Biomarker in heart failure

Dr Jeetam Singh Rajput
PG Dept of Internal Medicine
MLN Medical college

Heart failure, is a major and growing public
health problem and appears to result not only
from cardiac overload or injury but also from a
complex interplay among genetic,
neurohormonal, inflammatory, and biochemical
changes acting on cardiac myocytes, the cardiac
interstitium or both.
An increasing number of enzymes, hormones, biologic
substances, and other markers of cardiac stress and
malfunction, as well as myocyte injury — collectively
referred to as biomarkers — appear to have growing
clinical importance.

 To established or refute a diagnosis.
 To understand the underlying pathological
process.
 To determine the presence or level of severity
of disease.
 To detect adverse consequences.
 To guide or monitor response to treatment.

 Accurate, repeated 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.

 Consist of 5 type of structurally similar peptide
1) ANP( atrial natriuretic peptide)
2) BNP(brain type natriuretic peptide)
3) CNP(C-type natriuretic peptide)
4) DNP(danroaspis natriuretic peptide)
5) Urodilantin( isoform of ANP)
 With perspective of HF only ANP & BNP are important.

 BNP is a precursor of active BNP and N-terminal pro–
brain natriuretic peptide (NT-pro-BNP) - pre–
prohormone BNP is a 134-amino-acid peptide
synthesized in the myocytes and cleaved to
prohormone BNP of 108 amino acids.
 It released during hemodynamic stress when ventricles
are dilated, hypertrophic, or subject to increased wall
tension.

 cleaved by circulating endoprotease (corin) into two
polypeptides: the inactive NT-pro-BNP and the bioactive
BNP.
 BNP causes arterial vasodilation, diuresis, and natriuresis,
and reduces the RAAS and SNS.
 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.

 Natriuretic peptides - cleared by kidney.
 Hypervolemia and HTN in renal failure enhance
secretion BNP.
 There is mod. increase in circ BNP with age, in relation
to myocardial fibrosis or renal dysfunction.
 Pulmonary HTN may increase the plasma level of
BNP and varies inversely with BMI.
 BNP and NT-pro-BNP assays are commercially
available and are the most widely tested.
 Recommended in current guidelines

 Most useful in the evaluation of pts with dyspnea
presenting to the ED where measurement of BNP may
provide the advantages of convenience and rapid turn
around times facilitating clinical management.
 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.

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.

 Strategy of single measurement of BNP or NT-pro-BNP
in pts with acute dyspnea was assoc with shorter /
lower cost hospital stay.
 Decisions for hospital admission or referral to an OP
clinic are facilitated by natriuretic peptide levels.
 BNP level - also an accurate predictor of survival in
acute decompensated HF irrespective of LVEF.
 Adjusting for baseline variables, an almost linear
relation between BNP and in-hospital mortality
(Fonarow et al for ADHERE)

BNP - useful in the diagnosis and risk stratification of pts
with chronic HF and are better predictor of death than is
plasma norepinephrine or endothelin-1

 Systolic Heart Failure Treatment Supported by BNP
(STARS–BNP) trial by Jourdain et al
 In this study 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.
 BNP level is useful in screening asymptomatic subjects
at risk of HF such as elderly and those with HTN, DM
& asymptomatic CAD.
 May also be used to screen for acute or late cardiotoxic
effects associated with cancer chemotherapy.

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

 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 eg:- 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.

 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.

 Member of the interleukin-1 receptor family secreted
by cultured monocytes subjected to mechanical strain
with stretch.
 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.

 BNP and NT-pro-BNP – excellent assays
available and with substantial experience
superior to all other marker.
 Adrenomedullin and ST2 – analytical methods
not yet standardized but maybe supplementary
to the ANP’s.

 Myocyte injury - severe ischemia and
stresses on the myocardium such as inflammation,
oxidative stress and neurohormonal activation causes
myocyte injury.
 Cardiac troponins T and I - emerged as sensitive and specific
markers of myocyte injury.
 Improved greatly the diagnosis, risk stratification, and care
of patients with ACS.

