ADOLPH M. HUTTER, MD:
Hello, I'm Dolph Hutter.
Welcome to the American
JAMES L. JANUZZI, MD:
Thank you very much, Dolph.
ADOLPH M. HUTTER, MD:
Also is Dr. Alan Maisel, Professor of Medicine at the
ALAN S. MAISEL, MD:
Thank you for having me.
ADOLPH M. HUTTER, MD:
And Dr. Marc Silver, Clinical Professor of Medicine at the University of
Illinois School of Medicine and chairman of the Department of Medicine and
director of Heart Failure Institute at the Advocate Christ Medical Center,
Professor of Medicine at the University of Illinois, Chicago. Marc, thank you.
MARC A. SILVER, MD:
Nice to be here, Dolph.
ADOLPH M. HUTTER, MD:
Gentlemen, this is an exploding topic. Let’s, first of all, Marc, would you
just define for us what is BNP?
MARC A. SILVER, MD:
Well, BNP is a molecule that’s synthesized predominantly in the ventricles that
starts off as about 132 amino acids, and then at the membrane is cleaved into
two portions. There’s an inactive portion called N-terminal-proBNP
(NT-proBNP) and BNP which is a shorter amino acid
sequence that is really responsible for the physiologic actions.
ADOLPH M. HUTTER, MD:
Can you measure both of them?
MARC A. SILVER, MD:
They can both be measured, yes.
ADOLPH M. HUTTER, MD:
And is there a time difference in their release or anything like that or are
they both released at about the same time?
MARC A. SILVER, MD: The
release is about the same, yes.
ADOLPH M. HUTTER, MD:
Okay. Alan, what structural things in the heart cause a release of the BNP?
ALAN S. MAISEL, MD:
Sure. The reason that this is an active, very popular blood test is that the
signal to release the natriuretic peptides, both BNP
and NT-proBNP, is the same signal that gives us
symptoms of heart failure. In other words, the stretch of the myocyte which will translate usually into increased left
ventricular and diastolic pressure reflected back up to the atrium pulmonary
veins leading to transudation of fluid and shortness of breath. This stretching
of the myocyte, if you will, is what triggers the
release of BNP and NT-proBNP. Now, the predominant
release will be in the left ventricle.
ADOLPH M. HUTTER, MD:
Because there’s more myocytes.
ALAN S. MAISEL, MD:
There’s more myocytes. The right ventricle, and this
can cause confusion clinically sometimes, can also when under pressure or
ischemic secrete the natriuretic peptides, usually
not nearly to the level as we see in the left ventricle but some will be
secreted. Also, there is some preformed BNP that sits at the synaptic nerve
terminal in the atrium, so when someone presents, say, with flash pulmonary
edema, it would normally take the myocyte a long time
to gear up and make BNP – the better part of at least few hours – but some natriuretic peptide will be released from the atrium.
ADOLPH M. HUTTER, MD: I
see. Now, Jim, that’s a very good description of stretch. That’s the bottom
line is stretch, not ischemia, not necrosis, [but] stretch. Jim, how does this
relate now into clinical practice? How can we use these tools?
JAMES L. JANUZZI, MD:
Well, as Marc and Alan both said, there are good assays available now to test
for both BNP and NT-proBNP that are very sensitive
with good, rapid turnaround time. So when a person presents with a clinical
syndrome that is at least suggestive of increased ventricular filling
pressures, whether it’s acute heart failure which is the paradigm that was
originally studied with these markers, or now with better understanding, any
situation that leads to increased myocyte stretch,
whether it’s increased send diastolic filling pressure from acute ischemia,
pulmonary thromboembolism or other syndromes, testing
for these assays has proven to be very, very useful, often superior to clinical
judgment for correctly identifying the cause of shortness of breath, whether
it’s cardiovascular or non-cardiovascular in origin.
ADOLPH M. HUTTER, MD:
And, in fact, I guess the earlier studies were patients who came in the
emergency ward, right, with shortness of breath, and with lung disease, with
heart disease. Weren’t those some of the earlier studies that showed that BNP
correlated pretty well with heart failure?
