Biomarkers in Heart Failure

Transcription

1 Biomarkers in Heart Failure James L. Januzzi, Jr, MD Associate Professor of Medicine Harvard Medical School Director, Cardiac ICU Massachusetts General Hospital

2 Disclosures Research grants for clinical trials Roche Diagnostics Siemens Critical Diagnostics Consulting regarding biomarkers Roche Diagnostics Critical Diagnostics

3 Biomarkers in Heart Failure Kim and Januzzi, Curr Treat Options in Cardiovasc Med, 2011

4 Biology of the NP System Synthesis and Release pre-probnp probnp Signal peptide (26 amino acids) probnp NT-proBNP 1-76 BNP 1-32

5 Just what are we measuring? Blood from 12 heart failure patients analyzed using Biosite Triage (white bars) and quantitative mass spectroscopy (black bars) for BNP Niederkofler, et al, Circulation 2008

6 Biology of the NP System Synthesis and Release pre-probnp probnp Signal peptide (26 amino acids) probnp NT-proBNP 1-76 BNP 1-32 BNP DPP-IV Meprin A BNP 7-32 DPP-IV = dipeptidyl peptidase IV

7 What are we measuring? Blood from patients with heart failure (HF) analyzed using mass spectroscopy for immuno-reactive BNP Niederkofler, et al, Circulation 2008

8 Biology of the NP System Synthesis and Release pre-probnp probnp Signal peptide (26 amino acids) probnp NT-proBNP 1-76 BNP 1-32 probnp BNP DPP-IV Meprin A BNP 7-32 DPP-IV = dipeptidyl peptidase IV

9 What Are We Measuring? Triangle BNP Assay Value [pmol/ml] BNP probnp BNP Elecsys probnp Assay Value [pmol/ml] NT-proBNP BNP probnp BNP or probnp [pmol/ml] BNP or probnp [pmol/ml] Liang et al, J Am Coll Cardiol, 2007;49:1071

10 Biologic Importance of probnp HAEC 30 HCAEC cgmp (promol/10 6 cell) BNP probnp cgmp (promol/10 6 cell) BNP probnp Log[BNP or probnp] (nm) Log[BNP or probnp] (nm) 50 HUVEC 18 HASMC cgmp (promol/10 6 cell) BNP probnp cgmp (promol/10 6 cell) BNP probnp Log[BNP or probnp] (nm) Log[BNP or probnp] (nm) Liang et al, J Am Coll Cardiol, 2007;49:1071

11 Natriuretic Peptide Clearance BNP NPR Neutral endopeptidases Renal excretion NT-proBNP Less well understood Renal excretion partially responsible

12 Equal Renal Clearance of BNP and NT-proBNP In simultaneously sampled renal artery and vein: No difference between clearance of BNP and NT-proBNP BNP NT-proBNP van Kimmenade et al, JACC, 2009

13 Summary of NP Biology Characteristic BNP NT-proBNP Biological activity + - Stability Fragments probnp 108 detection Half life 20 Clearance No Yes Yes Yes No Yes min min Multiple Multiple Renal clearance + + Blood concentrations 5 to >10,000 5 to >70,000 Diagnostic value + + Prognostic value + +/++

14 Correlation of Natriuretic Peptides with Cardiac Structure and Function

15 Correlations of Natriuretic Peptides with Cardiac Structure and Function Left ventricle Size Systolic function Diastolic function Right ventricle Size Systolic function Atrial size and pressure Valve disease Aortic Mitral Tricuspid Heart rhythm Ischemic heart disease Pericardial disease

16 Correlations of Natriuretic Peptides with Cardiac Structure and Function Left ventricle Size Systolic function Diastolic function Right ventricle Size Systolic function Atrial size and pressure Valve disease Aortic Mitral Tricuspid Heart rhythm Ischemic heart disease Pericardial disease

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18 Results: Predictors of HF Predictor Odds Ratio 95% Confidence Intervals P value Elevated NT-proBNP < Interstitial edema on chest X-rayX < Orthopnea < Loop diuretic use at presentation Rales on pulmonary examination Age (per year) Cough Fever Januzzi et al, AJC 2005

19 Results: NT-proBNP Levels NT-proBNP (pg/ml) P< No prior CHF (N=355) Prior HF (N=35) Acute HF (N=209) Januzzi et al, AJC 2005 Not acute HF (N=390)