 Modest elevations of cT I levels are also found in patients with HF
without ischemia.
 Acc to Horwich et al – cT I was detectable (≥0.04 ng /ml) in approx
half of 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.

 with standard assay, c T T detectable in 10% of pts
chronic HF but with high-sensitivity assay, it was
detectable in 92% of these patients
 As sensitivity of c T analysis increases further, it will
probably be detectable in the most of the pts with HF
and along with the natriuretic peptides it will be used
routinely to assess the prognosis and response to
treatment of patients with heart failure.

 Myosin light chain kinase, heart fatty-acid binding protein,
and CK MB fraction — also circulate in stable patients with
severe HF.
 Like c T T, presence of these myocardial proteins in the
serum is an accurate predictor of death or hospitalization for
HF.
 Need to be validated with more studies.

 Inflammation is important in the pathogenesis and
progression of many forms of heart failure, and
biomarkers of inflammation have become the subject of
intense.

 C-reactive protein was described as an acute-phase
reactant synthesized by hepatocytes in response to the
proinflammatory cytokine interleukin-6.
 CRP exert direct adverse effects on vascular endothelium
by reducing nitric-oxide release and increasing endothelin-
1 production and Induces expression of endothelial
adhesion molecules (impt role in vascular diseases –
potential target for tx).

 Elevated levels of CRP lacks specificity (eg acute and
chronic infection, cigarette smoking, ACS, and active
inflammatory states frequently assoc with inc levels of
CRP).
 Multivariate analysis indicated that increased C-
reactive protein level is an independent predictor of
adverse outcomes in patients with acute or chronic
heart failure.
 C-reactive protein, a protein that appears in the serum
in a variety of inflammatory conditions detectable in
75% of patients with chronic heart failure and heart
failure was more severe in those with higher levels of
C-reactive protein.

 Framingham Heart Study, C-reactive protein (as well
as cytokines interleukin-6 and TNF-α) was noted to
identify asymptomatic older subjects in the community
at high risk of the future development of heart failure.
 Interleukin-6 and TNF-α levels could be used to predict
the future development of heart failure in
asymptomatic elderly subjects in some study.
 Blockade of TNF-α has not resulted in clinical benefit in
patients with heart failure.

 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.
 Pharmacologic reduction of Fas still in its infancy but may be
a new direction in the treatment of heart failure. Nonspecific
immunomodulating agent — pentoxifylline or IV
immunoglobulin— reduces plasma levels of Fas and CRP
and improved LV function in ischemic or DCMP.

 Results from an imbalance between reactive oxygen
species (superoxide anion, hydrogen peroxide,
hydroxyl radical) and endogenous antioxidant defense
mechanisms with deleterious effects on endothelial
function and pathogenesis / progression of HF.
 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.
 Inflammation and immune activation, RAAS , SNS and
increased catecholamine levels and peroxynitrite formed
from the interaction of the superoxide anion and nitric oxide
all may increase oxidative stress.
 Plasma-oxidized LDL, malondialdehyde and
myeloperoxidase (an index of leukocyte activation), urinary
levels of biopyrrins (oxidative metabolites of bilirubin), and
isoprostane levels in plasma and urine - surrogate markers
of ROS(reactive oxygen species).

 Increasing evidence suggest that xanthine oxidase
(catalyst for hypoxanthine and xanthine) plays a
pathological role in heart failure.
 Uric acid elevated with increased xanthine oxidase
activity and correlate with impaired hemodynamics
and independently predict adverse prognosis in HF.
 Although more studies are required, UA may prove to
be a simple, useful, nonspecific, clinical indicator of
excess oxidative stress.

 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.
 Abnormal increase in collagen synthesis deleterious to
cardiac function bec excessive fibrosis impairs ventricular
function. The propeptide procollagen type I is a serum
biomarker of collagen biosynthesis.
 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.

