1. Cardiac biomarkers in heart
failure : where are we now?
Dr Arun Kochar
MD;DM;DNB
Senior consultant, interventional cardiology
Fortis hospital, Mohali.

2. Heart Failure- Clinical syndrome
… can result from any structural
or functional cardiac disorder that
impairs ability of ventricle to fill
with or eject blood
•5 million Americans- have heart
failure
•500,000 new cases every year
• 30 billion dollars a year spent on heart
failure treatment
• 6,500,000 hospital days / year and
300,000 deaths/year
•Heart failure in India has been
conservatively estimated to affect up to
4.6 million people, with up to 1.8 million
new diagnoses made each year

3. What exactly is the term biomarker?
• The National Institutes of
Health define a biomarker
as a “characteristic that is
objectively measured and
evaluated as an indicator
of normal biologic processes,
pathogenic processes, or
pharmacologic
responses to a therapeutic intervention”
These are substances detectable in blood, urine,
or other bodily fluids. Tests measuring them
should be readily available, be quantitative,
reproducible and generally inexpensive,

4. Research papers related to
biomarker research published
over the last decade

6.  Accurate, reproducible measurements must
be available to clinicians at reasonable cost with
short turn-around time
 Biomarker must provide information that is not
already available from a careful clinical
assessment
 Measured level should aid in clinical decision
making

8. CHF: How it happens….

10. What exactly are BNP
and NT-proBNP…..
• BNP is a hormone produced in r in
response to ventricular overload, and NT-
proBNP is the fragment produced from the
cleavage of proBNP.
• BNP and NT-proBNP levels are elevated in
patients with HF and correlate with functional
and morphological left ventricular parameters
and they independently predict prognosis
• The BNP gene natriuretic peptide B (NPPB)
is the precursor molecule for both

11. The processing cascade of
natriuretic peptides

12. Punch lines….( BNP)
-BNP concentration increases, when there
is an abnormal cardiac dilatation.
-Factors as age, BMI, renal function can
alter levels resulting in “grey-zone” values.
- 100-400 ng/l = grey zone
- < 100 = to exclude HF
- Lower cutoff <50 to exclude HF = BMI>35
- the optimal times to assess BNP levels at
admission, 24 hours after admission and
at discharge.
- Dry and wet BNP

13. NT-proBNP
• Adding NT-proBNP levels to the
differential resulted in increase of 24.4%
with a diagnosis of HF and 47.5% with
lung failure. It helped diagnose 18% of
patients presenting with acute dyspnea.
• NT-proBNP had shown superior
prognostic power for all cause mortality
when compared with BNP.

15. BNP Consensus Algorithm.
Maisel A et al. Eur J Heart Fail 2008;10:824-839
© 2008 European Society of Cardiology

16. N-terminal proBNP interpretation in the patients with
acute dyspnea without severe renal failure

17. For NT-proBNP, apply one rule-out value (<300 pg/ml)
and one of three rule-in values based on age.
Maisel A et al. Eur J Heart Fail 2008;10:824-839
© 2008 European Society of Cardiology

18. Veterans Affairs Medical Center San
Diego algorithm for the diagnosis of
heart failure in an urgent-care setting

19. Wet versus optivolaemic BNP levels (optivolaemic = baseline).
Maisel A et al. Eur J Heart Fail 2008;10:824-839
© 2008 European Society of Cardiology