20 The Differential Diagnosis of an Elevated Natriuretic Peptide Unrecognized HF Prior HF LVH Valvular heart disease Atrial fibrillation Advancing age Myocarditis ACS Pulmonary hypertension Congenital heart disease Anemia Pulmonary embolism Cardiac surgery Sleep apnea Critical illness Sepsis Burns Renal failure Toxic-metabolic insults

21 The Differential Diagnosis of an Unexpectedly Low Natriuretic Peptide Obesity Non-systolic heart failure Mild acute heart failure Isolated right heart failure Partially treated heart failure

22 Results: Primary Endpoint Sensitivity (True Positives) NT-proBNP versus Clinical Judgment, p=0.006 Combined versus NT-proBNP, p=0.04 Combined versus Clinical Judgment, p<0.001 Combined, AUC=0.96 NT-proBNP, AUC=0.94 Clinical Judgment, AUC= Specificity (False Positives)

23 Effect of Selective NT-proBNP Testing On Costs/Outcomes: Results of the Randomized IMPROVE-CHF Trial Effect of Selective NT-proBNP Testing on Utilization/Costs Effect of Selective NT-proBNP Testing on Outcomes Moe, Howlatt, Januzzi, Zowall on behalf of the IMPROVE-CHF Investigators, 2007, Circulation

24 Where does NT-proBNP help most? Data from the Canadian IMPROVE-CHF Study Although NT-proBNP added incremental information at both ends of the spectrum of heart failure likelihood Clinician impression Low prob (n=343) (Accuracy =89%) Int prob (n=139) High prob (n=91) (Accuracy =95%) Model impression Not HF HF % Appropriately Reclassified LP (n=282) (2.1)* IP (n=58) HP (n=3) LP (n=38) IP (n=77) HP (n=24) LP (n=0) IP (n=18) HP (n=73) 1 72 (1.4)* Steinhart, et al, JACC, 2009.

25 Where does NT-proBNP help most? Data from the Canadian IMPROVE-CHF Study Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses suggested the biggest bang was in the indecision zone Clinician impression Low prob (n=343) (Accuracy =89%) Int prob (n=139) High prob (n=91) (Accuracy =95%) Model impression Not HF HF % Appropriately Reclassified LP (n=282) (2.1)* IP (n=58) HP (n=3) LP (n=38) IP (n=77) HP (n=24) LP (n=0) IP (n=18) HP (n=73) 1 72 (1.4)* Steinhart, et al, JACC, 2009.

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27 AHA Stages Disease severity Stage A Stage B Stage C Stage D At risk for heart failure Asymptomatic LV dysfunction Symptomatic heart failure End-stage heart failure Diabetes Coronary disease Hypertension Prior MI Hypertension Disease prevalence

28 NP s s and Prognosis Independent predictors of mortality and heart failure events across the HF spectrum Stage A Stage B Stage C Stage D Populations GUSTO IV Val-HEFT COPERNICUS PEACE FRISC-II II ICON Cohort studies HOPE Cohort studies PRIDE

29 NT-proBNP and Long Term Risk in Heart Failure NT-proBNP 300 ng/l NT-proBNP <300 ng/l Cumulative hazard P < Januzzi, et al., Clin Chem Days from enrollment 1460

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31 Why might natriuretic peptide testing assist with INPATIENT heart failure management? Earlier diagnosis Better triage As a target of therapy?

32 Why might natriuretic peptide testing assist with INPATIENT heart failure management? Earlier diagnosis Better triage As a target of therapy?

33 Therapies with Effects on B-Type Natriuretic Peptide Levels Therapy Diuresis ACE-I ARB β-blockers Aldosterone antagonists BiV pacing Exercise Rate control of AF BNP infusions Effect on BNP/NT-proBNP Some transiently,, most N-BNP, BNP then

34 The Importance of Serial NP Measurements for Prognostication in Chronic HF Masson, et al, J Am Coll Cardiol 2008

35 Therapies with Effects on B-Type Natriuretic Peptide Levels Therapy Diuresis ACE-I ARB β-blockers Aldosterone antagonists BiV pacing Exercise Rate control of AF BNP infusions Effect on BNP/NT-proBNP Some transiently,, most N-BNP, BNP then

36 Guided Therapy Results Positive Negative Troughton et al STARS-BNP Berger, et al, 2010 PROTECT STARBRITE PRIMA BATTLESCARRED TIME-CHF

