Mbbs pathology BNP

1. Natriuretic Peptide in CHF &ACS
Dr Virbhan Balai

2. Overview
• 4 human natriuretic peptides
1. Brain natriuretic peptide (BNP)
2. Atrial natriuretic peptide (ANP)
3. C-type natriuretic peptide (CNP)
4. Dendroaspis natriuretic peptide (DNP)

3. • BNP is a member of a family of 4 human
natriuretic peptides
• Shares a common 17-peptide ring structure.
• Discovered over 15 years ago

4. • BNP, important biomarker in the diagnosis
of CHF.
• Its utility has also been explored in-
1. Myocardial ischemia and infarction
2. Right-sided heart failure (eg, cor pulmonale)
3. Acute pulmonary embolism.

5. • Currently clinical trials are under way to
determine if serial BNP measurements have a
role in guiding the titration of CHF therapies.
• Recombinant BNP (nesiritide)- evaluated and
approved for adjunctive therapy for acute CHF.
• Although questions about its safety have
diminished its use for this indication.

6. • >10%
• Hypotension (4-35% )
• Serum creatinine raised (17-28% )
• 1-10%
• Nausea (4-13% )
• Ventricular tachycardia (3-10% )
• Headache (7-9% )
• Dizziness (3-6% )
• Insomnia (2- 6% )
• Back pain (4%)
• Ventricular premature beats (3-4% )
• Anxiety (3%)
• Angina (2%)
• Atrial fibrillation (1% or greater )
• Atrioventricular node (1% or greater )
• Bradycardia (1%)
• Somnolence (1%)
• Tremor (1%)

7. Normal Activity of Natriuretic Peptides
• The first NP was identified in 1983 - named
atrial natriuretic peptide (ANP).
• ANP is a 28-amino acid polypeptide
• ANP is secreted in response to atrial stretching
• Normal hearts secrete extremely small
amounts ofANP
• Elevated levels are found in patients with LVH
and mitral valve disease.

8. • BNP was first identified in pig brains in 1988
and therefore named BNP.
• Subsequently discovered to be present in high
concentrations in cardiac tissues, particularly
the ventricles.
• C-type natriuretic peptide (CNP)-act in the
peripheral vasculature
• Dendroaspis natriuretic peptide (DNP)- atria.

9. • Before its activation, BNP is stored as a 108–amino acid
polypeptide precursor
• Pro BNP, in secretory granules in both ventricles and, to a
lesser extent, in the atria.
• After pro BNP is secreted in response to volume overload
and resulting myocardial stretch
• It is cleaved to the 76-peptide, biologically inert N -terminal
fragment NT-pro BNP and the 32-peptide, biologically
active hormone BNP.

10. • High ventricular filling pressures stimulate the release
of ANP and BNP.
• Both peptides have diuretic, natriuretic, and
antihypertensive effects, which they exert by inhibiting
the renin-angiotensin-aldosterone system.
• They also have systemic and renal sympathetic activity.
• BNP may provide a protective effect against the
detrimental fibrosis and remodelling that occurs in
progressive heart failure.

11. • Although ANP was identified first,
concentrations of BNP in the myocardial tissue
were found to be higher than those of ANP.
• Therefore, BNP has been studied more
intensely than ANP as a clinically useful
marker of increased ventricular filling
pressure.
• An elevated BNP level is a marker of increased
LV filling pressures and LV dysfunction.

12. • Natriuretic peptide receptors and plasma endo peptidases actively
clear BNP from the circulation; the plasma half-life is thus short,
approximately 20 minutes.
• No receptor-mediated clearance of NT-pro BNP is known to occur,
and NT-pro BNP has a correspondingly prolonged half-life of 60-
120 minutes.
• As a result, plasma levels of NT-pro BNP tend to be 3-5 times
higher than BNP levels.
• Clearance of NT-pro BNP is primarily renal.
• Therefore, the renal clearance of NT-pro BNP confounds its
diagnostic utility in patients with renal insufficiency.
• As a laboratory specimen, NT-pro BNP is more stable during storage
than BNP.
• NT-pro BNP samples are stable at room temperature for 72 hours,
versus less than 4 hours for BNP samples.

