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Moderator:
Welcome to this disease state presentation on reverse cardiac remodeling in heart failure.

I am pleased to introduce our medical expert, Dr. James L. Januzzi, Jr., MD, the Hutter Family Professor of Medicine at Harvard Medical School, a provider in the Cardiology Division at Massachusetts General Hospital, and a faculty member at the Baim Institute for Clinical Research in Boston, Massachusetts.

This presentation will not include discussion of specific treatments, and is unbranded, disease state education.

This presentation is sponsored by Novartis Pharmaceuticals Corporation, and Dr. Januzzi was compensated for his time.

Dr. Januzzi:
Hi, there! I’m Jim Januzzi from the Mass General Hospital Heart Center, and I’m really glad to be speaking with you today about reverse cardiac remodeling in heart failure.

So, our objectives will be to provide an overview of heart failure.

We’ll review mechanisms and clinical implications of cardiac remodeling in heart failure.

We’ll talk about evidence for reverse cardiac remodeling, and describe the importance of various amounts of reverse remodeling, including the so-called “complete left-sided reverse remodeling.”

Lastly, we’ll review clinical outcomes associated with reverse cardiac remodeling, particularly in patients with heart failure with reduced ejection fraction.

Let’s start, first, with an overview of heart failure as a way to segue into the importance of cardiac remodeling.

In patients with heart failure, I remind you that this is a syndrome, rather than a specific diagnosis, and we arbitrarily divide patients with heart failure, defined as an inability to maintain cardiac output based on the left ventricular ejection fraction.

So, of course, the ejection fraction in a normal heart is anywhere from about 50% to 55% or higher; in patients with reduced ejection fraction, that’s defined, based on clinical trials largely, as an ejection fraction of 40% or lower. Heart failure with preserved ejection fraction is around 50%; some people now go down to 45% and higher.

So, these are different ways of categorizing patients with heart failure, and of course the pathophysiology of these patients differs somewhat considerably.

When we compare heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, again, there are different cut-offs for the ejection fraction to categorize these patients, but there are considerable differences when you look at these patients pathophysiologically.

In particular, when we look at the causes of heart failure, of course, they differ quite substantially between these two groups, and, importantly, the way that the heart muscle is damaged and changes in these patients, so-called “remodeling,” also differs considerably.

For example, in patients with heart failure with reduced ejection fraction, the remodeling is eccentric, which is to say that the ventricle enlarges in an asymmetric fashion. In contrast, patients with heart failure with preserved ejection fraction have more of a concentric remodeling, which is to say that the ventricle thickens and changes in a somewhat uniform, circumferential fashion.

The LV mass-to-volume ratio differs between these different syndromes, and, in contrast to heart failure with preserved ejection fraction, which may have relatively normal systolic function, of course, patients with reduced ejection fraction typically have a drop in their systolic function, leading to congestion and the other symptoms that might be found in such patients.

Mechanistically, there are differences between preserved and reduced ejection fraction but there are some common, important threads between both syndromes when it comes to how remodeling occurs.

In heart failure, cardiac remodeling is a pivotal process associated with progression of disease.

Remodeling, in of itself, is a structural change, but it includes molecular, cellular, and interstitial events that contribute to rather substantial changes, not just in the structure of the heart but also the function.

The changes that affect function may occur in multiple areas in the heart, including: cardiac chamber dimension change; wall thickness change; volumes of the chambers themselves; and again, I remind you, with increased radius comes increased pressure and increased stress on the myocardium; LV and LA mass may change; and, of course, as I have already noted, the ejection fraction may change.

Indeed, remodeling is an important process involved with loss of systolic function.

Causes of cardiac remodeling are numerous, so it is important to emphasize that, much like the broad range of different presentations we may see in heart failure, there is not one specific cause of cardiac remodeling in heart failure.

There are multiple stimuli that may lead to cardiac remodeling. These include: genetic causes; risk factors, such as hypertension; diabetes; coronary ischemia leading to myocardial injury; hemodynamic changes associated with valvular heart disease; and, ultimately, neurohormonal activation that follows all of these different stimuli.

This leads to activation of remodeling pathways, and there is a whole complex pathophysiology that is currently summarized that leads to remodeling, but this ultimately leads to cardiomyocyte injury, loss of cardiomyocyte function, and ultimately death of the cells, and then formation of myocardial fibrosis.

These conjugate pathways lead ultimately to what we call cardiac remodeling, which is a change in the heart geometry and ventricular dysfunction, either systolic dysfunction or diastolic dysfunction.