37 Guided Therapy Score Card Positive Negative Troughton et al STARS-BNP Berger, et al, 2010 PROTECT STARBRITE PRIMA BATTLESCARRED* TIME-CHF* *Positive for those patients aged <75 years

38 Other STARS BNP guided HF therapy: STARS BNP Diuretics ACEI BB Spiro Treatment modifications (n) Clinical group BNP group P <.01 Jourdain, et al, JACC, 2007 BNP Control T (days) Event free survival %

39 NT-proBNP and HF Outcomes TIME-CHF Endpoint 499 subjects with systolic HF, recent event, randomized to NT-proBNP versus Standard HF management 18 month follow up: Overall <75 years 75 years Hosp-free survival 0.92 ( ) 0.76 ( ) 1.06 ( ) Survival 0.68 ( ) 0.38 ( ) 0.80) ( ) HF hosp-free survival 0.66 ( ) 0.90) ( ) 0.72) ( ) 1 P =.008; 2 P =.01; 3 P =.002

40 NT-proBNP and HF Outcomes TIME-CHF Endpoint 499 subjects with systolic HF, recent event, randomized to NT-proBNP versus Standard HF management 18 month follow up: Overall <75 years 75 years Hosp-free survival 0.92 ( ) 0.76 ( ) 1.06 ( ) Survival 0.68 ( ) 0.38 ( ) 0.80) ( ) HF hosp-free survival 0.66 ( ) 0.90) ( ) 0.72) ( ) 1 P =.008; 2 P =.01; 3 P =.002

41 NT-proBNP and HF Outcomes Berger et al JACC 2010

42 Primary Endpoint events P =.009 SOC NT-proBNP Number of events events *Logistic Odds NT-proBNP NT-proBNP = 0.44 (95% CI= ;.84; P =.019) 0 Total CV Events *Adjusted for age, LVEF, NYHA Class, and egfr

43 Kaplan-Meier Analysis Event free survival NT-proBNP (N=75) Standard-of of-care (N=76) Log rank P = Days from enrollment

44 Age and outcomes Mean number of events SOC NT-proBNP P =.008 P =.005 Age < 75 years Age 75 years *No interaction between age and NT-proBNP guided care was found (P =.11)

45 Outcomes as a function of response to guided therapy 3000 Group Mean CV events NT-proBNP (pg/ml) Baseline Follow-up High/High 1.45 Low/High 0.57 High/Low 0.46 Low/Low 0.45

46 Meta-analysis analysis of guided therapy Felker et al, Am Heart Journal, 2009

47 Choices for physiologic Natriuretic peptides multimarker panels In order to be useful there must be a therapeutic imperative associated any marker we use Co-morbidity markers Remodeling markers ST2 Galectin 3 Injury markers Troponin Inflammatory markers Hemoglobin RDW Renal markers ET-1 Adipokines NT-proADM Genetic markers Pharmacogenomics Take your pick

48 Remodeling in ACS and HF

49 Selected biomarkers associated with ventricular remodeling Natriuretic peptides Fibrosis markers: osteopontin, sst2, galectin-3,?gdf-15 Troponins Matrix metalloproteinases Collagen turn-over markers: Type I collagen telopeptide Tenascin C Inflammatory markers: tumor necrosis factor receptors, CRP, cardiotrophin iotrophin-1 Neurohormonal markers: aldosterone, aldosterone/renin ratio, angiotensin II Others: tissue plasminogen activator

50 Selected biomarkers associated with ventricular remodeling Natriuretic peptides Fibrosis markers: osteopontin, sst2, galectin-3,?gdf-15 Troponins Matrix metalloproteinases Collagen turn-over markers: Type I collagen telopeptide Tenascin C Inflammatory markers: tumor necrosis factor receptors, CRP, cardiotrophin iotrophin-1 Neurohormonal markers: aldosterone, aldosterone/renin ratio, angiotensin II Others: tissue plasminogen activator

