Reshaping Faulty Heartbeats with Cell Therapy

Specially engineered cells are showing promise in early experiments to repair abnormal heart rhythms. "The injected cells survive and slow down abnormal heart rhythms," says Jeffrey Olgin, MD, the physician and researcher who heads the Cardiac Electrophysiology and Arrhythmia Service at UCSF. Olgin is collaborating with Lior Gepstein, MD, PhD, an Israeli stem cell researcher, to explore ways to use stem cells and other cell-based therapy to treat heart rhythm disorders. These disorders - called arrhythmias - kill hundreds of thousands of Americans each year. Gepstein and Olgin are developing cells with novel electrical properties. The cells can be integrated into existing heart tissue - and reshape the heartbeat. It's still early days for these studies. So far, the researchers have used their innovative approach to restore normal heartbeats in rats with heart rhythm abnormalities. The rats had ventricular tachycardia created by heart attacks, the most common cause of lethal arrhythmias. The technique has broader applications. It could potentially be used to treat atrial fibrillation, as well. Atrial fibrillation is the most common arrhythmia. Millions of Americans are affected by atrial fibrillation. And because the population is aging, the incidence of atrial fibrillation is increasing. Clinicians have had success in treating milder forms of certain arrhythmias with drugs, or with implantable devices such as pacemakers or defibrillators. But more serious or chronic cases of arrhythmias may become life-threatening despite such treatments. The contractions of individual heart muscle cells - called cardiomyocytes - are triggered by electrical signals transmitted from cell to cell. Arrhythmias arise when electrical pathways are altered. Alterations in the heart's electrical signaling often are due to cell damage or death, or the formation of scar tissue. Innovative Treatments Become the Norm Before Olgin began exploring the frontiers of stem cell research, UCSF electrophysiologists earlier pioneered the use of another treatment, catheter ablation. With catheter ablation, an electrode is threaded through a catheter into the heart. The electrode is used to locate and target the cardiomyocytes responsible for abnormal electrical signals. When the clinician triggers the release of radiofrequency energy from the electrode, the target is destroyed. The amount of tissue destroyed usually is small - maybe the size of the eraser at the end of a pencil. The first successful catheter ablation in a human was done in 1981 by Melvin Scheinman, MD, the founder of UCSF's electrophysiology program. With the most recent advanced technology, clinicians at UCSF use image-guided techniques and robotic guidance to identify and destroy culprit tissue. Catheter ablation has saved many lives. It is being used in a growing range of applications and can be used to cure many arrhythmias, including atrial fibrillation. However, there are still many cases of atrial fibrillation that cannot be successfully treated with catheter ablation. Furthermore, the amount of tissue that must be ablated can be extensive at times. Other types of arrhythmias - ventricular fibrillation, for instance - have not been successfully treated with ablation. Stem Cells Hold Promise While cell therapy is unproven, the potential upside could be much greater than current pharmaceutical or surgical approaches, according to Olgin. "With cell therapy, you're not destroying anything," Olgin notes. The researchers used connective tissue cells called fibroblasts, as well as stem cells, in their first attempts at modifying the electrical circuits. However, Olgin and Gepstein - from the Technion, part of the Israel Institute of Technology - took innovative liberties with the humdrum fibroblasts. Normal cardiomyocytes transmit electrical signals by opening and closing channels - essentially proteins with pores. When the channels open, electrically charged chemical ions pass through. Rapid movement of ions creates electrical currents. Currents cause more ion channels to open and close in a chain reaction. Through this process, electrical "action potentials" travel through cells - in a way similar to one falling domino bringing down the next in line. The result is a heartbeat. Drugs that act to block potassium channels are often used to slow electrical conduction and control arrhythmias. However, the drugs are imprecise. They affect potassium channels everywhere in the heart. Sometimes they can even cause arrhythmia in other heart chambers. Gepstein and Olgin decided to develop cells with new electrical properties. The goal was to have the cells act within the heart to help eliminate arrhythmia. Reshaping Heartbeats Gepstein's lab team genetically engineered novel potassium channels that don't occur naturally. The researchers used these new channels to customize the electricity-conducting properties of transplanted tissue. The cultured fibroblasts make the engineered channels in the same way that normal cardiomyocytes make normal potassium channels. The cells with the special properties can grow easily in a lab dish. The fibroblasts can couple with preexisting cardiomyocytes in the heart, creating tissue with unique and desirable electrical properties. In short - thanks to some fine-tuning in the genetic engineering - the tissue cannot transmit dangerously fast electrical signals. And unlike a drug, but similar to catheter ablation, the tissue can be precisely located for optimum benefit. Preliminary experiments show that the transplanted tissue can restore normal heart rhythm in the rodent model of ventricular tachycardia. If the technique pans out, there should be no shortage of the easily growing fibroblasts needed to prepare the treatment, according to Olgin. "For a given patient, I could do a skin biopsy, grow the fibroblasts in culture, put in the channel and give it right back," he says. "There is no need to deal with tissue rejection." Related Links: The Shock Felt 'Round the World
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