Importantly, I want you to remember the different processes leading to remodeling because when we start talking about reversal of remodeling, it is necessary to emphasize that if a cell is dead and there is fibrosis present in the myocardium, when we do things to

try to reverse this process, we are not going to be able to magically restore the presence of normal cardiomyocytes, so reversal of remodeling is a very different process than forward remodeling in some ways.

So, let’s get back to remodeling and the functional implications.

When we compare reduced and preserved ejection fraction, there are some differences.

In reduced EF, LV remodeling is driven by progressive loss of cardiomyocytes, as I have already said, and that eccentric hypertrophy and eccentric remodeling that I have mentioned lead to loss of systolic function, a reduction in cardiac output, and left ventricular volume overload.

In preserved ejection fraction heart failure, remodeling is thought to be driven by a number of different processes, but in many ways there are similarities. There is cardiomyocyte death and fibrosis, but importantly, because of the risk factors seen in patients with preserved EF heart failure, they are typically older, more likely to be female, actually, there is more diabetes, more hypertension.¹

This leads to concentric hypertrophy with diastolic abnormalities, so relaxation processes are impaired, ultimately followed by filling abnormalities and LV pressure overload, and indeed the stigmata of elevated left ventricular and diastolic pressure elevation is dilation of the left atrium, something that’s nearly universal in patients with preserved ejection fraction heart failure.

So why is remodeling so important?

Well, it is clearly known that cardiac remodeling is not only a pivotal process associated with progression of left ventricular dysfunction, but not surprisingly, it is associated with an increased risk for cardiovascular events in patients with heart failure, especially in those patients with reduced ejection fraction heart failure.

Now, I have already mentioned this concept of reverse remodeling, and I would like to start pivoting towards discussing this topic, because this is critically important.

Reverse remodeling in patients with reduced ejection fraction, judged, for example, by evidence of improvement in left ventricular size and function, is actually associated with better symptomatology, better prognosis, and lower risk for adverse outcome.

Ultimately, not surprisingly, this is associated with improved quality of life. So understanding how to promote reverse remodeling is critically, critically important.

It is important to emphasize that mechanisms of reverse cardiac remodeling remain to be clarified in patients with heart failure with preserved ejection fraction.

So, in contrast to reverse remodeling in heart failure with reduced ejection fraction, where we now have multiple therapies that may help to reverse cardiac remodeling in those patients with impaired systolic function, less is known about reverse remodeling in heart failure with preserved ejection fraction.

This may be due to uncertainties about the pathophysiology of HFpEF; the confounding comorbidities that frequently co-exist in HFpEF – and this is important because these comorbidities may not only lead to forward remodeling in HFpEF, but they may confound the treatment of HFpEF, so worse kidney function, for example.

Additionally, we have limited information about the myocardial biology in HFpEF, so unlike reduced ejection fraction, where we often have myocardium from heart transplantation or other cardiac procedures, patients with HFpEF do not undergo those procedures with any degree of frequency.

We really lack proper animal models and also we lack convincing results from therapeutic trials.

Of course, new targets are always being sought for treating and preventing HFpEF, and we’re hopeful, we really are, that we will be able to identify therapies to treat heart failure with preserved ejection fraction, and these therapies are currently under investigation.

Regardless of whether we talk about preserved or reduced EF, however, the goal, ultimately, to target remodeling is not only to improve cardiac performance, but ultimately, as a therapeutic target to improve prognosis.

There are many different reasons why remodeling may occur, as I have already discussed, but regardless of the causes – and let’s focus on reduced ejection fraction for a moment – regardless of the causes of the pathophysiology leading to remodeling, we now have therapeutic options including guideline-directed medical therapy, as well as device therapies, that might help us to reverse-remodel the ventricle and improve prognosis.

The hope would be, ultimately, that we can identify that currently empty box of therapeutic options for patients with preserved ejection fraction heart failure in order to promote reverse cardiac remodeling in patients with heart failure and preserved ejection fraction, and improve their prognosis the way that we have impacted prognosis in those patients with reduced ejection fraction heart failure.

So, let’s talk about the current evidence regarding remodeling and reverse remodeling, particularly with respect to how we might predict reverse remodeling and its clinical importance.

There are a number of variables that have now been identified that may help clinicians predict reverse remodeling as well as predict adverse remodeling, so it goes in both directions.

There are risk factors such as female sex, non-ischemic causes of heart failure, shorter-duration heart failure, specific left ventricular size and function variables, the absence of late gadolinium enhancement, and responsive, so lower or falling biomarkers like N-terminal proBNP, that all predict reversal of remodeling, whereas the opposite may predict adverse remodeling, so male sex, ischemic causes of heart failure, longer-duration heart failure.

