Dr Jeetam Singh RajputPG Dept of Internal MedicineMLN 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) ANPb) Trop Ic) CNPd) 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 acidd) NOT

3. Which of the following is truea) 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/lc) Cardiovascular risk is more when

conc>1mg/ld) 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-2b) ESRc) Fas(Apo-1)d) CRP

6. Which of the following is not an inflamatory marker.

a) Amyloid proteinb) Haptoglobinc) Fibrinogend) Ceruloplasmine) Ferritinf) Thyroglobulin

7. Which of the following marker has been shown to correlate best with pulmonary vascular resistance in pts with HF.

a) BNPb) ANPc) Endothelin 1d) 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 overdoseb) CHFc) MId) Cardiogenic shock

9. CHF is associated with increase in all of the following except

a) Serum Na+b) Right mean atrial pressurec) Uread) Nor epinephrine