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I'm Aware That I'm Rare: Marlene Rabinovitch, MD

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Dr. Rabinovitch joined Stanford University School of Medicine Faculty in the summer of 2002 as the Dwight and Vera Dunlevie Professor of Pediatric Cardiology, and Scientist at the Vera Moulton Wall Center for Pulmonary Vascular Disease. The main focus of her research program is on uncovering molecular pathways that lead to developmental and inflammatory mechanisms of vascular pathobiology, particularly pulmonary hypertension. In this episode, Dr. Rabinovitch discusses the importance of pediatric pulmonary hypertension research efforts. 


My name is Marlene Rabinovitch, and I’m a pediatric cardiologist. I do mostly research. The main focus of my research is on pulmonary vascular disease. My research program is at Stanford University School of Medicine. 

I was trained at Boston Children’s Hospital, Harvard Medical School, where I was on faculty and began my research and began my research in pulmonary hypertension. I was then recruited to the Hospital for Sick Children in Toronto, where I directed the Cardiovascular Research Program at the Hospital for Sick Children, again, with a major focus on the cellular and molecular mechanisms that underlie pulmonary vascular disease and pulmonary hypertension in particular, as well as other pathologies that have taught us a great deal about how damage is caused to blood vessels and what we can do the reverse it.

During that time, we carried out the first studies in experimental animals showing that we could actually reverse a fatal form of pulmonary hypertension. That generated a lot of interest in our work and in the potential for therapies that might not only prevent the progression of the disease but might actually reverse established disease. After my work there, I’ve worked 20 years, I was recruited to Stanford University School of Medicine because of a major endowment by a parent that had a child with pulmonary hypertension. That allowed me to get my research program off and running because none of my Canadian grants were transferrable to the U.S. Very soon, we established tremendous collaborations in genetics, and in microbiology, immunology, to really refocus on taking our research to a different level that would allow us to identify and to pursue very exciting new therapies for the treatment of pulmonary hypertension.

I think the opportunity really to understand the disease at different levels. At first, when we started, I really tried to categorize and characterize the disease. That involved really taking animals, exposing them to stimuli that would cause pulmonary hypertension, and trying to establish at what point the disease was irreversible and at what point we could prevent the progression, and then refining the way we diagnose pulmonary hypertension. In fact, we were able to show that many children have disease that is reversible, particularly those with congenital heart defects, if you can treat them very aggressively in the early postoperative period.

That’s some work that I actually did or continue to do with Dr. Ian Adatia. We used to monitor the children very intensively. We used to treat them with vasodilators, try and keep their pressures as low as possible for as long possible, and then gradually taper those medicines off. With the advent of nitric oxide, that has made all of that much, much easier, so we don’t even monitor them the same way anymore. We just can anticipate that these are children that may be reactive or have problems in the postoperative period, and we treat them. We also, through my early studies, identified the subgroup most at risk for the development of the disease that wouldn’t regress and so we become much more aggressive at treating children with congenital heart defects that are at risk for pulmonary vascular disease, pulmonary hypertension, much earlier. So we’re very aggressive about correcting their defects in early infancy, before nine months of age, often before six months of age. That’s been a development that has been very exciting, along with nitric oxide.

And then with the advent of prostacyclin, we’ve actually seen patients that have been able to tolerate intravenous therapy over a long period of time, adjunctive therapy with receptor blockers. I remember the first meeting we had trying to talk companies into developing endothelin receptor blockers as an oral treatment. A lot of what we struggled with is now commonplace in the treatment of patients with pulmonary hypertension, so it’s been very exciting to see these developments. But that having been said, it’s a disease that still isn’t cured and a disease that we still see patients deteriorating with despite all these aggressive therapies that cause hardship. The opportunity now to understand the biology at a very fundamental level and to intervene is very exciting. We use stem cells that are derived from patients. We’ve shown just recently, are excellent surrogates for the cells of the lung because there’s a very strong genetic basis of the disease. So we can use those cells to drug test and to stratify patients for the new therapies that are coming out. That looks very, very promising.

We’ve also been able to identify why a lot of patients in families that have the same mutation don’t develop disease, or a lot of subjects, so they’re carriers. If you take a mutation that causes the disease in a family, 80 percent of the individuals don’t develop the disease. It has the same mutation. So there’s a clue there as to what’s protecting those individuals that we could potentially harness for therapeutic advantage.

We’ve been able to also use stem cells from the carriers and the patients to identify what their protective pathways are and to develop therapies for all patients to try to harness those protective pathways. That’s been very exciting. I would say the advent of genetics proteomics now, and we can interrogate one circulating inflammatory cell in the blood system with 30, 40 different antibodies by tagging those antibodies with different mass elements and using the mass spectrometer to identify what those cells are and how they’re reacting. By identifying small subsets of cells, we’re able to get a signature of the disease that we can actually follow in terms of seeing whether or not it reverses as we’re treating the primary condition or whether or not the patients are developing more tolerance to the drugs.

We’ve been able to do, I think, quite a bit on the basis of tremendous collaborations that we’ve had with both immunologists, geneticists, stem cell biologists, developmental biologists, so it’s really been a wonderful way to advance the field by being able to take advantage of advances in other fields, particularly the basic sciences.

There’s been a lot of work on pulmonary hypertension directed at adult medicine, for sure. It is a rare disease, but it’s a different disease in children because it occurs very early. The severity of their blood pressure elevation in their lung is just the same as the adults, so the question is why are the children getting it so early? Is it an extreme spectrum of the same genetic abnormality, or is it a different abnormality entirely? We really need to figure that out. And can we tailor therapy differently to children who may be more responsive because their lungs are more plastic, their vessels are more plastic? The opportunity for remodeling is greater, but we’ve sort of lumped, in the past, the pediatric population and the adult population together and they’re very different. I think we’ve learned, even from animal studies, that infant animals respond very differently to therapies in adults. Some of them even reverse disease spontaneously whereas the adult animals don’t.

So understanding the unique features of the child is absolutely critical not just for the children but also in understanding the adult disease better and in treating it better and in identifying it earlier. So physicians taking care of children, to be aware of the problem so that they can pick it up earlier and to treat it more effectively and to look at treatments that are given to adults and actually tailor them to children by forming networks of individuals that can actually combine data from multiple groups of children is very, very important and absolutely essential if we’re going to make progress.

So both for genetic studies, for treatment studies, focusing on the child because of the unique needs of the child and the child’s family, but also because it gives us an unparalleled window on the disease, I think is very, very important. They’re very sad stories, both in childhood and in adults where this disease was missed until it was way too late, so awareness of the problem is absolutely essential and getting to it early and treating it appropriately.

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Originally published: March 5, 2018
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