Heart Failure biomarkers

1. Prof. U. C. SAMAL
MD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS
Ex- Prof. Cardiology & Ex-HOD Medicine
Patna Medical College, Patna, Bihar
Past President, Indian College of Cardiology
Permanent & Chief Trustee, ICC-Heart Failure Foundation
National Convener Heart Failure Sub Specialty, CSI
Executive Member (National), Cardiological Society of India
President, CSI Bihar / Vice President, API Bihar
1
“ Biomarkers in ADHF”

2. Acute Heart Failure Syndrome(s)
• Acute heart failure (AHF) is defined as a rapid
onset or change in the signs and symptoms of
HF, resulting in the need for urgent therapy.
• Symptoms are primarily the result of severe
pulmonary congestion due to elevated left
ventricular (LV) filling pressures (with or without
low cardiac output).
• AHFS can occur in patients with preserved or
reduced ejection fraction (EF).
• Concurrent cardiovascular conditions such as
coronary heart disease (CHD), hypertension,
valvular heart disease, atrial arrhythmias, and/or
noncardiac conditions (including renal
dysfunction, diabetes, anemia) are often present
and may precipitate or contribute to the
pathophysiology of this syndrome 2
ESC Guidelines

3. Rapid Assessment of Hemodynamic Status
Congestion at Rest
Low
Perfusion
at Rest
N
O
NO YES
Y
E
S
Signs/Symptoms of
Congestion:
Orthopnea / PND
JV Distension
Hepatomegaly
Edema
Rales (rare in chronic
heart failure)
Elevated est. PA
systolic( loud P2 and
RV lift)
Valsalva square wave
Abdominojugular
reflux
S3Possible Evidence of Low Perfusion:
Narrow pulse pressure Cool extremities
Sleepy / obtunded Hypotension with ACE inhibitor
Low serum sodium Renal Dysfunction (one cause)
Elevated LFTs Pulsus alternans
Warm & Dry Warm & Wet
Cold & Dry Cold & Wet
A B
CL
(Nohria A, Mielniczuk LM, Stevenson LW: Evalutiaon and monitoring of pts with AHF
syndromes Am J Cardiol 96:32G-40G,2005)

4. • diuretics
• ultrafiltration
Vasodilators
• nitroglycerin
• nesiritide
• nitroprusside
INOTROPES
• dobutamine
• dopamine
• levosimendan
• nitroprusside
Fluid retention or redistribution ?
“dry out” “warm up & “dry out”
Assessment of hemodynamic profile : therapeutic
implications
Adapted from Stevenson L W, Eur Heart j
4

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6. How sure are we about the diagnosis of
AHF
6
McCullough, Maisel et al. Circulation. 2002; 106:416-422

7. Diagnostic Uncertainty is Associated with
Poor Prognosis in Acute Dyspnea
7
Green et. al. Arch Int Medicine, 2006, 168:741

8. “A Characteristic that is objectively measured and
evaluated as an indicator or normal biologic processes,
pathogenic processes, or the response to a therapeutic
intervention.
In common usage, however, the term biomarker typically
refers to a quantifiable parameter that is measured from a
biological sample such as blood or urine, provide inside
into biologic process in health or disease.
What is a Biomarker : NIH definition
Atkinson et al, Clin Pharmacol Ther 2001
8
G.Michael Felker, Heart Fail Rev (2010)15:343-349

9. The Ideal Biomarker
2007 2011
 Sensitive and Specific  Either highly sensitive ( Diagnosis)
or Highly specific (Treatment effect)
 Reflects disease severity  Reflects abnormal physiology/
biochemistry
 Correlates with prognosis  Prognosis is most meaningful if
level is clinically actionable
 Should aid in clinical decision
making
 Should be used as a basis for
specific “Biomarker guided therapy”
 Level should decrease following
effective therapy
 “Bio Monitoring” during treatment is
an effective surrogate of
improvement
9Maisel JACC 2011

10. Intended prospective would be
 Diagnostic implication / discrimination
 Prognostic validation
 Guide to therapy
 To develop tailored therapy
 To assess disease severity/ morbidity/ mortality
 Relapse/ readmission
 Risk stratification
 Reversibility
10

11. 11
Number of HF biomarker reports in PubMed per year (left y axis) vs all
publications (right y axis) during the last decade
A relatively remarkable increase in HF biomarker publication is noted after
2001, when BNP testing was introduced into clinical practice.
No.ofPublications/Year
Year
No.ofPublications
Clinical Chemistry 58:1 127–138 (2012)
Number of HF biomarker