JAMES L. JANUZZI, MD:
Absolutely, and I can’t emphasize enough that while some of the largest
releases that we see of BNP and NT-proBNP are in
patients with acute heart failure, it’s necessary as clinicians to remember
that there are other disease states that are of similar clinical import like
acute coronary syndromes that can cause release. So we’re now getting a much
better understanding of the things that cause release of these peptides, and
while they are markedly elevated and extremely useful for identifying acute
heart failure in these patients, it’s a very versatile assay, that these assays
are very versatile and very useful for a broad range of disease states.
ADOLPH M. HUTTER, MD:
Marc, Jim referred to acute coronary syndrome, and I guess in my simplistic
way, I suppose if you had a heart that’s really not happy, kind of beat up,
it’s going to release more BNP than one that’s doing much better. Has that
turned out to be the case? I mean, is it a useful marker in that particular
area?
MARC A. SILVER, MD: It
is a useful marker. I think one of the things in acute coronary syndrome is we
don’t see the values go up as high, yet still in all, when there is elevation
above the baseline it turns out to be an important predictor both for
short-term and long-term outcomes. The one thing I’d like to underscore is you
talked about the patient presenting with shortness of breath, and I think as
much as there is value in the elevation of the BNP level, it not being elevated
is very important in terms of distinguishing the patient who presents with dyspnea, and perhaps its negative predictive power is most
valuable to a lot of clinicians as well.
ADOLPH M. HUTTER, MD:
In shortness of breath.
MARC A. SILVER, MD:
Exactly.
ADOLPH M. HUTTER, MD:
Well, that brings up the other comment. Now, anybody just jump in on this
thing. I certainly have seen people with heart failure with normal BNPs. In fact, I had a patient sent in. You know, tricuspid
regurgitation and the huge neck veins, a lot of edema, and the referring doc
said, “It’s impossible. His BNP was normal.” How do you explain that?
ALAN S. MAISEL, MD: I
could start. I mean, there are some caveats that we need to take into
consideration, but I like to believe that there are no false positive levels,
if you will. If there’s a situation where the heart will make BNP it will make
BNP, and unless there’s significant renal dysfunction where it would affect its
clearance, that BNP is up for a reason. We don’t always know the reason. For
instance, in left ventricular dysfunction what can elevate the BNP above and
beyond what you would normally see from the stretch could be associated right
ventricular dysfunction from pulmonary, from pulmonary hypertension. Also,
associated diastolic dysfunction will raise the BNP, and then associated mitral or tricuspid regurgitation or aortic stenosis. All that will raise the BNP levels to higher than
you might think. So as clinicians we need to understand this is not a
standalone test. We need to take other things into consideration. But at the
low end, as Dr. Silver said, the negative predictive value is very good. At the
high end, we can talk about cutoffs if you want. The positive predictive value
or the specificity can easily get 90 to 95%.
ADOLPH M. HUTTER, MD:
If it’s positive.
ALAN S. MAISEL, MD: If
it’s positive, but what we’re talking about I think here is what we like to call
this grey zone area where it’s sort of in between a good sensitivity and a good
specificity, and that’s where we have to take other clinical conditions in
mind.
ADOLPH M. HUTTER, MD:
So, Jim, how do I explain then this person that had heart failure – right-sided
heart failure – and a normal BNP? What’s the explanation of that?
