Half of My Heart - A New Paradigm for Hypoplastic Left Heart Syndrome

What happens when someone is born with only half of a working heart?  Remarkably, this is what happens in babies born with a rare congenital heart defect called Hypoplastic Left Heart Syndrome (HLHS). Physician/scientist Dr. Paul Grossfeld studies HLHS at his laboratory at the University of California San Diego, and his team has made some amazing, paradigm-shifting discoveries.  As you'll hear, these breakthroughs may very well lead to changes in the way this disease is treated, and potentially, eventually help prevent it altogether.  Full of beautiful personal stories and fascinating science, this episode of One Rare Heart will engage and illuminate.

Transcript

Derren Raser  0:08 
What happens when someone is born with only half of a heart? Today on One Rare Heart, we speak with physician/scientist Dr. Paul Grossfeld, who is at the forefront of research being done around a rare and complex congenital heart defect that causes babies to be born with only half of a working heart. Coming up in just a few heartbeats. . . don't go away.

This is Dr. Paul Grossfeld, pediatric cardiologist and scientist at Rady Children's Hospital in San Diego, California.

Dr. Paul Grossfeld  0:50 
"Dr. Paul," to my friends.

Derren Raser  0:55 
On a very atypically rainy morning for San Diego, armed with an umbrella, I made my way across the campus of the University of California, San Diego, to the Medical Teaching Facility building, where Dr. Grossfeld has his office and laboratory.

Dr. Paul Grossfeld  1:11 
I was actually raised by my parents who were both social workers. So they had no formal training in science or medicine. But they always had a passion for understanding the basis of the life sciences. And I vividly remember one of my earliest experiences, which I think exemplifies what sort of created that career path for me, is when my brother and I were quite young, I was probably about seven years old, my parents got us a microscope. And I will always remember this, my dad in showing us how to use the microscope, took out a pin, and he pricked his finger, and he put a drop of blood on a slide. And he wanted us to look at blood cells. And he said, "Guys, this is the miracle of life, which you're looking at." You know, I'll try not to get emotional here - it's emotional for me to reflect on that. So you know, that really inspired me. And then my brother's an architect, so obviously, it didn't quite resonate in the same way - he's doing fine. So I'm a board certified pediatric cardiologist by trade. And so over at Rady Children's, I take care of children from infancy/newborn age to adults, with usually congenital heart disease, so meaning they were born with it. Less commonly, and sometimes it can be acquired. And so that's a big part of what I do, both in the inpatient experience, as you know, taking care of her patients in the hospital from time to time. And then the rest of my clinical time is devoted to taking care of those same patients in the outpatient clinical setting.

Derren Raser  2:52 
One interesting thing about this journey is that it didn't start in pediatrics, or even in cardiology.

Dr. Paul Grossfeld  3:00 
So, that was at UT Southwestern in Dallas, and that is an outstanding medical school that was very weighted towards internal medicine. So all that time until the middle of my third year of medical school, I just almost assumed that I was wanting, going to want to do internal medicine. Until I did my first day of  my internal medicine rotation. And I quickly realized that I really didn't want to take care of patients who, in a large part, didn't want to take care of themselves. Fortunately, after I came back from our Christmas break, my next rotation was pediatrics. And I will always remember that first day of my pediatrics rotation, there were a few of us medical students, third year medical students. And the chairman of the Department of Pediatrics met with us that day, Chuck Ginsburg. And he said, guys, one of the most wonderful things about pediatrics is that you are taking care of patients that are on the up-curve of life. And that completely resonated with me.

And so, the combination of wanting to take care of kids who are so innocent, who are victims, that actually scares off some people, but to me that just completely fit with my personality. So as a fourth year medical student, I came out to San Diego, UCSD and I specifically was hoping to do infectious disease, pediatric infectious disease, and unfortunately, there weren't any spots open. And so, the only thing that they had opened was pediatric cardiology. And so, I was actually quite disappointed, because that's not what I wanted to do, I thought, until I came out to San Diego. And in that month in October of 1991, I realized not only did I already want to do pediatrics, I was open to this world now of pediatric cardiology. And San Diego seemed like a perfect fit for me. And so, here I am 20 almost eight years later doing what I want to do where I want it to be and, you know, that's a very incredibly fortuitous situation to be in.

Derren Raser  5:04 
In addition to being a pediatric cardiologist, Dr. Grossfeld leads, well, a bit of a double life.