20. Study Population Intervention Comparison Implication
Beck-da-Silva, 20058 (LVEF) of 40% or less
Symptomatic HF (New
York Heart Association
class II–IV) for at least 3
months or previous
hospital admission due
to HF
Age (mean): 65 years.
< 50% males
•-
•β-blocker dosage up-
titrated according to
plasma BNP levels plus
standard care
•-
•β-blocker dosage up-
titrated according
standard care
A trend toward better
quality of life was seen
in the BNP group as
compared to the
clinically guided group
Jourdain, 2007
STARS-BNP9
Symptomatic (New York
Heart Association
functional class II–III)
systolic HF defined by
left ventricular ejection
fraction (LVEF) <45%
Age (mean): 65 years
<50% females
•-
•Medical therapy was
increasingly used with
the aim of lowering
plasma BNP levels
(target <100 pg/ml)
•-
•Each class of therapy
modified according to
the judgment of the
investigator
•-
•Medical therapy was
adjusted on the basis
of the physical
examination and usual
para clinical and
biological parameters
BNP guided strategy
reduced the risk of
CHF-related death or
hospital stay for CHF
Pfisterer, 2009
TIME-CHF10
Dyspnea (New York
Heart Association class
≥II with current
therapy), a history of
hospitalization for HF
within the last year
Age (mean): 76 years
<50% females
Age subgroups: <75
years; ≥75 years)
•-
•BNP guided plus
symptom guided
medical therapy
•-
•Medical therapy to
reduce BNP levels to 2
times or less than the
upper limit of normal
(<400 pg/ml in patients
<75 years and
<800 pg/ml in patients
≥75 years) and
symptoms to NYHA
•-
•Symptom guided
medical therapy
•-
•Medical therapy to
reduce symptoms to
NYHA class of II or less
HF therapy guided by
N-terminal BNP did not
improve overall clinical
outcomes or quality of
life compared with
symptom guided
treatment
HF therapy guided by
N-terminal BNP
improved outcomes in
patients aged 60–75
years but not in those
aged 75 years or older

21. Effect of B-type natriuretic peptide-
guided treatment of chronic heart
failure on total mortality and
hospitalization: an individual
patient meta-analysis
• Richard W. Troughton1, et al.
• Eur Heart
J (2014)doi: 10.1093/eurheartj/ehu090First
published online: March 6, 2014
• Of 11 eligible studies, 2000 patients were
included, 994 randomized to clinically guided
care and 1006 to NP-guided care

22. FOREST plot of the primary endpoint, overall mortality, showing unadjusted individual and
mean hazards ratios with 95% confidence intervals for eight studies providing individual
patient data and two studies providing aggregate data.
NP-guided treatment is better….
© The Author 2014. Published by Oxford University Press on behalf of the European Society of
Cardiology.

23. Kaplan–Meier survival curves for the primary endpoint, overall mortality: (A) total group, (B)
below age 75 years (n = 982), (C) 75 years and above (n = 1018).
Natriuretic peptide-
guided treatment of
heart failure reduces
all-cause mortality in
patients aged <75
years and overall
reduces heart failure
and cardiovascular
hospitalization

24. Survival curve for all-cause
mortality in NP-guided or clinically
guided treatment of CHF
0.0 0.5 1.51.0 2.0
0.0
0.2
0.4
0.6
0.8
1.0
Proportionsurviving
Total group: HR: 0.62, 95%CI: 0.45-0.86, P=0.004
Age < 75 years: HR: 0.62, 95%CI: 0.45-0.85, P=0.004
Age > 75 years: HR: 0.98, 95%CI: 0.75-1.3, P=0.96
Throughton et al., Eur Heart J 2014
NP-guided
clinically-guided

25.  most useful in the evaluation of pts with
dyspnea presenting to the ED where they may
provide the advantages of convenience and
rapid turnaround times facilitating clinical
management
 Maisel et al showed in the Breathing Not
Properly study that BNP levels greatly
increased the accuracy of the diagnosis of HF in
pts presenting to ED with dyspnea;
 level > 100 pg/ml HF unlikely but level >400
pg/ml makes the diagnosis likely.

