ΟΙ ΒΙΟΔΕΙΚΤΕΣ ΚΑΡΔΙΟΛΟΓΙΑ ΣΗΜΕΡΑ ΔΗΜΗΤΡΙΟΣ ΤΟΥΣΟΥΛΗΣ. Καθηγητής Καρδιολογίας

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Nicholas Barrett
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1 ΕΘΝΙΚΟ ΚΑΙ ΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΙΑΤΡΙΚΗ ΣΧΟΛΗ Ά ΚΑΡΔΙΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ Διευθυντής: Καθηγητής Δημήτριος ΤΟΥΣΟΥΛΗΣ ΟΙ ΒΙΟΔΕΙΚΤΕΣ ΣΤΗΝ ΚΑΡΔΙΟΛΟΓΙΑ ΣΗΜΕΡΑ ΔΗΜΗΤΡΙΟΣ ΤΟΥΣΟΥΛΗΣ Καθηγητής Καρδιολογίας

2 Biomarkers in CV Diseases?

3 Biomarkers in HF HEART FAILURE

4 Biomarkers in HF Neurohormonal biomarkers Biomarkers of myocardial injury Biomarkers of inflammation & oxidative stress Other (fibrosis, cardiorenal, genetic etc)

5 Natriuretic Peptides 1. Atrial Natriuretic Peptide (ANP) 2. Brain Natriuretic Peptide (BNP) 3. C-Type Natriuretic Peptide (CNP) Chen H, Burnett Jr. Eur Heart J Suppl 2006

6 BNP in diagnosis In the Breathing Not Properly Study, a BNP cutoff of 100 pg ml was 76% specific and 90% sensitive for the diagnosis of 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. Maisel AS, et al. N Engl J Med 2002;347(3): Mueller C, et al. N Engl J Med 2004;350(7):

7 ROC Curve Analysis ΒΝΡ: 100 pg/ml N = 1, sensitivity BNP = 50 (pg/ml) BNP = 80 (pg/ml) BNP = 100 (pg/ml) BNP = 125 (pg/ml) BNP = 150 (pg/ml) AUC = 0.91 ( ) spesificity Maisel A et al. N Engl J Med. 2002;347:

8 BNP in diagnosis Μc Cullough AP et al Circulation. 2002;106:

9 BNP vs HF classification ΒΝΡ pg/ml (pg/ml) N Class Ι Class ΙΙ Class ΙΙΙ Class ΙV Maisel A et al. Am Heart J. 2001;141:

10 BNP in prognosis BNP is an independent predictor of death in patients with chronic heart failure, and is superior to atrial natriuretic peptide (ANP) for predicting mortality. Tsutamoto T et al. Circulation 1997;96: BNP is also an independent predictor of all-cause mortality in patients with asymptomatic or minimally symptomatic left ventricular dysfunction, being superior to norepinephrine and left ventricular volumes Tsutamoto T et al. Eur Heart J 1999;20:

11 NT pro BNP guided therapy All cause mortality Repeated HF hospitalization

12 Both BNP and NT-proBNP assays have a high degree of diagnostic accuracy and clinical relevance for both acute and chronic heart failure. BNP NT-proBNP

13 Masson S et al. Clinical Chemistry. 2006;52(8):

14 BNP in other conditions Myocardial infarction and ischaemia Pulmonary emboly Chronic obstructive pulmonary disease Renal dysfunction ARDS /septic shock Advanced age Maisel AS, McCullough PA. Cardiac natriuretic peptides:a proteomic window to cardiac function and clinical management. Rev Cardiovasc Med. 2003;4 Suppl 4:S3-12

15 BNP Cut Off-Points According to Body Mass Index Daniels et al. Am Heart J 2006;151:

16 Biomarkers in HF Neurohormonal biomarkers Biomarkers of myocardial injury Biomarkers of inflammation & oxidative stress Other (fibrosis, cardiorenal, genetic etc)

17 Troponins 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. The presence of plasma troponin in HF patients is considered a condition associated with poor prognosis Kawahara C et al. Am Heart J 2011;162(4): O'Connor CM et al. Circ Heart Fail Dickstein K, Cohen-Solal A, Filippatos G et al. Eur Heart J 2008;29(19):

20 hs-tnt and prognosis hs-tnt levels >20% in day 2 X 2 mortality 180 days

21 Biomarkers in HF Neurohormonal biomarkers Biomarkers of myocardial injury Biomarkers of inflammation & oxidative stress Other (fibrosis, cardiorenal, genetic etc)

22 Levels of TNF-α are related with echocardiographic indexes of both systolic and diastolic left ventricular function. Other cytokines implicated in the pathogenesis of CHF are IL-1 and IL-6.

23 ΝΟ primary end-point primary end-point

26 Biomarkers in HF Neurohormonal biomarkers Biomarkers of myocardial injury Biomarkers of inflammation & oxidative stress Other (fibrosis, cardiorenal, genetic etc)

27 ST2 NGAL Cystatin C micrornas Galectin -3 Siasos G, Tousoulis D, Oikonomou E, Kokkou E, Mazaris S, Konsola T

28 Januzzi JL, et al. J Am Coll Cardiol 2007;50(7): Mueller T, et al. Clin Chem 2008;54(4):752-6 ST2 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 oneyear all-cause mortality in HF.

