Nelson S. Abelardo, MD, FPCP, FPCC
UP-PGH Medical Center



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
Morrow & de Lemos
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.





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, a protein that appears in the serum in a variety of
inflammatory conditions detectable in 30 of 40 patients with chronic heart
failure and heart failure was more severe in those with higher levels of Creactive protein.
C-reactive protein was described as an acute-phase reactant synthesized
by hepatocytes in response to the proinflammatory cytokine interleukin-6
Multivariate analysis indicated that increased C-reactive protein level is
an independent predictor of adverse outcomes in patients with acute or
chronic heart failure.
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.



CRP exert direct adverse effects on vascular endothelium
by reducing nitric-oxide release and increasing endothelin1 production
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



In 1990, Levine et al. - elevated levels of circulating TNF-α in
patients with heart failure. TNF-α and three interleukins
(interleukins 1, 6, and 18) are considered to be proinflammatory
cytokines and are produced by nucleated cells in the heart.
The cytokine hypothesis of heart failure proposes that a
precipitating event — such as ischemic cardiac injury — triggers
innate stress responses, including elaboration of proinflammatory
cytokines, and that the expression of these cytokines is associated
with deleterious effects on left ventricular function and accelerates
the progression of heart failure.
Proinflammatory cytokines - myocyte apoptosis and necrosis;
interleukin-6 - hypertrophic response in myocytes
TNF-α - LV dilatation by activation of matrix
metalloproteinases.


Interleukin-6 and TNF-α levels could be used
to predict the future development of heart
failure in asymptomatic elderly subjects in one
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 DCM




Results from an imbalance bet 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
Damage cellular proteins and cause myocyte apoptosis and
necrosis.
Assoc with arrhythmias and endothelial dysfunction through
reduction of NOS activity and inactivation 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
Increasing evidence that xanthine oxidase (catalyst for
hypoxanthine and xanthine) plays a pathol 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, albeit 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 (proteolytic enzymes that degrade fibrillar
collagen) 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.



1960s reports 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
Swedberg et al. 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.
Plasma levels increased with HF and correlate directly with
pulmonary artery pressure, disease severity, and mortality
Val-HeFT investigators showed the most powerful predictors of
mortality and hospitalization for HF were BNP, big endothelin-1,
norepinephrine, endothelin-1, plasma renin activity, and
aldosterone. among 4300 patients
RALES found that administration of spironolactone in patients
with AMI reduced myocardial collagen synthesis, as reflected by
plasma procollagen type III, as well as postinfarct adverse left
ventricular remodeling suggesting beneficial action of
spironolactone in patients with severe heart failure.



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.



Myocyte injury - severe ischemia but it is also a
consequence of stresses on the myocardium such as
inflammation, oxidative stress and neurohormonal
activation.
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.
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


Latini et al – 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 entire population 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 1, 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




precursor of BNP and N-terminal pro–brain natriuretic
peptide (NT-pro-BNP) - pre–prohormone BNP, a 134amino-acid peptide synthesized in the myocytes and
cleaved to prohormone BNP of 108 amino acids.
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






Natriuretic peptides - cleared by kidney
Hypervolemia and HPN of renal failure
enhance secretion BNP
Mod increase in circ BNP with age, in relation
to myocardial fibrosis or renal dysfunction
Pulmonary HPN 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 POCT
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.




Versus standard care, a 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 bet 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
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




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
adrenomedullin and ST2 – analytical methods
not yet standardized but maybe supplementary
to the ANP’s



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






many appear to provide important information
regarding the pathogenesis of heart failure
identification of subjects at risk for heart failure
appear to be useful in risk stratification
useful in the diagnosis of heart failure
aid in monitoring therapy.
may be risk factors themselves and therefore may be
potential targets of therapy.
Biomarkers in Heart Failure June 2011
HFSA 2010 GUIDELINE RECOMMENDATION 4.3
Routine determination of plasma beta type natriuretic
peptide (BNP) or N-terminal pro-BNP (NT-proBNP)
concentration as part of screening evaluation for
structural heart disease in asymptomatic patients is not
recommended