13. BNP and NT-pro BNP Assay Methods
• First-generation assays for BNP were competitive radio
immunoassays that required extraction and purification of the
plasma sample.
• Second-generation assays were based on monoclonal antibodies and
radioisotope labels.
• Commercial versions of the monoclonal antibody assay first
appeared in 1994 and initially required 12-36 hours to complete.
• Third-generation assays, which provided results in as little as 15
minutes, became available in 2000.
• These rapid assays used immunofluorescent methods.
• All of the assays for BNP and NT-proBNP that are commercially
available for clinical use in the United States are rapid
immunoassays.

14. BNP and NT-pro BNP Levels in LV
Dysfunction
• NT-pro BNP levels - sensitivity of 75% and a
negative predictive value of 99% in diagnosis of
CHF.
• NT-pro BNP levels were compared with LV
function in 3051 patients pooled from 3 large
European data sets.
• Median values for patients with-
– Normal LV function- 20
– LV dysfunction -117
– Acute CHF -270 pg/mL

15. Recombinant BNP
• Recombinant BNP- nesiritide
• Nesiritide - US FDA approved for the
treatment of acute decompensated heart failure
with dyspnea in 2001.
• Nesiritide is a BNP measured by the BNP
assay.
• Measurement of BNP is not indicated in
patients who are receiving nesiritide.

16. BNP and NT-pro BNP Evaluation in the ED
• BNP testing in the acute care setting is derived
from the landmark Breathing Not Properly
study and later studies.
• Breathing Not Properly multicenter
prospective study involved 1586 patients
presenting to the ED with acute dyspnea.
• Establish the diagnosis of CHF when the
clinical presentation is ambiguous or when
confounding comorbidities are present.

17. Factors affecting BNP/NT-pro BNP assays
• Renal clearance of NT-pro BNP and, to a
lesser degree BNP
• BNP levels were inversely correlated with
estimated GFRs.
• BNP rule-out CHF cut offs
GFR 60-89 = 290 pg/mL
15-29mL/min = 515pg/mL
• For NT-pro BNP assays, optimal cut offs were
1360 and 6550pg/mL, respectively.

18. • BNP - inversely correlated with BMI.
• Mean BNP values are 3 times higher for lean
patients with CHF than for obese patients with
CHF (517 vs 176mg/mL).
• Obese patients with BMIs ≥ 25 kg/m2 had
median BNP levels below the recommended
rule-in threshold of 500pg/mL.

19. • AF confounds the utility of BNP assay for
diagnosing acute CHF exacerbation.
• AF was associated with increased BNP levels
in the absence of acute CHF.
• Ahigh cut off value to exclude CHF is
required.

20. BNP versus NT-pro BNP assays
• Similar confounding effects of age, sex, and
renal insufficiency.
• NT-pro BNP is most sensitive for the detection
of mild LVdysfunction and structural heart
disease.
• BNP is less sensitive to the effects of renal
insufficiency than NT-pro BNP.

21. Evidence-Based BNP and NT-pro BNP Cut off
Values for Diagnosing Heart Failure

22. Likelihood ratios
• BNP levels very reliable in differentiating heart
failure from pulmonary disease.
• < 100pg/mL to rule out heart failure and >
500pg/mL to rule in heart failure.
• LR-negative = 0.13 and LR-positive = 8.1.
• Intermediate range of 100-500pg/mL with LR-
positive of only 1.9.
• Therefore, an intermediate BNP result alone
cannot be used to rule in or rule out heart failure.

23. • Any 2 or more clinical features, a heart failure
history, and a mid-range BNP level - Had a
cumulative LR-positive of 10
• A mid-range BNP level, no history of heart
failure, and 0 or 1 clinical criterion - Had an
intermediate cumulative LR-negative of 0.7,
which was not clinically useful.
• Serial BNP measurements for monitoring the
treatment of heart failure is not well established.

24. Risk Stratification and Outcome Prediction
• Direct correlation between BNP and NT-pro
BNP levels and clinical outcomes in patients
with CHF.
• Useful as triage instruments to help guide the
emergency physician.

25. Framingham Heart Study
• Prospective study, 3346 patients without heart failure
• To determine the usefulness of BNP in predicting the risks for all-cause
mortality.
• Patients were followed up for a mean period of 5.2 years.
• After adjustment for known cardiovascular risk factors, high levels of BNP
were associated with a
– 27% increase in risk of all-cause mortality
– 28% increase in risk for a first cardiovascular event
– 77% increase in the risk of CHF
– 66% increase in the risk ofAF
– 50% increase in the risk of stroke or TIA.
• BNP levels were not predictive of coronary heart disease.
• ? ? BNP testing has a role in risk stratification and screening for
cardiovascular & cerebrovascular disease in asymptomatic populations.