29 Mortality rates at one year as a function of ST 2 and NT-proBNP concentrations Januzzi J et al: J Am Coll Cardiol 2007;50

30 Biomarkers in HF and Kidney disease lneutrophil gelatinase-associated lipocalin (NGAL) lcystatin C lkidney injury molecule 1 (KIM-1)

31 NGAL in HF Yndestad A et al. European Heart Journal (2009)

32 Changes in Galectin-3 > 15% predict mortality and hospitalization

33 Biomarkers in HF GUIDELINES

34 Measurement of natriuretic peptide (BNP, NT-proBNP, or MR-proANP) should be considered to: 1) Exclude alternative causes of dyspnoea (if the level is below the exclusion cut-point HF is very unlikely) 2) Obtain prognostic information (CLASS IIa, Level of Evidence: A)

35 In the acute setting: MR-proANP may also be used cut-off point 120 pmol/l <120 pmol/l = heart failure unlikely

38 CONCLUSION A variety of biomarkers reflects different pathophysiologic states of HF syndrome and different stages in the progression of the disease Only NP and cardiac troponins are widely used in every day clinical practice as the majority of the rest biomarkers are not easily available, are expensive, or their clinical value is low. Combination of several biomarkers is needed to strengthen the clinical value of established biomarkers in HF patients. If improvement of prognosis is a therapy target, NP therapy guidance could be useful Tousoulis D, Oikonomou E, Siasos G Stefanadis C. Curr Med Chem.

39 BIOMARKERS IN ATHEROSCLEROSIS

40 BIOMARKERS Adhesion molecules Proinflammatory cytokines IL family MCP-1 ADMA BH4

41 Tousoulis D..Stefanadis C. JACC (2014) in

44 ICAM (ng/ml) IL1b (pg/ml) Inflammatory Parameters p<0.05 p< FH Controls FH Controls Charakida M, Tousoulis D, Stefanadis C. Atherosclerosis 2009

53 CRP 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):

56 mmendations for Measurement of C-Reactive Protein (continued) I IIaIIb III I IIaIIb III I IIaIIb III In asymptomatic intermediate-risk men 50 years of age or younger or women 60 years of age or younger, measurement of CRP may be reasonable for cardiovascular risk assessment. In asymptomatic high-risk adults, measurement of CRP is not recommended for cardiovascular risk assessment. In low-risk men younger than 50 years of age or women 60 years of age or younger, measurement of CRP is not recommended for cardiovascular risk assessment.

57 Conclusion To day none biomarker predicts the evolution of premature atherosclerosis

58 BIOMARKERS IN ACUTE CORONARY SYNDROMES

59 Biomarkers of valnurable plaque Necrosis Myocardial Stress Inflammation Thrombotic markers

61 % Prognostic Value of Troponin T or I in ACS: A Meta-Analysis Neg Pos (Trop I + T) RR 3.8 ( ) RR 3.9 ( ) Death Death/MI Heidenreich PA, Alloggiamento T, Melsop K, et al. The prognostic value of troponin in patients with non-st elevation acute coronary syndrome: a meta-analysis. J Am Coll Cardiol. 2001;38:

66 Reichlin et al, JACC 2009

67 Biomarkers of vulnerable plaque Necrosis Myocardial Stress Inflammation Thrombotic markers

68 Mortality (%) B-type Natriuretic Peptide (BNP) and Mortality in ACS Patients 10 8 P<.001 Quartile 4 (n=630) Days After Randomization Quartile 3 (n=632) Quartile 2 (n=632) Quartile 1 (n=631) Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndrome. N Engl J Med. 2001;345:

71 Biomarkers of vulnerable plaque Necrosis Myocardial Stress Inflammation Thrombotic markers

72 Interleukins Increased level of IL-6 in unstable patients is correlated with prognosis Biasucci L, et al, Circulation 1996; 94:

73 Giovanna Liuzzo, et al. J Am Coll Cardiol 1999;34:

74 Cytokines in Acute coronary syndromes Tousoulis D, et al, J Am Coll Cardiol 2004; IJCA 2007

78 Biomarkers of vulnerable plaque Necrosis Myocardial Stress Inflammation Thrombotic markers

80 There were no significant differences ATIII, PrtC, fvii and PrtS levels between patients with unstable angina or acute myocardial infarction. However, patients with acute myocardial infarction had significantly higher levels of vwf and tpa Tousoulis et al. Int J Cardiol. 2007;115(2):203-7.

81 THE ROLE OF GENETICS AND MOLECULAR BIOLOGY

82 C286T polymorphism on CRP promoter gene and CRP levels in CAD and AMI Acute myocardial infarction Stable coronary artery disease Kovacs et al Atherosclerosis 178 (2005)

84 Carriers of the 894Τ allele, appear with higher endothelial activation/ destruction than the carriers of 894GG during AMI. Tousoulis D, Antoniades C,..Stefanadis C, JACC 2005

85 Here comes your

86 Conclusions Hs c-tn measured at presentation and after 3h form the new standard of care The multiple approach analysis of biomarkers is promising with the additional use of copeptin The mrna conduct the process of instability The genetic approach is promising

ΒΙΟΔΕΙΚΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ. ΔΗΜΗΤΡΙΟΣ ΤΟΥΣΟΥΛΗΣ Καθηγητής Καρδιολογίας

ΕΘΝΙΚΟ ΚΑΙ ΚΑΠΟΔΙΣΤΡΙΑΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΙΑΤΡΙΚΗ ΣΧΟΛΗ Ά ΚΑΡΔΙΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ Διευθυντής: Καθηγητής Δημήτριος Τούσουλης ΒΙΟΔΕΙΚΤΕΣ ΣΤΗΝ ΚΑΡΔΙΑΚΗ ΑΝΕΠΑΡΚΕΙΑ ΔΗΜΗΤΡΙΟΣ ΤΟΥΣΟΥΛΗΣ Καθηγητής Καρδιολογίας