27.  Systolic Heart Failure Treatment Supported by
BNP (STARS–BNP) trial by Jourdain et al
randomly assigned outpatients with NYHA cl II/III HF to
current clinical guidelines (control group) or to goal of
decreasing BNP < 100 pg/ml
primary end point (HF death or hosp admission for HF)
occurred in 24% of patients in whom the BNP level was
lowered vs 52% of the control group (p < 0.001)

28.  predischarge level of BNP was a strong,
independent predictor of postdischarge
outcomes
 patients with HF whose BNP level does not
decline to < 600 pg/ml should receive
intensified treatment before discharge
 useful in screening asymptomatic subjects at
risk of HF such as elderly and those with HPN,
DM & asymptomatic CAD
 may also be used to screen for acute or late
cardiotoxic effects associated with cancer
chemotherapy

30. HFPEF…
• Patients with HFPEF overall have lower levels of
BNP than do HF patients with reduced LVEF, but
for a given BNP level, the associated risk of all-
cause mortality and HF hospitalization is at least
as high in patients with HFPEF as it is in those with
low LVEF.
• Use of cardiac peptides (BNP or NT-proBNP) to
guide pharmacologic therapy in patients with
HFPEF is associated with a significant reduction
of mortality and HF-related hospitalization,
especially in patients younger than 75 years.

31. In chronic HF…
• 90-day combined event rate with BNP
<200 pg/mL was 9% versus 29% for >200.
• A reduction of 25% (24 hours ) 46%( at
discharge) compared with the admission,with
the absolute value of less than 300 pg/mL is
very strong favorable prognosis.
• Val-HeFT trial reported them strongest
mortality and hospitalization predictors.
• 35% increase in risk of mortality with an
increase of 100 pg/mL from baseline.
• BNP level >189 pg/mL at 2 months with >15%
change from baseline had worst survival
despite being stable after discharge for HF

32. ACC 2013 recommendations
Ambulatory/Outpatient
BNP- or NT-proBNP guided HF therapy can be useful to
achieve optimal dosing of GDMT in select clinically
euvolemic patients followed in a well-structured HF
disease management program.
The usefulness of serial measurement of BNP or NT-
proBNP to reduce hospitalization or mortality in patients
with HF is not well established.
Measurement of other clinically available tests such as
biomarkers of myocardial injury or fibrosis may be
considered for additive risk stratification in patients with
chronic HF.
I IIa IIb III
I IIa IIb III
I IIa IIb III

33. Causes for Elevated Natriuretic
Peptide Levels
Cardiac Noncardiac
 Heart failure, including RV
syndromes
 Acute coronary syndrome
 Heart muscle disease, including
LVH
 Valvular heart disease
 Pericardial disease
 Atrial fibrillation
 Myocarditis
 Cardiac surgery
 Cardioversion
 Advancing age
 Anemia
 Renal failure
 Pulmonary causes: obstructive
sleep apnea, severe pneumonia,
pulmonary hypertension
 Critical illness
 Bacterial sepsis
 Severe burns
 Toxic-metabolic insults, including
cancer chemotherapy and
envenomation

34. Recommendations for Biomarkers in HF
Biomarker, Application Setting COR LOE
Natriuretic peptides
Diagnosis or exclusion of HF
Ambulatory,
Acute
I A
Prognosis of HF
Ambulatory,
Acute
I A
Achieve GDMT Ambulatory IIa B
Guidance of acutely decompensated
HF therapy
Acute IIb C
Biomarkers of myocardial injury
Additive risk stratification
Acute,
Ambulatory I A
Biomarkers of myocardial fibrosis
Additive risk stratification
Ambulatory
IIb B
Acute
IIb A

35. Ambulatory/Outpatient
In ambulatory patients with dyspnea, measurement of
BNP or N-terminal pro-B-type natriuretic peptide (NT-
proBNP) is useful to support clinical decision making
regarding the diagnosis of HF, especially in the setting of
clinical uncertainty.
Measurement of BNP or NT-proBNP is useful for
establishing prognosis or disease severity in chronic HF.
I IIa IIb III
I IIa IIb III

36. NT-proBNP concentrations in normal subjects.
McDonagh T et al. Eur J Heart Fail 2004;6:269-273
© 2004 European Society of Cardiology

