Hunting for early biomarkers of Duchenne muscular dystrophy

Trackers are fabled for their ability to detect faint traces of the object of their search to stay on the trail. Now engineering and medicine have paired up to track early biomarkers of cardiomyopathy (CM) in patients with Duchenne muscular dystrophy, to better define its onset and rate of progression. The goal is to get an early leg up on the disease to guide proactive therapeutic intervention and improve patient outcomes.

Duchenne muscular dystrophy (DMD) was first described by Guillaume Benjamin Amand Duchenne, a French neurologist, in the 1860s. A genetic disorder, it manifests itself in progressive muscle degeneration and weakness. This is caused by changes to a cohesive protein called dystrophin, which links the filaments of other support proteins to help maintain the integrity of muscle cells. The dystrophin deficiency leads to myocardial necrosis — the death of heart muscle cells — and fibrosis, which eventually are fatal.

DMD symptoms typically appear in children around the age of 2 or 3, and the disease primarily affects boys. In Europe and North America, according to the Muscular Dystrophy Association (MDA), DMD occurs in about 6 out of every 100,000 individuals. There are a number of strategies being pursued to treat this disease, including gene therapy, exon-skipping (RNA splicing so cells “skip” faulty sections), and gene repair, but currently there is no cure. Even so, the MDA reports that life expectancy is increasing, thanks to these advances in cardiac and respiratory care.

Medical providers currently lack standard imaging biomarkers to forecast CM’s early onset or developmental pace. To facilitate these diagnoses, we have developed an innovative method to measure strain in three dimensions — an engineering technique used to assess the changes to tissues and structures when subjected to forces. We used cine (motion capture) cardiac magnetic resonance (CMR) images to determine which metrics would provide early insight into characterizing DMD CM for treatment with cardio-protective medications and interventions.

Graphic depicts cardiac changes in DMD. (Image created by Goergen Lab MD/PhD student Conner Earl using BioRender.)

Interestingly, Duchenne himself used photography — which had only recently been invented — to capture images for his research into muscular atrophy. Today, many generations of technology later, engineering and medicine are joining forces to do something very similar to better understand and help devise therapies for the disease that carries his name.

Over the past several years, we had developed methods for high-sensitivity spatiotemporal mapping of time-gated (tracking over a heartbeat) 3D cardiac echocardiographic data. These methods have allowed us to identify subtle imaging biomarkers in a variety of cardiac-disease animal models of myocardial infarction (heart attack), aortic aneurysm, and atherosclerosis.

Recently, we applied these techniques to the CMR images of 6-8-mm-thick stacked “slices” of cardiac tissue to characterize the biomechanical pathologic changes in DMD patients. We compiled 3D+time sequences for regional strain analysis on images for 43 male DMD patients and 25 male healthy controls. Our research team segmented epicardial and endocardial borders across a representative cardiac cycle and used custom-built image analysis software to evaluate the heart kinematics.

Graphic depicts colorized surface strain map of 3D left ventricle at peak systole (top) and polar plot (bottom). (Image created by Conner Earl using Purdue Engineering’s MATLAB toolbox.)

We were able to calculate regional, circumferential and longitudinal strain, and found that the DMD subjects had a range of cardiomyopathy severity. Our research revealed statistically significant differences between DMD and control patients in systolic strain rates across all regions analyzed, as well as significant differences between DMD and control groups in radial strain, circumferential strain, and surface strain.

Image shows strain measurement in the heart. (Image created by Conner Earl.)

Identifying these strain differences between DMD CM and control patients provides insight into early abnormalities related to Duchenne muscular dystrophy. The aberrations offered up novel biomarkers for assessing changes, especially in the areas of basal circumferential and basal area surface strains. We demonstrated that the 3D+time CMR imaging analysis platform we developed can help characterize sensitive and specific strain rate metrics in DMD patients — significant enough to differentiate those patients from healthy ones.

The identification of these abnormalities also provides novel biomarkers for evaluating changes in DMD over time, and it could be used in clinical trials and accelerate innovation toward a therapeutic advance in cardiomyopathy management.

Craig J. Goergen, PhD

Leslie A. Geddes Associate Professor

Director of Clinical Programs

Principal Investigator, Purdue University Cardiovascular Imaging Research Laboratory (CVIRL)

Weldon School of Biomedical Engineering

College of Engineering

Purdue University

Adjunct Associate Professor of Surgery

Indiana University School of Medicine

Larry W. Markham, MD

Phillip Murray Professor of Pediatric Cardiology

Professor of Pediatrics and Medicine

Indiana University School of Medicine

Division Chief for Pediatric Cardiology

Riley Hospital for Children at Indiana University Health



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