ΒΙΟΔΕΙΚΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚΗ...
Transcript of ΒΙΟΔΕΙΚΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚΗ...
ΒΙΟΔΕΙΚΤΕΣ ΣΤΗΝ
ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ
ΕΘΝΙΚΟΕΘΝΙΚΟ ΚΑΙΚΑΙ ΚΑΠΟΔΙΣΤΡΙΑΚΟΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝΑΘΗΝΩΝ
ΙΑΤΡΙΚΗΙΑΤΡΙΚΗ ΣΧΟΛΗΣΧΟΛΗ
ΆΆ ΚΑΡΔΙΟΛΟΓΙΚΗΚΑΡΔΙΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗΚΛΙΝΙΚΗ
ΔΗΜΗΤΡΙΟΣ ΤΟΥΣΟΥΛΗΣ
ΚΑΘΗΓΗΤΗΣ ΚΑΡΔΙΟΛΟΓΙΑΣ
� NOTHING TO DECLARE
Braunwald E. N Engl J Med 2008;358:2148-2159.
Several biomarkers have
recently been examined
for their efficacy to
improve diagnosis,
determine the
pathophysiologic state of
HF, improve clinical
decision making, clinical
outcome, direct treatment
and assess prognosis of
HF patients
Biomarkers in HFBiomarkers in HFBiomarkers in HF
•• Related to pump failureRelated to pump failure
•• Related to inflammationRelated to inflammation
•• Related to myocyte necrosisRelated to myocyte necrosis
•• Related to oxidative stressRelated to oxidative stress
•• OtherOther
Biomarkers in HFBiomarkers in HFBiomarkers in HF
•• Related to pump failureRelated to pump failure
•• Related to inflammationRelated to inflammation
•• Related to myocyte necrosisRelated to myocyte necrosis
•• Related to oxidative stressRelated to oxidative stress
•• OtherOther
1. Atrial Natriuretic Peptide (ANP)
2. Brain Natriuretic Peptide (BNP)
3. C-Type Natriuretic Peptide (CNP)
4. Urodilatin (Uro)
Chen H, Burnett Jr. Eur Heart J Suppl 2006
� Secreted by myocytes of ventricles
� Shear stress is the stimulus
Grewal J et al. BC Medical Journal. 2004;46:24–29.
BNP in Heart Failure
� In the Breathing Not Properly Study, a BNP cutoff of 100 pg
⁄mL was 76% specific and 90% sensitive for the diagnosis of
acute HF in patients presenting to the emergency department
with dyspnea.
� In Acute Shortness of Breath Evaluation (BASEL) study
documented that in acute decompensated HF patients
assessment of BNP levels can lead to rapid diagnosis and
early treatment.
� The utility of BNP in gauging the severity of disease has
been documented through its relationship to left ventricular
end-diastolic pressure
Maisel AS, et al. N Engl J Med 2002;347(3):161-7.
Mueller C, et al. N Engl J Med 2004;350(7):647-54.
BNP
Log BNP, pmol/l
LV
EF
, %
0
20
40
60
80
100
0 1.0 2.0 3.0
y = –0.7, P < 0.001
Davis M et al. Davis M et al. LancetLancet. 1994;343:440. 1994;343:440−−444.444.
0
200
400
600
800
1000
1200
12.3 95.4 221 459.1 1006.3 (pg/mL)
N Class Ι Class ΙΙ Class ΙΙΙ Class ΙV
ΒΝΡΒΝΡ
pg/mlpg/ml
Maisel A et al. Maisel A et al. Am Heart J. Am Heart J. 2001;141:3672001;141:367−−374.374.
� The N-terminal pro-BNP (NT-proBNP), is
released into the circulation and its
measurement has diagnostic and prognostic
value in HF.
� NT-proBNP has been found to be useful in
the evaluation of a patient presenting with
dyspnea in the acute setting
Dickstein K, Cohen-Solal A, Filippatos G et al. Eur Heart J 2008;29(19):2388-442.
Gustafsson F et al : Heart Drug 2003;3:141-146.
Both BNP and NT-proBNP assays have a high degree of diagnostic accuracy and clinical relevance for both acute and chronic heart
failure.
Masson S et al. Clinical Chemistry. 2006;52(8):1528–1538.
Daniels and Maisel JACC 2007
Causes of elevated natriuretic peptide levels in the
acute setting •acute coronary syndrome
•atrial or ventricular arrhythmias
•pulmonary embolism
•severe chronic obstructive pulmonary disease with elevated right heart pressures,
renal failure, and sepsis
Causes of an elevated natriuretic level in the non-
acute setting •old age (>75 years)
•atrial arrhythmias
•left ventricular hypertrophy
•chronic obstructive pulmonary disease
•chronic kidney disease
Daniels et al. Am Heart J 2006;151:999 –1005.
