Prof. U. C. SAMALMD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVSEx- Prof. Cardiology & Ex-HOD Medicine Patna Medical College, Patna, BiharPast President, Indian College of CardiologyPermanent & Chief Trustee, ICC-Heart Failure FoundationNational Convener Heart Failure Sub Specialty, CSIExecutive Member (National), Cardiological Society of IndiaPresident, CSI Bihar / Vice President, API Bihar

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“ Biomarkers in ADHF”

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

Rapid Assessment of Hemodynamic Status

Congestion at Rest

LowPerfusio

nat Rest

NO

NO YES

YES

Signs/Symptoms of Congestion:Orthopnea / PNDJV DistensionHepatomegalyEdemaRales (rare in chronic heart failure)Elevated est. PA systolic( loud P2 and RV lift)Valsalva square waveAbdominojugular refluxS3Possible Evidence of Low Perfusion:

Narrow pulse pressure Cool extremitiesSleepy / obtunded Hypotension with ACE inhibitorLow 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)

• 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

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How sure are we about the diagnosis of AHF

6McCullough, Maisel et al. Circulation. 2002; 106:416-422

Diagnostic Uncertainty is Associated with Poor Prognosis in Acute Dyspnea

7Green et. al. Arch Int Medicine, 2006, 168:741

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“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

G.Michael Felker, Heart Fail Rev (2010)15:343-349

The Ideal Biomarker2007 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

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

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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. o

f Pub

licat

ions

/ Yea

r

Year

No. of Publications

Total PubMed Publications

HF Biomarker Publications

Clinical Chemistry 58:1 127–138 (2012)

Number of HF biomarker

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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 cellularremodeling

• 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…?

Nature Review Cardiology Vol.9 June 12 pg 349

Recommendations for Biomarkers in HF

13AHA 2013

ESC Guidelines 2012

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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

16Clinical Chemistry 58:1 127–138 (2012)

proBNP1-134

Respective advantages of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide in clinical usage.Parameter BNP NT-proBNPSample stability Higher sample stabilityAccuracy 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

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Effect of cardiac and extra cardiac parameters on BNP and NT-proBNP Raised in

Cardiac FactorsLower 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) p46519

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“HF management ‘guided’ by natriuretic peptides would be superior to standard HF therapy alone.”

van Kimmenade, R. R. & Januzzi, J. L. Jr. Clin. Chem. 58, 127–138 (2012).

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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

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NT-proBNP and prognosis after ADHF treatment

28Salah. et al, Heart, 2014

NT-proBNP and prognosis after ADHF treatment

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Therapies with effects on B-Type Natriuretic Peptide Levels

Therapy Effect on BNP/ NT -proBNPDiuresis

ACE-I /ARB

Beta Blockers

Aldosterone Antagonist

BiV pacing

Exercise

Rate control of AF

NP infusions

Serelaxin

LCZ696 NT-proBNP/ BNP

Neuregulin

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PROTECT Secondary End Points: HF Hospitalization and

Rehospitalization

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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“HF-CBS-SRS”Quantitative results in~ 15 minutes! EDTA Whole 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 RangeCKMB 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 SOB TRIAGE/ AMI/ AKI

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6 Biomarkers 750 +750 bucks

* Galectin3/BNP+NGAL being uploaded to the test platform

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Intelligent Nephelometry TechnologySmart Card CalibrationEconomic 10 Parameter Assay Panelser- friendly 3 Step Assay ProcedureNo 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” MeasuresACR

&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

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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;115:949:52

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“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.”

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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 BACH Trial. Academic Emergency Medicine 2009;16(4):S11

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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.

Cum

ulat

ive

Mor

talit

y (%

)

Days in Hospital

Adapted and reprinted with permission from Peacock WF, DeMarco T, 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.

Sens

itivi

ty

Specificity

Sens

itivi

ty

Specificity

European Journal of Heart Failure (2012) 14, 1240–1248

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Galectin-3 Level with Renal and Cardiac Indices

Van Kimmenade JACC 2006

Deat

h/re

curre

nt h

eart

failu

re

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.

Surv

ival

Pr

obab

ility

Days

Adapted and reprinted with permission from Hartmann O, Landsberg J, Mueller C, et al. Procalcitonin identifies Acute Heart Failure Biomarkers in Patients with Acute Heart Failure in Need of Antibiotic Therapy: 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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Soluble ST2 in AHFS

Rehman et al, JACC 2008

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