Braunwald E. N Engl J Med 2008;358:

ΕΘΝΙΚΟ ΚΑΙ ΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΙΑΤΡΙΚΗ ΣΧΟΛΗ Ά ΚΑΡΔΙΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ ΒΙΟΔΕΙΚΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ ΔΗΜΗΤΡΙΟΣ ΤΟΥΣΟΥΛΗΣ ΚΑΘΗΓΗΤΗΣ ΚΑΡΔΙΟΛΟΓΙΑΣ

NOTHING TO DECLARE

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 Braunwald E. N Engl J Med 2008;358:2148-2159.

Biomarkers in HF Related to pump failure Related to inflammation Related to myocyte necrosis Related to oxidative stress Other

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

BNP 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.

100 LVEF, % 80 60 40 y = 0.7, P < 0.001 20 0 0 1.0 2.0 3.0 Log BNP, pmol/l Davis M et al. Lancet.. 1994;343:440 444. 444.

ΒΝΡ pg/ml 1200 1000 800 600 400 200 0 12.3 95.4 221 459.1 1006.3 (pg/ml) N Maisel A et al. Am Heart J. 2001;141:367 374. 374. ClassΙ ClassΙΙ ClassΙΙΙ ClassΙV

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 nonacute 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.

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 Chem 2007;14(14):1567-72 Tousoulis D, Böger RH, Antoniades C, Siasos G, Stefanadis C. Nat 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;50:607-613 613

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

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 treatment Kawahara 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.

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.

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-15 Growth differentiation factor-15 is a new 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. Michalea 1, G. Siasos 1, D. Tousoulis 1, E. Oikonomou 1, C. Chrysohoou 1, S. Kioufis 1, A. Miliou 1, N. Gouliopoulos 1, AG. Papavassiliou 2, C. Stefanadis. J Am Coll Cardiol (suppl) Annual Scientific Sessions of the American College of Cardiology. Chicago, April 2012

Copeptin

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 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. Tentzeris et al. Eur J Heart Fail. 2011 Jul;13(7):726-33. Urban Alehagen et al JAMA 2011

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

Galectin-3 Galectin-3 appeared a useful method for improving risk stratification of patients with chronic HF in a substudy of the COACH trial 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 *Adjusted for age, sex, and b-type natriuretic peptide levels Arch Intern Med 2008; 168:316-324

Galectin-3 Eur Heart J. 2012 May 7. [Epub ahead of print]

Biomarkers in HF Related to pump failure (BNP) Related to inflammation (TNFa) ST2 Related to myocyte necrosis (troponin) Related to oxidative stress Other (further studies) Galectin-3

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