Dr. Paul Grossfeld  5:40 
The other hat that I wear is to try to understand what is really the genetic basis, which is usually the cause, in these children with congenital heart disease. And so my other life consists of this world up here at UCSD, where I have a research lab that is all patient-driven to try to figure out what the basis is, at really the molecular and cellular level, of heart defects. And we are very hopeful through our research to translate that back to improving care and ideally to prevent it someday.

Derren Raser  6:17 
From my conversation with Dr. Grossfeld, I learned that he is one of a rare breed of Doctor who is both clinical physician and research scientist. One thing that drew me to his research in particular is that he studies a very rare and complex heart defect called Hypoplastic Left Heart Syndrome, or HLHS for short. It's the same defect that my daughter Grace was born with, and it requires a series of very complicated surgical interventions to address. With Hypoplastic Heft Heart Syndrome, something happens very early on in the development of the heart that prevents the structures on the left side of the heart from developing properly. This means that when a baby with HLHS is born, oftentimes it's only with half of a heart muscle that looks and works as it should. Here's Dr. Grossfeld to explain.

Dr. Paul Grossfeld  7:09 
I think the best way to describe it is to know that there are four chambers of the heart, and the main pumping chamber is the left ventricle. Also on that side are the valves that allow blood to flow into the ventricle, when it's supposed to, and to be open to allow blood to flow out to the body, through the biggest vessel in the heart called the aorta. So there's the mitral valve, which allows blood to come into the left ventricle, there's the aortic valve, which allows blood to be pumped out through the aorta to supply the body. And basically what happens in Hypoplastic Left Heart Syndrome is that ventricle does not develop properly along with those associated so called left-sided structures, so that basically the heart is unable to pump blood out to the body. And, without immediate intervention, that is almost a uniformly fatal congenital heart defect, usually in the first few days of life if it's not addressed immediately.

Derren Raser  8:18 
As scientists have begun to study the genetics behind congenital heart disease, they've discovered something fascinating. Some genetic mutations associated with certain genetic syndromes have a propensity toward left-sided heart defects. And some genetic syndromes have a high occurrence of HLHS in particular. Over the years, Dr. Grossfeld has developed a passion for studying Hypoplastic Left Heart Syndrome, and now devotes much of his time in his laboratory to studying its underlying genetics. But what makes Hypoplastic Left Heart Syndrome so compelling?

Dr. Paul Grossfeld  8:56 
So, it was always an interest of mine, just in terms of the clinical challenges, to somehow save the baby that is otherwise destined for certain death within the first few days of life. You know, sort of intellectually, it represents something that has gone totally wrong in the normal development in the most important part of the heart. So there's, I think, some fascinating biology that goes along with that. And of course, you know, their heart defects and their heart defects. But, for me, if you're going to choose one, you might as well choose one of the most severe ones. And in fact, to this day, Hypoplastic Left Heart Syndrome is the most common cause of death in all infants born with any type of congenital heart defects. Almost 1% of all infants are born with some kind of a congenital heart defect. And there are some studies that suggest that in the United States, just from the 1000 or so babies that are born every year with Hypoplastic Left Heart Syndrome, the direct medical costs on this country are over a billion dollars. The impact on society, just from this one heart defect alone, is dramatic.

Derren Raser  10:06 
Over the years, improvements in clinical care and surgical techniques have greatly improved the survival rates of babies born with HLHS and many more are now making it to adulthood. However, this heart defect can never be completely fixed. The three stages of surgery that most children with HLHS undergo are only palliative, which means that they create a series of ingenious workarounds for this complex physiology, but they are not curative. A further serious challenge is that, for many children who do successfully make it through the three required surgeries, as their right ventricle carries the pumping load of the entire heart, eventually becomes fatigued, worn out. This happens for many children at the cusp of young adulthood. And as heart function declines, many end up needing a heart transplant. So, even as survival rates grow, new and serious challenges are emerging. And there are still many who don't make it through the surgeries.

Dr. Paul Grossfeld  11:05 
The challenging thing is, we certainly can't cure every patient. So, we're failing in that regard, right? There's so much more to do. And so, we're humbled by that reality check that, as far as we progress, there's so much more.