So, it’s important for clinicians to start putting these variables together in order to help them to understand which patients are most likely to respond to therapy and which patients might not.

Indeed, again, the summary of variables associated with reverse cardiac remodeling is well known, and important to keep in mind as we apply the therapeutic options available to us, the so-called guideline-directed medical therapy.

It’s important to emphasize that we now know that guideline- directed medical therapy may improve remodeling indices in patients with heart failure with reduced ejection fraction.

The evidence supports that GDMT, in parallel with its impact on prognosis, influences cardiac remodeling, fostering reversal of remodeling which is associated with not only better prognosis but fewer symptoms in heart failure.

GDMT and its effect on remodeling indices is not yet established in patients with heart failure with preserved ejection fraction, however.

Importantly, clinicians will tell you in heart failure management, it is not sufficient to merely be on a therapy, but also to titrate to target therapies as much as is possible.

So, for example, in one study of beta-blocker therapy, higher-dose beta-blocker application was associated with more reverse cardiac remodeling as opposed to those patients treated with lower-dose beta-blockers.

So, there are clear associations, not only with the therapy choice, but also with the dose administered, and this is one of the reasons why we stay very focused on achieving target dose in patients with heart failure during the course of application of GDMT.

Another therapy that has clearly been associated with reverse cardiac remodeling is cardiac resynchronization therapy.

CRT exerts variable but often quite significant effects on ventricular size and function, and so we talk about responders to CRT demonstrating reduced LV size, improved left ventricular function, reduced atrial function, and together with the reverse remodeling that occurs in these patients and the reduction in mitral annular size, mitral regurgitation is actually improved as well.

Now importantly, there are variable effects across patients. Some patients have complete response and others show intermediate or no response at all to CRT, and that actually is quite prognostically meaningful.

So, for example, when we look at patients treated with cardiac resynchronization therapy, again, there are variable responses.

Some patients have complete atrial and ventricular reverse remodeling, some only have ventricular reverse remodeling, some only have atrial reverse remodeling, which is really quite interesting actually and may have something to do with reductions in mitral regurgitation, and then others have no atrial or ventricular reverse remodeling, the so-called non-responder.

Now, as a clinician might tell you, and as you might expect, when you look at these different classes of response, we can actually break down prognosis quite substantially to different levels of improvement.

In particular, the concept of complete left-sided reversal remodeling is an attractive paradigm for the concept of reverse remodeling and there is a really interesting analysis from the MADIT CRT study that examines the clinical implications of complete left-sided reverse remodeling.

Again, I remind you, complete left-sided reverse remodeling is reversal of remodeling in both the left ventricle and the left atrium.

In this analysis, patients were examined as a function of changes in their left atrial volume as well as their left ventricular volume.

There was quite a wide spread of reverse remodeling in those patients with changes in their left atrial volume as well as their left ventricular volumes.

Seen here are quartiles of left atrial volume change, and in the lowest quartile there was lesser left ventricular reverse remodeling.

The more left atrial volume change, you definitely saw more left ventricular reverse remodeling, but there was still some that had discordance. In other words, the atria got better, but the ventricles didn’t.

And, when we break these patients down as a function of outcomes, we can appreciate that, really, those patients that have complete left-sided reverse remodeling have the best prognosis. No surprise there.

Patients with either left atrial or left ventricular reverse remodeling had intermediate outcomes, and the non-responders, those patients that had non-response in both left atrial and left ventricular remodeling indices, were the ones that had the worse prognosis, and so this parsing of the chambers of the heart and examining how each reverse remodels is critically important.

Let’s talk a bit more now about reverse remodeling in clinical outcomes and how we might monitor patients with reverse remodeling under treatment with GDMT.

Seen here are important data from a group in Barcelona who examined the ejection fraction trajectory of patients with heart failure with reduced ejection fraction initiated on guideline-directed medical therapy and followed for more than 15 years.

What the investigators demonstrated was that an inverted U- shaped trajectory of ejection fraction is seen in patients initiated on typical guideline-directed medical therapy. This is to say that after treatment, the ejection fraction often substantially improves; this is the definition of reverse remodeling, and in some cases quite sustained over many years.

However, this inverted U-shaped trajectory after many years begins to appear, which is to say that after an initial improvement of ejection fraction, there is a long-term deterioration in some patients.

Notably in this study, when the ejection fraction began to deteriorate, the risk for heart failure hospitalization or death began to rise.