37. Galectin-3
• Inflammatory and fibrotic processes are
central to cardiac remodeling and the
development of HF
• Galectin-3, secreted by activated
macrophages, causes cardiac fibrosis
• Increasingly being used as a s surrogate
indicator of cardiac remodeling and
fibrosis
• PROVE IT-TIMI22 , higher galectin-3 levels
in ACS showed a positive relationship with
the development of HF.
• “remodeling” and “non-remodeling” HF

38. High sensitivity troponin
- When comparing hs cTnI and NT-proBNP
to cardiac troponins measured using
conventional assay in 258 HF pts. hs cTnI
was single best independent prognostic
predictor
- hs c Tnl is independently predictive of
higher risk of death and 1-year mortality
and provide additional prognostic
information in patients with ADHF

39.  Modest elevations of cT I levels are also found in
patients with HF without ischemia.
 Horwich et al – cT I was detectable (≥0.04 ng /ml)
in approx half of 240 patients with advanced,
chronic heart failure without ischemia.
 cT I remained an independent predictor of death.
 cT T levels > 0.02 ng /ml chronic HF associated
with a hazard ratio for death of more than 4

40. An ideal HF bio marker
should …
-Be measurable at a reasonable
cost on short notice;
-Add new information to the clinical workup;
-Aid in the management of patients with HF.
-Identify possible underlying/reversible causes
of HF;
-Confirm the presence or absence of the HF
syndrome;
-Estimate the severity of HF and risk of disease
progression

41. Expectations of the ideal
biomarker
• Patient acceptability
• In vivo and in vitro stability
• Adequate analytical (functional) sensitivity
• Reproducibility and accuracy
• Feasibility
• Complete assay automation
• International standardization
• Low cost
• Low biological variation
• Reference range and cut-off values tested for gender, age,
and ethnicity dependence
• Good diagnostic and prognostic accuracy
• Cost-effectiveness

42. Date of download:
4/11/2014
Copyright © The American College of Cardiology.
All rights reserved.
From: Heart Failure
JCHF. 2013;1(1):1-20. doi:10.1016/j.jchf.2012.10.002
Seven Major Classes of Biomarkers Contributing to the Biomarker Profile in HF
Figure Legend:

43. Bio markers prospective…
Biomarker Molecule type Size Tissue source
Natriuretic peptides
N-Terminal pro-ANP Peptide 98 amino acids Heart (atria)
Pro-ANP99–126 Peptide 28 amino acids Heart (atria)
Pro-ANP80–96 Peptide 17 amino acids Heart (atria)
Pro-ANP26–55 Peptide 30 amino acids Heart (atria)
BNP Peptide 32 amino acids Heart (ventricles)
Pro-BNP Peptide 108 amino acids Heart (ventricles)
NT-pro-BNP Peptide 76 amino acids Heart (ventricles)
Cardiotonic steroids
DLIF Steroid-like 800 g/mol Adrenal cortex
OLF Steroid-like 500 g/mol Adrenal cortex/hypothalamus
Cytokines
TNF-α Protein 157 amino acids Endothelial cells, macrophages,
myocytes
IL-6 Protein 184 amino acids Macrophages, endothelial cells,
T lymphocytes, myocytes
Potential blood biomarkers of HF.

44. Selected Biochemical Markers Currently Available for Heart Failure
Standard laboratory markers
Uric acid
Red blood cell distribution width
Neurohormones
Catecholamines (norepinephrine, epinephrine)
Renin, ACE activity, angiotensin II, and aldosterone
Natriuretic peptides
Endothelin-1
Vasopressin/copeptin
Cardiotrophin-1
Novel vasodilators (adrenomedullin and mid-regional pro-adrenomedullin,
urotensin-II, urocortin)
Inflammatory biomarkers
High-sensitivity C-reactive protein
Myeloperoxidase
Galectin-3
Metabolic biomarkers
Leptin
Adiponectin
Insulin-like growth factor-1 (IGF-1)
Other miscellaneous biomarkers
G-protein coupled receptor kinase-2 (GRK-2)
Cardiac troponin I or troponin T and Myotrophin

45. THANK YOU
Be healthy and happy… Have a
Blessed life and a rocking
Baisahaky