Imaging of fiber tracts in the lateral wall of a living heart.
The fibers are color-coded based on the angle with which
they spiral around the left ventricle, also known as the
helix angle. This architectural pattern, which allows the
heart to contract optimally, is frequently altered after
a heart attack or in those with heart failure.
A team of researchers at Massachusetts General Hospital has taken a giant leap toward the possibility of noninvasively assessing the efficacy of stem cell therapy in the heart. In their report, published in the April 29th edition of the journal Circulation, the team was able to provide the first example of serial diffusion tensor magnetic resonance imaging (DTI) tractography as a monitoring tool in an animal model of heart disease as well as in healthy human volunteers.
DTI-tractography is a magnetic resonance imaging (MRI) technique in which the diffusion of water molecules can be measured and used to detect the orientation of nerve and muscle fibers. “The implementation of DTI in the heart, however, is technically very challenging because of the heart’s motion,” says David Sosnovik, MD, program director of Cardiac Imaging in the Mass General-MIT Martinos Center for Biomedical Imaging and the Mass General Cardiovascular Research Center, the paper’s lead author. “The signal produced by the diffusion of water molecules along the myofibers of the heart is approximately 100,000 times smaller than the signal produced by the motion of the heart as it beats. Our aim was to develop a way to make DTI tractography work in the heart by reliably detecting this small signal, and then using it to study the impact of stem cell therapy in the heart.”
The team, led by Sosnovik, studied their technique in normal mice and in healthy human volunteers. They then used the technique in infarcted mice to determine how the fiber architecture of the heart is affected by a heart attack and how it heals. “These initial experiments laid the foundation for us to use DTI-tractography to study the impact of stem cell therapy in the heart,” Sosnovik explains. Mice with heart attacks were injected with bone marrow mononuclear cells (BMMCs), a group of cells from bone marrow that have the advantage of being widely available. At the time the Mass General researchers began their study, four large clinical trials were being conducted with BMMCs. “It is extremely satisfying to note that the unique information provided by DTI-tractography allowed us to reach the identical conclusions to those made in all four of these large clinical trials but with vastly greater speed, efficiency and mechanistic insight,” says Sosnovik.
Through a rapid transition of bench research to clinical trials, stem cell therapy has become a promising approach for the regeneration of injured myocardium, the muscular tissue of the heart. Stem cell therapy can be considered effective if transplanted cells not only survive in the injured muscle but also integrate structurally and functionally with the surrounding tissue.
“All of the techniques that have been used to assess the efficacy of stem cell therapy in the heart were primarily designed to detect heart damage – not to detect regeneration,” says Sosnovik. “This is the first time the fibers in the heart have been imaged in vivo after cell therapy, rather than taking a biopsy of the heart and looking at it under the microscope - we now have a very powerful and new diagnostic technique that can really help the stem cell community assess the impact of any new stem cells and therapies that are developed.”
The multidisciplinary nature of the research required a large team effort from scientists at the Mass General and Brigham and Woman’s Hospital (BWH). Others playing a major role in the work included Choukri Mekkaoui, George Dai, Tim Reese, Van Wedeen, Howard Chen and Ronglih Liao. “This paper represents the collective efforts of a large team of investigators including MRI physicists, stem cell biologists and cardiologists,” Sosnovik says. “I can think of few better environments in the world to do this sort of research than Mass General.” Sosnovik also noted that new acquisition schemes, developed by Mekkaoui, Reese and other leading physicists in the Cardiovascular Imaging Program, are now allowing DTI-tractography of the human heart to be performed in far less time and with far greater accuracy than even 6 months ago. “I am very optimistic that we will soon be able to use this technique in a broad range of patients with cardiovascular disease and facilitate the development of new therapies to help them.”