Molecular Imaging Meets Cardiac Stem Cell Therapy
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“[Although cardiac stem cell trials focus on different types of stem cells, various mechanisms and end points], the ideal outcome of every cardiac stem cell therapy is an improvement in the patient’s condition,” Wu says. Improved cardiac function could translate into better survival, and reductions in chest pain and shortness of breath that offer improved quality of life for cardiovascularly compromised patients. In addition, stem cell therapy is less invasive than conventional surgical procedures.
As researchers continue to explore the role of stem cell therapy in cardiac medicine, molecular imaging will take center stage. That’s because transplanted cells must be tracked and monitored in vivo. Here is a closer look at various clinical trials focused on the potential of cardiac stem cell therapies that offer a better understanding of how various molecular imaging modalities will contribute to and measure the eventual clinical utility of cardiac stem cell-based therapies.
Cardiac stem cell therapy defined
One of the basic facts of biology and aging is that adult tissue does not self-regenerate well. The theory behind cardiac stem cell therapy is simple. Injecting stem cells into damaged heart tissue could repopulate the myocardium, initiate revascularization and improve cardiac function.
Earlier cardiac stem cell trials showed mixed results with several studies failing to validate the utility of cardiac stem cell transplants. Two studies (New England Journal of Medicine and The Lancet) did not show improvement after injection of mononuclear bone marrow cells. In contrast, the TOPCARE-AMI Trial showed significant improvements in left ventricular ejection fraction and end systolic volume in acute myocardial infarction patients who were injected with either circulating progenitor cells or bone marrow-derived progenitor cells.
Future studies are needed to show which stem cells and molecular mechanisms contribute to improved cardiac function, says Wu. Some researchers suspect that stem cells isolated from cardiac tissue may be better suited to treat heart disease patients. Current trials aimed at better defining the roles of various stem cells and their mechanisms of action include:
- Osiris Therapeutics, Inc. (Baltimore, Md.) Phase II Acute Myocardial Infarction Trial delivers bone-marrow-derived mesenchymal stem cells to patients one to eight days after an initial heart attack. The goal is to prevent fibrotic scars and preserve cardiac function. Researchers will use cardiac MRI to assess end systolic volume and left ventricular ejection fraction.
- Mytogen, Inc. (Charlestown, Mass.) Phase II_3-D Guided Catheter-Based Delivery of Autologous Skeletal Myoblasts for Ishemic Cardiomyopathy (CAuSMIC) targets patients not eligible for angioplasty or coronary bypass surgery with poor quality of life after medical therapy or cardiac resynchronization therapy. It will deliver autologous skeletal muscle stem cells to scarred regions of the heart using a 3D-guided catheter. A small, Phase I trial showed beneficial ventricular remodeling after stem cell therapy.
- MARVEL, a large Phase II/III clinical trial, involves 330 patients and 35 heart failure centers in a randomized, double-blind, placebo-controlled, multi-center study. The trial focuses on the safety and efficacy of Bioheart, Inc.’s MyoCell autologous clinical cell therapy in the treatment of congestive heart failure. The minimally invasive procedure presents less risk and less trauma to a patient than open heart surgery. Animal studies of MyoCell indicated increased cell retention, survival and engraftment.
- Baxter Healthcare Corporation (Chicago) ACT34-CMI Trial (Autologous Cellular Therapy with CD34+ Cells in Chronic Myocardial Ischemia) aims to determine whether or not blood-derived stem cells can alleviate the effects of myocardial ischemia by growing into microscopic blood vessels. The new vessels could improve blood flow to damaged areas of the heart.
- In a Phase I trial at Jewish Hospital in Louisville, Ky., surgeons will remove a small piece of cardiac tissue during bypass surgery and send the tissue to a lab at Harvard University in Boston, where researchers will extract cardiac stem cells. After several months, the cardiac stem cells will be injected back into the patient’s cardiac scar tissue via a catheter. The hope is that the therapy will spur cardiac tissue regeneration, reduce scar tissue and improve cardiac function. The trial follows animal testing that showed a 5 to 10 percent improvement in ejection fraction after the stem cell procedure.
- At Cedars-Sinai Heart Institute in Los Angeles, the REVITALIZE trial will inject patients with their own bone marrow-derived stem cells after a heart attack to attempt to repair the heart muscle and improve function.
The molecular imaging connection
Extraction and injection of stem cells are just the first steps in cardiac stem cell therapy trials. “Stem cell researchers and the cardiovascular community need to understand where cells go and what happens to them after they are injected into the patient,” says Wu. Researchers need a non-invasive means to assess the survival, distribution and differentiation of implanted stem cells. Molecular imaging technologies may provide the best means of tracking stem cells. That’s because the data acquired during molecular imaging studies may be best suited to functional evaluation of transplanted cells. Modalities used in preclinical trials include MRI, SPECT and PET; and each brings its own advantages and disadvantages.