26. REDHOT study
• Rapid Emergency Department Heart Failure
Outpatient Trial (REDHOT) to examine the
prognostic role of BNP in the ED.
• Multicenter
• Undertaken by Breathing Not Properly
investigators.
• This investigation indicated that BNP level is a
strong predictor of 90-day patient outcome with
regard to cardiac mortality and subsequent ED
visits and/or re hospitalization for acute CHF.

27. BASEL study
• B-Type Natriuretic Peptide forAcute Shortness of
Breath Evaluation (BASEL) study
• Patients were randomly assigned to undergo
standard evaluation or evaluation aided with rapid
bedside BNP measurement.
• BNP measurement significantly decreased rates of
admission (75% vs 85%) and admission to the
ICU (15% vs 24%).
• Length of hospitalization was also significantly
shortened with BNP measurement.

28. Copenhagen Hospital Heart Failure study
• NT-pro BNP level was predictive of 1-year
mortality in patients with heart failure.
• LVEF provided no additional prognostic value
over NT-pro BNP values in this small subset of
patients with heart failure.

29. Rothenburger et al study
• German researchers evaluated NT-pro BNP levels
in 550 extremely ill patients with severe DCMP in
whom cardiac transplantation was being
considered.
• At 1 year, patients with levels less than
1000pg/mL had a less than 1% mortality rate
• Patients with levels of 1000-5000 pg/mL had a
2% mortality rate
• Patients with levels greater than 5000 pg/mL had
a 28% mortality rate.

30. O’Brien et al study
• Did not reveal a statistically significant
relationship between the admission NT-pro
BNP level and outcome.
• However, the discharge NT-pro BNP level was
a statistically significant predictor of adverse
outcome.

31. Bettencourt et al study
• In this study, change in NT-pro BNP level was the
strongest predictor of death and/or hospital
readmission in hospitalized patients with CHF.
• Levels of NT-pro BNP were measured on
admission and again at hospital discharge.
• Patients were stratified as those whose NT-pro
BNP levels decreased ≥30% between admission
and discharge, those with an increase ≥30%, and
those with any change < 30%.

32. NT-pro BNP for Monitoring Therapeutic Response
• Data from a Spanish study suggested that serial NT-pro
BNP—or BNP—levels may be useful adjuncts in
monitoring therapeutic responses in patients admitted to
the hospital with acute CHF.
• NT-pro BNP levels were highly predictive of LV
dysfunction.
• Patients with complete symptom resolution had mean
decreases in NT-pro BNP values of 56%.
• Patients whose conditions were stabilized but still
symptomatic had intermediate mean decreases of 37%.
• Patients whose decompensation persisted at 7 days had
decreases of 21%.

33. Acute coronary syndrome
• BNP levels as a marker of left LV dysfunction
associated with myocardial ischemia inACS.
• However, BNP levels do not enable sufficient
discrimination on their own to rule ACS in or
out.

34. • In patients with confirmedACS, the natriuretic
peptides may have a role in risk stratification.
• After adjustment for other risk factors, a
baseline NT-pro BNP level of greater than
250pg/mLwas associated with an adverse
cardiac event.
• Patients with persistently elevated NT-pro
BNP levels over 72 hours had a worsened 30-
day prognosis.

35. • In patients with non–ST-elevationACS.
• BNP levels > 80pg/mL were predictive of
adverse cardiac outcomes.[beyond those
predicted on the basis of troponin levels alone
(even after as long as 6 months)].
• However, treatment strategies did not
significantly differ when retrospectively
stratified by BNP level.

36. • The NT-pro BNP level had prognostic
information beyond conventional risk factors.

37. RV dysfunction and pulmonary disease
• Patients with primary pulm. HTN had NT-pro
BNP concentrations 40 times higher than those
of patients with terminal parenchymal lung
disease.
• NT-pro BNP Levels also useful in predicting
uncomplicated clinical courses of patients with
a diagnosis of acute PE.

38. • NT-pro BNP < 500pg/mLhad a NPV of 97%
for complications due to PE.
• The NT-pro BNP level remained an
independent predictor for adverse outcome
even after the analysis was adjusted for age,
sex, history of CHF, and severity of PE.
• NT-pro BNP levels are significantly higher in
patients with RV dysfunction.