Derren Raser  11:33 
This need for continued progress and better treatment is what drives Dr. Grossfeld's research, and his team has made some tremendous discoveries. A gene called ETS1 has emerged as an important factor in regulating the early development of the heart. When this gene is removed, or the function is altered in some way, the heart develops in abnormal ways. In order to understand how this change occurs in our living heart, and what it means for the heart's function, Dr. Grossfeld's lab has taken some amazing steps forward. Using some sophisticated techniques Dr. Grossfeld has been able to manipulate a counterpart gene in both mice and frogs, to recreate something very similar to HLHS in the hearts of these animals. This allows his team to study and more deeply understand the mechanisms and outside forces that both cause and are at play in the progression of HLHS. As well as how the ETS1 gene is working. And there are some significant implications. I asked Dr. Grossfeld to explain.

Dr. Paul Grossfeld  12:33 
Sure, without stepping up to a chalk. My lab specifically works on mice, because they have a four chamber mammalian heart, that's very similar to a human heart. And the other powerful tool that we have in mice is that we can do genetics. So, we know all the genes in the mouse genome. It's about 80%, identical to the human genome. And we can, through some very sophisticated elegant technologies, manipulate genes to study their function in normal heart development and in how perhaps the loss of the function of these genes underlie certain congenital heart defects. One of the first things we did when we discovered this gene called ETS1 is we wanted to figure out what population themselves does this have a role in for normal heart development. And so we found two, and one of those populations of cells is actually the inner lining of the chamber of the heart, called the endocardium. And it's already been shown that the endocardium, during the early stages of heart development, is critical for regulating the development of the ventricle. And what we've shown, what we're learning now, is that with the loss of the ETS1 gene, that normal endocardial function to regulate the development of the ventricle is imperative. And that is actually leading us, and others, to what I think is a completely new paradigm for understanding Hypoplastic Left Heart Syndrome.

Derren Raser  14:05 
Part of the story has been shaped by how the research community has traditionally understood the etiology, or cause of this disease. Up until now, there has been a prevailing view of what has been causing the left-sided structures in Hypoplastic Left Heart Syndrome to be underdeveloped.

Dr. Paul Grossfeld  14:20 
People have embraced this hypothesis, or theory, called "no flow, no grow." And the thinking is that when the heart is developing, normally there is blood that is already flowing into that developing heart, that actually serves as a stimulus to promote normal growth. And what people have hypothesized, for some good reasons, is that if that normal flow into the heart is impaired, then that will compromise the ability of that heart to normally develop and grow. But, it turns out, that does not explain a lot of what we do see.

Derren Raser  14:57 
What's really turning the traditional paradigm of "no flow, no grow" on its head is a significant discovery that Dr. Grossfeld has made regarding the ETS1 gene, and one particular effect it has on the development of that inner lining of the heart.

Dr. Paul Grossfeld  15:12 
When people call it "Hypo"-plastic Left Heart, that suggests that the structures are actually small. But, in some aspects, the chamber volume itself is small, but going along with that, the actual wall of the art chamber is massively thickened. And now in our animal models, we're starting to replicate that. And in fact, when you knock out or lose the ETS1 gene function in the endocardium cells, we actually get overgrowth of the ventricle. And so, as a colleague of mine here at Rady Children's, suggested, and she is right on with this, Denise Malicki in Pathology, that maybe it should be called "Hyper"- plastic Left Heart Syndrome.

Derren Raser  15:53 
Dr. Grossfeld believes that this new paradigm for understanding HLHS actually offers a bridge between the old "no flow, no grow" hypothesis, and his new observations.

Dr. Paul Grossfeld  16:05 
It would actually reconcile this debate about "no flow, no grow," because what is already being shown, although people I don't think I've really looked at the whole picture to understand, that decrease flow into the heart will actually impair endocardial function. So, in that regard, it is true that decreased flow can affect the development of the heart. But, what are studies, and others are coming to the realization of, is that it's this endocardium population of cells that may be the smoking gun.

Derren Raser  16:39 
There are some very exciting implications of these realizations. Identifying the genes at play in HLHS, and understanding their role in the disease, will allow researchers to identify targets for new pharmaceuticals, which could allow for the development of much more effective medicines, which could vastly improve the treatment and long term management of HLHS.

Dr. Paul Grossfeld  17:01 
What I think will eventually happen is, even if we don't have a cure, what I could envision is that we will develop, as we learn more about the biology of why a right ventricle fails early in some patients and not so and others, that we will be able to define therapeutic, pharmacologic targets. So, it will get to the point where you may have the disease, but you can live with the disease. I think they're already great examples like that today with HIV, and diabetes. But, I think if we focus more on understanding the disease itself, we will identify those targets that will lead to much better pharmacologic interventions to make it a disease that can really be lived with.

