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