Date: July 10-11, 2014
Location: Bethesda, MD
The National Heart, Lung, and Blood Institute (NHLBI), in collaboration with Parent Project Muscular Dystrophy, convened a Working Group meeting on July 10-11, 2014, in Bethesda, MD, to explore the current issues relevant to cardiac disease in patients with Duchenne Muscular Dystrophy (DMD). The goals of the Working Group were to identify knowledge gaps in our understanding of the natural history, diagnosis, and treatment of DMD-associated cardiac disease and to develop a research agenda to address these gaps, supporting NHLBI Strategic Plan Goals 1, 2, and 3. The Working Group consisted of experts in pediatric and adult cardiology, including those with expertise in heart failure, advanced imaging and electrophysiology, molecular cardiology, and basic and translational science, regulatory specialists, and patient advocates.
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder diagnosed in childhood. It affects approximately one in every 4,600 live male births (about 20,000 new cases worldwide each year). DMD causes loss of mobility and cardiac and pulmonary dysfunction, leading to significant disability. DMD is caused by a mutation in the gene that encodes the dystrophin protein. The loss of dystrophin results in a cascade of events that lead to progressive muscle damage and deterioration. As a result, those with the condition suffer a loss of strength. DMD affects all striated muscle, including respiratory muscles and myocardium. Without supportive care, young men with DMD typically die in their third decade of life. Historically, the most common cause of death has been cardiac and respiratory failure. However, as respiratory support has improved, cardiac disease (cardiomyopathy leading to heart failure and arrhythmias) has become an increasingly important source of morbidity and mortality.
The Working Group discussed a number of topics related to cardiac issues in DMD and identified critical knowledge gaps. The topics discussed included the following:
- natural history of cardiac disease and the role of fibrosis and genetics in disease pathogenesis;
- small and large animal models that replicate aspects of the human disease;
- monitoring and surveillance of cardiac function and arrhythmias through imaging and measurement of biomarkers;
- medical therapy, including extrapolation from guidelines for adult heart failure management, novel signaling pathways as potential targets, novel muscle therapies, and the impact of skeletal muscle therapy on cardiac function;
- non-medical therapies, including heart transplantation, pulmonary management, and use of ventricular assist devices and implantable cardioverter-defibrillators, and ethical issues relating to these therapies; and
- regulatory challenges involved in standardizing care guidelines, developing new drugs, and administering clinical trials relating to this rare disease.
The Working Group made several recommendations to address the identified knowledge gaps.
- Cardiac care guidelines. Current cardiac care for patients with DMD is highly variable and based on insufficient evidence. Given the impact of cardiac disease on morbidity and mortality, a proactive approach to evaluation and management, rather than a reactive approach, is warranted. Improving standardization of care founded on the most currently available data could have a significant public health benefit for the DMD community. The Working Group recommended that an expert panel refine and update guidelines for cardiac care after reviewing currently available data and expert consensus opinion. The expert panel should include appropriate expertise from the pediatric and adult cardiology, neuromuscular, rehabilitation, and pulmonary communities. The guidelines should address medical management, including the use of steroids and angiotensin-converting-enzyme inhibitors. The guidelines should also address cardiac surveillance, particularly imaging with cardiac MRI. Clinical guidelines should encompass early intervention as well as management of the advanced DMD patient. The expert panel should create these initial guidelines but should also arrange for ongoing updates of the guidelines based on new evidence. Patient care organizations will be vital in the dissemination of such guidelines.
- Cardiac endpoints in clinical trials. Clinical trials of muscle therapies for patients with DMD, especially those trials testing therapies in younger DMD patients, often have inadequate cardiac monitoring and rarely have cardiac endpoints—that is, defined clinical outcomes that indicate the effect of the treatment. The Working Group recommended that all Phase II or III trials of muscle therapies have sufficient cardiac monitoring with cardiac MRI. Any protocol excluding cardiac monitoring should have a sound rationale that is reviewed by appropriate cardiac experts. Those who design trials should also consider incorporating additional cardiac endpoints into the trial design when appropriate.
- Animal models. Current standard operating procedures (SOPs) for the use of various DMD animal models either lack detailed protocols for cardiac monitoring or have out-of-date methodologies. The Working Group recommended that those who conduct animal research on DMD refine and update SOPs. Specifically, the SOPs should call for the use of state-of-the-art imaging protocols to assess cardiac function in the mouse and dog model of DMD. In addition, the Working Group recommended the creation of a repository of detailed descriptive methods from the various laboratories working with these protocols. Patient care organizations could monitor and manage this repository.
- Clinical research questions. The Working Group identified a number of important clinical research questions to address cardiac care in DMD:
- What early evaluation and therapeutic strategies can slow or prevent cardiac disease progression?
- What is the best method to risk-stratify patients for arrhythmia complications and sudden cardiac death?
- Does early pulmonary intervention prevent cardiac disease progression?
- Using state-of-the-art genotyping/sequencing techniques combined with better cardiac phenotyping, can genotype be associated with cardiac phenotype?
- How should female carriers be monitored for cardiac disease?
- Clinical research infrastructure. The Working Group identified important infrastructure needs to facilitate clinical research:
- A registry to assist with standardized data collection and patient follow-up. Several patient registries, supported by patient advocacy groups or academic institutions, currently exist. Linking data between registries and other datasets may expand research opportunities. Patient-centered registries may reduce regulatory burdens. In addition, combining efforts with European organizations and centers would increase statistical power.
- A biorepository to centrally store DNA and tissue specimens. The Working Group noted the importance of studying human tissue for improving the pathophysiological understanding of human disease. Tissue cores, obtained at the time of ventricular assist device placement, explanted hearts, or autopsy materials should be stored and made available to the scientific community.
The Working Group committee will develop a report of the meeting for publication in an appropriate professional journal.
Division of Cardiovascular Sciences
Jonathan Kaltman, MD
Working Group Members:
- Elizabeth McNally, MD, PhD, University of Chicago
- Larry Markham, MD, Vanderbilt University
- D. Woodrow Benson, MD, PhD, Children's Hospital of Wisconsin
- Charles Canter, MD, St. Louis Children's Hospital
- Linda Cripe, MD, Nationwide Children's Hospital
- Dongsheng Duan, PhD, University of Missouri
- Jonathan Finder, MD, Children's Hospital of Pittsburgh
- William Groh, MD, MPH, Krannert Institute of Cardiology
- Eric Hoffman, PhD, Children's National Medical Center
- Dan Judge, MD, Johns Hopkins
- David Kass, MD, Johns Hopkins
- Roxanne Kirsch, MD, Children's Hospital of Philadelphia
- Naomi Kertesz, MD, Nationwide Children's Hospital
- Joe Metzger, PhD, University of Minnesota
- Jill Rafael-Fortney, PhD, Ohio State University
- Subha Raman, MD, Ohio State University
- Christopher Spurney, MD, Children's National Medical Center
- Lee Sweeney, PhD, Penn Rare Disease Center
- Shari Targum, MD, Food and Drug Administration
- Kathryn Wagner, MD, PhD, The Kennedy Krieger Institute
Parent Project Muscular Dystrophy Staff:
- Brian Denger
- Pat Furlong
- Sharon Hesterlee, PhD
- Kathi Kinnett, MSN, CNP
- Kristin Burns, MD
- Glen Nuckolls, PhD
- Gail Pearson, MD, ScD
- John Porter, PhD
Last Updated: August 2014