Derren Raser  17:42 
And with the progress he's made in his research, Dr. Grossfeld believes that the conversation doesn't have to only be about helping people live with the disease, but that remarkably, it can now also be about preventing it.

Dr. Paul Grossfeld  17:54 
As we understand more about the very basic, fundamental processes, it does raise the hypothetical possibility that with very early intervention, we might be able to prevent this.

Derren Raser  18:09 
One potential approach to prevention might be the administration of medications prenatally in high risk pregnancies.

Dr. Paul Grossfeld  18:16 
It might be analogous to why pregnant women now take folate to prevent neural tube defects.

Derren Raser  18:23 
But identifying which pregnancies would benefit from this type of intervention will require some changes in early screening processes.

Dr. Paul Grossfeld  18:31 
What we're going to need to do is to improve our current imaging modalities, so that rather than making this diagnosis at 20 weeks gestation, we might have to make this diagnosis that six or eight weeks post-conception or even sooner. And we even have the technologies potentially to do that. Now, we can image newborn mouse hearts very early on. So, that gives us, in this scale, the same kind of resolution that you would need to potentially look at a six week fetus human heart that's feeding, and to potentially be able to identify, at that time, when there may be a window of opportunity to intervene. The other whole approach might be to identify so-called biomarkers. And again, we hope that will come from our research that might allow us to identify an at-risk pregnancy very, very early on.

Derren Raser  19:22 
Through the research in his lab, Dr. Grossfeld has brought the research community much closer to helping make some of these things a reality. And some of his recent breakthroughs are opening doors to a level of understanding that was previously out of reach.

Dr. Paul Grossfeld  19:36 
I am very, very excited about the prospects of now having what I think would be a very novel and powerful opportunity to learn things about hypoplastic left heart syndrome that nobody has ever even envisioned.

Derren Raser  19:53 
As Dr. Grossfeld continues his research, he's not only inspired by what might be done for those babies who might yet be born with his heart defect, but he can't help but also reflect on the profoundly personal experiences he's had over the years of his ongoing care for some of his early patients with HLHS, and seeing the ways in which his work continues to impact their lives.

Dr. Paul Grossfeld  20:15 
You know, the first baby I ever diagnosed with Hypoplastic Left Heart Syndrome was in July of 1996. So, she is 23 years old now. Beautiful, intelligent, doing great and, unfortunately, I have to pass her off now to my adult congenital heart disease colleagues, but I'm really hanging on to her. I don't want to give her up, but you know, you talk about gratifying - to go from that first day on a Saturday afternoon at Kaiser, when she came in at five days old dying, in shock because her doctors was closing. And, you know, the bonds that you formed with the families are just incredible. And to see how far she's come, is just, you know, is beyond words.

Derren Raser  20:58 
The arc of Dr. Grossfeld's journey in medicine and research is grounded in the deeply personal, like that first seed of curiosity that was planted by his father's own passion for understanding the underpinnings of life, and his experiences of both celebrating and mourning with the families he cares for. He continues to be driven and inspired by these personal experiences. And in some ways, he sees that journey coming full circle.

Dr. Paul Grossfeld  21:19 
So, my wife's parents, bought our son, who's now 13, a microscope a few years ago. My son tends to get bloody noses every so often. So, without my having any say in this, recently, just like a couple months ago, he gets a bloody nose. He goes and grabs a microscope slide, and catches a drop of blood to look at the blood from his bloody nose under the microscope. So, I thought, oh my God, if my father were alive today, I think he would just be bursting with enthusiasm and love for that moment.

Derren Raser  22:03 
The world of medicine needs more doctors like Paul Grossfeld, a physician who cares deeply about his patients and their families, and a researcher who connects that care to an ardent inquisitiveness and desire to find ways to improve treatment and subsequently lives. Unfortunately, despite the very important work that Dr. Grossfeld is doing, funding for this type of research, in general, is scarce. And an important part of his funding comes from passionate families and from people like you. Please visit the One Rare Heart website to learn more about how you can support Dr. Grossfeld and his groundbreaking work.

All the music in today's episode were my original compositions, with the exception of the song you're listening to now, "Heart Of Mine," which is by my friend and amazing artist, Erin Bode. I'm Derren Raser, thank you so much for joining me today. You've been listening to One Rare Heart.

Dr. Paul Grossfeld  23:05  
You know, in the long term future, how we can apply that knowledge to early intervention or just better therapies, so that someday we will never have to have this conversation, right? That would be the greatest way for me to ride off into the sunset.