madjid M, Awan I, Willerson JT, Casscells SW.
  Leukocytecount and coronary heart disease
  implications for risk assessment. J Am Coll
  Cardiol 200444(10)19451956
• 2. Cannon CP, McCabe CH, Wilcox RG, Bentley JH,
  Braunwald E. Association of white blood cell
  count with increased mortality in acute
  myocardial infarction and unstable angina
  pectoris. OPUS-TIMI 16 Investigators. Am J
  Cardiol 200187(5)636639, A10.
• 3

10
??????? ??????? ?

• ????????? ??????? ? ???????? ????????
  ???????????? ????????? ? ? ?????????? ?
  ?????????????????? ????? ? ???????? ?
  ???????????? ????? .
• ?????????? ???????? ????????? ????? ?????? ??
  SAA ? ???.
• ?????????? ???? ?? ???? ????????? ???
  ?????????????? ?? ???????? ? ?????????? ?????? ?
  ????????? ?? ???? ????????.
• Gabay C, Kushner I. Acute-phase proteins and
  other systemic responses to inflammation. N Engl
  J Med 1999 340(6)448-454.
• Rifai N, Joubran R, Yu H, Asmi M, Jouma M.
  Inflammatory markers in men with angiographically
  documented coronary heart disease. Clin Chem
  1999 45(11)1967-1973.
• Morrow DA, Rifai N, Antman EM, et al. Serum
  amyloid A predicts early mortality in acute
  coronary syndromes a TIMI 11A substudy. J Am
  Coll Cardiol 2000 35(2)358-362.

11
CD40 ??????

• CD40 ?????? ? ?? ????????? ??
  ?????-????????e? ??????, ????? ????? ????? ????
  ? ???????? ??????????.
• ??? ?????? ???? ?? ?????? ??????? ????????? ????
  ?? sCD40L ? ????????? ?? ????? ????????? ???????,
  ?????? ??? ????????-?????? ?????.
• ???????? ? ?????????? ?????? ???? ??????????
  ???????? ??????? ???? ?? sCD40L ? ????????? ?
  ???????? ??? ???????? ?????? ? ????????.
• ?????????? ???? ??? ?????????? ? ???????? ???? ??
  sCD40L ??? ????????????? ,?? ???? ?? ????
  ????????? ??? ??????? ? ?????????? .
• Muller F, Ueland T, et al. Enhanced levels of
  soluble and membrane-bound CD40 ligand in
  patients with unstable angina. Possible
  reflection of T lymphocyte and platelet
  involvement in the patho- genesis of acute
  coronary syndromes. Circulation 1999
  100(6)614-620.
• Varo N, de Lemos JA, Libby P, et al. Soluble
  CD40L risk prediction after acute coronary
  syndromes. Circulation 2003 108(9)1049-1052.

12
??????????? ???????? ?? sCD40L ??? ???????? ?
????? ????????? ???????? ?????????? ???? ??
?????????? ? ???????? ???? ?? sCD40L ?? ????????
??? ??????? Abciximab (Reopro)
Muller F, Ueland T, et al. Enhanced levels of
soluble and membrane-bound CD40 ligand in
patients with unstable angina. Possible
reflection of T lymphocyte and platelet
involvement in the patho- genesis of acute
coronary syndromes. Circulation 1999
100(6)614-620. Varo N, de Lemos JA, Libby P, et
al. Soluble CD40L risk prediction after acute
coronary syndromes. Circulation 2003
108(9)1049-1052.
13
?????????? ????????

• ???????????? ???????? ?????????? ?????????????
  ??? ???????? ? ?????????? ?? ?????? ?????? ?
  ???????????? ?????.
• ??? ????????? ?????????? ???????? ?? ???????
• ?????????????? ?????????? ???????? 1 (ICAM-1) ?,
• ??????-???????? ?????????? ???????? 1 (VCAM-1),
• ??????????? ?????????? ??????????
  ????????1(ELAM-1),
• ?????????????????? ????? ???????? ????????
  ????????? ?? ICAM-1 ? VCAM-1
• ???????? ? ?????? ???? ?? CRP ???? ???????
  ????????? ???? ???? ??? ?????? ???? ?? ICAM-1 .
• ??? ????? ? ??? ?????????? ???? ?? sVCAM-1
  ,sICAM-1 ?? ?????????? ? ????? ???? ?? ??
  ?????.
• Ballantyne CM, Entman ML. Soluble adhesion
  molecules and the search for biomarkers for
  atherosclerosis. Circulation 2002
  106(7)766-767.
• Hwang SJ, Ballantyne CM, Sharrett AR, et al.
  Circulating adhesion molecules VCAM-1, ICAM-1,
  and E-se- lectin in carotid atherosclerosis and
  incident coronary heart disease cases the
  Atherosclerosis Risk in Communities (ARIC)
  study. Circulation 1997 96(12)4219- 4225.

