Dr. Peacock: Greetings! I’d like to welcome everybody to this Roundtable Discussion. Today, we’re going to be talking about a new and promising marker called galectin-3. We have some of the world’s experts on this. Some of the basic research that has been done and some of the clinical aspects of this new marker are going to be discussed today, so it’s going to be an enjoyable and cutting-edge dialogue.
With me is Dr. Rudolf de Boer, from University Medical Center, Groningen, The Netherlands, who has done some of the basic science work; Dr. Salvatore Di Somma, who is an emergency physician at San Andrea Hospital at the University Sapienza in Rome; and Dr. Alan Maisel, a world-renowned biomarker researcher from the University of California San Diego at the Veterans Administration. I am Frank Peacock, a Professor in Emergency Medicine and the Director of Research at the Baylor College of Medicine.
Welcome, gentlemen. I’d like to open this up with Dr. Boer, starting with some discussion on what he knows about this marker.
Dr. de Boer: Yes, thank you, Dr. Peacock, for your introduction. I will briefly introduce galectin-3 to you, although I’m sure most of you have become familiar with it to some extent. It was actually not so long ago that galectin-3 was scientifically discovered in the 1980s. When it was discovered, its function was not fully recognized. It was only 8 years ago that galectin-3 was associated with heart failure development and cardiac remodeling.1
Galectin-3 is a member of the galectin family, which is a large family comprising about 20 galectins. Galectin-3 is unique because it’s a so-called chimera-type galectin, meaning that upon lectin binding, it forms multidimers, shaping a mesh, which is thought to add to the stiffness of the interstitial matrix, and in the case of heart failure, it adds stiffness to the extracellular myocardial matrix.2 Galectin-3 can be activated by all kinds of lectins, and in the normal heart, these ligands are believed to be major cellular proteins such as laminin and collagens. In damaged organs in general, and in heart failure in particular, galectin-3 is predominantly released by macrophages and the activating lectins are clearly more abundant, and this is generally thought to be the mechanism of galectin-3 activation in heart failure.
As I mentioned, a first seminal paper1 on the potential role of galectin-3 in heart failure was published in 2004. In a rat model with transition from compensated to decompensated heart failure, galectin-3 was the most strongly differentially expressed gene in this transitional phase. With further experimentation, the investigators showed that adding galectin-3 into the pericardial sac rendered superphysiological levels of galectin-3, and with this perturbation, they were able to provoke adverse cardiac remodeling with collagen deposition and left ventricular dysfunction. So, not only does galectin-3 seem to be associated with heart failure development, but may also be a part of the pathophysiology of cardiac remodeling and heart failure. This, of course, is very interesting.
Furthermore, galectin-3 seems to be a factor that is very dominant in the matrix: it does not predominantly act on cardiomyocytes, but on fibroblasts and the matrix compartment of the heart. It is strictly colocalized with sites of fibrosis where injury occurs, and it was shown that the primary source of galectin-3 in the heart includes all kinds of inflammatory cells, mainly macrophages, at the site of injury, for example, post-myocardial infarction or in hypertensive models. However, some other cells also produce galectin-3 including cardiac fibroblasts and mast cells. Mast cells are clearly less abundant, and fibroblasts are very abundant but produce a rather low amount of galectin-3. So overall, the primary source of galectin-3 is believed to be macrophages. As it is currently understood, when galectin-3 is produced, it turns cardiac fibroblasts into matrix-producing myofibroblasts, which then adds to the remodeling, specifically extracellular matrix production and fibrogenesis, not so much left ventricular hypertrophy, and this may contribute to the ultimate culmination into overt heart failure.
This is a general scheme of how we think of galectin-3 right now. As said before, interestingly, galectin-3 is associated with the disease process, but when activated, it has also been shown to add to the pathophysiology. Besides the naturally occurring binding lectins, investigators have developed neutralizing lectins that may bind to galectin-3 and render it inactive. This approach may actually downregulate galectin-3 activity with the aim to attenuate the galectin-3—driven progress of cardiac remodeling and to halt heart failure development. Recently, these neutralizing lectins have been tested in several animal models of hypertension, and it was shown that galectin-3 can be inhibited; this is associated with the attenuation of end-organ damage.3,4
Besides cardiac fibrosis, it has been observed that galectin-3 is also activated in liver fibrosis,5 kidney fibrosis,6 and lung fibrosis.7 Experimental studies using pharmacological compounds specifically targeting galectin-3 in non-cardiac disease have also been quite successful in attenuating tissue fibrosis.7 I think this adds an extra level of interest to this protein—that is, it’s not only a marker of disease severity, but also some kind of culprit biomarker, suggesting that it is part of the pathophysiology of heart failure, and can be a target of specific therapy.
Dr. Peacock: Perfect, Dr. Boer, that’s a really nice review of what we know up to this point about galectin-3. I think the next question is—is it ready for the clinical world? And if so, how would we be using it? Dr. Di Somma, what do you think about this and the use of galectin-3 in the emergency department?
Dr. Di Somma: That’s a very important question, because for patients presenting to an emergency department for shortness of breath due to acute heart failure, the physician has 3 main important jobs to do. First, a quick diagnosis is needed to start immediately with treatment because from papers in the literature,8 it is very clear that how fast you are in making the diagnosis and starting the treatment is going to have an important impact on both the patient’s outcome and length of stay. So, the first job is to give an appropriate diagnosis, but of no less importance is to immediately perform a risk specification, which is very important in terms of determining how aggressive your treatment must be, as well as the disposition based on this certification analysis of your patients with acute heart failure.