MRI studies use enriched contrast to track stem cells in the myocardium and differentiate the transplanted cells from the background. MRI, however, is not ideal for cardiac stem cell imaging for several reasons. It’s difficult to quantify cell division to accurately assess distribution and growth using MRI. In addition, contrast agents may transfer to other cells, which may make it difficult to differentiate injected stem cells from cardiac cells. Finally, MRI is contraindicated in patients with ICDs or pacemakers, excluding a fair number of cardiac stem cell transplant candidates.
PET and SPECT exploit radionuclide labeling; both modalities are highly sensitive and can use a variety of imaging agents. Stem cells can be labeled with a radioisotope and then tracked. In addition, improved spatial resolution in the 1 to 2 mm range enables cell tracking. Some of the drawbacks of radionuclide imaging are similar to the disadvantages of MRI. That is, radiotracers may be transferred to non-target cells, reducing imaging accuracy. In addition, there are biocompatibility concerns. The radioisotope may adversely impact stem cell viability, differentiation and distribution. Finally, because radioisotopes decay over time, they are not suitable for long-term tracking of injected stem cells.
Another possibility for imaging cardiac stem cells is reporter gene labeling. The technique encodes a protein that interacts with an imaging probe to generate a signal. The signal is captured by MRI, PET, SPECT or an optical imaging device. Although in its infancy, the reporter gene imaging technique holds great promise and may provide additional data about therapeutic mechanisms of cardiac stem cells. For example, a specific protein might target cell differentiation to more accurately define what happens to stem cells after implantation. The reporter gene imaging technique, however, must cross multiple hurdles before it can be deployed and used clinically. Safety is a primary concern. Researchers need to find stable probes that don’t cause an immune response or interfere with cardiac stem cell function.
None of the current imaging techniques is ideal, says Wu. “The ideal modality for tracking stem cells is non-toxic, biocompatible and highly specific to the target cells. In addition, the ideal agent should detect single cells and show a decrease in signal with cell loss and increase in signal with cell proliferation.”
In the current environment, the best course may be to match the imaging modality to research priorities. That is, MRI can be used to provide an accurate location of cell delivery. PET or SPECT-based radionuclide imaging may be best suited to short-term assessments of transplanted cells. Reporter gene imaging, on the other hand, may offer the best long-term data about cardiac stem cell therapy. In the future, says Wu, multimodality techniques that exploit the advantages of each modality and minimize the drawbacks of individual modalities may offer the best path toward a solid clinical understanding of cardiac stem cell distribution, function and differentiation over time.
Whatever molecular imaging mechanism is used, cardiac stem cell therapy appears to be poised to enter the therapeutic arsenal for cardiovascular disease in the next few years. Smart providers are looking ahead and considering the potential clinical, imaging and business implications of cardiac stem cell therapy.
| Inside a Cardiac Stem Cell Trial: The Imaging Connection |
| The world’s first clinical trial using adult cardiac stem cells is underway in at the University of Louisville in Kentucky. The groundbreaking trial takes aim at healing the tissue of heart failure patients. In the trial, doctors will remove a small piece of tissue during bypass surgery and ship the tissue to researchers at Harvard University in Boston, who will isolate and grow stem cells. Three to four months after the initial bypass surgery, the Kentucky team led by Roberto Bolli, MD, chief of the division of cardiology and director of the Institute for Molecular Cardiology at University of Louisville, will re-inject patients with the stem cells. Ideally, the cardiac stem cells will trigger heart tissue regeneration, reduce the size of the scar tissue and improve cardiac function. Although the Phase 1 trial of 20 patients focuses on the safety of the procedure, imaging plays a central role. The trial will employ multiple modalities—MRI, echocardiography and myocardial perfusion SPECT imaging to assess the effectiveness of the therapy. Imaging studies are slated for pre-stem cell injection and four months, one year and two years after injection of the cardiac stem cells. Every patient will have an echocardiogram and SPECT study, and eligible patients also will undergo an MRI study. MRI is the gold standard for assessing ventricular function and volume, says Bolli. It also helps cardiologists measure the size of the scar or infarct. The downside of MRI is that not all cardiac patients are MRI candidates. The scan is contraindicated in patients with pacemakers or ICDs. In those patients, echo will be used to provide similar data to that acquired by a cardiac MRI. MRI patients will undergo echocardiogram as a confirmatory study. Myocardial perfusion SPECT imaging plays a critical complementary role, offering information perfusion and ischemia not attainable via MRI. The various imaging mechanisms are central to the ultimate evaluation of the stem cell therapy and will provide critical data about post-therapy scar tissue and cardiac function. |
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| Defining the tomograph location of transplanted embryonic stem (ES) cells in the myocardium. (a) Two weeks after cell transplant, animals underwent [18F]-FHBG reporter probe imaging (top row) followed by [18F]-FDG myocardial viability imaging (middle row). Fusion of [18F]-FHBG and [18F]-FDG images (bottom row) shows the exact anatomic location of transplanted ES cells expressing HSVtk reporter gene (arrow) at the anterolateral wall in horizontal, coronal and sagittal views. From Cao F et al, Circulation 2006;113:1005-1014. |