 In 1960s it was reported that patients with HF had
abnormally elevated levels of plasma norepinephrine
at rest and further elevations occurred during exercise.
The urinary excretion of norepinephrine was also
increased.
 Cohn et al. subsequently demonstrated that plasma NE
level was an independent predictor of mortality in case
of HF.
 It also observed that the renin–angiotensin–aldosterone
system becomes activated in patients with heart failure.

 Endothelin-1 is a powerful stimulant of vascular smooth-
muscle contraction and proliferation and ventricular and
vessel fibrosis and is a potentiator of other neurohormones.
 Endothelin-1 Plasma levels increased with HF and correlate
directly with pulmonary artery pressure, disease severity,
and mortality.
 Most powerful predictors of mortality and hospitalization
for HF were BNP,ANP , norepinephrine, endothelin-1,
plasma renin activity, and aldosterone.
 RALES found that administration of spironolactone in
patients with AMI reduced myocardial collagen synthesis,
as reflected by plasma procollagen type III.

 Arginine vasopressin is a nonapeptide synthesized in the
hypothalamus and stored in the posterior pituitary gland
and that has antidiuretic and vasoconstrictor properties.
 Excess release of arginine vasopressin intensifies heart
failure associated with dilutional hyponatremia, fluid
accumulation, and systemic vasoconstriction.
 Whereas plasma levels of arginine vasopressin are elevated
in patients with acute or chronic heart failureand are
associated with poor clinical outcomes, blockade of the
vasopressin 2 receptor relieves acute symptoms but does not
appear to alter the natural history of severe heart failure.
Thus, it is not yet clear whether the vasopressin 2 receptor
should be considered to be a therapeutic target.

 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.

 Traditional approach to the classification of HF focused
on the pathological cause of failure of the cardiac pump
(CAD), pathophysiological characteristics (e.g., systolic
HF), and the acuity and severity of HF
 A biomarker profile may be a valuable addition to this
approach
 Biomarkers for heart failure are usually considered
individually. A multimarker strategy may be useful in
refining risk stratification among patients with acute
coronary syndromes and there is a growing interest in
this approach for categorizing heart failure

1. Most specific marker for heart failure.
a) ANP
b) Trop I
c) CNP
d) NT pro BNP

2. Which of the following is true.
a) BNP is secreted from human brain so it is
named as BNP.
b) BNP is secreted from ventricle that’s why it is
known as BNP.
c) BNP is made up of 22 amino acid
d) NOT

3. Which of the following is true
a) ANP is release in response to increase
ventricular stress.
b) Half life of ANP is 30 min.
c) Half life of ANP is more than BNP.
d) Half life of BNP is more than NT BNP.
e) NOT

4. False about CRP
a) It is an acute phase reactant.
b) Normal plasma conc <0.2mg/l
c) Cardiovascular risk is more when conc>1mg/l
d) Higher conc lead to peripheral vascular
disease.
e) Low level can be measure by highly sensitive
test laser nephelometry.

5. Which of the following is not a marker for HF
a) ST-2
b) ESR
c) Fas(Apo-1)
d) CRP

6. Which of the following is not an inflamatory
marker.
a) Amyloid protein
b) Haptoglobin
c) Fibrinogen
d) Ceruloplasmin
e) Ferritin
f) Thyroglobulin

7. Which of the following marker has been shown
to correlate best with pulmonary vascular
resistance in pts with HF.
a) BNP
b) ANP
c) Endothelin 1
d) Endothelin 2

Ans is “C” heart failure is associated with
increase level of endothelin 1. it is among most
potent endogenous vasoconstrictor .
Pulmonary circulation is the primary source of
expression of this neurohormone and found to
be correlated with pulmonary vascular
resistance.

8. A pt comes with sudden resp distress . On
examination b/l basal crept present and
alveolar wedge pressure is normal the likely
cause is
a) Narcotic overdose
b) CHF
c) MI
d) Cardiogenic shock

9. CHF is associated with increase in all of the
following except
a) Serum Na+
b) Right mean atrial pressure
c) Urea
d) Nor epinephrine

Biomarker in heart failure

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