• Recently midregional pro-atrial natriuretic peptide (MR-pro-ANP) has rendered prognostic significance
• Midregional epitopes of pro-hormones may be more stable to degradation by exoproteases, unlike epitopes in the N- or C-terminals of pro-ANP used in previous immunoassays.
• In patients after acute myocardial infarction, a lower readmission rate for HF in those in the lower 3 quartiles of MR-pro-ANP and the highest HF readmission rates in those with both biomarkers (MR-pro-ANP and NT-pro-BNP) elevated in the highest quartile.
Khan SQ, et al. J Am Coll Cardiol 2008;51(19):1857-64.
Biomarkers in HFBiomarkers in HFBiomarkers in HF
•• Related to pump failureRelated to pump failure
•• Related to inflammationRelated to inflammation
•• Related to myocyte necrosisRelated to myocyte necrosis
•• Related to oxidative stressRelated to oxidative stress
•• OtherOther
� Inflammatory mediators have pathogenetic role and
contribute to the progression and clinical
presentation of HF giving rise to the “cytokine
hypothesis” according to which the progression of
HF is due, at least in part, to the destructive action
of pro-inflammatory cytokines
Braunwald E. N Engl J Med 2008;358:2148-2159
D. Tousoulis, AM Kampoli, G. Siasos...A.G. Papavassiliou, C. Stefanadis
Current Medicinal Chemistry 2009
The Cytokine Hypothesis of Heart Failure.
Braunwald E. N Engl J Med 2008;358:2148-2159.
� Levels of TNF-α are related with echocardiographic indexes
of both systolic and diastolic left ventricular function.
� Activated macrophages are the main source of TNF-a
production
� The failing heart can also produce TNF-a, which in excessive
levels can promote left ventricular remodelling and can have
negative inotropic effects
Tousoulis D…Stefanadis C. International Journal of Cardiology 100 (2005) 347– 353
Chrysohoou C et al. Heart Vessels 2009;24(1):22-6.
• Other cytokines implicated in the pathogenesis of
CHF are IL-1 and IL-6.
• Plasma adhesion molecules are increased in patients
with heart failure
• High levels of soluble vascular cell adhesion
molecule-1 and P selectin have been shown to
correlate with the severity of heart failure
� Circulating cytokines may contribute to reduced synthesis
and release of NO
� TNF-a is able to impair the stability of eNOS and to down
regulate eNOS expression
� Inflammatory mediators are also implicated in the
endothelial dysfunction observed in HF as cytokines induce
the production of adhesion molecules from the endothelium,
alter the balance between endogenous vasodilators (such as
NO) and vasoconstrictors (e.g. endothelin-1), causing a state
of vasoconstriction
Siasos G, Tousoulis D et al.Curr Med ChemCurr Med Chem 2007;14(14):1567-72
Tousoulis D, Böger RH, Antoniades C, Siasos G, Stefanadis C. Nat Clin Pract Cardiovasc MedNat Clin Pract Cardiovasc Med.
2007 May;4(5):274-83
� CRP has central role in the inflammatory cataract
� Framingham Heart Study shown that patients free
from ischemic heart disease and increase levels of
CRP (serum CRP level ≥5 mg/dL) had 2.8 times
increased risk of development of HF during a
follow-up period of approximately 5 years
compared to subjects with normal CRP levels.
Vasan RS, et al Circulation 2003;107(11):1486-91.
� The ST2 is a member of the interleukin-1
receptor family
� Concentrations of ST2 have been reported to
be elevated in patients with HF.
� Increased ST2 plasma concentrations are
independently and strongly associated with
one-year all-cause mortality in HF.
Januzzi JL, et al. J Am Coll Cardiol 2007;50(7):607-13.
Mueller T, et al. Clin Chem 2008;54(4):752-6
Januzzi J et al: J Am Coll Cardiol 2007;50:607Januzzi J et al: J Am Coll Cardiol 2007;50:607--613613
Inflammatory biomarkers IL6, IL8, and MCP1 were
not only raised when HFNEF patients were
compared with arterial hypertension patients but also
elevated when arterial hypertension patients were
compared with age-adjusted reference values
Reflects chronic myocardial remodeling process and
are unaffected by the patient’s instantaneous volume
status
Biomarkers in HFBiomarkers in HFBiomarkers in HF
•• Related to pump failureRelated to pump failure
•• Related to inflammationRelated to inflammation
•• Related to myocyte necrosisRelated to myocyte necrosis
•• Related to oxidative stressRelated to oxidative stress
•• OtherOther
� About 1 g of myocardial mass corresponding to 64 million cells is being lost
per year in the human heart
� Additional myocardial damage from necrosis or apoptosis due to acute or
chronic heart failure is believed to be responsible for higher cardiac troponins
in HF patients.