14
?????????? ?? ???-??????? ???????? ??????? ??
??????????? ? ??? ????? ??????????, ?????
????????? ?? ??????????? ?????? ? ???????? ?????

• ?? ????? ???? ????????? ??????????? ????????
  ??????????. ???? ??????????? ?? ?????????????? ??
  ???? ?????????? ? ???? ? ??? ?????? ? ????????
  ???????????????? ?? ????? ? ???? ?? ??????????
  ?????????.
• CRP IL ???????????? TNF ?????-??????????
  ?????? Fas ???? ?? TNF-???????????? ???????
  MMP ????????? ???????????????? MPO
  ???????????????? CK-MB ???????-?????? MB cTn
  ???????? ????????? H-FABP ???????? ???????,
  ???????? ???????? ???????? BNP ?????????????
  ?????? ??? B NT-proBNP N-?????????? proBNP
  ST2 ???? ?? IL-1-???????????? ???????, ????????
  IL-33

15
???
16
?????????? ?? ????????????

• ??????????? MIRACL ??????, ?? HDL-????????????
  ??? ???????????? ???????? ?? ???????????? ??
  ????? ????????? ???????? ??? ???????? ?? ???????
  ??? ???????.
• ?????????? LDL-??????? ????? ? ???????? ??
  ????????????????? ??????.
• ??? ???? ??????? ?? ??????????? ? ????? ??????
  ?? ??????????.
• ??????????? ?2 ?? ????????? ?? ?????????
  ?????? ? ?????????????????? ?????.
• ???? ?????? ? ?????? ? ???????? ?? ??????? ?
  ?????????? ?? ????????-??????? ???? ??? ????????
  ? ????? ???? ? ????? ??????????????? ??? ???????.
• Ballantyne CM, Hoogeveen RC, Bang H, Coresh J,
  Fol- som AR, Heiss G, Sharrett AR.
  Lipoprotein-associated phospholipase A2,
  highsensitivity C-reactive protein, and risk for
  incident coronary heart disease in middle-aged
  men and women in the Atherosclerosis Risk in
  Communities (ARIC) Study. Circulation 2004
  109837-842.
• Blake GJ, Dada N, Fox JC, Manson JE, Ridker PM. A
  prospective evaluation of lipoprotein-associated
  phospholipase A2 levels and the risk of future
  cardiovascular events in women. J Am Coll
  Cardiol 2001 381302-1306.

17
??????? ?? ????????? ???????? ?????????

• H-FABP ???????? ??????? ???????? ????????
  ????????
• H-FABP ? ????????? ??????? ? ???????????????
  ,????????? ?? ?????????? ?? ???????? ????????.
  ?????????????? ?????????????? ?? H-FABP ??
  ???????? ????????? ? 93 ??-??????, ????????? ??
  ???????-?????? ?? ? ?????????? ?????????1.
• H-FABP ??? ??-????? ?????????????? ?? TnT ?
  ??????? ???????? ?? ?????? ????????? ???????3.
• ?????????? ??????? ???? ?? H-FABP ? ?????????? ?
  ??????? ???? ?? ?????????? ?? ????? ? ?????
  ???????? ????????? ??? ???????? ? ????? ?????????
  ???????, ?????????? ?? ??????????? ??????? ????
  ?? cTn ? BNP.847

