Stem Cell Research
Fashioning Organs

Technology

Research Briefs

Volunteers with Vision

Around & About
POV


A computer simulation of electrical activity in a heart cell shows arrhythmogenic activity, bottom, can develop in African Americans who take certain medications and have a certain heart ion channel gene variant. The drug had no effect on a simulated cell with a wild type gene, top.

A small percentage of African Americans have a genetic predisposition for heartbeat arrhythmias that may occur when they take certain drugs or have other cardiac conditions, according to Columbia University Health Sciences and Harvard researchers.

Arrhythmias are a common cause of sudden death, killing almost half a million Americans every year. In the past five years, scientists have traced several inherited arrhythmias to mutations and common variations in ion channels in the heart. In a search for additional variants, or polymorphisms, linked to arrhythmia, the team of investigators found one unique to African Americans. The findings, published Aug. 23 in Science, reveal that approximately 13 percent of African Americans carry this variation, which occurs in a sodium channel in the heart. The variation was not found in control groups of Caucasians and Asians. The variant was determined to be associated with an eightfold greater risk of developing "acquired" cardiac arrhythmias.

As collaborators, Dr. Robert S. Kass, co-author of the paper and pharmacology chairman in P&S, and Drs. Colleen Clancy and Michihiro Tateyama, postdoctoral researchers in his laboratory, found the altered protein subtly changes the electric current in heart cells that coordinate heart rhythm. They first detected the change in isolated cultured cells, but the cellular experiments could not reveal if the altered current would produce arrhythmias in patients. They then used a computer simulation of the heart's electrical activity. Using the simulation, they found the altered current by itself is harmless but can trigger arrhythmia when coupled with low potassium; certain medications, including some antibiotics and antidepressants; and certain other cardiovascular disorders.

"Because the mutation has a subtle effect, most carriers will never have an arrhythmia," Dr. Kass says. "However, it will be useful in the development of genetic screens to detect and minimize arrhythmia risk."

—Susan Conova


Scientists have known for some time that people who inherit a certain variation (apoE4) of a protein known as apolipoprotein E, which transports cholesterol in and out of cells, are at greater risk of developing Alzheimer's disease.

Now, Columbia University Health Sciences researchers have found that older people with apoE4 who ate more calories and fat have a greater risk of developing Alzheimer's disease than those who ate the least calories and fat. Using a 61-item food questionnaire, Dr. Richard Mayeux, Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology at P&S and the Mailman School of Public Health, and Dr. Jose A. Luchsinger, assistant professor of medicine at P&S and a researcher at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, examined the role of diet and Alzheimer's risk in 980 individuals aged 65 and older. The food intake questionanaire was administered during the first year of the study. Participants were followed for four years, on average.

They found the risk of Alzheimer's disease is double for those with the apoE4 variant who said they ate the most calories and fat compared with those with the variant who said they ate the lowest amounts. The results, which were published in the August Archives of Neurology, suggest it may be possible to reduce the risk of Alzheimer's disease in people who are genetically susceptible by having them ingest less calories and fats.

Dr. Mayeux has begun a larger follow-up study to confirm the results and examine other macro- and micronutrients. The new prospective study is following 2,500 people, age 65 and older who have the apoE4 variant but are free of Alzheimer's disease. The participants will be tracked for five to 10 years to assess a range of biological factors, including diet, and Alzheimer's disease risk.

—Matthew Dougherty


Researchers have had some success in slowing cancer growth in animal and human studies using anti-angiogenesis drugs that prevent growth of a tumor's blood supply. However, some tumors, such as the common pediatric tumor neuroblastoma, are particularly difficult to treat.

Researchers at Columbia University Health Sciences and Regeneron Pharmaceuticals Inc. of Tarrytown, N.Y., now may have a better approach to treat neuroblastoma. Dr. Darrell Yamashiro, assistant professor of pediatrics, pathology, and surgery at P&S, and Dr. Jessica Kandel, Irving Assistant Professor of Surgery at P&S, and colleagues have shown in mice that a new Regeneron drug is more effective against neuroblastoma than two other experimental drugs. The Regeneron protein fusion drug, called VEGF Trap, contains portions of two blood vessel growth factor receptors that bind vascular endothelial growth factor (VEGF). The drug acts like a sponge to soak up VEGF and prevent vessel growth.

To make a mouse model of neuroblastoma, the researchers injected human neuroblastoma cells into the mouse's kidney. The tumor establishes itself by co-opting existing blood vessels and producing VEGF to spur growth of new blood vessels. The researchers tested the three drugs, which all act to block VEGF, by injecting them into the peritoneum, the membrane that lines the abdominal cavity walls. They found the Regeneron drug, VEGF Trap, disrupts the co-opted vessels and, thus, more effectively inhibits tumor growth.

VEGF Trap does not have major effects on normal, pre-existing blood vessels, although, Dr. Yamashiro says, it is not clear why. The drug has a minimal effect on normal vessels, he posits, because most such vessels do not need much VEGF while tumor vasculature is relatively unstable and requires more VEGF.

Other researchers have been able to target the co-opted vessels before with drugs but results have been difficult to reproduce, Dr. Yamashiro says. He and Dr. Kandel previously found neuroblastoma to some extent can dodge the effects of older anti-angiogenesis drugs by relying on co-opted kidney blood vessels. (See In Vivo, April 15 issue, http://cpmcnet.columbia.edu/news/in-vivo/Vol1_no7_apr15 _02/index.html.)

Dr. Yamashiro, senior author, and Dr. Kandel reported their results in the Aug. 20 Proceedings of the National Academy of Sciences.

—Matthew Dougherty


[Top]