Update on Biomarkers in Heart Failure. Professor T A McDonagh, King s College Hospital. London

Transcription

1 Update on Biomarkers in Heart Failure Professor T A McDonagh, King s College Hospital. London

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3 Known Knowns,,,, for Biomarkers in HF Natriuretic Peptides Troponins

4 BNP...

5 ANP/BNP/ in CHF First to be discovered De BOLD (1980s) Not developed as BNP CHF Inferior accuracy Lower stability MR-ANP similar diagnostic accuracy to BNP : retrospective sample of 251 subjects with acute dyspnoea Gegenhuber et al Clin Chem 2006 MR-ANP-predictor of mortality in CHF, adds prognostic information to NT-proBNP (large study) McDonagh et al Lancet 1998 Von Haeling et al JACC 2007

6 Sensitivity BACH Study-1641 Acutely Breathless Patients Sensitivity A MR-proANP (pmol / L) MR-proANP (pmol / L) A B Measurement AUC 95% CI p BNP Measurement AUC % CI p< MR-proANP BNP < < MR-proANP < NT-proBNP < NT-proBNP < r = Specificity Maisel A et al JACC 2010;55:2062 BNP (pg BNP / m 1600 patients B

7 Multiple Biomarkers for LV Dysfunction in AHF 251 consecutive ER-dyspnoea BNP, MR-proANP, MRproADM, copeptin, CT-roET-1, ST2, adiponectin, chromogranin A, proguanylin and prouroguanylin. BNP and MRproANP were the only independent diagnostic markers of HF. Mueller et al Heart 2009;95: with HF

8 ESC Heart Failure Guidelines Diagnostic Flow Chart

9 NT-Pro-BNP and Prognosis in an Advanced Heart Failure Population Only independent predictor of ACM was an NT-proBNP value above the median (RR=4.6, p=0.01). Gardner et al EHJ October 2003

10 How to use the information clinically to treat patients? General Monitoring A single baseline value Value which fails to fall/rises Specific Monitoring Can we use BNP concentrations to titrate therapy?

11 BNP and Readmission for HF Admissions for DHF- 105 derivation cohort 97 validation cohort Serial and predischarge BNPs measured Pre-discharge BNP best predictor of readmission (AUC=0.85), only significant variable in multiple regression model, (HR=15.2 [8.5-27], p=0.0001) Patients greatest in BNP -better outcome cf those with a more modest reduction (HR=0.18 [ ], p=0.001) Logeart et al JACC 2004;43:635

12 BNP and Monitoring for Heart Failure? General Monitoring A single baseline value Value which fails to fall/rises Specific Monitoring Can we use BNP concentrations to titrate therapy?

13 Bio-marker guided therapy in CHF: A meta-analysis of randomized controlled trials Felker GM et al. Am Heart J 2009;158: studies randomizing 1627 patients met criteria for inclusion. Pooled analysis showed a significant mortality advantage for biomarker guided therapy (hazard ratio 0.69, 95% CI ) compared to control.

14 Areas of Uncertainty in ESC 2012 Guideline Remote monitoring Using implanted device No implanted device Serial monitoring of natriuretic peptides Note: Anti-coagulation in CHF patients with low LVEF and SR cannot be recommended. (WARCEF)

15 Troponins and Acute Heart Failure Kociol R et al JACC 2010;56:1071

16 Mechanisms of Troponin Release in AHF

17 Troponins and Prognosis in AHF ADHERE Registry: US registry for acute hospitalizations, ctn at admission Peacock WF et al NEJM 2008;358:2117

18 Troponins in AHF-worth measuring in AHF to detect ACS Kociol R et al JACC 2010;56:1071

19 Biomarkers in Heart Failure Diagnosis, difficult to beat BNP Added value Prognosis (Troponin also useful) Unmet need Therapy Monitoring Reflecting pathophysiology and disease progression Therapeutic tools

20 Novel Biomarkers MMPs TIMPs CRP Cystatin C Tenascin C Galectin 3 Ghrelin Osteopontin PCIP ICTP ST2 Adiponectin Copeptin Apelin Troponin IL6 TNF Endothelin Resistin Relaxin RAGE Leptin MCP 1 GDF-15 Myeloperoxidase Urocortin

21 Mid Regional Pro-Adrenomedullin 786 consecutive CHF out patients: MR-proADM (HR = 2.12, P < 0.001) and LVEF (HR = 0.96, P = 0.006) were significant markers of death at 24 months Aldbrecht C et al :EJHF(2009) 11,

22 ST2 ST2-IL 1 receptor family member Transmembrane (ST2L) and soluble (sst2) forms ST2 gene (chromosome 2) upregulated in experimental model of HF ST2 binds IL33, released by cardiomyocyte stretch Interruption of ST2 gene-myocardial fibrosis and hypertrophy Increased post MI