It seems possible now to discriminate between patients arriving in the Emergency Department with signs and symptoms of acute heart failure with galectin-3 levels of <17.8 pg/mL compared to patients with a galectin-3 level greater than this cutoff. Patients with a galectin-3 level of <17.8 pg/mL have a better prognosis after 30 days on follow-up examination, which, from the emergency physician’s point of view, is of great importance in immediately understanding the severity of the patient’s condition, because the disposition for these patients should be different.
Galectin-3 levels could be influenced by age and the kidney function. So if the patient is very old (> 75 years) and his estimated glomerular filtration rate is below 30 mL/min, the galectin-3 levels could be higher than expected. This could be related to the ongoing fibrotic process in the kidney that galectin-3 is mirroring. Moreover, in patients presenting with concomitant oncologic disease, galectin levels could be also higher.
For acute heart failure treatment, we now have many options, but in majority of the cases, the therapy is based on the use of intravenous diuretics. The current guidelines recommend high doses of intravenous diuretics, but also consider the possibility that, if immediately after a patient presents to the emergency department, you are able to make a correct diagnosis and determine the treatment and the following disposition based on biomarkers, the dosage of diuretic should also be based on appropriate patient risk stratification. A galectin-3 level of >17.8 pg/mL for instance indicates that a patient is at high risk for hospitalization, so you must be more cautious with this patient, possibly with a more aggressive intravenous diuretic treatment. Furthermore, the emergency department physician could also decide on the basis of a galectin-3 level of >17.8 pg/mL whether or not to discharge these patients only after infusion or to admit this patient to the hospital. On the contrary, since the job of the emergency department physician is mostly to rule out less severe cases, a galectin-3 level of <17.8 pg/mL (indicating less heart fibrosis) would probably indicate that it is safe to discharge a patient after just a small increase in the diuretic treatment dosage.
The use of galectin-3 will also have an important impact on the problem of overcrowding in the emergency department. In the recertification of patients coming to the emergency department with acute heart failure, there is an important possibility that adding the opportunity to measure galectin-3 can positively impact treatment from the emergency department physician.
Dr. Peacock: I think you brought up some extremely important points. You have to make a diagnosis first. Galectin-3 does not diagnose heart failure, but as you said, once you’ve established the probability that the patient has heart failure, galectin-3 is an outstanding prognostic agent. As Dr. de Boer said, it reflects generalized fibrosis, and there is a lack of specificity in that situation. However, once you’ve decided that the diagnosis is heart failure, then it’s an excellent prognostic, and if you define the cutoff point as 17.8 pg/mL, it identifies patients who would be at lower or higher risk for adverse outcomes subsequent to discharge.
This is really important for emergency medicine because we really don’t have anything that tells us what the future will look like in heart failure, except for B-type natriuretic peptide (BNP), which is really poor at predicting the next 2 weeks, and troponin, which is excellent, but is only elevated in a very small minority of cases using the contemporary assays available in the United States at this time.
Dr. Maisel: You can also make a case that once a diagnosis of heart failure is made—it’s sort of a moderate or mild-to-moderate heart failure, the BNP level is just a little above the grey zone, maybe 500 or 600 pg/mL, and the patient responds well to the diuretic—this isn’t like a troponin-positive acute coronary syndrome patient where, even if it’s just slightly positive, you’re still going to admit them. But, if you could show a propensity to have fibrosis in the short term and long term in this case of heart failure, and especially, if the patient is new to the system, then you may want to admit the patient to make sure this person gets on excellent therapy—and I’ll be talking about the role of mineralocorticoid receptor antagonists in a few minutes.
I think it’s significant to say, “Maybe this guy should not go home.” His level is above 17.8 pg/mL, and he has mild heart failure. He’s prone to just go downhill with each recurrent heart failure admission, and we need to take a closer look. If, in fact, you don’t admit him, then this is a person I would bring back within probably the first week to keep a close eye on.
Dr. Peacock: Dr. Maisel, what are you going to do when Dr. Di Somma sees a patient in the emergency department, their galectin-3 level is 27 pg/mL, and he sends the patient upstairs? Now, you’re at the receiving end.
Dr. Maisel: I’m going to treat him very fully and completely. When there is any stimulus of wall stretch by fluid overload or vasoconstriction or low contractility, I’m going to try to treat it because all of these are probably down-the-road, stimulators for collagen turnover. The patient with a high galectin-3 level is much more likely—and Dr. Boer touched on this—to have myofibroblasts activated and start producing collagen. Here, you may want to pay attention to the state of heart failure. I would give these patients the full diagnosis-related group—5 days in the hospital with a very thorough work-up. They may be early candidates for anti-fibrotic drugs such as aldosterone blockade.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
Dr. Maisel: I’m going to treat him very fully and completely. When there is any stimulus of wall stretch by fluid overload or vasoconstriction or low contractility, I’m going to try to treat it because all of these are probably down-the-road, stimulators for collagen turnover. The patient with a high galectin-3 level is much more likely—and Dr. Boer touched on this—to have myofibroblasts activated and start producing collagen. Here, you may want to pay attention to the state of heart failure. I would give these patients the full diagnosis-related group—5 days in the hospital with a very thorough work-up. They may be early candidates for anti-fibrotic drugs such as aldosterone blockade.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
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