51 Troponins and HF Study Peacock, et al, Peacock, et al, Troponin assay Both Troponin T Perna, et al, Troponin T Bertinchant, et al, Troponin T You, et al, Troponin I Sakhuja, et al, Troponin T Healey, et al, Both Goto, et al, Troponin T Ishii, et al, Troponin T Lowbeer, et al, Troponin T Gheorgiade, et al, Both Ishii, et al, Both Upper reference limit % elevated Multiple 6.2% 0.10 ng/ml 11% 0.20 ng/ml 15% 0.03 ng/ml 17%* 0.50 ng/ml 35% 0.01 ng/ml 46% 0.02 ng/ml (T), 0.3 ng/ml (I) 51% (T), 46% (I)* 0.01 ng/ml 56% 0.01 ng/ml 60% 0.01 ng/ml 62% 0.01 ng/ml (T), 0.03 ng/ml 44% (T),74% (I) 0.01 ng/ml (T), 0.03 ng/ml (I) 80% (T), 71% (I) Januzzi, et al, Submitted

52 Troponins and HF Study Peacock, et al, Peacock, et al, Troponin assay Both Troponin T Perna, et al, Troponin T Bertinchant, et al, Troponin T You, et al, Troponin I Sakhuja, et al, Troponin T Healey, et al, Both Goto, et al, Troponin T Ishii, et al, Troponin T Lowbeer, et al, Troponin T Gheorgiade, et al, Both Ishii, et al, Both Upper reference limit % elevated Multiple 6.2% 0.10 ng/ml 11% 0.20 ng/ml 15% 0.03 ng/ml 17%* 0.50 ng/ml 35% 0.01 ng/ml 46% 0.02 ng/ml (T), 0.3 ng/ml (I) 51% (T), 46% (I)* 0.01 ng/ml 56% 0.01 ng/ml 60% 0.01 ng/ml 62% 0.01 ng/ml (T), 0.03 ng/ml 44% (T),74% (I) 0.01 ng/ml (T), 0.03 ng/ml (I) 80% (T), 71% (I) Januzzi, et al, Submitted

53 Troponins and Remodeling in Ambulatory Stage C HF Troponins were associated with impaired hemodynamics and risk for remodeling over time in ambulatory HF Horwich, et al, Circulation, 2003

54 High sensitivity troponin in ambulatory stage C/D heart failure The vast majority of patients with chronic HF in Val-Heft had measurable hstnt Outcomes linear with value of troponin Prognostic value of hstnt was additive to natriuretic peptides Latini et al, Circulation 2007

55 ST2 plays a role in reducing cardiomyocyte hypertrophy and fibrosis Abnormalities in ST2 experimentally result in severe cardiac remodeling and heart failure Intact sst2 sst2 knock out

56 Additive Value of ST2 to NP s in Acute HF The combination of an elevated ST2 and natriuretic peptide was a considerably stronger predictor of death than either alone.

57 ST2 Trends as a Function of Mortality sst2 (ng/ml) Death 0.1 Survival First Day 2 Day 3 Day 4 Day 5 Last Boisot, et al, J Card Failure, 2008 Time

58 sst2 predicts remodeling and response to aldosterone blockade in acute MI 13 % change Low/placebo Low/eplerenone High/placebo High/eplerenone -5 ΔLeft ventricular end systolic volume index ΔLeft ventricular end diastolic volume index Weir et al, JACC, 2010

59 Galectin-3 3 and long term outcomes in ADHF Galectin-3 3 and mortality P < Event free survival Gal-3 elevated/nt-probnp elevated Gal-3 elevated/nt-probnp low Gal-3 low/nt-probnp elevated Gal-3 low/nt-probnp low Days from enrollment Shah, et al, Submitted

60 GDF-15 and Other Cardiac Markers for Prognostication in Chronic HF Anand, et al, Circulation, 2010

61 Multiple Biomarkers to Predict Mortality in Acute Dyspnea 70 % Mortality at 1 year Markers: NT-proBNP hscrp ST2 Hemoglobin BUN P <.001 for trend One point assigned if: 986 ng/l 14 mg/l 0.20 ng/ml <12/13 mg/dl (F/M) 20 mg/dl Rehman, et al, Clin Chem Acta, Multimarker Score

62 Patient with heart failure Chronic monitoring History, physical exam Care plan Physiologic biomarker panel Pharmacogenomics screen

63 Molecular diagnostics and cancer treatment Cancer patient Blood test Clinical information Surgical resection Patient blood DNA analysis Germline sequence data allows drug classes and dosing to be tailored to that patient Tailored therapy Tumor genotype identifies specific Achilles heel for that tumor Standard pathology Slide courtesy of David Louis, MD Molecular pathology

64 Biomarkers in Heart Failure James L. Januzzi, Jr,, MD Associate Professor of Medicine Harvard Medical School Director, Cardiac ICU Massachusetts General Hospital