� Several studies have confirmed the increased levels of cardiac troponins in
patients with acute or chronic HF regardless of the cause (ischemic vs.
nonischemic)
� The presence of plasma troponin in HF patients is considered a condition
associated with poor prognosis in HF according to the European Society of
Cardiology guidelines
� An increase in cardiac troponins may indicate an acute coronary event,
myocarditis or an episode of HF decopensation, thus monitoring of cardiac
troponins is useful in assessing the seriousness of the disease and in directing
the appropriate treatmentKawahara C et al. Am Heart J 2011;162(4):639-45.
O'Connor CM et al. Circ Heart Fail 2011.
Dickstein K, Cohen-Solal A, Filippatos G et al . Eur Heart J 2008;29(19):2388-442.
Biomarkers in HFBiomarkers in HFBiomarkers in HF
•• Related to pump failureRelated to pump failure
•• Related to inflammationRelated to inflammation
•• Related to myocyte necrosisRelated to myocyte necrosis
•• Related to oxidative stressRelated to oxidative stress
•• OtherOther
� MPO is elevated in HF patients, while levels of MPO are positively
correlated with NYHA stage.
� In patients with HF intermediate NT-pro-BNP, MPO has an additive
predictive value on mortality.
� Similarly, a prospective study of 667 patients presenting to the
emergency department with dyspnea concluded that although the
diagnostic accuracy of MPO for acute HF was limited, MPO
concentrations above the lowest tertile (MPO>99 pmol/L) were
associated with significantly increased 1-year mortality and its predictive
value is additive to BNP.
� Recently, it was also shown that combining high sensitivity CRP and
MPO measurements provided distinct and complementary prognostic
value in chronic systolic HF.
Reichlin T, et al. Clin Chem 2010;56(6):944-51.
Tang WH, et al. J Am Coll Cardiol 2007;49(24):2364-70.
Tang WH, et al Congest Heart Fail 2011;17(3):105-9.
Biomarkers in HFBiomarkers in HFBiomarkers in HF
•• Related to pump failureRelated to pump failure
•• Related to inflammationRelated to inflammation
•• Related to myocyte necrosisRelated to myocyte necrosis
•• Related to oxidative stressRelated to oxidative stress
•• OtherOther
� Plasma ET-1 concentrations are generally increased in
patients with HF
� Plasma ET-1 appears to be related to the severity of the HF,
correlating positively with NYHA class and plasma
angiotensin II, and negatively with left ventricular ejection
fraction and exercise capacity.
� C-terminal pro-endothelin-1 (CT-proET-1) constitutes a
novel predictor of increased 12-month cardiovascular
mortality in patients with congestive HF. High CT-proET-1
together with high NT-pro-BNP enable to identify patients
with congestive HF and particularly unfavorable outcomes.
Tousoulis D at al. Int J Cardiol 2005;100(3):347-53.
Milo-Cotter O et al. Cardiology 2011;119(2):96-105.
Jankowska EA, Filippatos GS et al. PLoS One 2011;6(1):e14506.
� Imbalance between the activity of MMPs and their tissue inhibitors
(TIMPs) contribute to myocardial remodeling.
� MMP-2 and -9 levels were significant predictors of diastolic HF in
hypertensive patients.
� TIMPs, are also elevated in HF patients.
� Levels of TIMP-1 were predictive of diastolic HF in hypertensive
patients
� Although, absolute values of MMPs and TIMPs are of prognostic
significance in HF patients sometimes their ratio is more important.
Serum MMP-1/TIMP-1 ratio was inversely correlated with ejection
fraction and directly correlated with left ventricular end-diastolic
diameter in hypertensive HF subjects.
Martos R, et al. Circulation 2007;115(7):888-95.
Lopez B, et al. J Am Coll Cardiol 2006;48(1):89-96.
Noji Y, et al. Circ J 2004;68(4):355-60.
Ahmed SH, et al. Circulation 2006;113(17):2089-96.
Growth differentiation factor-15Growth differentiation factor-15
•• Growth differentiation factorGrowth differentiation factor--15 is a new 15 is a new
biomarker in cardiovascular disease.biomarker in cardiovascular disease.
• GDF-15 levels are associated with
prognosis independently of many other
clinical characteristics and biomarkers of
the severity of the disease.
