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Genetic variant determines prognosis after heart attack
By Lone Frank

For patients who suffer a heart attack, the chances for long-term survival seem to depend on which variant of the gene for apolipoprotein E (apoE) they carry. A recent study suggests that one common variation doubles the risk of dying within a five-year period, but that carriers can completely overcome this risk because they respond particularly well to treatment. The findings raise the issue of genetic testing of heart patients.

The key turned out to be the e4 allele

For five and a half years a team of Danish and Finnish researchers have followed the progress of 966 patients who initially survived a heart attack (myocardial infarction). The collaborative study, recently published in Circulation, is an offshoot from the much larger Scandinavian Simvastatin Survival Study, which investigated the overall effect of the drug simvastatin—one of the cholesterol lowering statins that are commonly used for treatment of heart patients. In the genetic study patients underwent tests to clarify their status with respect to the apoE gene. Known since the seventies, the apoE protein has multiple roles, but its main function is to assist in the body's metabolism of lipids. There are several apoE alleles and, according to study leader Lars Ulrik Gerdes, of the Departments of Internal Medicine and Cardiology at Aarhus University Hospital, "Previous investigations of their distribution in the population spurred the idea that they could play a role for long-term survival."

The research team set out to test two hypotheses. First, whether the apoE genotype is a determinant for the long-term outcome of a coronary event, and second, if the response to statin treatment is dependent on genotype. The key turned out to be the e4 allele. For some time scientists have known that this allele, which is found in 30 to 35 percent of the Scandinavian population, almost doubles the susceptibility to coronary heart disease. Within the observation period of the present study, 16 percent of placebo-treated e4 carriers died compared with only 9 percent of non-carriers treated with placebo. Most patients died of a second myocardial infarction. However, for patients treated with statin a completely different picture emerged, and while the drug reduced the mortality among e4 carriers by two thirds, non-carriers experienced a reduction of only one third. This resulted in a similar survival rate for all treated patients regardless of carrier status. "The robust beneficial effect among e4 carriers was seen across the board and could not be ascribed to age, nationality or other variables," explains co-author Ole Færgeman of Aarhus University Hospital.

a tricky issue

Director of the J. David Gladstone Institutes, cardiologist Robert Mahley, a leading expert on apoE, calls the study an important research observation. "It indicates that there may be subgroups of patients who respond differently to statins, and this is especially interesting in relation to the continuing search for the mechanisms of apoE." As yet, Færgeman admits, the researchers "cannot explain our findings in terms of the underlying biology." One initial hypothesis was that there was a connection to patient's levels of cholesterol and other lipids in the blood, but data analysis revealed this was not the case. The team now suspects the apoE protein to be involved in some malignant pathogenic processes that lead to coronary death. Results of earlier studies have suggested that e4 carriers are particularly prone to develop disseminated coronary lesions. "We think it most likely that our observations reflect an ability of statin treatment to inhibit the progression of such lesions in e4 carriers," says Gerdes.

"The new findings could very well have clinical implications," says cardiologist and long-time investigator of statins Terje Petersen of Oslo's Aken Hospital. He alludes to apoE genetic testing of heart patients but concedes it is a tricky issue. Testing would enable doctors to identify and treat e4-carrying patients otherwise at high risk of dying. But there is a catch. The e4 allele is also known to increase the risk for Alzheimer's disease and, "because we would automatically disclose this knowledge, I do not believe in apoE genotyping of heart patients at this point," says Mahley. However, according to Gerdes, the Departments of Internal Medicine and Cardiology in Aarhus are considering to offer apoE genotyping. While Færgeman acknowledges the issue is not unproblematic, he stresses that with all the proper information there is a good case for offering the genetic test to patients who have had a heart attack. "It could greatly improve clinical management. Today many patients prefer not to receive drug treatment but better their condition by keeping a strict diet, and knowledge of apoE carrier status would allow us to focus on the high-risk e4 carriers and motivate them for statin treatment," he says.

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Gerdes, L.U. et al. The apolipoprotein e4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction. Circulation 101, 1366-1371 (March 2000).

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