23 ST2 and Survival at 1 year AUC=0.78, inferior to NT-pro-BNP Januzzi et al JACC 2007;50:607

24 ST2 and Severity of AHF 346 patients with AHF, follow up 1 year and data on CRP and NT-proBNP Rehman et al JACC 2008;52:

25 ST2 and Mortality

26 Additive value to B-type peptides Multivariable Cox model containing established clinical and biochemical predictors (including natriuretic peptides), ST2 remained a predictor of mortality (HR: 2.04, 95% CI: 1.30 to 3.24, p 0.003), Equally predictive in patients with HF and preserved or impaired systolic function

27 Galectin-3 Association macrophage activation and myocardial fibrosis to the pathogenesis of HF. Galectin-3 likely mediator Galectin-3 - β-galactoside-binding animal lectin family. 106 HF, mean LVEF was 35±9%. Log galectin-3 - correlated with log PIIINP (p=0.006), log TIMP-1 (p=0.025), log MMP-2 (p=0.016), and NYHA Class (p=0.034 not age, sex or LVEF Adjusting for age, sex, smoking status and LVEF, the relationship between galectin-3 and ECM turnover biomarkers (including PIIINP, TIMP, and MMP-2) remained significant Yin YH et al Clinica Chimica Acta 409 (2009) 96 99

28 Galectin-COACH Substudy 592 HF patients ADHF, followed for 18 months. (107 HFPEF) Primary end-point - all-cause mortality and HF hospitalization Galectin-3 is an independent marker for outcome in HF and appears to be particularly useful HFPEF De Boer et al Annals of Medicine, 2011; 43: 60 68

29 sace2 ACE2- integral membrane protein-antagonizes AII prevents the development of HF in animal models Mice deficient in ACE2 -increased Ang II levels and a severe cardiac contractility defect that is reversed by the genetic deletion of ACE Intracardiac overexpression of ACE2 prevents Ang II induced HT and cardiac fibrosis, direct in vivo cardioprotective role for ACE2 Traditionally thought to be tissue bound-need for invasive cardiac tissue sampling, little is known about whether ACE2 is involved in the pathophysiology of HF in humans.

30 Plasma Assay Developed a sensitive and specific assay to measure sace2 activity in human plasma Screened a heterogeneous group of patients suspected of having clinical HF (228) 70% (159) had validated heart failure Epelman S et al J Cardiac Fail 2009;15:565e571

31 sace2 and Functional Class and Clinical Correlates

32 ACE 2 Associations independent of other disease states and medication use. sace2 activity was increased in patients with both IHD and DCM also in patients with HFPEF Suggests that a cardioprotective RAAS is active in HF

33 ACE2 113 patients with CHF ( [LVEF] 35%, NYHA II-IV). Death, CTX, and HF hospitalizations over 34 ± 17 months. After adjusting for NT-proBNP and LVEF, sace2 activity remained an independent predictor of adverse clinical events (HR = 1.7 [95% CI: ], P =.018) Interest as biomarker, pathophysiological role and potential therapy/therapeutic target. Epelman S et al J Cardiac Fail 2009;15:565e571

34 Apelin in HF Ligand for the APJ receptor, Potent inodilator, M RNA upregulated following sucessful LVAD therapy May be involved in maintaining normal LV function Chong V et al Eur J Heart Fail (2006) 8 (4):

35 Transcardiac Gradients and Apelin Chandrasekeran B et al J Cardiac Failure 2010.

36 Plasma apelin (pg/ml) CRT, Reverse Remodelling and Plasma Apelin p<0.002 P=0.87 N=8 N=13 Chandrasekeran et al In press EJHF

37 Renal Biomarkers-NGAL Number of possibilities, Cystatin C, Urocortin NGAL-Neutrophil gelatinase-associated lipocalin, a marker of acute kidney injury GALLANT Study 186 patients with decompensated HF 29 events (HF readmissions + all-cause death) at 30 days (16%) Plasma NGAL at the time of discharge is a strong prognostic indicator of 30 days outcomes (additional information to BNP) Maisel A et al EJHF (2011) 13,

38 Expression profiles of 16 candidate mirnas in plasma of HF patients and control subjects Tijsen, A. J. et al. Circ Res 2010;106:

39 Diagnostic accuracy of mirnas Tijsen, A. J. et al. Circ Res 2010;106:

40 Novel Biomarkers Natriuretic Peptides Gold standards Others Moving beyond NPV for diagnosis Prognosis Disease monitoring Pathophysiological mechanism and targets Beyond plasma, serum into the proteome Challenge will be to integrate the information!