Articles

NT pro-BNP (N terminal pro-BNP)

What is it?

BNP initially stood for "brain natriuretic peptide", a peptide isolated originally from porcinie brain tissue that has the effect of increasing  sodium excretion (natriuresis) at the kidney.  It's since been renamed "B-type" natriuretic peptide (still BNP) with the recognition that the principal source of the circulating peptide is the cardiac ventricles.  Physiologically BNP acts as a natural antagonist of the renin-angiotensin system and decreases blood volume and vascular resistance through vasodilatory, natruretic, and diuretic properties.  BNP is an example of a "biomarker", a substance used as an indicator of a biologic state.  The bottom line is that circulating BNP levels, or metabolites, tell us something about the severity of heart disease!

In the dog, pre-pro-BNP is synthesized as a 134 amino acid peptide (132 amino acids in the cat), principally within cardiac ventricular myocytes.  Pre-pro-BNP is cleaved prior to extracellular transport and the first 108 amino acids  (counting from the amino terminal) are secreted as pro-BNP.  Pro-BNP is cleaved further, by a neutral endopeptidase (NEP), into a biologically inactive amino-terminal peptide containing 76 amino acids (N-terminal pro-BNP or NT pro-BNP) and the complementary active peptide, BNP (C-terminal BNP or C-BNP). 

The principal stimulus for  manufacture and release of pro-BNP from ventricular myocytes is mechanical stress -- distention of the heart.  Physiologically, BNP co-regulates vascular blood volume and vascular resistance by promoting sodium and fluid excretion when the venous compartment is distended with blood, as sensed by the distended ventricles.  As such, circulating BNP levels act as a chemical barometer for venous pressure, i.e. congestion.  BNP may also be released in response to hypertrophy, ischemia, or  neurohormones.  

As cardiac disease progresses and congestion worsens,  BNP is secreted in ever increasing quantities, acting to return blood volume and pressure towards normal.  While this system acts to alleviate congestion, it cannot override  contributions from all the other players in the "hemodynamic defense reaction" and  edema obviously ensues with sufficiently severe heart disease.  This appears to be due in part to decreasing sensitivity to the actions of BNP with worsening heart disease.

There are several noteworthy biochemical properties of this system:

• BNP Is highly species specific and biochemical assays designed for humans cannot be used effectively to measure the peptide in veterinary species.
• To a large extent, BNP is manufactured de novo immediately prior to secretion; there is not a large store of BNP available for immediate release.  This is in contrast to its cousin, ANP ( atrial natriuretic peptide or A-type natriuretic peptide), that is stored in  granules within atrial myocytes, ready for  immediate release.  BNP doesn't respond to rapid fluctuations in cardiac distention to the degree that ANP does.  BNP levels may also exhibit a lag period after acute congestion before  the assay indicates a problem.
• Active BNP has a short half-life on the order of 20 minutes, being rapidly cleared by renal excretion, and is relatively unstable chemically.  Consequently an assay for BNP per se is not optimal for detecting the biochemical signal.  In contrast, NT pro-BNP has a longer half-life and serves as the preferred biomarker for detection.  (Analogy: The bullets are long gone, but the spent cartridges are still on the ground for all to see.)

What do I do with this?

NT pro-BNP is correlated with the degree of cardiac distention associated with congestion; assaying for NT pro-BNP constitutes a blood test for the severity of heart disease!   NT pro-BNP levels become elevated in dogs and cats with common heart diseases such as mitral valve endocardiosis ( in dogs), cardiomyopathy, aortic stenosis, and heartworm disease.

The indisputable application of this test is to help differentiate between primary cardiac versus respiratory disease in a patient with dyspnea, i.e. as an emergency, "point of care" test.  You would run this blood test in your practice, like a snap test for heartworm disease, and determine whether to grab for the furosemide versus prednisone.  Unfortunately, a point of care test does not yet exist in veterinary medicine.  However IDEXX has been marketing their assay since summer of 2008 and here are some of the suggested applications: 

IDEXX Recommendations: 

For cats or dogs with any of the following presenting signs:
An audible murmur
Arrhythmia
Exercise intolerance
Lethargy
Breathlessness
Dyspnea
Coughing
Pale mucous membranes
Visible signs of poor perfusion
 
Or in any of these situations:
All cases of suspect congestive heart failure
To differentiate respiratory disease from heart disease
All patients with murmurs and arrhythmia
All cats over the age of four
All cats with a gallop rhythm
All breeds predisposed to heart disease and showing clinical signs

In addition, the website includes technical information, test and sample handling specifics, journal articles, and a link to a terrific educational Webinar given by cardiology specialist Dr. Mark Oyama.

You can check out test cost by going to the IDEXX VetConnect site, , click on the "Lab Services" tab, "Directory of Services" link, and then enter "BNP" or "proBNP" in the "Search for Tests" window.  At this time (May 2009), a canine or feline CardioPet proBNP assay costs you $46.90.  However IDEXX  has bundled the test with a wide range of other screening and diagnostic products. 

My own views on this test

• NO ONE is suggesting this test as a substitute for a good clinical workup including a careful history, physical examination,  thoracic radiographs, EKG (for arrhythmia evaluation specifically), echocardiography, or specialist consultation.  While the application of the test will undoubtedly evolve, you should currently consider this as an ancillary test, i.e. in addition to the aforementioned, or as a screening test, i.e. to screen for heart disease that isn't coming up on history or physical exam ( especially cats!).
• I don't yet use this test regularly for my own cases.  However that's because I'm a cardiologist.  In evaluating the test, the "gold standard" for whether the NT pro-BNP assay was "correct" was taken to be the opinion of one or more cardiologists following a complete evaluation, i.e. including an echocardiogram.  (Don't forget cardiologists can be wrong too!) 
• There have been occasions when I  was very desirous of a proBNP test result, but I wanted it on the spot.  The way this usually comes up for a cardiologist is that clinical findings are discordant -- there's definitely heart disease but it's not at all clear that it's severe enough to be causing the clinical signs.  My usual approach under that circumstance is to treat for severe heart disease and I'll  logically need to do that regardless of what the proBNP tells me ( although the test result could definitely bend my opinion).  The other situation for me is where it's clear that heart disease is present in conjunction with non-cardiac disease and I can't sort out which is the major contributor to clinical signs. 
• It's common and expected for non-cardiologists to have more difficulty differentiating cardiac versus noncardiac causes of clinical signs.   I would estimate that 10-20%  of patients transferred to my cardiology service at Tufts did not have primary heart disease as the cause for their clinical signs.   Again this is the clear application of the test, but you'd probably like to know the answer right away and we don't have a point of care test yet.
• I've recommended the test to practitioners over the phone when it wasn't possible to determine whether heart disease was severe and the client wasn't ready for a cardiology referral.  The test result might be enough to get the client to go for the cardiology referral, or it might suggest that they need to go elsewhere to get to the root of the problem.   Example cases include pleural effusions (or circumstances where the heart is obscured on radiographs) or  ventricular arrhythmias in a breed not typically associated with cardiomyopathy.   In each of these situations, the practitioner may be wondering whether to refer for cardiology versus abdominal ultrasound and I can't help over the phone.
• As you see it's been suggested that the test be used to monitor "response to therapy".  I think we need to gain experience with the test before this application becomes a reality.  However I can certainly picture circumstances where heart disease has been treated vigorously but clinical signs persist.  Here, we still have the best application for the test--differentiating heart disease/failure from something else.