Miller School Studies Provide New Transplant Guidance for Pediatric Heart Diseases

Three groundbreaking studies by Miller School researchers provide significant new guidance on heart transplantation for children afflicted with one of the three forms of cardiomyopathy, diseases of the heart muscle.

Published in the prestigious academic journals Circulation and American Heart Journal, the studies analyzed extensive patient data in the Pediatric Cardiomyopathy Registry, leading to new fact-based recommendations about pediatric heart transplants. Characterized by an enlarged, thick or rigid heart muscle, cardiomyopathies affect about one of every 50,000 children, nearly 40 percent of whom receive a heart transplant or fail medical management and die within two years of developing symptoms.

“These studies are game changers for physicians, surgeons and parents as they point the way to improve transplant outcomes,” said Steven E. Lipshultz, M.D., professor of pediatrics and the George Batchelor Endowed Chair in Pediatric Cardiology. Lipshultz, who is also director of the Batchelor Children’s Research Institute, established the NIH-funded registry in 1994 so researchers could pool and learn from clinical data collected from pediatric cardiomyopathy patients across North America.

Based at the Miller School and coordinated by James D. Wilkinson, M.D., M.P.H., professor of pediatrics and epidemiology in the Division of Pediatric Clinical Research, the registry has enrolled more than 3,500 children under 18 who have been diagnosed with dilated, hypertrophic or restrictive cardiomyopathy at one of nearly 100 participating pediatric cardiac centers.

Lipshultz and Wilkinson were among the co-authors of the first study, which was published in Circulation in July. Titled “Outcomes of Restrictive Cardiomyopathy in Childhood and the Influence of Phenotype: A Report from the Pediatric Cardiomyopathy Registry,” the study examined 3,375 patients, comparing transplant outcomes based on several risk factors such as prior heart failure and thicker heart walls.

Restrictive cardiomyopathy – in which the walls of the heart are stiff due to scar tissue, genetic defects or other causes – restricts incoming blood flow, often causing lung congestion, shortness of breath, and a high risk of sudden death in children.

“This study found that transplant-free survival is poor for restrictive cardiomyopathy in childhood and overall outcomes are worse than for all other forms of cardiomyopathy,” Wilkinson said. “The study further found that children with restrictive cardiomyopathy and heart failure are twice as likely to fail medical management and need a transplant compared with patients who didn’t have heart failure. That strongly suggests that these pediatric patients should be listed for an early heart transplant.

“That’s a very important finding, because these patients typically receive transplants only after a heart fails and they are put on life support systems. The data now clearly indicates that patient outcomes for this rare condition are better if you don’t wait for the heart to fail.”

Also published in Circulation in July, the second study, “Early Predictors of Survival to and After Heart Transplantation in Children with Dilated Cardiomyopathy,” compared the clinical presentations and transplant outcomes of 261 children with dilated cardiomyopathy who were listed in the registry and also in the Pediatric Heart Transplant Study, an independent, prospective, event-driven database for pediatric heart transplantation that currently includes 42 participating transplant centers. A high percentage of children who have dilated cardiomyopathy – a heart larger than normal or a dilated left ventricle – are initially brought to a doctor after heart failure.

“Pediatric patients with dilated cardiomyopathy on life supportive therapy usually go to the top of the list for transplants, because they are very sick when they are admitted to a hospital’s intensive care unit,” Lipshultz said. “But a certain percentage of these children don’t do well after a transplant. We wanted to know if there were any ways to predict who would have a good outcome from a transplant and who would not.”

The Miller School study found that dilated cardiomyopathy patients with myocarditis – an inflammation of the heart accompanied by destruction of heart muscle that can be caused by a viral infection – had poorer transplant outcomes than patients whose dilated cardiomyopathy was not related to myocarditis. The reason could be that the patient’s immune system was actively combating the infection, reducing the ability of immunosuppressant drugs to support a transplanted heart, Lipshultz said.

“We would recommend delaying a transplant surgery for a child with dilated cardiomyopathy and myocarditis to see if the underlying inflammation recedes,” Lipshultz said. “Even if these patients stay on life support for a longer period, they may have a better opportunity for a positive outcome if the inflammation or viral infection is reduced prior to transplant. That conclusion is not intuitively obvious, but based on an exhaustive analysis of the case data.”

The third study, “Outcomes in Children with Noonan Syndrome and Hypertrophic Cardiomyopathy: A Study from the Pediatric Cardiomyopathy Registry,” was published online in August in American Heart Journal, with Wilkinson and Lipshultz as first and last authors, respectively.

The study compared the clinical outcomes of 74 children with Noonan syndrome — a systemic genetic syndrome that is the leading cause of genetic-syndrome-associated hypertrophic cardiomyopathy –– with 792 children whose cardiomyopathy resulted from other genetic or unknown causes. Children with hypertrophic cardiomyopathy, which is associated with thickened heart walls, may have few symptoms, but are at high risk for dangerous heart rhythms and sudden death.

Pediatric patients diagnosed with Noonan syndrome and hypertrophic cardiomyopathy before age 6 months with heart failure had a 69 percent mortality rate at one year—a much worse outcome than the hypertrophic cardiomyopathy patients without Noonan syndrome.

“Our findings strongly suggest that these infants with Noonan syndrome, hypertrophic cardiomyopathy and heart failure should have an aggressive therapeutic approach including potential early listing for cardiac transplantation, even if their symptoms have transiently improved,” Wilkinson said. “These pediatric patients may also require a defibrillator to stay alive until a transplant can be performed if they have life-threatening abnormal heart rhythms because of a risk for sudden death.”

The Pediatric Cardiomyopathy Registry and its associated studies have been funded continuously since 1994 by the NIH’s National Heart, Lung, and Blood Institute. In addition to its administrative coordinating center at the Miller School, the registry has clinical coordinating centers at Harvard’s Children’s Hospital Boston and the Cincinnati Children’s Hospital Medical Center, as well as a data and statistical coordinating center at the New England Research Institutes.

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