Two independent teams at Harvard Medical School (HMS) made major finds in the field of stroke research in studies released this month.

An international team of researchers led by Dr. Klaus Lindpaintner, of HMS and the Harvard-affiliated Brigham and Women's Hospital, found that a gene mutation is responsible for doubling the risk of strokes in humans.

The finding was announced at a press conference held in Philadelphia by the American Heart Association on September 16 in conjunction with a similar study released by the University of South Carolina that determined that gene therapy could help reduce the risk of strokes in laboratory rats.

The mutation that Lindpaintner's team found is in the atrial natriuretic peptide (ANP) gene. ANP is a hormone that relaxes blood vessels and increases the body's excretion of sodium, thus lowering blood pressure. The ANP gene contains instructions for producing ANP.

HMS investigators analyzed 696 participants from the Physicians Health Study--a study of 22,000 health professionals conducted at the Brigham and Women's Hospital since 1982-half of whom had experienced strokes. The HMS investigators used a person's age and whether or not he or she smoked as categories to compare the 348 individuals who experienced strokes with the 348 who had not.

The researchers found a particular mutation in the gene coding for ANP that doubled the risk of stroke in the overall population as well as in a subgroup that was classified as low-risk for strokes.

This is the first human gene implicated in an increased risk for strokes. Lindpaintner's group had previously found that ANP protected a strain of rats prone to high blood pressure from suffering strokes; rats with the mutant form of the ANP gene were not protected.

Researchers at the University of South Carolina, led by faculty advisor Lee Chao, performed their own study, which provides more evidence linking the ANP gene to strokes. They found that delivering the ANP gene into rats by gene therapy not only resulted in the functional production of ANP but drastically reduced the number of rats which died of strokes by 69 percent over the untreated control group.

Their finding is spurring debate over the possibility of using gene therapy in humans who have undergone genetic testing and are known to contain the mutant copy of the ANP gene, placing them at higher risk for a stroke.

This mutation is just one of several risk factors implicated in strokes. Not having the mutant gene does not ensure that a person is risk-free. A combination of risk factors, including environment and genetic makeup, have been linked to strokes.

In a press release from the American Heart Association meeting, lead author Dr. Speranza Rubatu, from the Department of Experimental Medicine and Pathology at La Sapienza University, Rome, and Instituto Neurologico Mediterraneo, Neuromed, at Pozzilli, Italy, says, "We believe that this is an important finding toward the development of a more comprehensive way of assessing a person's overall risk of developing a stroke. The identification of genes and their molecular variants that contribute to strokes help us diagnose the risk earlier and suggest lifestyle modifications or develop new medicines to reduce the overall risk of stroke."

Another team of HMS researchers has discovered an early step in the stroke's deadly pathway. Their study, which has the potential to provide a potent new target for drug therapies, is published in this week's issue of the Proceedings of the National Academy of Sciences.

The study expands on the idea that after a stroke occurs, certain brain cells that are not killed immediately by bursting blood vessels may be killed through exposure to compounds released by dying cells.

Their research focuses on glutamate, an excitatory neurotransmitter. Scientists had believed that it might be possible to limit cell death after a stroke by stopping glutamate from killing neighboring cells, but until now, little was known about the intracellular routes through which glutamate carries out its deadly "excitotoxic" effects.

However, a team of researchers led by Beverly M. Murray, an HMS research fellow in neurology, and Edwin J. Furshpan, Robert Pfeiffer professor of neurobiology at HMS, have discovered that a member of the MAP kinase family known as ERK may be involved in the activation of one or more of these excitotoxic pathways.