Cardiac biomarkers in heart failure : where are we now?

Dr Arun Kochar

MD;DM;DNB

Senior consultant, interventional cardiology Fortis hospital, Mohali.

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

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,

Research papers related to biomarker research published over the last decade

CLINICALLY USEFUL BIOMARKER CRITERIA( NIM 2013)

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

CHF: How it happens….

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

The processing cascade of natriuretic peptides

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

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.

BNP Consensus Algorithm.

Maisel A et al. Eur J Heart Fail 2008;10:824-839

© 2008 European Society of Cardiology

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

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

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

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

Wet versus optivolaemic BNP levels (optivolaemic = baseline).

Maisel A et al. Eur J Heart Fail 2008;10:824-839

© 2008 European Society of Cardiology

Study Population Intervention Comparison Implication

Beck-da-Silva, 20058 (LVEF) of 40% or lessSymptomatic HF (New York Heart Association class II–IV) for at least 3 months or previous hospital admission due to HFAge (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, 2007STARS-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, 2009TIME-CHF10

Dyspnea (New York Heart Association class ≥II with current therapy), a history of hospitalization for HF within the last yearAge (mean): 76 years<50% femalesAge 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 class of II or less

• -•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 treatmentHF therapy guided by N-terminal BNP improved outcomes in patients aged 60–75 years but not in those aged 75 years or older

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

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.

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

Survival curve for all-cause mortality in NP-guided or clinically guided treatment of CHF

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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

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.

Therapy directed by BNP level is superior to guideline-directed therapy

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)

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

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.

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

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

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

Recommendations for Biomarkers in HFBiomarker, Application Setting COR LOE

Natriuretic peptides

Diagnosis or exclusion of HFAmbulatory,

AcuteI A

Prognosis of HFAmbulatory,

AcuteI A

Achieve GDMT Ambulatory IIa B

Guidance of acutely decompensated HF therapy

Acute IIb C

Biomarkers of myocardial injury

Additive risk stratificationAcute,

Ambulatory I A

Biomarkers of myocardial fibrosis

Additive risk stratification 

Ambulatory   IIb B

AcuteIIb A

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

NT-proBNP concentrations in normal subjects.

McDonagh T et al. Eur J Heart Fail 2004;6:269-273

© 2004 European Society of Cardiology

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

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

Cardiac Troponins 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

An ideal HF bio marker should …

-Be measurable at a reasonablecost 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

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

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:

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.

Selected Biochemical Markers Currently Available for Heart Failure Standard laboratory markers    Uric acid    Red blood cell distribution widthNeurohormones    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-3Metabolic 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

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