12. Neurohormones
• Norepinephrine
• Renin
• Angiotensin II
• Copeptin
• Endothelin
Vascular system
• Homocysteine
• Adhesion molecules
• (ICAM, P-selectin)
• Endothelin
• Adiponectin
• C-type natriuretic
peptide
Inflammation
• C-reactive protein
• sST2
• Tumor necrosis
factor
• FAS (APO-1)
• GDF-15
• Pentraxin 3
• Adipokines
• Cytokines
• Procalcitonin
• Osteoprotegerin
Myocardial stress
• Natriuretic
• peptides
• Mid-regional
• pro-adrenomedullin
• Neuregulin
• sST2
Myocardial injury
• Cardiac troponins
• High sensitivity cardiac troponins
• Myosin light-chain kinase 1
• Heart-type fatty acid binding protein
• Pentraxin 3
Matrix and cellular
remodeling
• Galectin-3
• sST2
• GDF-15
• MMPs
• TIMPs
• Collagen
propeptides
• Osteopontin
Cardio-renal syndrome
• Creatinine
• Cystatin C
• NGAL
• ß-Trace protein
Oxidative stress
• Oxidized LDL
• Myeloperoxidase
• Urinary biopyrrins
• Urinary and plasma
isoprostanes
• Plasma malondialdehyde
HF: A systemic illness / Syndrome…?
12
Nature Review Cardiology
Vol.9 June 12 pg 349

13. Recommendations for Biomarkers in HF
13
AHA 2013

14. ESC Guidelines 2012

15. 15

16. The processing cascade of natriuretic peptides
Signal peptide
proBNP1-108 Glc-proBNP1-108
proBNP1-108
Glycosylation
Glc-proBNP1-108
Corin
Corin/Furin Glycosylation
NT-proBNP1-76
BNP1-32
NT-proBNPx-x
BNP3-32 BNP7-32
DPP-IV Meprin-A
Proteolysis
Intracellular
16ClinicalChemistry 58:1 127–138 (2012)
proBNP1-134

17. Respective advantages of B-type natriuretic peptide and N-
terminal pro-B-type natriuretic peptide in clinical usage.
Parameter BNP NT-proBNP
Sample stability Higher sample stability
Accuracy of measurements Lower variation coefficient in
automated tests
Predictive values Slightly better for
asymptomatic structural
heart disease and chronic
heart failure.
Thresholds Single threshold Greater differentiation of
thresholds (Heart failure, left
ventricular dysfunction and
age.
Dynamic of plasma
concentrations
Closer correlation with filling
pressure
Covariables Less interference in
moderate/ severely reduced
GFR
17

18. 18

19. Effect of cardiac and extra cardiac
parameters on BNP and NT-proBNP
Raised in
Cardiac Factors
Lower Ejection Fraction, Larger Left ventricular mass, Atrial size,Atrial fibrillation,
Coronary heart disease ,Valvular heart disease,Acute coronary syndrome, Cor
pulmonale (acute/ chronic), COLD (right heart strain)
Extra Cardiac factors
Age, Female gender, Low glomerular filtration, Hematocrit low, Hyperthyroidism,
Cushing syndrome. Liver cirrhosis with ascites, paraneoplastic syndrome,
Subarachnoidal bleeding, Sepsis, Rheumatic diseases, Stroke
Reduced in
Extra Cardiac factors
Obesity,ACE-I/ATRB, Diuretics, Hypothyroidsm, Primary hyperaldosteronism
Biomarkers in medicine 3.5 (Oct 2009) p465
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24. “HF management ‘guided’ by natriuretic peptides would be superior
to standard HF therapy alone.”
24van Kimmenade, R. R. & Januzzi, J. L. Jr. Clin. Chem. 58, 127–138 (2012).

25. 25

26. Mean BNP Levels and New York Heart
Association (NYHA Class)
Maisel AS, et al. N Engl J Med. 2002;347:161-167
NYHA Class Correlative BNP
Levels (pg/mL)
Class I 244 ± 286
Class II 389 ± 374
Class III 640 ± 447
Class IV 817 ± 435
26

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28. NT-proBNP and prognosis after ADHF
treatment
28
Salah. et al, Heart, 2014

29. NT-proBNP and prognosis after ADHF
treatment
29

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34. Therapies with effects on B-Type Natriuretic
Peptide Levels
Therapy Effect on BNP/ NT -proBNP
Diuresis
ACE-I /ARB
Beta Blockers
Aldosterone Antagonist
BiV pacing
Exercise
Rate control of AF
NP infusions
Serelaxin
LCZ696 NT-proBNP/ BNP
Neuregulin
34

35. BNP Status
This pilot study demonstrates that home BNP testing is feasible and that trials using
home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight
monitoring is complementary to BNP, but BNP changes correspond to larger changes in
risk, both upward and downward. (Heart Failure [HF] Assessment with B-type
Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231)

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39. “HF-CBS-SRS”
Quantitative results in~ 15 minutes! EDTAWhole Blood , No Centrifugation
Anywhere, anytime, in time
Point of Care System for rapid, accurate
results
• Easy
• Portable
• Reliable Results in about minutes
Fluorescence Sandwich immunoassay
Test Normal Range
CKMB ng/mL (0.0 - 4.3)
MYO ng/mL (0.0 – 107)
TNI ng/mL (0.00 - 0.40)
BNP pg/mL (0.00 - 100)
DDIM ng/mL (0.0 - 400)
NGAL* ng/mL (0-149)
PANEL OF SOBTRIAGE/ AMI/ AKI
15
6 Biomarkers 750 +750 bucks
* Galectin3/BNP+NGAL being uploaded to
the test platform
39

