Βιοδείκτες στην καρδιακή ανεπάρκεια διαγνωστικά και θεραπευτικά δεδομένα. Χριστίνα Χρυσοχόου Επιμ Α Α Παν. Καρδιολογικής Κλινικής, ΙΓΝΑ

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1 Βιοδείκτες στην καρδιακή ανεπάρκεια διαγνωστικά και θεραπευτικά δεδομένα Χριστίνα Χρυσοχόου Επιμ Α Α Παν. Καρδιολογικής Κλινικής, ΙΓΝΑ

2 Παθοφυσιολογία καρδιακής ανεπάρκειας

3 Kaye and Krum Nature Reviews Drug Discovery 6, (2007)

4 Biomarker Definition: Biomarker is a substance used as an indicator of a biologic state Proteins Nucleic acids Carbohydrate Lipids Small molecules

5 Criteria a biomarker should fulfill to be useful clinically reasonable cost must provide information that is not already available from a careful clinical assessment knowing the measured level should aid in medical decision making

Non-Specific Blood Biomarkers in Heart Failure BUN, creatinine, microalbuminuria Bilirubin, INR, albumin, AST/ALT Fasting cholesterol panel Sodium,

7 Non-Specific Blood Biomarkers in Heart Failure BUN, creatinine, microalbuminuria Bilirubin, INR, albumin, AST/ALT Fasting cholesterol panel Sodium, potassium Hemoglobin Iron deficiency panel Thyroid panel Uric acid Leukocyte count C-reactive protein Tang W, Biomarkers Med 2009; Braunwald, HF Clin NA 2009

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.

11 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. 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): Mueller C, et al. N Engl J Med 2004;350(7):

12 Μετρήσεις NPs στην τρίτη ηλικία J. Hogenhuis et al. Eur Jl of Heart Fail 9 (2007)

13 Cofounders of Plasma BNP Levels Increase BNP Increasing age Female gender Renal insufficiency Thyroid disorders Atrial fibrillation Cardiac surgery Anemia Decrease BNP Stunning Obesity Diuretics RAAS drugs Pulmonary hypertension Pulmonary embolism Mitral regurgitation Right ventricular failure Genetic predisposition Beta-blocker therapy (transient) Anti-androgen therapy Troughton et al, J Am Coll Cardiol 2004

14 Prognostic value of BNP in CHF Val-HeFT

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

21 1. Natriuretic peptide levels increase with age 2. Natriuretic peptide levels are reduced in obese patients 3. Treatment may reduce natriuretic peptide concentration 4. Natriuretic peptide concentrations may not be markedly elevated in patients with HF-PEF

22 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. sst2 Januzzi JL, et al. J Am Coll Cardiol 2007;50(7): Mueller T, et al. Clin Chem 2008;54(4):752-6

24 Mechanism of Cardiac Troponin Release in Heart Failure Kociol, et al. J Am Coll Cardiol 2010;56:1071 8

26 In-Hospital Mortality According to Troponin I Quartile Peacock WF, De Marco T, Fonarow GC, et al. N Engl J Med 2008

Inflammatory mediators have pathogenetic role and contribute to the progression and clinical presentation of HF giving rise to the cytokine hypothesis according to which

28 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 Inflammatory biomarkers Braunwald E. N Engl J Med 2008;358:

29 CRP, interleukin-6 & TNF-α 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. Direct adverse effects on the vascular endothelium by reducing nitric-oxide release and increasing endothelin-1 production IL6 & TNF-a identify asymptomatic older subjects in the community who were at high risk of the future development of heart failure Vasan RS, et al Circulation 2003;107(11):

33 Myeloperoxidase MPO is elevated in HF patients, while levels of MPO are positively correlated with NYHA stage. In patients with HF intermediate NTpro-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): Tang WH, et al. J Am Coll Cardiol 2007;49(24): Tang WH, et al Congest Heart Fail 2011;17(3):105-9.

34 Serum Uric Acid Levels Correlates With Left Atrial Function and Systolic Right Ventricular Function in Patients With Newly diagnosed Heart Failure: The Hellenic Heart Failure Study Chrysohoou C, Congest Heart Fail ;14(5):

36 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

37 Galectin-3 Galectin-3 appeared a useful method for improving risk stratification of patients with chronic HF in a substudy of the COACH trial Adjusted* hazard ratio (HR) for death or heart-failure hospitalization at 18 months by baseline galectin-3 level quartiles vs quartile 1 ( ng/ml) Galectin-3 quartile (ranges, ng/ml) HR (95% CI) p Quartile 2 ( ) 1.67 ( ) Quartile 3 ( ) 2.08 ( ) Quartile 4 ( ) 2.67 ( ) < *Adjusted for age, sex, and b-type natriuretic peptide levels Arch Intern Med 2008; 168:

38 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.

