Sarah Franklin is investigating the responses of different sets of patients. She explains what she's searching for and how what she Linds may one day beneLit patients.">

Apr 25, 2017 — For most people, a diagnosis of advanced heart failure signals an inevitable decline with no chance for recovery. However, a few years ago, doctors found a small yet signiLicant proportion of these patients can bounce back if their heart is given a chance to rest with help from a left ventricular assist device (LVAD). Scientist Sarah Franklin is investigating the responses of different sets of patients. She explains what she's searching for and how what she Linds may one day beneLit patients.

Interview

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Interviewer: Heart failure is devastating no matter how you look at it. But it turns out that physicians can reverse the course of disease in a small fraction of patients. What makes these people different? I'm talking to Dr. Sarah Franklin who's researching ways to find out. So heart failure, what makes this a particularly interesting problem for you?

Dr. Franklin: So heart failure is the number one leading cause of death in the United States, and it has a significant burden on human health as well as a financial burden. And I think that one of the most exciting parts about studying the heart is that in recent years, we have started to realize that this organ which we typically have thought in the past was not able to regenerate itself or have regenerative capacity, actually is much more intricate than we thought. And we are starting to understand and realize that the heart actually is able to, in some circumstances, regenerate or essentially jump back after disease.

Interviewer: I mean this is just with a certain fraction of patients, is that right?

Dr. Franklin: Yes. So most individuals that experience heart failure or heart disease have two options. Unfortunately, these options aren't very exciting. But if you have a failing heart, you either can have a heart transplant, so have a new heart implanted, or you can have a left ventricular assist device, or essentially a mechanical pump implanted in your chest that pumps for your heart. And as you can imagine, both of these are life changing experiences and neither of them are really something that you want to look forward to.

However, there is a very small fraction of individuals that experience heart failure. But when a pump is implanted in their chest, as opposed to just maintaining function or prolonging life temporarily, their heart is actually able to regenerate itself or recover because there's stress that's actually taken off the heart from the pump. And this is the population that, as you mentioned, is quite small, but it's a really incredible phenomenon.

We didn't use to know that this occurred. And now that we know that actually a heart that's failing that we use to believe could never recover from that, actually some hearts do have this capacity. And if we can identify why and how this happens, then we can potentially understand how we can get more hearts to do this or go through this process. Or potentially just intervene at an earlier stage where maybe a lot more hearts have this capacity.

Interviewer: And so how are you looking at that?

Dr. Franklin: We are very excited to be involved in research to understand this phenomenon. Our lab is primarily using proteomics, a mass spectrometry. And as an LVAD device is implanted in someone's chest, naturally a piece of the heart tissue must be removed for that pump to be placed. And so we are able to take a piece of that tissue and to look at all the proteins that are expressed in the heart. And we look at thousands of phosphorylated proteins, we identify what the protein is. We identify how abundant it is. And then we actually compare between samples, and so this gives us thousands of data points that we can use to create a very unique signature for someone's heart.

Interviewer: So it's that molecular signature that possibly could become the basis of some sort of test to decide who might get this special treatment and who may not, possibly?

Dr. Franklin: Yes. So this molecular signature has a number of advantages. So at this point, the most exciting use of it is that we actually can predict at this point, and we've done this to 10 patients so far, we can predict whether or not they will actually recover from having an LVAD implanted in their chest. And so initially, just having a unique signature, we can kind of think of something similar like a fingerprint. So a fingerprint is made up of many different lines and curves that altogether make a very unique signature that is unique for one individual.

But we can take this molecular signature at the protein level and really identify who will respond and how to these therapies. So initially, there's a predictive power here. But the other advantages of this signature is that by looking at the individual proteins, we can try to understand at a knowledge level what is happening in these hearts. How are they failing? What's the difference between those that can recover and not recover? And how are those specifically involved in the function of physiology of the heart?

So on a knowledge level, we get to understand much more about heart disease and that can allow us to even create better therapies, by targeting maybe specific proteins or pathways.

Interviewer: So when you compare the molecular signatures of those who will just recover and those who won't, how large are these differences? Are there subtle differences, or is it really a striking difference between the two?

Dr. Franklin: So we initially look at thousands of phosphorylated proteins. But our goal has been to create the smallest panel possible that still allows us or gives us predictive power. And so we've reduced this panel down to about 24 phosphorylated proteins that allow us to distinguish between patients who will recover and those that won't.

Interviewer: One thing I wanted to bring out is something that we talked about earlier that instead of you going in with a preconceived notion of what might be different between these patients, you're letting the heart tell you what's different, so it's an unbiased study. Why is that important?

Dr. Franklin: We love mass spectrometry. It's one of the things that we get giddy about in the lab. We have lots of experience with mass spectrometry and proteomics, but we love the fact that it is an unbiased technique. We don't say beforehand we're only interested in this protein or only interested in this pathway, which in some areas can be helpful or in some labs is useful.

But we are really excited about the fact that we can go in unbiasedly and say we have no preconceived notions about what we may find. But we are going to apply this technique that will allow us to just sit back and have the heart tell us what's happening, tell us what proteins are being involved in this disease process. Have the list of proteins that are likely involved, identified through this technique as opposed to us picking or choosing what might be involved beforehand.

One of the things that I get really excited about is how impactful this study could be. As I mentioned, we're in the early stages but I can only imagine if you were in a patient's shoes, if you were the one that was having to make the choice of whether or not to have the LVAD surgery or to try and hold that longer for heart transplant, or where you might actually be listed on that heart transplant list. I can only imagine that that could be really stressful time in your life having to make those decisions.

And our hope is that we'll be able to provide more information or alternatives to actually helping us figure out who would benefit from an LVAD implantation or maybe provide additional information to influence where someone may be on a heart transplant list. And so really the idea of personalized medicine or helping the individual person and having information that would directly impact their specific situation is really what we're striving to do.

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