40. Intelligent Nephelometry Technology
Smart Card Calibration
Economic 10 Parameter Assay Panel
ser- friendly 3 Step Assay Procedure
No Sample dilution
Test Normal Range
ASO I/mL (50 - 1000)
CRP mg/L (0.5 - 320)
RF I/mL (10-120)
HbA1c % (3-13%)
IgE I/mL (1-1000)
MICROALBMIN mg/L (5-200)
Lp(a) Mg/dl (1-100)
CYSTATIN C mg/L (0.0-10)
FERRITIN I/mL (1-1000)
D-DIMER ng/mL
REPORT OF MISPA PANELREPORT OF MISPA PANELREPORT OF MISPA PANEL
REPORT OF MISPA PANEL SERUM/ URINE
REPORT OF MISPA PANEL
“HF-CBS-SRS”
Measures
ACR
&
Routine rine
Parameters
• 95% Correlation with conventional immunoturbidimetric test
• Analyze spot rine sample
• Works on batteries or power cable
• Provides Printed report
“15/23 Minutes Exercise”
10 Biomarkers 1000 Bucks
40

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42.  Appear early in the phase of the disease
 Be rapid test, obtainable from usual samples of blood and
urine.
 Preferably to be housed on single platform.
 Be inexpensive
 Be sensitive and specific and reproducible
 Should Indicate timing of the insult
 Should provide newer information
 Be quantifiable and denote the severity of disease
 Help in risk in stratification
 Be predictor of outcome
 Be a useful tool for therapeutic monitoring
 Help in classification of cardiorenal syndrome
Multi-markers strategies
Modified Morrow and de Lemos criteria: Circulation 2007;115:949:5242

43. “Appropriate methodologies for the clinical and
statistical evaluation of so called “Multi- marker
strategies” have not been systematically defined.”
“the objective is only to create more actionable
knowledge”
“the evaluation of multi-marker strategies will vary
based on the intended use.”
43
Multi-marker strategies in heart failure:
clinical and statistical approaches
Lary A.Allen,G.Michael Felkar, heart Fail Rev (2010)15:343-349

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Time-dependent C-statistic (area under the receiver operator characteristic curve at various
times after an ED visit for acute dyspnea) plot comparing MR-ProADM, Copeptin, BNP,
troponin, and the combination of MR-proADM and CT proAVP for predicting death at
various time points.
MR-proADM, Copeptin, and their combination predict short term death, although after 90
days all have similar mortality prediction as troponin.
Natriuretic peptides are poor short term mortality predictors.
AUC
Days
Adapted and reprinted with permission form Peacock WF, Nowak R, Neath S, et al. ED prediction of Short Term Mortality in Acute
Heart Failure: Results of the International BACHTrial. Academic Emergency Medicine 2009;16(4):S11

47. 47
Kaplan Meier plot demonstrating the time dependent mortality prediction of
the initial troponin level in patients hospitalized with acute heart failure.
Troponin positive patients were more likely to suffer in-hospital mortality.
CumulativeMortality(%)
Days in Hospital
Adapted and reprinted with permission from Peacock WF, DeMarcoT, Fonarow GC, et al, for the ADHERE
investigators. Cardiac troponin and outcome in acute heart failure. N Eng J Med 2008; 358(20): 2117-2126

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Diagnostic accuracy of biomarker testing for ‘LVDD with possible HF’ in the obese.
Shown are receiver operating characteristic (ROC) curves and the corresponding
areas under the curve for measurements of N-terminal pro brain natriuretic peptide
(NT-proBNP) and growth-differentiation factor-15 (GDF-15) levels. Also shown are the
sensitivity and specificity of these measures. The upper panels displays the
univariate analysis and the lower panel displays multivariate models accounting for
age, sex, body mass index, type 2 diabetes, and systolic blood pressure.
Sensitivity
Specificity
Sensitivity
Specificity
European Journal of Heart Failure (2012) 14, 1240–1248

53. Galectin-3 Level with Renal and Cardiac Indices
53
Van Kimmenade JACC
2006
Death/recurrentheartfailure
Days from Enrollment

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Adjusted acute mortality in patients presenting to the ED with heart failure
and an elevated PCT, stratified by whether the patients received antibiotics
(yes) or not (no). Patients with elavated PCT have lower mortality when
receiving antibiotics.
SurvivalProbability Days
Adapted and reprinted with permission from Hartmann O, Landsberg J, Mueller C, et al. Procalcitonin identifiesAcute Heart
Failure Biomarkers in Patients with Acute Heart Failure in Need of AntibioticTherapy:Observational Results from the
BACH(Biomarkers in Acute Heart Failure)Trial.Getting ahead in lung infection; spoken sessions, S123.Thorax 2009;64: A62-A64.

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58. Soluble ST2 in AHFS
58
Rehman et al, JACC 2008

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