Miller School pediatric researchers have been awarded two multicenter grants totaling more than $14.2 million to identify genetic mutations associated with pediatric cardiomyopathy and develop better and more targeted treatment for children diagnosed with one of the rare but devastating diseases of the heart muscle.
Awarded by the NIH’s National Heart, Lung, and Blood Institute (NHLBI) to principal investigator Steven E. Lipshultz, M.D., professor of pediatrics and director of the Batchelor Children’s Research Institute, and a team of the nation’s other pediatric cardiomyopathy experts, the four-year grants are designed to significantly increase the understanding of one of the leading causes of heart failure, death and heart transplantation in children. Characterized by an enlarged, thick or rigid heart, cardiomyopathies affect one of about 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.
“Despite all the advances in cardiology, cardiomyopathies are still major causes of death or heart transplantation of children,” said Lipshultz, a renowned pediatric cardiology researcher who holds the George Batchelor Endowed Chair in Pediatric Cardiology. “The two-year time frame between presentation and transplantation or death has not improved in 35 years, and the mortality rate of cardiomyopathy-related heart failure exceeds the combined mortality of all childhood cancers. With these two grants, we hope to identify the genetic factors that determine the development and progression of the disorder, and pinpoint the biomarkers that could lead to earlier, more accurate diagnoses, and better interventions.”
With the grants, researchers will use or augment data in the NHLBI-funded Pediatric Cardiomyopathy Registry, which Lipshultz established in 1994 so researchers could pool and learn from information 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 cardiomyopathy at one of nearly 100 participating pediatric cardiac centers.
With the first $8.8 million, four-year grant, “Genotype-Phenotype Associations in Pediatric Cardiomyopathy,” Lipshultz, Wilkinson and their team of cardiomyopathy experts from 11 pediatric cardiology centers in the U.S. and Canada will attempt for the first time to genetically profile a large cohort of 600 pediatric cardiomyopathy patients, and their parents and other relatives, to identify the genetic variants that caused or worsened their disease. Ultimately, the researchers hope that knowledge will improve the ability to identify children who develop the disorder suddenly, and deteriorate rapidly.
“Some patients live a full life expectancy after symptomatic presentation; others do well with medical management, and still others progress to transplantation right away. But they frequently look the same,” Lipshultz said. “So what is the difference? Do the affected children with bad outcomes have clusters of gene mutations? These are some of the questions we hope to answer.”
With the other $5.4 million “Cardiac Biomarkers in Pediatric Cardiomyopathy” grant, researchers hope to determine whether established and novel cardiac biomarkers can predict short- and long-term outcomes in 300 children newly diagnosed with dilated and hypertrophic cardiomyopathy. If so, the biomarkers could help determine the most appropriate, evidence-based clinical care for children with cardiomyopathy, including when to consider heart transplantation as a therapeutic option.
As Wilkinson notes, pinpointing sensitive and specific cardiac biomarkers, or panels of biomarkers, would be the most cost-effective and, of particular importance for children, the least invasive approach to early detection of cardiac dysfunction.
“Right now we have to follow kids with echocardiograms, so the idea would be to find simple biomarkers – a hormone, enzyme or inflammatory protein – that can be detected with a simple blood test,” Wilkinson said. “That would not only cut down on echocardiograms, but tell us now when things are going wrong, before the symptoms start. The ultimate goal is to develop practice guidelines based on the most appropriate evidence-based clinical care for pediatric cardiomyopathy patients.”
Globally, cardiomyopathy is the leading indication for heart transplantation for children from 2 to 18. In 2010, cardiomyopathy and myocarditis were the fourth most common global causes of cardiovascular disease in people of all ages, with 410,000 attributable deaths.