BNP and Cardiac Function

1
BNP and Cardiac Function

• Dr TA McDonagh
• Consultant Cardiologist
• Royal Brompton Hospital
• London, UK

2
Natriuretic Peptides
N-terminal pro BNP (1 - 76)
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BNP Pathophysiology

• High degree of homology with ANP
• Both genes on Chromosome 1
• Secretion
• ANP mainly stored in granules, then released
• BNP constuitively produced
• rapid activation of pro-BNP gene, de novo
  synthesis and secretion by myocytes
• Normal state-ventricles and atria produce low
  levels, cardiac disease, main source of increased
  production ventricular myocardium
• Main stimuli
• Stretch (? wall stress)
• Hypoxia
• AII, catecholamines, endothelin
• Main effects through NP-A receptor, some through
  NP-B
• cGMP mediated

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stretch
antiproliferative
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Clearance
Pro-BNP
Furin/Corin
NT-Pro-BNP
BNP
NEP 24.11
NP-C
Kidneys
NT-pro-BNP t1/269.6mins vs 4.8 for BNP
Pemberton et al Hypertension 200036355
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Non cardiac influences on secretion/clearance

• Age
• Gender
• Renal Function
• Obesity

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Natriuretic Peptides in Heart Disease

• Focus on heart failure and systolic dysfunction
• Potential
• diagnosis
• screening for asymptomatic LVD
• prognosis
• monitoring of Rx
• therapeutic tools
• acute heart failure

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Heart FailureESC Guidelines in Diagnosis

• Symptoms of heart failure (at rest or during
  exercise)
• Objective evidence of cardiac dysfunction at
  rest
• Response to treatment when the diagnosis is in
  doubt

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Gold Standard
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Fuzzogram
Elderly Comorbidities (30 have COPD) Obesity
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Acute Dyspnoea

• BNP in the assessment of acute breathlessness
• Attempt to distinguish heart failure from COPD
• BNP?22pg/ml predicted HF with a 93 sensitivity,
  90 specificity

Davis et al Lancet 1994
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Population-Based StudiesPossible new HF in
Primary Care

• 122 cases referred to a rapid access HF clinic
  with a GP diagnosis of HF
• Clinical assessment, CXR and echo
• Panel of 3 experts gold standard diagnosis
• BNP?22pmol/l, 97 sensitive, 84 specific ,NPV
  97, PPV 70

Cowie et al Lancet 1997
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Post MI Heart Failure

• LVF Sens Spec PPV NPV
• ANP 79 71 50 90
• N-ANP 76 76 54 89
• BNP 85 73 54 93
• N-BNP 82 69 50 91

Richards et al Circ 1998
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Population-Based StudiesGeneral Population

• Population
• 1252 aged 25-74,randomly
• sampled from N.Glasgow.
• Echocardiography
• Gold Standard for LVSD
• LVEF (Simpsons Rule Method)
• Prevalence of LVSD 3.1 (39)
• Symptomatic 49 (18)
• Asymptomatic 51 (19)
• BNP standard RIA (Peninsula)

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BNP and N-ANP to detect LVD in asymptomatic
individuals over 55 years with IHD
Specificity
100
BNP sensitivity 89, specificity 73
BNP
N-ANP
Sensitivity
50
0
50
100
0
PSA 0.94
Other Screening Tests
BNP 0.88
AUC
Mammography 0.85
McDonagh et al Lancet 1998
Cervical Smears 0.70
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Rapid BNP/NT-pro-BNP Assays

• BNP (Biosite)
• No extraction required
• Blood or plasma (EDTA) 250µl
• Time 15mins
• NT-pro-BNP (Roche)
• ELISA
• Time 20mins
• BNP (Bayer)
• BNP (Abbot)

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Population-based StudiesUK Natriuretic Peptide

• 306 patients, GP suspected heart failure
• 5 UK centres
• 1 Cardiologist per centre using ESC guidelines
• 104 confirmed HF (34)
• NPV for BNP (0.87)
• NPV for NT-pro-BNP (0.97)

Zaphiriou et al EJHF 20057537
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BNP and Heart Failure with Preserved Systolic
Function

• Breathing Not Properly Study
• 1586 subjects
• 452 adjudicated HF diagnosis
• 165 (36.5) LVEFgt45
• BNPgt100pg/mlsensitivity of 86, NPV of 96 and
  accuracy of 75 for diagnosing HF with preserved
  EF
• BNP modest discriminatory value at separating
  SHF from HF with preserved EF (AUC-0.66)
• Major role is in ruling out HF versus no HF

Maisel et al JACC 2003412010
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ve NT-proBNP in SOB Group 221/3051 European
BNP Meta-analysis
Hyper-BNP-aemia

• Risk Factor n () Cumulative n ()
• Heart Failure 67 (30.3) 67 (30.3)
• LVH 28 (12.7) 95 (43.0)
• ?LVEDD 12 (5.4) 107 (48.4)
• Valve Abn 1 (0.5) 108 (48.9)
• Pulmonary HT 2 (0.9) 110 (49.8)
• MI 43 (19.5) 153 (69.2)
• Angina 17 (7.7) 170 (76.9)
• HT 21 (9.5) 191 (86.4)
• CV Rx 5 (2.3) 196 (88.7)
• DM 2 (0.9) 198 (89.6)
• Pulmonary Disease 3 (1.4) 201 (91.0)
• Renal Dysfunction 4 (1.8) 205 (92.8)
• Hx of cardiac disease 3 (1.4) 208 (94.1)
• Remainder 13 (5.9) 221 (100)