GDF-15 Member of the TGF-β cytokine family Expressed in most tissues Expression in myocytes is triggered by ischemia, stretch, inflammation, and neurohormonal activation May protect myocytes against

39 GDF-15 Member of the TGF-β cytokine family Expressed in most tissues Expression in myocytes is triggered by ischemia, stretch, inflammation, and neurohormonal activation May protect myocytes against apoptosis and hypertrophy Predictive of mortality in patients with chronic HF independent of established biomarkers Serial changes are associated with prognosis Could lead to the development of unique treatments for patients with chronic HF

40 The Association Between Elevated Fibrosis Markers and Heart Failure in the Elderly: The Cardiovascular Health Study Serum fibrosis markers were measured in 880 participants of the Cardiovascular Health Study (mean age 77 ± 6 yrs, 48% female). Fibrosis markers [carboxylterminal peptide of procollagen type I (PIP), carboxyl-terminal telopeptide of collagen type I (CITP), and amino-terminal peptide of procollagen type III (PIIINP)] are significantly elevated in elderly individuals with diastolic or systolic HF. The Median Values and Interquartile Range of CITP. Significant differences have been found between: a) healthy control group (without CVD factors) and diastolic HF, systolic HF and control group (p<0.0001, p<0.0001, and p=0.0006, respectively); b) control group (with CVD factors) and diastolic HF and systolic HF (p< for both). Circ Heart Fail July ; 2(4):

41 Renal Dysfunction in Heart Failure Triposkiadis F Med Clin N Am 96 (2012)

42 Epidemiology of renal dysfunction in heart failure ADHERE

43 Worsening Renal Function and Prognosis in HF Journal of Cardiac Failure Vol. 13 No

Biomarkers for kidney dysfunction Kidney injury molecule 1 is a protein detectable in the urine after ischemic or nephrotoxic insults to proximal tubular cells and seems to be highly specific for

44 Biomarkers for kidney dysfunction Kidney injury molecule 1 is a protein detectable in the urine after ischemic or nephrotoxic insults to proximal tubular cells and seems to be highly specific for ischemic AKI. Combined with NGAL which is highly sensitive, it may represent an important marker Cystatin C appears to be a better predictor of glomerular function than serum creatinine because its blood levels are not affected by age, gender, race, or muscle mass Neutrophil gelatinase-associated lipocalin (NGAL) appears to be one of the earliest markers JACC Vol. 52, No. 19, 2008

46 Strength of evidence for individual biomarkers Maisel, A. S. & Choudhary, R. (2012) Nat. Rev. Cardiol. doi: /nrcardio

Measurement of BNP and NT-proBNP can be useful in the evaluation of patients presenting in the urgent care setting in whom the clinical diagnosis of HF is uncertain (CLASS I, Level of Evidence: A)

50 Measurement of BNP and NT-proBNP can be useful in the evaluation of patients presenting in the urgent care setting in whom the clinical diagnosis of HF is uncertain (CLASS I, Level of Evidence: A) Measurement of BNP and NT-proBNP can be helpful in risk stratification (CLASS IIa, Level of Evidence: A) The value of serial measurements of BNP to guide therapy for patients with HF is not well established.(class IIb, Level of Evidence: C)

52 Cost-effectiveness of N-terminal pro-b-type natriuretic-guided therapy in elderly heart failure patients: results from TIME- CHF 467 patients (age 76 ± 7 years, 66% male) with left ventricular ejection fraction of 45% were randomized to receive intensified NTproBNP-guided therapy or standard, symptom-guided therapy. NT-proBNP-guided therapy was dominant (i.e., more effective and less costly) over symptom-guided therapy, saving $2,979 USD per patient, with incremental effectiveness of life-years and QALYs. Cost-effectiveness of NT-proBNP-guided therapy was most pronounced in patients <75 years old and in those with <2 significant comorbidities, being dominant in all sensitivity analyses. In the worst-case scenario (excluding residence costs in those with 2 comorbidities), the incremental cost-effectiveness ratio was $11,935 per life-year gained. JACC Heart Fail Feb;1(

53 Cost-effectiveness of N- terminal pro-b-type natriuretic-guided therapy in elderly heart failure patients: results from TIME-CHF

54 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

55 Planned future biomarker studies Maisel, A. S. & Choudhary, R. (2012) Nat. Rev. Cardiol. doi: /nrcardio

57 Multiple Biomarkers for Risk Prediction in Chronic Heart Failure 1513 chronic systolic heart failure patients, contemporary biomarker panel consisting of high-sensitivity C-reactive protein, myeloperoxidase, B-type natriuretic peptide, soluble fms-like tyrosine kinase receptor-1, troponin I, soluble toll-like receptor-2, creatinine, and uric acid. Cox models, patients in the highest tertile of the multimarker score had a 13.7-fold increased risk of adverse outcomes compared with the lowest tertile (95% confidence interval, ). Addition of the multimarker score to the Seattle Heart Failure Model led to a significantly improved area under the receiver operating characteristic curve of versus (P=0.003) Circulation: Heart Failure. 2012; 5:

58 Tailored therapy for heart failure: an ongoing evolution

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