39. Clinical Uses of BNP and NT-proBNP Testing
• General recommendations
• Care must be taken to interpret results in the context of the assay
being used (BNP vs NT-pro BNP) and the patient’s confounding
factors and comorbidities (including obesity and renal
insufficiency).
• BNP levels < 100pg/mL & > 500pg/mL have a 90% NPV & PPV
for the diagnosis of CHF.
• For intermediate levels between 100- 500pg/mL, clinicians must
also consider underlying LV dysfunction, effects of renal
insufficiency, or RV dysfunction secondary to corpulmonale or acute
PE.
• If clinical suspicion is high for CHF but the natriuretic peptide
levels are lower than expected, obesity or flash pulmonary edema
should be considered.

40. • BNP and NT-pro BNP levels are increased in the
presence of renal insufficiency, NT-pro BNP
levels more so than BNP.
• NT-pro BNP levels can be elevated simply on the
basis of the normal age-related decline in GFR.
• When the calculated GFR < 60mL/min, NT-pro
BNP levels can be extremely elevated.
• For BNP, increasing the rule-out cut off value to
200pg/mL is recommended when the GFR <
60mL/min.

41. • Natriuretic peptide levels may be elevated in the intermediate range
in chronic pulmonary disease when RV overload occurs.
• NT-pro BNP and BNP levels may also be elevated in acute PE.
• Although elevations are not diagnostic for PE, high levels are
predictive of a worsened prognosis, particularly when in conjunction
with elevated troponin levels.
• In about 20% of patients with pulmonary disease, natriuretic peptide
levels are elevated.
• Elevations in this context imply CHF, combined CHF and lung
disease, corpulmonale, or acute PE.
• BNP and NT-pro BNP may be used to identify patients with
diastolic dysfunction, but cut off points remain to be age adjusted
and subsequently related to diastolic filling abnormalities.

42. • Patients with BMI > 30kg/m2 have low levels of
BNP and NT-pro BNP.
• Although serial determinations are likely to be
useful, a diagnosis of CHF must be carefully
considered in the appropriate context, even when
levels are below cut off levels.
• Natriuretic peptides are independent predictors of
mortality in CHF.
• Increased or persistent elevation in natriuretic
peptide levels despite treatment suggests
progression of disease or resistance to treatment.

43. • In the acute setting, failure of BNP or NT-pro BNP
levels to decrease with treatment is a poor prognostic
factor that requires intensification of treatment.
• Natriuretic peptide levels should not be measured daily.
• One suggested algorithm is to measure levels on
admission, after 24 hours of treatment, and at discharge.
• Decreased natriuretic peptide levels are predictive of
excellent outcomes.
• BNP levels should not be measured while patients are
receiving recombinant infusions of BNP (eg, nesiritide).
• However, NT-pro BNP levels are not affected by
nesiritide.

44. • InACS, troponin, CK-MB, and myoglobin are markers of
myocardial necrosis and are highly predictive of adverse
cardiac events.
• As a marker of LV dysfunction, natriuretic peptides are not
helpful in diagnosing myocardial ischemia andACS.
• However, BNP and NT-pro BNP levels may be useful for
risk stratification in patients withACS.
• BNP or NT-pro BNP screening is not appropriate for low-
risk, asymptomatic patients.
• Screening may have some value in populations with certain
risk factors (eg, previous MI, diabetes, long-standing
uncontrolled HTN)

45. ACCF/AHA recommendations
• Guidelines from theACCF and theAHAlist as a class I
recommendation the use of BNP or NT-pro BNP values
in the diagnosis of heart failure in ambulatory patients
with dyspnea, especially when the diagnosis is
uncertain, as well as their use in establishing the
prognosis or disease severity in ambulatory patients
with chronic heart failure.
• The guidelines assign a class IIa recommendation to the
use of BNP or NT-pro BNP in determining optimal
dosing for select ambulatory patients who are clinically
euvolemic and are undergoing medical therapy in a
well-structured heart-failure management program.

46. • For hospitalized/acute patients, the ACCF/AHA
guidelines list as a class I recommendation the use of
BNP or NT-pro BNP in the diagnosis of acutely
decompensated heart failure, especially when the
diagnosis is uncertain, as well as the use of BNP or NT-
pro BNP and/or cardiac troponin in establishing the
prognosis or disease severity of acutely decompensated
heart failure in such patients.
• However, the guidelines state that the usefulness of
BNP or NT-pro BNP in guiding therapy in
hospitalized/acute patients with acutely decompensated
heart failure has not been well established.

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