McDonagh et al,EJHF 20046269
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ESC Guidelines Task Force Report
Suspected HF
Assess presence of cardiac diseaseECG, CXR,
natriuretic peptides
NormalHeart Failure unlikely
Tests abnormal
NormalHeart Failure unlikely
Cardiac Imaging by echo, RNVG, MRI
Tests abnormal
Additional diagnostic tests where appropriate eg
(coronary angiography)
Assess aetiology, degree, precipitating factors,
type of cardiac dysfunction
Choose Rx
Adapted from Eur HJ 2001221527
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BNP and Severity of CHF

• BNP ? with NYHA Class
• And with ? LV function
• 153 patients referred for RNVG
• BNP (RIA)

Valli et al Clin Chim Acta 200130619
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Natriuretic Peptides and Prognosis in CHF

• BNPgtANP for mortality
• BNP independent predictor of death

Tsutamoto et al Circulation 1997
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BNP and Sudden Death

• 452 LVEF35
• 89 deaths
• 44 (49) sudden
• Log BNP only independent predictor of sudden
  death (p0.006)
• (SBP, LVEF, N-ANP, N-BNP, Big ET)

Berger et at Circulation 20021052393
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Selection for CTX
Only independent predictor of ACM was an
NT-proBNP value above the median (RR4.6, p0.01).
Gardner et al EHJ October 2003
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BNPlt10pg/ml
10?BNPlt20pg/ml
20?BNPlt30pg/ml
BNP?30pg/ml
Log Rank Test Statistic 55, plt0.0001
McDonagh et al Heart June 2001
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Natriuretic Peptides in Heart Disease

• Focus on heart failure and systolic dysfunction
• Potential
• diagnosis
• prognosis
• monitoring of Rx
• therapeutic tools

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Monitoring of Therapy for CHF/LVD

• Biochemical Swan Ganz Catheter
• What does Rx for CHF do to ANP/BNP
  ? Natriuretic Peptides
• Diuretics ? BHJ 199369414
• ACEI ? BHJ 199369414
• Digoxin ? AHJ 1997134910
• ATII blocker ? JACC 200035714
• Spironolactone ? JACC 2001371128
• Beta-blockers ? Am J Cardiol 200392406

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Change in BNP and Outcome in Decompensated CHF
Discharge BNP and readmission
72 admissions with CHF
22 deaths or readmissions
no endpoints
BNP ?
BNP ?
Mean ? 233pg/ml
Mean ? 215pg/ml
Cheng et al JACC 200137386
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Treatment Monitoring

• 69 patients LVEF?40, CHF II-IV
• BNP guided/standard Rx
• by BNP level (lt200pmol/ml) or heart failure
  score (lt2)
• ? ACE, ?loop diuretic, add digoxin, add
  metolozone, add spironolactone, add ISMO, add
  felodipine
• Follow up for CV events(median 9 months)
• 6 months, 27 of BNP vs 53 of clinical group
  experienced a first CV event (p0.034)

Troughton et al Lancet 20003351126
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STARS-BNP Multicentre Study

• 220 NHYA II-III
• Optimal Rx by CHF specialists
• Randomized to medical treatment according to
  either current guidelines or a goal of decreasing
  BNP plasma levels lt100 pg/ml
• O/P visits _at_ 1month for 3 months, then every 3
  months.
• The primary combined end point was CHF-related
  death or hospitalisation.
• Mean dosages of ACEIs, BB significantly higher in
  the BNP group (p lt 0.05),
• Mean increase in furosemide dosage was similar
• Follow-up (median 15 months), significantly fewer
  patients reached the combined end point in the
  BNP group (24 vs. 52, p lt 0.001).

Jourdain P et al JACC 200749 1733-1739
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Monitoring of LVEF changes with BNP

• 107 consecutive patients
• Correlations between BNP and reduced LVEF
• Neither baseline values nor serial measurements
  can safely substitute EF monitoring in patients
  undergoing anthracycline therapy

r0.76 Plt0.001).
BNP (r0.20 Pgt0.05).
Daugard et al EJHF 2005
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BNP and Long Term Follow Up Post Anthracyclines

• BNP in 54 disease-free breast cancer survivors,
  during long-term follow-up after epirubicin (360
  mg/m2 or 450 mg/m2 cumulatively) and chest
  irradiation
• From a median follow-up of 2.7 to 6.5 years,
  median BNP was X 3 (plt0.001).
• HF developed in 2
• Compared to the epirubicin 360 mg/m2 group, BNP
  was higher (p0.006) in the 450 mg/m2 group

Perik et al Anticancer Res 2005
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NT-pro-BNP and Anthracylines

• 100 consecutive patients receiving
  anthracycline-based chemotherapy
• Echo and biochemical measurements at baseline and
  1 year of FU
• Mean LVEF ?immediately after completion of
  anthracycline therapy (mean dose 226.1 /- 8.3
  mg/m(2)) and further ?during FU (65.9 /- 0.6
  Vs. 61.6 /- 0.7 P lt 0.001)
• No symptoms in study
• Mean NT-proBNP levels no significant change
  after anthracycline administration.
• 13 patients (15.3) a marked, transient increase
  of NT-proBNP was obtained after the first
  anthracycline cycle without cardiac dysfunction
  presumably due to altered cardiac loading
  conditions during chemotherapy

Dodos et al Clin Res Cardiol 2008
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BNP and Mediastinal Rx

• 197 patients before and after Rx for oesophageal
  ca.
• BNP was significantly increased gt 9 months after
  radiotherapy
• Higher in patients who had high FDG accumulation
  corresponding to the irradiated field.
• BNP concentration might be an early indicator of
  radiation-induced myocardial damage.

Jingu et al Int J Radiat Oncol Biophys 2007
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Conclusion

• B-type Natriuretic Peptide in Heart Failure
• Potential
• diagnosis
• prognosis
• monitoring of Rx
• therapeutic tool