In addition, these investigators identified variables predictive of reverse cardiac remodeling, so shorter heart failure duration, non- ischemic cardiomyopathy. These were patients that were much more likely to show an improvement in ejection fraction, so much so in fact that patients sometimes show a complete recovery of their ejection fraction.

So, do these patients still have heart failure?

In fact, the concept of heart failure with recovered ejection fraction is something that has gained a lot of attention recently, and suffice to say, as I have already noted, reverse cardiac remodeling is not a cure of forward cardiac remodeling.

These ventricles typically are still abnormal, still have fibrosis and, indeed, a randomized trial called the TRED-HF study showed that in patients with recovered ejection fractions, withdrawing guideline- directed medical therapy is typically associated with a return of heart failure, with a drop in ejection fraction, really implying that heart failure with recovered ejection fraction is really probably better thought of as a remission of heart failure, rather than a recovery from heart failure.²

So it’s an important point. If your patient’s ejection fraction normalizes, they should have their medications continued because, if stopped, the likelihood is they would probably develop symptomatic heart failure soon after.

There are ways to evaluate therapeutic response after guideline- directed medical therapy to track reverse remodeling and also to monitor for the return of forward remodeling.

Biomarkers are an attractive option because they are widely available, may be measured at every office visit, and they are actually easy to interpret.

The link between biomarkers and remodeling has recently become much stronger.

In the GUIDE-IT HF study, patients with heart failure with reduced ejection fraction were managed with guideline-directed medical therapy, and after 90 days of intensified therapy an N-terminal proBNP was measured in these patients and, indeed, what we observed in GUIDE-IT was that the lower the NT-proBNP by 90 days after intensification of heart failure therapy, the better.

Patients had better outcomes, patients had less heart failure hospitalization, less mortality events, and importantly, if a patient was able to achieve a lower NT-proBNP value, their outcomes were dramatically impacted over an approximate 2-year follow-up.

When we look at, for example, all-cause mortality, those patients achieving an NT-proBNP concentration below 1000 pg/mL had a 66% relative risk reduction from all-cause mortality, and when we look at the composite endpoint of cardiovascular death or heart failure hospitalization, those achieving an NT-proBNP under 1000 mg/mL had a 74% relative risk reduction.

So, how do we reconcile these findings?

How do we explain these findings?

Well, in the GUIDE-IT study, we also had the ability to look at the long-term changes in remodeling parameters, and indeed, we found that those patients with a greater reduction in NT-proBNP also had a greater improvement in left ventricular structure and function by 1 year after intensified heart failure therapy.

Stated another way, those patients with larger reductions in NT- proBNP had greater improvements in ejection fraction and greater reductions in left ventricular volumes.

These are the measures we use to monitor left ventricular remodeling.

What about that cut-off of 1000 pg/mL that I mentioned to you? Again I remind you, patients achieving 1000 pg/mL of their NT- proBNP not only had less mortality events but also fewer heart failure hospitalizations.

Well, we found in GUIDE-IT that reverse cardiac remodeling accelerated substantially in patients who had been treated to achieve an NT-proBNP below 1000 pg/mL, really linking up the clinical outcomes with the mechanistic changes seen in the left ventricles in these patients, so patients with lower NT-proBNP values not only had more reverse cardiac remodeling but, as we’d expect, better prognosis, really illustrating a useful clinical finding for clinicians when we are seeing patients in the office and evaluating their response to guideline medical therapy.

So, in summary, cardiac remodeling refers to molecular, cellular, and interstitial events that contribute to clinically relevant changes in cardiac chamber geometry and function.

Sustained remodeling leads to progressive, irreversible dysfunction and is associated with an increased risk of cardiovascular death and heart failure hospitalization.

Different patterns of remodeling lead to different functional implications, including systolic dysfunction in patients with heart failure and reduced ejection fraction, and diastolic dysfunction in patients with heart failure and preserved ejection fraction.

Changes in NT-proBNP over time may actually help clinicians identify remodeling before it is clinically evident, and may also be useful to serve as a monitor for the presence and reversal of ventricular remodeling during GDMT.

Lastly, such GDMT, so therapeutic strategies in heart failure with reduced ejection fraction, have shown efficacy in reversal of cardiac remodeling.

Incomplete understanding of heart failure with preserved ejection fraction remodeling, however, has hindered progress in identifying effective treatment options, but we remain optimistic about identifying such treatments for patients with heart failure and preserved ejection fraction.

So, I hope you’ve found this interesting and I’m really glad you joined me today.