A brief on bio-markers of Heart failure...First of all, I thank the Authors of all the books from which I picked the points to make this presentation.. This presentation includes classification of bio-markers and explanation according their importance.. Thank you

1. Presented by,
Dr. LIKHIT T
House surgeon
Medicine D unit
MMCRI

2.  HF defined as a complex clinical syndrome that results from structural
or functional impairment of ventricular filling or ejection of
blood, which in turn leads to the cardinal clinical symptoms of
dyspnea and fatigue and signs of HF, namely edema and rales.
 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

4.  “A biomarker is a substance used as an indicator of a biologic state.
 It is a characteristic
 That is objectively measured and
 evaluated as an indicator of normal biologic processes, pathogenic
processes, or pharmacologic responses to a therapeutic intervention.”
 “Cardiac markers are substances released from heart muscle when it
is damaged as a result of myocardial Infarction.”

5. 1. Accurate repeated measurements at reasonable cost.
2. Must provide additional information (Information that is not already available from
a careful clinical assessment.)
3. Measured level should aid in clinical decision making.

6.  High cardiac specificity and sensitivity
 High concentration in the myocardium
 Absence from non-myocardial tissue
 Rapid release into plasm following myocardial injury
 Correlation between plasma level and extent of myocardial injury for
prognosis
 Detectable by rapid, simple and automated assay method.

7.  Diagnosis:
– To establish or refute a diagnosis.
– To understand the underlying
pathophysiologic processes.
 Risk Stratification / Screening:
– To determine the presence or level of
severity of disease.
– To detect adverse consequences
 Monitoring / Therapeutic Guidance:
– To guide or monitor responses to treatment.

8. CK (CPK)
CK-MB
Troponin-I/T
LD (LDH)
Myoglobin
ALT/AST
Others.

10.  *Biomarkers in this category aid in elucidating the pathogenesis of HF.
 †Biomarkers in this category provide prognostic information and
enhance risk stratification.
 ‡Biomarkers in this category can be used to identify patients at risk for
HF.
 §Biomarkers in this category are potential targets of therapy.
 ¶Biomarkers in this category are useful in the diagnosis of HF and in
monitoring therapy.

11.  A sudden occlusion of a coronary artery by thrombus or by
embolization causes an acute myocardial infarction.
 DIAGNOSIS OF ACUTE MYOCARDIAL INFARCTION:
 Triad of Chest pain, ECG manifestations and elevations
of biomarkers of cardiac injury
 Chest Pain: highly variable and subjective
 ECG: Objective ST or T-wave changes
 Biomarker elevations: Objective data defining
ACS/AMI,
 Laboratory investigations shows non specific markers
like increased ESR , leukocytosis and CRP

12.  LIMITATIONS:
• 1/3 of patients with AMI do not present with chest pain.
• Only ½ present with Q waves or ST elevation.
• ½ of patients with suggestive chest pain have non-diagnostic ECG.
• With use of new markers ,additional 1/3 are diagnosed to have MI.
• Perioperative MI and post PCI MI – Symptoms may be absent and ECG
changes may non specific.

13.  Biomarkers of myocardial injury.
› markers of myocardial necrosis
› markers of myocardial ischemia
 Biomarkers of haemodynamic stress
 Inflammatory and prognostic Biomarkers

14.  NATRIURETIC PEPTIDES
 ST- 2
 ADRENOMEDULLIN

15.  The natriuretic peptides (NP) are a group of structurally similar but
genetically distinct peptides.
 The NP family includes 5 types.
1) ANP : atrial natriuretic peptide (28 a.a.)
N-terminal proANP (98 a.a.)
2) BNP : brain natriuretic peptide (32 a.a.)
N-terminal proBNP (76 a.a.)
3) CNP : C-type natriuretic peptide (22 and 53 a.a.)
4) DNP(danroaspis natriuretic peptide)
5) Urodilantin(isoform of ANP)

17.  BNP is a precursor of active BNP and N-
terminal pro– brain natriuretic peptide (NT-
pro-BNP).
 cleaved by circulating endoprotease (corin)
into two polypeptides: the inactive NT-pro-
BNP and the bioactive BNP.
 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.

