Inspired by the story and advocacy of a mother who lost two sons to the rare disorder characterized by a thickening of the heart walls, the Miller School’s Steven E. Lipshultz, M.D., led a national team of pediatric researchers to develop guidelines for assessing and stratifying the risk factors that predict poor outcomes for children newly diagnosed with hypertrophic cardiomyopathy (HCM), which has many causes. Their study, “Risk stratification at diagnosis for children with hypertrophic cardiomyopathy: an analysis of data from the Pediatric Cardiomyopathy Registry,” was published September 3 online in advance of print in The Lancet, the world’s leading independent medical journal, to coincide with the study’s presentation at one of the world’s largest gatherings of cardiologists.
By analyzing the cases of more than 1,000 children from 98 centers in the U.S. and Canada enrolled in the Pediatric Cardiomyopathy Registry over a 19-year period, the researchers found that children who were diagnosed at younger than one year of age, had specific inborn errors of metabolism, mixed types of cardiomyopathy, low weight or body mass index, congestive heart failure, and abnormal echocardiographic measures had the worst prognoses. Those children who presented with two or more of these risk factors at diagnosis had the lowest survival rates. Conversely, 97 percent of children with HCM diagnosed over age one had excellent, transplant-free outcomes two years after diagnosis.
“Based on our experience with adults, we do not think of hypertrophic cardiomyopathy as a cause for heart transplant. Yet for a select group of high-risk children with HCM, a heart transplant is key for survival,” said Lipshultz, the George E. Batchelor Professor of Pediatrics and public health sciences and Director of the Batchelor Children’s Research Institute. “With the exception of certain untreatable inborn errors of metabolism, children presenting with specific risk factors should be evaluated for early heart transplantation and followed more closely than children without these characteristics.”
Lipshultz, who established the Registry in 1994 and has had continuous funding from the NIH’s National Heart, Lung, and Blood Institute to conduct precisely this kind of evidence-based research, also presented the study September 3 at the European Society of Cardiology Congress 2013 in Amsterdam. He and his co-authors, including the Miller School’s James D. Wilkinson, M.D., M.P.H., professor of pediatrics and public health sciences, who is a co-investigator and the administrative director of the Registry, hope the guidelines will be adopted immediately, giving more children like Kevin and Bryan Yu a fighting chance.
Like his older brother Bryan, Kevin died of cardiac arrest just weeks shy of his first birthday. Unlike Bryan, Kevin was diagnosed with hypertrophic cardiomyopathy at birth, but his cardiologists at a top children’s medical center with a well-established heart transplant program did not list him for transplant because he seemed to respond well to medication. As it turns out, both boys had risk factors identified by the study as predictive of a poor outcome at diagnosis. The boys’ father also was diagnosed with HCM as a teen-ager but, like many adults with the condition, has always lived symptom- and medication-free.
“Before this study, nobody knew which factors were more important or less important in predicting dismal outcomes,” Lipshultz said. “Now we know that many of the characteristics Bryan and Kevin had were risks for failing medical management and needing a heart transplant. Had their cardiologists had access to this study, they likely would have taken a different course of action. Our goal is to prevent other children like Bryan or Kevin from dying.”
Lisa Yue, the boys’ mother, shared the same goal when, about a year after Kevin’s 2001 death, she sought Lipshultz’s help in accelerating research and improving the diagnosis and treatment of cardiomyopathies in children, which in addition to the hypertrophic form comes in other forms, including dilated and restrictive. The Children’s Cardiomyopathy Foundation Yue and her husband Eddie Yu established supports the Registry and helped fund The Lancet study, as did the National Heart, Lung, and Blood Institute.
“My son Kevin is the perfect example why this study was needed,” said Yue, a former international business executive who lives in New Jersey. “If this report had been published a decade ago, it would have been clear that Kevin had to be listed earlier for a heart transplant because he fit into that very high risk group with multiple risk factors: he had a mixed form of hypertrophic cardiomyopathy, was under one year of age, had lower weight and abnormal echocardiographic measurements.”
Another important element of the study, Yue said, is that it breaks hypertrophic cardiomyopathy into different patient sub-categories. “Before, physicians looked at adults and children with HCM as one patient group, but their outcomes really vary. This paper shows that they are not all the same. Those diagnosed with HCM at over one year old have an excellent chance, but for those under one, you really have to pay attention to which predictive risk factors are present.”
Gail Pearson, M.D., Sc.D., a pediatric cardiologist and Director of the Adult and Pediatric Cardiac Research Program in the National Heart, Lung and Blood Institute’s Division of Cardiovascular Sciences, cited the study as “a good example of public-private collaboration to address one of the most serious and complex heart conditions that affects children.”
“Where we don’t have good treatment options, such as with hypertrophic cardiomyopathy, determining risk level takes on more importance. The long-term follow-up made possible through the Pediatric Cardiomyopathy Registry has improved our ability to determine which children are at the highest risk for needing a heart transplant and for dying from this condition and thus need more intensive monitoring or earlier listing for transplantation,” Pearson said.
Robert G. Weintraub, M.B.B.S., of The Royal Children’s Hospital and Murdoch Children’s Research Institute in Melbourne, Australia, and Christopher Semsarian, M.B.B.S., Ph.D., of The Royal Prince Alfred Hospital in Sydney, Australia, and the Agnes Ginges Centre for Molecular Cardiology at the University of Sydney, wrote an accompanying commentary that agrees with Pearson’s assessment. In their commentary, “Aetiology Specific Outcomes in Paediatric Cardiomyopathy: Getting to the Heart of the Matter,” they said the study provided “new and important information” that “should facilitate early risk stratification and closer monitoring, enabling timely and appropriate listing for heart transplantation.”
Lisa Yue fervently hopes so. “Cardiomyopathy is so rare that each center might only see a handful of these kids. Finally, there are guidelines to help physicians determine the best course of treatment for children with hypertrophic cardiomyopathy.”
To date, the Pediatric Cardiomyopathy Registry, which is based at the Miller School, has enrolled more than 3,500 children under 18 years of age who were diagnosed with cardiomyopathy from 100 centers across North America.
Also a co-author on the study from the Miller School was Juanita Hunter, M.D., a pediatric cardiology fellow at UM/Jackson Memorial Medical Center’s Holtz Children’s Hospital. Researchers from Harvard Medical School, Cincinnati Children’s Hospital Medical Center, Boston Children’s Hospital, the New England Research Institutes in Watertown, Massachusetts, Genzyme, a Sanofi company, the Albert Einstein School of Medicine in New York City, and Washington University School of Medicine in St. Louis also contributed.
The study was supported by the National Heart, Lung, and Blood Institute grant HL53392 and by the Children’s Cardiomyopathy Foundation.