1. Tanaka, T, Sohmiya, K., Kitaura, Y, Takeshita,
H., and Morita, H., et al. ClinicalEvaluation of
Point-of-Care-Testing of Heart-Type Fatty
Acid-Binding Protein(H-FABP) for the Diagnosis of
Acute Myocardial Infarction. J Immunoassay
Immunochem27, 2006 225. 2. Ecollan, P., Collet,
J. P., Boon, G., Tanguy, M. L., and Fievet, M.
L., et al.Pre-Hospital Detection of Acute
Myocardial Infarction with Ultra-Rapid HumanFatty
Acid-Binding Protein (H-FABP) Immunoassay. Int J
Cardiol 119,2007 349354. 3. Niizeki, T.,
Takeishi, Y, Arimoto, T, Takabatake, N., and
Nozaki, N., et al. Heart-Type Fatty Acid-Binding
Protein Is More Sensitive Than Troponin T to
Detectthe Ongoing Myocardial Damage in Chronic
Heart Failure Patients. J CardFail13, 2007
120127. 4. O'Donoghue, M., De Lemos, J. A.,
Morrow, D. A., Murphy, S. A., Buros, J. L.,et al.
Prognostic Utility of Heart-Type Fatty Acid
Binding Protein in Patients withAcute Coronary
Syndromes. Circulation 114, 2006 550557.
18
?????????? ?????????????? ????? ?????????????
??????? ? ??????????? ?? ???????????????????
?????????? ??????? ????? ?? ????? ????????
ox-LDL. ???????? ? Helicobacter pylori (HP),
Chlamydia pneumoniae (CP) ? cytomegalovirus
(CMV), ????? ?? ???????? ????????????? ???????.
?????????????? ??????? ? ????????? ? ??
?????????? ?????? ?? ?????????? ????????? ??
CRP, ??????? ??????? ? ? ?????????? ? ??????
????. .
19
?????????????? ?? ???????????????
????????, ????????? ? ?????????????? ?? ???????
????? ?????????? ? ???? ?????????
???????????????? ?????? ????? ?? ????? ??????????
?? ?????? ?? ??????????? ?? ????????.
20
??????? ??????? ?, ????????? ? ????????????

• ?????????? ??????? ?, ????????? ? ????????????
  (PAPP-A), ? ????????????????, ????? ??
  ?????????? ? ???????? ?? ??????????????????
  ?????.
• ?????? ?? PAPP-A ? ????????????? ??-?????? ???
  ???????? ? ?????????? ?????? ? ????? ?????????
  ???????.
• ??? ???????? ? ?????????? ???????? ??
  ??????????? ?? ????????? ??????? ??? ??????? ??
  ???????????? ? ????????????? ????? ? ??????????
  ??? ????????????? ???????? ???? ?? PAPP-A.
• ??? ??????????????? ???????? ? ????? ?????????
  ??????? ? ????????? ?????????? ???? ,?? ????????
  ???? ?? PAPP-A ? ????????? ????????? ?? ???????
  ????? ?? ????? ?? 6-????????? ????????????.
• Prescott MF, Sawyer WK, Von Linden-Reed J, et
  al. Effect of matrix metalloproteinase inhibition
  on progression of atherosclerosis and aneurysm in
  LDL receptor-deficient mice overexpressing MMP-3,
  MMP-12, and MMP-13 and on restenosis in rats
  after balloon injury. Ann NY Acad Sci 2010
  878179-190.

21
PAPP-A

• ??? ?????????? ? ???????? ???????? ????? ??????
  ?? PAPP-A ? ????? ???????? ? ????????????? ???
  ??????????? ?????????? ?????, ?? ??P?-? ?????? ?
  ???????? ?????.
• ???? ????????? ? ?????????? ????????? ?
  ???????? ?? ???????????????, ????? ??? ?????????
  ??? ????????? ?? ??????????? ?????.

1. Bayes-Genis A, Conover CA, Overgaard MT, et
al. Pregnancy-associated plasma protein A as a
marker of acute coronary syndromes. N Engl J Med
2001345(14)10221029 2. Lawrence JB, Oxvig C,
Overgaard MT, et al. The insulin-like growth
factor (IGF)dependent IGF binding protein-4
protease secreted by human fibroblasts is
pregnancy-associated plasma protein-A. Proc Natl
Acad Sci USA 19999631493153
22
PlGF ???? ???????? ???????? ?? ????????????