JAMES L. JANUZZI, MD:
Well, a few thoughts, Dolph. The first point is that,
you know, as Alan said, we need to use our good clinical sense when we see a
patient who really looks as if they’ve got heart failure yet their bio markers,
their BNP or NT-proBNP suggests otherwise. And then
one needs to consider the fact that there are a number
of different circumstances that have been described to be associated with lower
natriuretic peptide values in the presence of heart
failure. Some important ones to keep in mind include diastolic heart failure, that is heart failure with preserved systolic
function, where we can often see an overlap in the normal ranges, if you will,
between patients with and without heart failure. As well, the case you
described is a perfect example where right-heart failure, isolated right-heart
failure, cannot infrequently show a degree of overlap with the normal range,
particularly in both cases, in patients with incompletely treated heart
failure. Some patients with diastolic heart failure may present with marked
elevations of natriuretic peptide, but as you treat
them and they are improving but not yet totally improved, we can see a rapid
resolution of the elevations of their natriuretic
peptide values. There are other circumstances. We have described, as has Alan’s
group, that patients with increased body mass index,
obesity, may be associated with a low natriuretic
peptide concentration in the presence of heart failure, and this seems to
involve both BNP and NT-proBNP. So in the obese
patient with heart failure, unfortunately a group where natriuretic
peptides might be very useful to help identify a cause of shortness of breath,
there seems to be a bit of a handicap in using these tests, and it’s an
important thing to keep in mind.
ADOLPH M. HUTTER, MD:
Is it the fat or is it the muscle? Is it lean weight or is it fat?
JAMES L. JANUZZI, MD:
Well, it’s an interesting question. There was a paper just published from the
Dallas Heart Study – James De Lemos was the principal
investigator – looking at the associations between lean body masses as well as
body mass index by obesity. As far as we can tell, because BNP and NT-proBNP have different mechanisms for clearance, therefore
something affecting the clearance of one should not affect the other. The fact
that both peptides seem to fall in parallel with rising body mass index in a
wide variety of patient types, whether it’s normals, hypertensives, people with acute coronary syndromes in our
data in heart failure, it seems that this is probably reduced secretion of the natriuretic peptides in obesity. Whether that’s related to
the aberration in the neural-hormonal signaling in patients with obesity is not
well understood.
ADOLPH M. HUTTER, MD:
Gentlemen, is there a cause for a false elevation of BNP? It’s excreted in the
kidneys. Renal disease, is that?
ALAN S. MAISEL, MD:
Renal disease is probably, and again, I don’t like to use the word “false
elevations” because I think we like physicians to know that if the BNP elevated
we need to know why. For any given GFR decrease there will be some natriuretic peptide retained. Now, the point is that if you
don’t know a patient the first time you see them and there’s renal dysfunction,
you might not be exactly clear on what that natriuretic
peptide level means. However, when you get to know the patient and if you know
their baseline, what we like to call the “dry natriuretic
peptide” or the euvolemic level, even with renal dysfunction
as the volume increases you can follow the patient and you can make good
clinical decisions.
ADOLPH M. HUTTER, MD:
So you’re making a good argument then not only is it an acute marker but it’s
also something you ought to get for the individual baseline, sort of like your
PSA, I guess. It’s not the absolute number, it’s the baseline. Marc, when is
the best time for us to draw that blood?
MARC A. SILVER, MD:
Well, that’s a good point. Certainly for heart failure patients when they get
admitted it’s a valuable tool to assess whether or not they have heart failure
or not. Too, if you know a previous BNP level or an NT-proBNP
level, you can compare those and really see if that’s the cause for their
admission. There may be a time to do it during the hospitalization to see if
your therapy is effective, because if their level has not dropped then probably
you’re not doing enough of the right things.
ADOLPH M. HUTTER, MD:
How long does it take to drop? I mean, within a day or two?
ALAN S. MAISEL, MD:
Well, the half-life of the proteins are very short, usually measured in about
20 minutes or so, and so five half-lives usually within a couple of hours you
can see a change in the endogenous levels.
ADOLPH M. HUTTER, MD:
So if you’re treating somebody with heart failure, they come in and their BNP
is 2,000, would you check it serially in the hospital?
JAMES L. JANUZZI, MD:
Alan and I both have strong beliefs about how frequently it should be checked.
I know because we’ve given similar more lectures on this topic and I’m sure
Marc feels the same. There’s probably less useful information in irrational
exuberance in checking it every few hours, even every eight hours, but there
are good data in well-designed studies demonstrating that baseline for diagnosis
and triage at 24 hours after presentation to show a definitive change in the
positive direction, and particularly at a time when you feel the patient is
clinically improved enough to be sent home at discharge.