18.  BNP levels greatly increased the accuracy of the diagnosis of HF in pts
presenting to ED with dyspnea.
Decisions for hospital admission
or referral to an OP clinic are
facilitated by natriuretic peptide
levels.

21.  Patients with HF whose BNP level does not decline to < 600 pg/ml
should receive intensified treatment before discharge.
 BNP level - also an accurate predictor of survival in acute
decompensated HF irrespective of LVEF.
 BNP level is useful in screening asymptomatic subjects at risk of HF
such as elderly and those with HTN, DM & asymptomatic CAD.
 35% increase in risk of mortality with an increase of 100 pg/mL from
baseline.

23. 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

24. • 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
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
CARDIAC

25.  It is made as a precursor form prepro -ANP, consist of 126 amino acid.
 Mainly secreted in response to stretching of the atrial wall and other
stimulatory factor are sympathetic stimulation, hypernatremia ,
endothelin, exercise.
 Normal level of ANP in blood is 22-27pg/ml.
 Level of ANP rises in cardiovascular disease e.g.:- HTN, CAD, Heart
failure
 Its concentration rises in both acute and chronic HF, but mostly in
acute HF.
 It is less sensitive and specific marker for HF than that of BNP.

26. MR-proANP
(Midregional-proANP)
 • Longer half life and more stable than ANP
 • BACH study: Useful in “Grey zone” and obesity
 • PRIDE : MR pro ANP predicted 4 year mortality
 • Can combine NT pro BNP and MR pro ANP for superior diagnostic
accuracy
 • Can be used as biomarkers guided therapy (no trials yet)

28.  Peptide of 52 amino acids and a component of precursor,
proadrenomedullin, which is synthesized and present in the heart,
adrenal medulla, lungs, and kidneys.
 Potent vasodilator, with inotropic and natriuretic properties.
 Production is stimulated by both cardiac pressure and volume
overload.
 Circulating adrenomedullin is elevated in patients with HF and is higher
with more severe HF.

29.  ST 2- Member of IL-1 receptor family
 Has immunomodulatory function & cell surface marker for TH2
Lymphocytes
 Includes in two forms: Membrane bound (ST2L) and soluble ST2 form
(sST2)
 Ligand for ST2L is IL33 :- resistance to apoptosis and reduction in
fibrosis. sST2 is a decoy receptor, neutralizes benefits of IL33
 Induced by mechanical stretch.
 ST2>35ng/ml associated with adverse clinical outcomes in HF.

30.  Not affected by age, renal function or BMI
 Can predict prognosis independently or in combination with NT pro
BNP
 Weaker marker for diagnosis
 Superior to galectin 3 in patients with chronic HF
 Increased ST2 seen with severe HF. In ED pts with STEMI and dyspnea,
ST2 levels were strongly predictive of mortality.
 With HF, increased ST2 during a 2-week period was an independent
predictor of subsequent death or the need for cardiac transplantation.

31.  Biomarkers of myocardial injury
› markers of myocardial necrosis
› markers of myocardial ischemia
 Biomarkers of haemodynamic stress
 Inflammatory and prognostic Biomarkers

32.  Markers of myocardial necrosis
› Myoglobin
› Creatine kinase – MB
› Cardiac troponins
 Markers of myocardial ischemia
o Ischemia Modified Albumin (IMA)
o Heart-type fatty acid binding protein (H-FABP)

33.  Earliest to Rise
 Small-size heme protein found in all tissues mainly assists in oxygen
transport
 It is released from all damaged tissues.
Increases often occur more rapidly than TI and CK
released from damaged tissue within 1 hour
Normal value:
 17.4-105.7 ng/ml
 Timing: › Earliest Rise: 1-3 hrs.
 Peak 6-9 hrs.
 Returns to normal :-12 hrs.