• PlGF ????????? ??????? ?? ???????????????? ??????
  ? ????????, ???????????? ?? ????????? ? ??
  ??????? ? ????????? ????????????? ???????????.
  ?????? ???? ??????? ?? ???????? ? ????????? ?
  ?????????????? ?? ???????.
• ??????????? ?? PlGF ??????? ??????? ?? ??
  ??????? ? ???????? ??????? ??????????????.
• PlGF ? ???? ?? ????????? ?????? ?????????
  ???????? ???????, ????? ???? ? ??????????
  ???????? ??? ????? ? ?????????? ?????????????.
• PlGF ??????? ???? ???????? ???????? ??
  ???????????? ? ?? ?????????????? ?
  ?????????????????? ?????. ????????? ???? ?? PlGF
  ?? ???????? ??? ???????? ? ????? ?????????
  ???????.
• ?????? ?? PlGF ? ?????????? ? ????? ????????
  ?????????? ?? ?????????????? ?? ?????????? ?
  ????????????? ????? ? ?? ?????????? ?
  ????????? ??????????.
• Luttun A, Tjwa M, Moons L, et al.
  Revascularization of ischemic tissues by PlGF
  treatment, and inhibition of tumor angiogenesis,
  arthritis and atherosclerosis by anti-Flt1. Nat
  Med 2002 8831-840.
• Maglione D, Guerriero V, Viglietto G, Delli-Bovi
  P, Per- sico MG. Isolation of a human placenta
  cDNA coding for a protein related to the vascular
  permeability factor. Proc Natl Acad Sci USA
  1991 889267-9271.

23
?????????? ?? ????????? ???????

• ????????? ?? ???????? ?? ???????????????
  ????????? ?? ??????????, ??????? ?? ???????? ?
  ????? ????, ?? ??????????? ??????????????? ?
  ????? ????????? ???????, ?????? ??????????? ?????
  45, ?????????? ?? ????? ???? ????? ?????????
  ???????, ? ??????? ???????? ?????????? ??????.
• ???????????? ?? ????????? ? ???? ?????????.

24
?????????? ????? ?????????????? ?
?????????? ???????? ?? ?????? ????????? ???????
??????? ?????????? ???????? ????????? ??
???????????????? ?? ?????????? ? ?????? ????? ?
????????? ?? ??????????, ??????????????? ????????
? ????? ????? ????????? ???????. ????????????,
(Graff et al.) ???????????? ? ??????????? ????
??????? (?????? ?????), ??????? ?? ? ??-????????
???????????? ?? ?? ?????????? ??? ??????? ??
????? (????????? ?????), ????? ???????? 100
??????? ?? ??????????, ??? ?????? ???????? ??
????????, ? 100 ???????????????, ??? ??????
???????? ?? ???????????????. ?? ?? ??????
???????? ?? ??????? ????????? ?? ????????????
????????, ?????? ????????? ?? ????????????????
????????? 50 ?? ????????? ?? ????????? ??? 50.
25
??????????? ??????? ?? ?????????

• ???????? ?????????
• CD40L
• ?????
• ?????????-??????????? ???????
• ????????????????
• ????????????? ??????? BNP ? proBNP
• ??????? ??????? ?, ????????? ? ????????????.

26
??????????? ??????? ?? ?????????
?-????????? ??????? ???????? ????????? CD40L ????? ?????????-??????????? ??????? ???????????????? ????????????? ??????? BNP ? proBNP ??????? ??????? ?, ????????? ? ????????????
27
??????? ?? ???????? ?????

• ?????????????
• ????????????? ?? ?????????? ? ????????????? ?
  ???????????.
• ??? ????? ????????? ??????? ?????? ??
  ????????????? ????????? ? ???????? ?? ???????? ?
  ?? ???????????? ????????? ?? ?????????.
• Beltowski J, Jamroz A. Adrenomedullin - what do
  we know 10 years since its discovery? Pol J
  Pharmacol 2004 565-27.

28
??????? ?? ???????? ?????

• ST2
• ST2 ? ???? ?? IL-1-???????????? ??????? ? ??
  ?????????? ?? ??????????????? ???? ???????? ????
  ?? ???????? ???? ??? ???? ???????????? ?? ?????
  ????????? ???????.
• ST2 ??????? ???????? ?? ??????????? II ?
  ???????? ????????? ??????????? ? ??????? ???
  ??????? ??????? ?????.

