Transferred Gene Prevents Hearts From Overstimulation in Animal Study

Nov. 30, 2000 -- Researchers' hearts are aflutter over the first successful use of gene therapy to treat dangerously fast and unstable heart rhythms that could lead to heart attack or stroke.

Using a harmless cold virus, the researchers delivered a gene that helps to control electrical activity within the heart into five pigs, the non-primate animal with hearts most like those of humans. One week after being infected, the hearts were stimulated to go into a very fast and chaotic type of rhythm called atrial fibrillation, but the animals that received the gene had heart rates that were 20% slower after as compared to before the procedure.

The results are similar to those seen with beta-blocker drugs that are commonly prescribed to treat arrhythmias, say J. Kevin Donahue, MD, and colleagues at Johns Hopkins University School of Medicine and the Institute of Experimental and Clinical Pharmacology and Toxicology in Erlangen, Germany. The research is described in the December issue of the journal Nature Medicine.

The study suggests that gene therapy could one day reduce the need for antiarrhythmia drugs or surgery in people who are prone to unstable heart rhythms, and also might be used to treat defects in other areas of the heart, note Italian physicians in an editorial accompanying the study.

"[The] findings of Donahue et al. have made an important advance by proving a hypothesis that will lead to further development in the field of cardiac gene therapy," write Silvia G. Priori, MD, and Carlo Napolitano, MD, from the department of cardiology at the University of Pavia in Italy.

To understand why atrial fibrillation is so dangerous, it's helpful to know that the heart is essentially an electrically controlled pump with four chambers -- two upper chambers called atria and two lower chambers called ventricles. The chambers contract in syncopation, atria first, followed quickly thereafter by the ventricles, to push blood out into circulation. The pumping action is controlled by the body's special pacemakers that govern and coordinate the speed of contraction and the volume of blood pumped through the organ at any given time.

Arrhythmias can occur when there is either a structural flaw in the pacemakers (for example, from a birth defect) or when a heart attack, injury, or major infection damages the cells that control the heart's electrical activity. In atrial fibrillation, electrical signals in the atria are fired in a very rapid, uncontrolled fashion, and the signals, which are supposed to travel next to the ventricles, are sent irregularly, resulting in an irregular heartbeat. Left untreated, atrial fibrillation can lead to a heart attack or can cause blood to pool in the heart and clot, which could lead to a stroke.

Arrhythmias can be controlled with beta-blockers which, as their name implies, block an electrical signal within the heart. Alternatively, implantable or external defibrillators -- machines that deliver a powerful shock to the heart -- can force a heart in "afib" back into a normal rhythm, or the patient can be treated with a procedure known as ablation, in which a portion of the pacemaker containing abnormal tissue is destroyed using either energy from radiowaves, or surgery.

Gene therapy, however, holds the promise of long-term control of arrhythmias without the need for drugs (which in some people can actually cause arrhythmias) or invasive procedures.

"I think it's a great idea, what I would call a biotech ablation," says Robert J. Levy, MD, professor of medicine at the University of Pennsylvania School of Medicine and a pediatric cardiologist at Children's Hospital of Philadelphia, who reviewed the study for WebMD. "Ablations with microwave energies or radio-frequency energies are very destructive, and in this case gene therapy is a much more thoughtful therapeutic approach: rather than destroying a lot of tissue, to reconstruct it with an appropriate program as they showed in the study."

Donahue tells WebMD that he was inspired to develop the theory while visiting the laboratory of his collaborators in Erlangen. "They were using this gene for something completely different, and it struck me that this was something that if overexpressed in the [heart] would cause slowing of conduction [of electrical signals], so I asked them if I could borrow the virus; I tried it out, and it worked pretty much the way I thought it would," he says.

The researchers chose the gene because it blocks the activity of an enzyme that speeds up heart rate when the organ is under stress. Donahue says that they currently are working to develop a new version of the gene therapy using a different but equally harmless virus that could allow the antiarrhythmic effects to last longer. If the following studies are successful, trials in primates, including humans, could begin in a few years.

(From Excite.com)