34.  Acute myocardial infarction
 Skeletal muscle damage, muscular dystrophy, inflammatory
myopathies
 Renal failure, severe uremia
 Shock and trauma

35.  Troponin is a complex of three regulatory proteins that is integral to
non-smooth muscle contraction in skeletal as well as cardiac muscle.
 Troponin is attached to the tropomyosin sitting in the groove between
actin filaments in muscle tissue.
 Troponin has three subunits.
 TnC, TnT, and TnI
1.Troponin-C has calcium binding ability and has no diagnostic value
2.Troponin-T binds the troponin tropomyosin complex,
3.Troponin-I is an inhibitory protein

36.  Cardiac Troponin I (cTnI) is a cardiac muscle protein.
 The cTnI has a additional amino acids residues on its N-terminal that
are not exist on the skeletal form.
 The half life = 2 – 4 hours
 Serum increase = 2 – 8 hours

37.  Cardiac Troponin T (cTnT) is present in
fetal skeletal muscle.
 In healthy adult skeletal muscle
cTnT is absent.
 Biological half life and early serum
increases of cTnT are similar
to that of cTnI.
 Normal Level:
cTnT < 0.01ng/ml
cTnI < 0.1ng/ml

38.  90% SENSITIVITY AND 95%
SPECIFICITY FOR MI 8 HOURS AFTER
ONSET OF S&S.
 IF NEGATIVE RULES OUT MI
 OBTAINS TWO NEGATIVE TROPONIN
VALUES 4 – 6 – 8 APART
 EVEN A SMALL ELEVATION
INDICATES MYOCARDIAL DAMAGE
TROPONIN I
 LEVELS MAY HELP TO STRATIFY RISK
 LESS SPECIFIC THAN TROPININ I
 INCREASED IN ANGINA
 INCREASED IN CHRONIC RENAL
FAILURE
 HIGHLY SENISITIVE FOR DETECTING
ISCHEMIA
TROPONIN T

39.  Troponin-I levels begin to rise 2-4 hours after onset of MI and roughly
80% of patients with AMI will have positive values at 3 hours
 Elevations in Troponin-I and Troponin-T can persist for up to 10 days
after MI
 For retrospectively diagnosing AMI
 Troponin T and I are not detected in healthy individuals
 Significant increase in Troponins reflects myocardial necrosis.

40.  Pulmonary embolism
 Pulmonary hypertension
 Renal failure
 Sepsis/septic shock
 Sepsis-related myocardial
dysfunction
 Systemic inflammatory diseases
 Trauma
 Arrhythmias
 Congestive heart failure
 Coronary artery disease
 Coronary vasospasm
 Critically ill patient
 Hypertension
 Myocarditis
 Pericarditis

41.  Since normal people have virtually nil levels of troponin in serum, it is
thought that detectable levels indicate chronic disease even if not
acute myocardial damage
 Degree of elevation of Troponin value can give prognostic information.
1. LESS THAN 0.07 ng/ml: NEGATIVE
2. 0.07 - 0.5 ng/ml: CONSISTENT WITH POSSIBLE CARDIAC DAMAGE AND POSSIBLE
INCREASED CLINICAL RISK.
3. >0.5 ng/ml: CONSISTENT WITH CARDIAC DAMAGE, INCREASED CLINICAL RISK
AND MYOCARDIAL INFARCTION.

42.  Patients with troponin rises benefit more from Glycoprotein IIb IIIa
inhibitors such as,
o Abciximab
o Eptifibatin
o Clopidogrel

43.  Creatine kinase (CK/CPK) is an enzyme which catalyses' the conversion
of creatine to phosphocreatine degrading ATP to ADP
 Two subunits, B(brain type) or M(muscle type), Making three different
isoenzymes: CK-MM, CK-BB and CK-MB
 Skeletal muscle expresses CK-MM (98%) and low levels of CK-MB (1%)
 The myocardium has CK-MM at 70% and CK-MB at ~30%

44.  CK-MM in Muscle pathology
o Crush syndrome / compartment syndrome
o Dermatomyositis / polio myositis
o Duchene muscular dystrophy / Becker muscular dystrophy
o Statins ( HMG coenzyme reductive Co-A )

45.  High specificity for cardiac tissue
 Begins to rise 4-6 hours after onset of infarction
 Peaks at about 24 hours
 Returns to baseline at 48-72 hours
 Can be used to indicate early re-infarction if level normalizes and then
increases again

46.  CK Normal Range: 0-215 U/L
 CKMB < 25 U/L
 If CK-MB is elevated or
 The ratio of CK-MB to total CK (relative index) is more than 2.5–3 it is
AMI.
 A high CK with R.index below this value suggests that skeletal muscle
damage.

