January 28, 2015

Pioneering study shows disease that causes sudden cardiac death in children can be prevented with new drug therapy

A recently published study with major implications for ameliorating or preventing gene-triggered hypertrophic cardiomyopathy, a chronic form of heart muscle disease characterized by abnormal thickening and enlargement of the heart muscle that may also interfere with the function of the heart, suggests that pediatric cardiologists may soon be able to use drug therapy to block the onset of these abnormalities.

Hypertrophic cardiomyopathy can cause heart failure by stiffening the heart muscle and interfering with normal heart function. The condition sometimes causes sudden cardiac death when abnormal muscle cells and scar tissue lead to dangerous heart rhythms. Hypertrophic cardiomyopathy is the most common genetic disease of the heart, affecting one in 500 children. It is the most common cause of sudden cardiac death in young people and athletes.

The new study - the first of its kind and co-written by the Children's Hospital of Michigan DMC Pediatrician-in-Chief Steven Lipshultz, M.D. - showed that in many patients carrying these genes the abnormalities did not develop, or if they did develop they improved if treated for one to three years with a calcium channel-blocking drug called diltiazem. The drug helps block the effect of the gene mutations on the growth of heart muscle fibers.

"With this study, we are opening a new chapter in the book about heart care," said Dr. Lipshultz, who also chairs the Department of Pediatrics at the Wayne State University School of Medicine. "For the first time, we now have convincing evidence that drug therapy can protect patients from genetic mutations that lead to the abnormal heart development found in hypertrophic cardiomyopathy, a set of diseases that place affected children at increased risk for heart failure and sudden death.

"This study shows that if someone is carrying a mutated gene for hypertrophic cardiomyopathy but hasn't yet developed the disease - in other words, a patient who is 'genotype-positive but phenotype-negative' - we can prevent or delay the onset of the disease later in life by administering the drug therapy during the patient's earlier years. Further, the drug may also reduce the severity of associated diseases.

"This proof-of-concept study, funded by the United States National Heart, Lung, and Blood Institute of the National Institutes of Health and published in the Journal of the American College of Cardiology: Heart Failure, is an important milestone in the development of genetically-based therapies aimed at reducing the harmful effects of cardiac mutations," Dr. Lipshultz said.

The study, "Diltiazem Treatment for Pre-Clinical Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers", looked at the effectiveness of diltiazem in reducing the development of heart muscle abnormalities in 38 children and young adults with genetic mutations that can lead to eventual heart failure. The study found that after these patients were treated daily with the drug for periods ranging from 12 to 42 months, "... left-ventricular end-diastolic diameter improved toward normal" - a key step in preventing heart muscle abnormality or left ventricular hypertrophy with possible scar tissue formation, which can cause heart failure and sudden death.

The authors of the study, led by Carolyn Ho, M.D., of Harvard Medical School and including investigators from Wayne State University School of Medicine, Johns Hopkins University School of Medicine, Sydney Medical School, University of Navarra and the Howard Hughes Medical Institute, concluded: "Pre-clinical administration of diltiazem is safe and may improve early left ventricular remodeling (preventing heart muscle growth abnormality) in hypertrophic cardiomyopathy. This novel strategy merits further exploration."

Describing the breakthrough, Dr. Lipshultz said, "The gene mutations that cause the growth of too much heart muscle (hypertrophy) in children or young adults contribute to the leading cause of sudden death in young adults in the United States. But this study tells us that if you can prevent the onset or ameliorate the course of cardiomyopathy in a child with a gene mutation you may be able prevent or reduce the risk for heart failure and sudden death that will occur in some affected children.

"The first thing we aim for in pediatrics is prevention, and this study describes a truly exciting prospect - the likelihood that we will soon begin treating children with a heart failure-causing gene mutation long before the development of the muscle abnormality that causes the failure."

Dr. Lipshultz, an internationally recognized expert on pediatric cardiac care who 25 years ago led the effort to found the nation's only NIH-funded registry of pediatric cardiomyopathy and who has published numerous studies in pediatric cardiology and pediatric oncology, described the study as "a compelling example of how clinical research can help children. Such advancements continue to create a better future for our patients.

"What's very promising here is the idea that if you know you carry the gene, and you know you can get treated for it early, then you have a good chance of winding up with a more normal heart in spite of the genetic mutation," he said. "More science here may be capable of transforming life with less fear and disease because hypertrophic cardiomyopathy changes the lives, routine and future of affected children and their families, and also the way the world thinks about it.

"As a pediatrician who's treated many children with heart abnormalities that can have tragic consequences, I can't think of a better example of how cutting-edge research is helping establish innovative care with new therapies to create better outcomes for patients right here at the Children's Hospital of Michigan."