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Gene therapy successfully treats arrhythmia in pig hearts
By Bijal P. Trivedi

Researchers have used gene therapy to treat heart arrythmias in pigs. The therapeutic gene was delivered directly into the pacemaker region of the pig's heart, which controls how fast or slow the heart beats, and successfully reduced the heartbeat during a severe attack of arrhythmia. While researchers are still at least five years from human trials, they are hopeful that gene therapy will provide a long term and safer alternative to beta-blockers and pacemakers, which are used to prevent and control episodes of arrhythmia.

Arrhythmia is an abnormal heartbeat of any type—too fast, too slow or just irregular. If the heart pumps too slowly, too little blood reaches the body; if the heart pumps too quickly, it doesn't have time to fill up with blood before it pumps, which also leads to blood shortages around the body. The heart can handle a few minutes of accelerated heartbeat, but repeated episodes can cause heart failure when the heart is simply too weak to pump blood properly, and this can lead to dizziness, collapse or death.

Kevin Donahue and his colleagues at the Johns Hopkins University School of Medicine found that introducing an inhibitory gene into the AV node-the pacemaker region that lies between the upper and lower chambers of the heart and controls pumping—can slow the heart during a particular serious arrhythmia called an atrial fibrillation.

During an atrial fibrillation the upper chambers of the heart receive a chaotic barrage of electrical signals which causes the pig's heart to quiver uncontrollably up to 600 times per minute; this translates into about 200 beats per minute compared to its normal 120 when resting.

In Donahue's study, the researchers used a catheter to deliver the new gene directly into the AV node. The 10 pigs received either a gene for the inhibitory G protein or a control. One week later an atrial fibrillation was chemically triggered in the 10 animals while researchers measured their heart rates. Animals that received the inhibitory gene had heart rates that were reduced about 20 percent; from about 200 to 160 beats per minute. Pigs receiving the control gene showed no reduction in heart rate. The research is presented in the December issue of Nature Medicine.

The AV node receives electrical messages triggered by opposing cellular chemicals. Adrenalin causes the heart to speed up and acetylcholine causes it to slow down. In the cells of the AV node the inhibitory G protein blocks the adrenalin response, allowing the acetylcholine to prevail and the heart to slow down.

Donahue's team will continue to work with pigs to investigate whether their gene delivery method will be useful for other cardiac problems. The pig heart is almost the same size as the human heart and has a similar architecture making it a useful model for researchers.

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Donahue, J.K. et al. Focal modification of electrical conduction in the heart by viral gene transfer. Nat Med 6, 1395-1398 (December 2000).

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