47.  False positive (for MI) CK-MB elevation can be seen in:
1. Significant skeletal muscle injury
2. The MB fraction is determined to be expressed during the process of
muscle regeneration
3. Cardiac injury for reason other than MI
4. Defibrillationn
5. Blunt chest trauma
6. Cocaine abuse

48. LD (LDH)
 Used along with aminotransferases to diagnose AMI.
 LD is non-specific for cardiac tissue , which contains LD-1.
 Pancreas, kidney, stomach tissue and red cells also contain LD-1.
 In AMI, LD rises at about 24 hours,
 peaks at 3-6 days,
 remains elevated for up to 2weeks.
 ALT/AST :- Used as surrogate markers of cellular damage in the past.
Very non-specific so not used for assessment of myocardial damage
any longer and remains elevated for up to 4-5 days.

49. Ischemia Modified Albumin (IMA)
Heart Type Fatty Acid Binding Protein (HFABP)

50.  This marker of Ischemia , is produced when circulating serum albumin
contacts ischemic heart tissues.
 IMA can be measured by the Albumin Cobalt Binding (ACB) assay that
is based on IMA’s inability to bind to cobalt
 MECHANISM – due to structural change in the amino terminal end of
albumin.
 IMA levels rise within hours & Remain elevated for hours. FDA in
2010 has approved a multimarker approach for using the combination
of ECG, the cTnI , and the IMA levels achieving a sensitivity of 95% for
ACS

51.  H-FABP is a very stable abundant [138] low molecular weight protein
(14 – 15 kDa) in the cytoplasm of myocardial cells.
 Appearing as early as 90 min after symptom onset and peaking within
6 hours. Plasma level returns within 24 hours.
 An ideal candidate both for early assessment or exclusion of AMI and
for the measurement of a recurrent infarction.
 The myoglobin/heart FABP ratio has been used to differentiate
between heart muscle and skeletal muscle Injury.

52.  In contrast to myoglobin, hFABP has 4 times higher concentration
gradient.
 Thus, whilst both are released almost simultaneously, the percentage
rise in hFABP is much sharper and higher.
 Peak rise in hFABP = 30 fold vis-à-vis 15 fold with myoglobin.

53.  Yes, there are 2 conditions where false positives can occur while
testing for hFABP.
• Excessive physical activity – due to damage to the skeletal muscle cells
and release of hFABP with subsequent rise in the levels of hFABP ;
• Renal Insufficiency – when deficient kidneys are not able to flush out
the normal levels of hFABP presented for excretion by release from the
skeletal muscles and subsequent increase in hFABP .

54.  C – Reactive Protein
 Homocysteine

55.  CRP is an acute-phase protein produced by the liver.
 Plasma levels can increase rapidly to 10000x levels.
 CRP previously known to be a marker of high risk in cardiovascular
disease.
 More recent data may implicate CRP as an actual mediator of
atherogenesis.
Clinical Uses
› Screening for cardiovascular risk in otherwise “healthy” individuals
› Predictive value of CRP levels for disease severity in pre-existing
Coronary artery disease.

56.  Elevated levels predictive of
• Long-term risk of first MI
• Ischemic stroke
LIMITATIONS
 Low specificity
Elevated levels of CRP lacks specificity (e.g. acute and chronic infection,
cigarette smoking, ACS, and active inflammatory states frequently associated
with increase levels of CRP).
 No evidence that lowering CRP levels decreases CV risk
CRP RISK for CVD
Less than 1.0 mg/L Low
1.0-2.9 mg/L Intermediate
Greater than 3.0 mg/L High

57.  Intermediary amino acid formed by the conversion of methionine to
cysteine.
 Recognized as an independent risk factor for the development of
atherosclerotic vascular disease and venous thrombosis.
 Homocysteine implicated directly in vascular injury including:
› Intimal thickening
› Disruption of elastic lamina
› Smooth muscle hypertrophy
› Platelet aggregation

58.  Vascular injury induced by leukocyte recruitment, foam cell formation,
and inhibition of NO synthesis
 Normal levels less than 6 micromol/l
 Treatment includes supplementation with folate, B6 and B12.