ADOLPH M. HUTTER, MD:
And that’s what you’re talking about, the dry weight, getting down to a dry
weight.
ALAN S. MAISEL, MD: The
only problem with that, and I totally agree with what Jim says, it’s a lot
easier to see the fall when you’re acutely treating someone. You can see 50 to
100 pg/hr. But, you know, when you’re measuring it on the outpatient side,
there is a variability in the measurement and there are studies ongoing to try
to discern this, but it may be in a given person from day to day up to about a
50% or so change from one to the other. So to call just because a BNP level
goes from 300, if that’s your baseline, to 400 in clinic, we don’t necessarily
worry. But the clinician needs to know that because I’ve seen house staff want
to make changes because they saw a BNP level go from 200 to 250 and they’re
stable, so we have to be wary of that.
MARC A. SILVER, MD: I
think that’s a really important point. You know, we’re very excited about
having bio markers, but we don’t want to use them to the exclusion of clinical
evaluation of the patient, and then even combine the biomarkers. Even with
acute coronary syndrome I think what we’ve learned is that you add BNP to troponin and you have a much potent set of biomarkers than
BNP alone.
ADOLPH M. HUTTER, MD:
Yes. So, you know, you have the patient and you’re seeing them in clinic now.
You could tell by the neck vein exam, etc. whether or not they’re euvolemic. Would you get a baseline BNP at a few different
visits to find out what their outpatient BNP is? And then secondly I’m going to
ask, and if so, if the patient comes back and all of a sudden the BNP has gone
from 300 to 800 and yet the clinical exam is the same, should I do anything
about it? So, should we repeat checking these things?
JAMES L. JANUZZI, MD:
So the use of outpatient monitoring with either NT-proBNP
or BNP is largely restricted to anecdotal experience at present as well as only
one small pilot study that’s been published. There are other trials that have
been reported in national meetings but not yet published yet as well as several
ongoing clinical trials including one at our own institution using the natriuretic peptide level in the clinic to help triage
patients to more aggressive therapies if they do not show a fall in their natriuretic peptide levels in response to therapy with
drugs with proven mortality benefit in heart failure. I would say the example
you gave of somebody whose BNP or NT-proBNP went
from, say, you know, 200 to 300 of a BNP value to, say, four times that in
clinic despite looking otherwise hemodynamically or
clinically stable. I would be very concerned about that patients who is showing
a four times rise in their values. Having said that, what to do about it is
really at this point something that we’re focusing on in clinical studies.
ADOLPH M. HUTTER, MD:
Yes. What do you think we should do in the meantime to give us the definitive
answer?
ALAN S. MAISEL, MD:
Well, I think, it’s again, it’s not a standalone test and I agree with Jim. I
have a little less threshold of maybe doubling of your BNP without symptoms I
start to look for other causes. We do always measure BNP with renal function
because sometimes, for instance, when we see a patient in clinic, an elevation,
they don’t feel good so a case manager will have them come in and get a natriuretic peptide level and we also get creatinine because they might be over-diuresed,
and if they’re over-diuresed their renal function may
be bad and they’ll start to retain it.
ADOLPH M. HUTTER, MD:
Good point.
ALAN S. MAISEL, MD: So
that BNP elevation could be a cause of that.
ADOLPH M. HUTTER, MD:
So check the creatinine, BUN and BNP at the same
time.
ALAN S. MAISEL, MD:
That’s what we usually do.
ADOLPH M. HUTTER, MD:
That’s a good idea.
ALAN S. MAISEL, MD: And
again, it’s still mostly anecdotal but a lot of us have had good experience
with this and we worry. You know, for instance, it’s likely that I might start
a patient on, say, an angiotensin-receptor blocker
already being on ACE and beta blockers if their BNP is higher than I want it,
because…
ADOLPH M. HUTTER, MD:
You would change your therapy then.
