First gene therapy to calm pigs' out-of-sync hearts

November 30, 2000

"The number one killer in developed countries is cardiac death, generally sparked by an event that leads to arrhythmia."

Scientists at Johns Hopkins have developed a gene therapy that, within a week, quells abnormal rhythms in pig hearts, the animal hearts most similar to human. It's believed to be the first use of gene therapy for cardiac arrhythmias, the researchers say, and one with "a strong possibility" of transfer to human heart disease.

"We've effectively treated an arrythmia in a well-tested animal model, using genes delivered by routine catheter methods -- no open chest, no contrivances, just simple modifications of existing technology," says Eduardo Marban, M.D., Ph.D., one of the scientists.

"This is the first proof-of-concept work," says Marban, "and the first clear step toward a clinically useful approach."

A report of the research appears in the December issue of the journal Nature Medicine.

Arrhythmias arise from two sources, the researchers say. One is a basic structural abnormality in the heart's pacemakers. The other develops after a heart attack or other insult to the heart. "Shortly after such an event," says team leader Kevin Donahue, M.D., "cellular changes, such as scarring, take place in the heart and make tissue more prone to arrhythmias. The number one killer in developed countries is cardiac death, generally sparked by an event that leads to arrhythmia."

Approximately one in every hundred people in this country suffers from arrythmias of one sort or another, according to the American Heart Association. While some heart rhythm disturbances are relatively benign, others, by disrupting the heart's coordinated pumping, are an immediate cause of collapse and death.

"Drug treatments can help, but don't fix the underlying causes of the problem," Donahue adds, "and continued use can actually encourage arrhythmias in some people. Pacemakers or defibrillators are expensive and invasive," he adds, "and carry a not-insignificant risk of complications."

In the pig study, the researchers used a standard viral carrier to introduce copies of a gene directly into one of the heart's pacemakers, a small area of tissue called the atrioventricular (AV) node. The AV node receives and filters impulses coming from the heart's upper chambers, then relays impulses to the lower chambers of the heart, where they trigger contractions. In diseased hearts, however, heart rhythms in the upper chamber may get altered in such a way that the filtering/relaying ability is overwhelmed. This can lead to abnormally fast, irregular heart rates.

The researchers picked a gene, called an inhibitory G protein gene, because it switches on in pacemaking tissue whenever the nervous system signals for a slowing of the heart rate. The gene makes a protein that's the biological equivalent of a monkey wrench, blocking a step in an adrenalin-triggered set of reactions that normally speed heart rate.

At the start of the study, the researchers primed 10 pig hearts with agents that increased their uptake of the gene and its carrier system. They then threaded a catheter into the artery that feeds the heart's AV node, infusing the node with an adenovirus carrying the inhibitory gene. Some pigs received the same viral carrier, but with a non-heart-affecting gene as a control.

Tissue studies a week later verified the gene in place in nearly half of the AV node cells. "The AV nodes in the test hearts carried impulses at a significantly slower rate and were far less excitable than those in hearts without the added genes," Donahue says.

The true test came, he says, when the researchers electrically and chemically stimulated the hearts to produce atrial fibrillation, a serious arrhythmia. In atrial fibrillation, both upper heart chambers quiver chaotically, up to 600 times a minute. This overwhelms the AV node's ability to filter incoming stimulation and causes the ventricles to speed up. The test animals with the inhibitory G protein showed a 20 percent decrease in heart rate compared with the control animals.

Commonly prescribed beta-blocker medications can bring a similar overall result, the researchers say. "But, we believe the gene therapy that ultimately would help humans would, unlike beta blockers, be a long-term solution. Also, because gene therapy is localized to a specific place in the heart, it would avoid the side effects that come when beta-blockers travel to other parts of the body," says Donahue.
Other scientists on the research team were Alan W. Heldman, M.D., Heather Fraser, Ph.D., Amy Thomas, B.S., Julie Miller, M.D. and Jeffrey Rade, M.D. Thomas Eschenhagen with the Friedrich-Alexander University in Erlangen, Germany, also participated.

Funding for the study was by the National Institutes of Health, Johns Hopkins University and the Alberta Heritage Foundation for Medical Research.

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