59.  TNF-α receptor family expressed on a variety of cells, including
myocytes.
 When activated it mediates apoptosis and plays an important role in
the development and progression of heart failure.
 Elevated serum levels reported in patients with heart failure, and high
levels associated with severe disease.
 The inhibition of soluble Fas in animals reduces postinfarction
ventricular remodeling and improves survival.
 Nonspecific immunomodulating agent — pentoxifylline or IV
immunoglobulin— reduces plasma levels of Fas and CRP and improves
LV function in ischemic or DCMP.

60. Oxidative stress damage cellular proteins and cause myocyte apoptosis and
necrosis.
Assoc with arrhythmias and endothelial dysfunction through inactivation of
NOS activity and reduction of nitric oxide.

61.  MPO is an enzyme that aids WBC’s in destroying bacteria and virus.
 MPO catalyzes the conversion of hydrogen peroxide and chloride ions
(Cl-) into hypochlorous acid particles.
 MPO is released in response to infection and inflammation.
 Normal plasma MPO levels are 51633pmol/ml.

62.  Extracellular matrix provides a “skeleton” for
myocytes (for size / shape) brought about by
a balance between matrix
metalloproteinases and tissue inhibitors of
metalloproteinases. Enzyme greater than
inhibitors associated with ventricular
dilatation and remodeling .
 Increased extracellular-matrix breakdown or excessive collagen synthesis
associated with impaired LV function and adverse clinical outcomes in
patients with heart failure and are important targets of therapy.
 The propeptide procollagen type I is a serum biomarker of collagen
biosynthesis.

63.  Chromogranin A : a polypeptide hormone produced by the
myocardium, with potent neg inotropic properties and elevated
plasma levels in patients with HF.
 Galectin-3: a protein produced by activated macrophages, plasma
levels reported to predict adverse outcomes in patients with HF.
 Osteoprotegerin: a member of the TNF receptor superfamily
implicated in development of LV dysfunction and predicts survival in
pts with HF after AMI.

64. • Stable C terminal pro-peptide of AVP
• AVP associated advanced HF: causes hyponatremia
• AVP –short life and unstable, cannot be measured
• BACH trial : elevated copeptin predicted higher mortality
• Can be used as marker for biomarker guided therapies

65. • Member of TGF beta cytokine family
• Levels increases under stress (MI, HF)
• Correlates well with myocardial fibrosis :- can be used in HFpEF
Prognosis of HF using GDF 15 independent of NT proBNP

66. Syndecan 1 and Syndecan 2
• Members of proteoglycan family involved in cell matrix interactions and
heart remodeling
• Better predictors of events in HFpEF
• COACH study: Women with low levels of Syndecan 1 have worse
prognosis

68. ENZYME BASELINE INITIATION OF RISE PEAK RETURN TO BASELINE
MYOGLOBIN 1 – 3 hours 6 – 9 hours 12 hours
Troponin T and I
( TnT, TnI )
2 – 4 hours 48 hours 7 – 10 days
CK-MB 2—4 hours 24 hours 48 – 72 hours
AST/SGOT In 12 hours 48 hours 4 – 5 days
LDH 24 hours 3 – 6 days 2 weeks

70.  When comparing cTnI and NT-proBNP. cTnI is single best independent
prognostic predictor.
RECOMMENDATION FOR DIAGNOSIS:
In patients presenting with dyspnea, measurement of natriuretic peptide
biomarkers is useful to support a diagnosis of HF.
RECOMMENDATION FOR PROGNOSIS :
Measurement of BNP or NT-proBNP is useful for establishing prognosis or
disease severity in chronic HF.
Measurement of baseline levels of natriuretic peptide biomarkers and/or
Cardiac Troponin on admission to the hospital is useful to establish a
prognosis in acutely Decompensated HF.

71. RECOMMENDATION FOR PREVENTION OF HF: ( ACC/AHA )
1) For patients at risk of developing HF, natriuretic peptide biomarker
screening and early intervention may prevent HF.
2) During a HF hospitalization , a predischarge NP level can be useful to
establish a postdischarge prognosis.
3) In patients with chronic HF , measurement of other clinically available
tests, such as biomarkers of myocardial injury or fibrosis, may be
considered for additive risk stratification.

72.  Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine
(11th edition)
 Harrison’s Principle of Internal Medicine(19th edition)
 Medscape.com
 ACC/AHA guidelines (2017)
 Medicomic