� Neutrophil gelatinase-associated
lipocalin (NGAL)
� Cystatin C
� Kidney injury molecule 1 (KIM-1)
Yndestad A et al. European Heart Journal (2009)
� Shlipak et al. JACC Vol. 45, No. 2, 2005
� NGAL and Cystatin-C are associated with arterial
stiffness and biomarkers of cardiac remodeling (MMP-
9).
� Elevated arterial stiffness is correlated with BNP levels
in HF patients
� These findings highlight a possible common
pathogenetic mechanism of arterial, cardiac and renal
dysfunction in HF.
S. Michalea1, G. Siasos1, D. Tousoulis1, E. Oikonomou1, C. Chrysohoou1, S. Kioufis1, A. Miliou1, N. Gouliopoulos1,
AG. Papavassiliou2, C. Stefanadis. J Am Coll Cardiol (suppl)
Annual Scientific Sessions of the American College of Cardiology. Chicago, April 2012
Copeptin
C-terminal fragment of the arginine
vasopressin precursor hormone
•Independent role as a prognostic
marker in patients with chronic HF
•Potential role as a molecular marker
for tailored therapies with vasopressin
antagonism
Copeptin
Tentzeris et al. Eur J Heart Fail. 2011 Jul;13(7):726-33.
Urban Alehagen et al JAMA 2011
• Combined use of hs-cTnT and copeptin might
predict clinical outcome of patients with chronic stable
heart failure.
•Among elderly patients with symptoms of heart
failure, elevated concentrations of copeptin and the
combination of elevated concentrations of
copeptin and NT-proBNP were associated with
increased risk of all-cause mortality.
Copeptin
Copeptin
Galectin-3
•β-galactoside-binding lectin produced by
several tissues
•Promotes cardiac fibroblast proliferation and
collagen synthesis (maladaptive remodeling)
•Predicts mortality independent of natriuretic
peptides in patients with chronic HF
•Does not appear to be modified by treatment
•Potential role as a target for therapy
*Adjusted for age, sex, and b-type natriuretic peptide levels
Galectin-3 quartile
(ranges, ng/mL)
HR (95% CI) p
Quartile 2 (15.2–20.0) 1.67 (1.08–2.59) 0.0207
Quartile 3 (20.0–25.9) 2.08 (1.35–3.21) 0.0010
Quartile 4 (25.9–66.6) 2.67 (1.74–4.09) <0.0001
Galectin-3 appeared a useful method for improving risk stratification of
patients with chronic HF in a substudy of the COACH trial
Arch Intern Med 2008; 168:316-324
Galectin-3
Eur Heart J. 2012 May 7. [Epub ahead of print]
Galectin-3
Biomarkers in HFBiomarkers in HFBiomarkers in HF
•• Related to pump failure Related to pump failure (BNP)(BNP)
•• Related to inflammation Related to inflammation (TNFa) ST2(TNFa) ST2
•• Related to myocyte necrosis Related to myocyte necrosis (troponin)(troponin)
•• Related to oxidative stressRelated to oxidative stress
•• Other (further studies) Other (further studies) GalectinGalectin--33
� A variety of biomarkers reflecting different pathophysiologic
states of HF syndrome and different stages in the progression
of the disease have been evaluated for their ability to predict
morbidity, mortality and future cardiovascular events in HF
patients.
� Only NP and cardiac troponins are used in clinical practice
as the majority of the rest biomarkers are not easily available,
are expensive, or their predictive value is low.
� In addition future research in the combination of several
biomarkers is needed to strengthen the predictive value of
established biomarkers in HF patients.
Tousoulis D, Oikonomou E, Siasos G…Stefanadis C. Curr Med Chem. 2012
Research group
Prof. Christodoulos Stefanadis, MD, PhD, FACC, FESC (Director)
Prof. Dimitris Tousoulis, MD, PhD, FACC
Prof. Athanasios G. Papavassiliou, MD, PhD
Gerasimos Siasos, MD, PhD
Evangelos Oikonomou, MD
Charalampos Anoniades, MD, PhD
Elias Gialafos, MD, PhD
Georgios Marinos, MD, PhD
Konstantinos Zisimos, MD
Marina Zaromitidou, MD
Konstantinos Maniatis, MD
Thodoris Paraskevopoulos, MD
Nikos Papageorgiou, MD
Aleksis Verveniotis, MD
Stamatios Kioufis, MD
Stavroula Mihalea, MD
Christina Kolia, MD
Aris Plastiras, MD
Dimitris Athanasiou, MD
Nikolaos Gouliopoulos, MD
Stathis Dimitropoulos, MD
Panagiotis Tourikis, MD
Eleni Kokkou, PreMD
Marilena Kolia, PreMD
� EDITORS
DIMITRIS TOUSOULIS
CHRISTODOULOS STEFANADIS
� Francis/Taylor 2013