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. Letís, first of all, Marc, would you just define for us what is BNP?
MARC A. SILVER, MD: Well, BNP is a molecule thatís synthesized predominantly in the ventricles that starts off as about 132 amino acids, and then at the membrane is cleaved into two portions. Thereís 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 thereís more myocytes.
ALAN S. MAISEL, MD: Thereís 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 Ė the better part of at least few hours Ė but some natriuretic peptide will be released from the atrium.
ADOLPH M. HUTTER, MD: I see. Now, Jim, thatís a very good description of stretch. Thatís 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 itís 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 itís 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 itís 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. Werenít those some of the earlier studies that showed that BNP correlated pretty well with heart failure?
JAMES L. JANUZZI, MD: Absolutely, and I canít emphasize enough that while some of the largest releases that we see of BNP and NT-proBNP are in patients with acute heart failure, itís 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 weíre 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, itís 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 thatís really not happy, kind of beat up, itís going to release more BNP than one thatís 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 donít 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 Iíd 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, ďItís impossible. His BNP was normal.Ē 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 thereís a situation where the heart will make BNP it will make BNP, and unless thereís significant renal dysfunction where it would affect its clearance, that BNP is up for a reason. We donít 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 itís positive.
ALAN S. MAISEL, MD: If itís positive, but what weíre talking about I think here is what we like to call this grey zone area where itís sort of in between a good sensitivity and a good specificity, and thatís 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 Ė right-sided heart failure Ė and a normal BNP? Whatís 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 theyíve 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 Alanís 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 itís 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, itís an interesting question. There was a paper just published from the Dallas Heart Study Ė James De Lemos was the principal investigator Ė 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 itís 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 thatís 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? Itís excreted in the kidneys. Renal disease, is that?
ALAN S. MAISEL, MD: Renal disease is probably, and again, I donít like to use the word ďfalse elevationsĒ 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 donít know a patient the first time you see them and thereís 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 ďdry natriuretic peptideĒ 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 youíre making a good argument then not only is it an acute marker but itís also something you ought to get for the individual baseline, sort of like your PSA, I guess. Itís not the absolute number, itís the baseline. Marc, when is the best time for us to draw that blood?
MARC A. SILVER, MD: Well, thatís a good point. Certainly for heart failure patients when they get admitted itís 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 thatís 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 youíre 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 youíre 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 weíve given similar more lectures on this topic and Iím sure Marc feels the same. Thereís 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 thatís what youíre 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, itís a lot easier to see the fall when youíre acutely treating someone. You can see 50 to 100 pg/hr. But, you know, when youíre 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 thatís your baseline, to 400 in clinic, we donít necessarily worry. But the clinician needs to know that because Iíve seen house staff want to make changes because they saw a BNP level go from 200 to 250 and theyíre stable, so we have to be wary of that.
MARC A. SILVER, MD: I think thatís a really important point. You know, weíre very excited about having bio markers, but we donít 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 weíve 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 youíre seeing them in clinic now. You could tell by the neck vein exam, etc. whether or not theyíre euvolemic. Would you get a baseline BNP at a few different visits to find out what their outpatient BNP is? And then secondly Iím 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 thatís 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 weíre 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, itís again, itís 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 donít 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 theyíre over-diuresed their renal function may be bad and theyíll 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: Thatís what we usually do.
ADOLPH M. HUTTER, MD: Thatís a good idea.
ALAN S. MAISEL, MD: And again, itís still mostly anecdotal but a lot of us have had good experience with this and we worry. You know, for instance, itís 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, becauseÖ
ADOLPH M. HUTTER, MD: You would change your therapy then.
ALAN S. MAISEL, MD: I would, and thatís because as a clinician, I know that when I get that BNP level low and theyíre not symptomatic, that they tend to do better. And I believe that from Jimís 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. Itís not ready for prime time.
ADOLPH M. HUTTER, MD: But in the meantime, weíll all have to make decisions in the absence of data while weíre waiting for the data. Marc, do you agree with this? Would you wrap up therapy if the BNP was up?
MARC A. SILVER, MD: Iíd do it. I donít do it solely based on the BNP. I think we all agree that itís 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 thereís something that tells you that something is off and the BNP is up, I would say letís 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 itís only on the left side. We have normal JVs pressure and theyíre still easily short of breath. You cath and their wedge is 22 and their jugular venous pressure is 5, so BNP really tells us whatís going on in that side that we canít see on our clinical exam, even with clear lungs.
JAMES L. JANUZZI, MD: And itís powerfully prognostic. I mean, one thing that weíve 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 itís 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. Thereís 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. Itís seen and now weíve talked about acute coronary syndrome. Itís 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. Itís a great discussion. Even I understood everything that youíve said. And thank you very much for joining us. Iím Dolph Hutter.
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.