Research: Preventing the unpreventable – discovering new treatments for pediatric heart problems

WINTER 2002 - Packard Children's Hospital has earned a reputation as a place that brings hope and healing to kids who cannot find help anywhere else. The future of pediatric medicine, however, lies in being able to prevent disorders that are as yet unpreventable, and to find treatments to contain or reverse conditions that are now irreversible. The paths to discovering these new treatments start in basic medical research. Packard Children's Hospital, Stanford University, and Silicon Valley offer a uniquely rich environment for such medical research, one that has attracted bright medical scientists from research universities throughout the country.

Understanding Cardiopulmonary Disorders

One of the prize recruits to Packard this year is Marlene Rabinovitch, M.D., Ph.D., formerly head of cardiovascular research at The Hospital for Sick Children in Toronto. Rabinovitch brings with her a strong program of research in the molecular and cellular underpinnings of cardiopulmonary disorders in children.

Researcher Marlene Rabinovitch, M.D., Ph.D., brings to Packard her expertise in understanding the molecular biology of cardiopulmonary disorders in children.

Rabinovitch's laboratory has demonstrated how damage to blood vessels from inflammation, toxins, low oxygen, or high blood pressure can cause structural changes that narrow arteries. "When certain vascular tissues are disrupted, the natural reaction of muscle cells surrounding the artery is to try to repair the damage by multiplying, which constricts the arteries," Rabinovitch says.

Narrowed arteries can create yet higher blood pressure, causing further damage and creating the basis for a progressive degenerative disease. When this occurs in the lungs, the result is pulmonary hypertension. Although pulmonary hypertension is rare in children, it can be devastating for kids and their families.

"Our focus is on trying to understand the basic mechanisms of pulmonary hypertension so that we can identify it better and reverse it more effectively," Rabinovitch says.

She has shown that researchers may be able to block certain molecular events that lead to pulmonary hypertension. Research by Rabinovitch and her colleagues could result in a new class of drugs that will stop or reverse the multiplication of muscle cells that narrow arteries, a development that could have implications far beyond pulmonary hypertension.

"Many of the enzymes we study also play a part in organ rejection after heart transplantation and other cardiovascular diseases," Rabinovitch says. She and her colleagues are now studying the effectiveness of these compounds in the lab and setting the stage for future human trials.

When researchers such as Rabinovitch develop new drugs they often face another challenge: how to deliver the drugs to the correct tissues and to release those drugs into the tissue at a steady rate. Stanford scientists are developing new devices that can be implanted via catheter to deliver the right dosage of a drug over months, keeping children away from the hospital for a longer period of time. For cases in which effective drugs don't yet exist, Stanford researchers are investigating genetic therapies that will allow kids' bodies to make their own missing or therapeutic proteins.

Bioengineering Missing Parts

One strong desire of pediatric cardiac surgeons is to be able to invent new materials to help in reconstruct cardiovascular malformations. "Cardiac defects in children are developmental, which usually means parts are missing," says surgeon Frank Hanley, M.D. "We can do reconstructive surgery, but we can't create a part if there's nothing there to work with." The interest in inventing artificial organs and tissues is the focus of the new children's surgical research program at Packard. This program fits well with Stanford's long history of innovation in other engineering and materials science programs, and with the school's record for moving those innovations from the laboratory to the world at large.

Ultimately, surgeons are interested in bioengineered parts that are grown from living cells and tissues. "Kids have special needs as heart patients because unlike adults they keep growing," Hanley says. "Now we use synthetic parts or those from cadavers, but they are not ideal because they degenerate or don't grow, meaning the child has to have multiple surgeries."

Flying Through the Heart

Using technology borrowed from Silicon Valley, Packard researchers are developing computerized medical imaging technologies to help surgeons repair heart defects in children. Images obtained with ultrasound, computed tomography (CT) scanners, or magnetic resonance imaging (MRI) are usually two-dimensional, but can be combined by computer into highly detailed 3-D images. "You can actually fly through the arteries and the heart's chambers, as if you were in a tiny airplane," says cardiologist Daniel Bernstein, M.D. "This lets the surgeon know exactly what he will see once he goes in."W

Such imaging lets cardiologists construct a model of a child's cardiovascular system, recording blood velocity and pressure in a specific network of arteries and veins. Surgeons then can model the outcomes of various surgical interventions and choose the best one before surgery even begins.

It is precisely this combination of strengths in biomedical sciences and engineering that makes Stanford so productive in finding medical breakthroughs and delivering them to patients. "You can't find such a concentration of doctors, engineers, and private companies anywhere in the world," says Jeffrey Feinstein, M.D., an associate director of the pediatric cardiac catheterization lab and director of the Wall Center for Pulmonary Vascular Disease at Stanford (see sidebar, p. 13). "There's no doubt in our minds that we are going to be able to do things for children that can't be done anywhere else."