Weinberg, E. O., Shimpo, M., De Keulenaer, G. W.,
MacGillivray, C, and Tominaga, S., et al.
Expression and Regulation of ST2, an
Interleukin-1 Receptor Family Member, in
Cardiomyocytes and Myocardial Infarction.
Circulation 106, 2002 2961-2966. Schmitz, J.,
Owyang, A., Oldham, E., Song, Y, and Murphy, E.,
et al. IL-33, An Interleukin-1-Like Cytokine That
Signals via the IL-1 Receptor-Related Protein ST2
and Induces T Helper Type 2-Associated Cytokines.
Immunity 23, 2005 479-190. Kakkar, R. and Lee,
R. T. The IL-33/ST2 Pathway Therapeutic Target
and Novel Biomarker. Nat Rev Drug Discov 7, 2008
827-840. Sanada, S., Hakuno, D., Higgins, L. J.,
Schreiter, E. R., and McKenzie, A. N., et al.
IL-33 and ST2 Comprise a Critical Biomechanically
Induced and Cardioprotective Signaling System. J
Clin Invest 117, 2007 15381549. Miller, A. M.,
Xu, D., Asquith, D. L., Denby, L., and Li, 897.
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Atherosclerosis. J Exp Med 205, 2008
339-346. Chackerian, A. A., Oldham, E. R.,
Murphy, E. E., Schmitz, J., and and Pflanz, S.,
et al. IL-1 Receptor Ac- 898. cessory Protein and
ST2 Comprise the IL-33 Receptor Complex. J
Immunol 179, 2007 2551-2555. Chackerian, A. A.,
Oldham, E. R., Murphy, E. E., Schmitz, J.,
Pflanz, S., et al. IL-1 Receptor Accessory 899.
Protein and ST2 Comprise the IL-33 Receptor
Complex. J Immunol 179, 2007 2551-2555. Shimpo,
M., Morrow, D. A., Weinberg, E. O., Saba- tine,
M. S., and Murphy, S. A., et al. Serum Levels of
900. the Interleukin-1 Receptor Family Member ST2
Predict Mortality and Clinical Outcome in Acute
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2186-2190. 901. Rehman, S. U., Mueller, T., and
Januzzi, J. L., Jr. Characteristics of the Novel
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Acute Heart Failure. 7. Am Coll Cardiol 52, 2008
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29
???? ?????????? ????????

• ??????? ????????? ?? ???? ? ?????????? ??
  ????????-???????? ??????, ?????????? ?? ??
  ??????? ? ?? ?? ???????? ??????? ????
  ???????????? ?????? ?????? ?????????????
  ????????? ? ????????????? ??????.
• ???????? ? ???????? ? ???????????? ?????????
  ?????? ?? ?????????? ?? ??????????.
• ? ???????????? ???????? ?? ?????? ?? ????? ?????
  ???? ??????????.
• ???????? ? ??? ?????????.
• Morgenthaler NG, Struck J, Jochberger S, Dunser
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• Morgenthaler NG. Copeptin a biomarker of
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• Holwerda DA. A glycopeptide from the posterior
  lobe of pig pituitaries. I. Isolation and
  characterization. Eur J Biochem, 2003 28334-9.

30
???????? ?? ?????????? ? ???????? ? ????????????
31
????????

• ??? ???????? ? ?????????????? ????????? ???????
  ?????? ?? ???????? ? ???????? ???? ??????? 4 ????
  ???? ???????? ?? ?????????? ? ???????, ? ?????
  ???????? ? ??? ??? ?? ?? ???????.
• ??? ?????????? ?? ????? ??????????? ??????
  ??????????? ?????????? ???? ? ?????? ??
  ????????? ??? ?????????????? ?? ???????? ?
  ???????? ????????? ????????? ???????????? ??
  ????? ????????? ??????? ? ????????? ???????????
  ???????? gt99.
• ?????????? ? ????????? ????? ?????? ?? ????????
  ? ???????? ?? ????????????? ???????????? ????
  ????? ????????? ???????.
• Reichlin T, Hochholzer W, Stelzig C, Laule K,
  Freidank H, Morgenthaler NG, et al. Incremental
  value of copeptin for rapid rule out of acute
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  5460-8.
• Kelly D, Squire IB, Khan SQ, Quinn P, Struck I,
  Mor- genthaler NG, et al. C-terminal
  provasopressin (co- peptin) is associated with
  left ventricular dysfunction, remodeling. and
  clinical heart failure in survivors of myocardial
  infarction. J Card Fail 2008 14739-45.

32
?????? ?? ????????????

• ??-????? ????? ?? ???????????? ???????
  ?????????? ???? ??????? ??? ??????? ?? ?????? ? ?
  ???????? ????????.
• ???????? ? ?? ?????????? ? ?????? ?????????????
  ??? ?????????? ???????????.
• ??????????,????? ????????????? ?????????? ? ?????
  ? ????? ???? ? ????? ?? ????? ??????????? ?
  ???????? ????????? ?? ??????? ?? ??????? ???????.