ALAN S. MAISEL, MD: I
would, and that’s because as a clinician, I know that when I get that BNP level
low and they’re not symptomatic, that they tend to do better. And I believe
that from Jim’s study, from the BATTLE-SCARRED study, from the STAR study
presented this summer where the group in Paris ratcheted up the drug treatment
to lower BNP that those patients tended to do better.
ADOLPH M. HUTTER, MD:
All right.
ALAN S. MAISEL, MD: We
still need more data. It’s not ready for prime time.
ADOLPH M. HUTTER, MD:
But in the meantime, we’ll all have to make decisions in the absence of data
while we’re waiting for the data. Marc, do you agree with this? Would you wrap
up therapy if the BNP was up?
MARC A. SILVER, MD: I’d
do it. I don’t do it solely based on the BNP. I think we all agree that it’s
not a standalone. But if there is some discrepancy in how the patient feels
despite their exam, they look euvolemic and yet their
symptoms have progressed or there’s something that tells you that something is
off and the BNP is up, I would say let’s look and see what else I can do to
alter therapy.
ADOLPH M. HUTTER, MD:
You know, and from a clinical standpoint, we certainly have patients who have
heart failure and it’s only on the left side. We have normal JVs pressure and
they’re still easily short of breath. You cath and
their wedge is 22 and their jugular venous pressure is 5, so BNP really tells
us what’s going on in that side that we can’t see on our clinical exam, even
with clear lungs.
JAMES L. JANUZZI, MD:
And it’s powerfully prognostic. I mean, one thing that we’ve made reference to
on a number of occasions but really address, you know, putting aside the
diagnostic piece, it is a very strongly prognostic measure in patients with
heart failure, so strong that in most studies where it’s been compared to other
standards for prognosis it always seem to come out on top as a predictor of
death.
ADOLPH M. HUTTER, MD:
Sounds like a pretty good breakthrough, good diagnostic, good physiology
explained, excretion mechanisms explained, prognostic value pretty well
established and the value as a marker for treatment endpoint seems to be
getting more and more evidenced-based. Fair?
ALAN S. MAISEL, MD: Yes,
fair. The prognostic goes beyond heart failure though. There’s been studies
where you take normal individuals. You know, CRP gets all the credit these
days, but when you match BNP or NT-proBNP up against
CRP in adults and you look for cardiovascular mortality and you adjust for
other risk factors for body weight, things like aspirin use, natriuretic peptides come out on top for normal people.
This is seen in the Framingham study and other studies. It’s seen and now we’ve
talked about acute coronary syndrome. It’s seen in cases like just diabetes,
you know.
ADOLPH M. HUTTER, MD:
Okay, so stay tuned in an exciting area. Thank you all very much. It’s a great
discussion. Even I understood everything that you’ve said. And thank you very
much for joining us. I’m Dolph Hutter.
Related References/Reading:
1. Silver MA, Maisel
A, Yancy CW, et al, on behalf of the BNP Consensus
Panel. BNP Consensus Panel 2004: A clinical approach for the diagnostic,
prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. Congest Heart Fail. 2004 Sep-Oct;10(5 Suppl 3):1-30.
2. Das SR, Drazner
MH, Dries DL, et al. Impact of body mass and body composition on circulating
levels of natriuretic peptides: results from the
Dallas Heart Study. Circulation.
2005 Oct 4;112(14):2163-8.
3. McCullough PA, Nowak RM, McCord J, et
al. B-type natriuretic peptide and clinical judgment
in emergency diagnosis of heart failure: analysis from Breathing Not Properly
(BNP) Multinational Study. Circulation.
2002 Jul 23;106(4):416-22.
4. Maisel AS, Krishnaswamy
P, Nowak RM, et al., on behalf of the Breathing Not Properly Multinational
Study Investigators. Rapid measurement of B-type natriuretic
peptide in the emergency diagnosis of heart failure. N Engl J Med.
2002 Jul 18;347(3):161-7.