Plasma Proneurotensin Is Associated With Increased Risk of CVD in Women

A study published on Oct. 9 in The Journal of the American Medical Association found that new population data from Sweden suggest an important association between the satiety hormone neurotensin and cardiovascular disease (CVD), diabetes, breast cancer and all-cause mortality. The association is stronger in women than in men, but it is not clear if elevated levels of neurotensin also place men at higher risk of these diseases. The observational study was based on serum values of proneutotensin, a precursor to neurotensin.

The study found that proneurotensin is associated with an elevated risk of CVD, all-cause mortality and cardiovascular mortality. Among the 4,361 participants who did not have CVD at baseline, 591 developed a first cardiovascular event during a median follow-up of 15.6 years. After full adjustment, each standard deviation increase in proneurotensin was associated with a hazard ratio 1.71. There was a significant interaction of female gender with the incidence of CVD in the cohort (p<0.001) but not with male gender. When stratified by gender, women showed a hazard ratio of 1.33 for each increase in standard deviation of proneurotensin while there was no increase in risk for men.

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There were similar findings for all-cause mortality (1.08) and cardiovascular mortality (1.13) among women, but not for men. Researchers concluded that the excess mortality risk for women is due largely to increased cardiovascular risk. Women, but not men, showed similarly increased hazard ratios for diabetes (1.41) and breast cancer (1.44) for each standard deviation increase in proneurotensin.

Neurotensin has been associated with both satiety and breast cancer in animal models, but this may be the first epidemiological study on the fasting concentration of proneurotensin, a stable terminal fragment of the precursor of neurotensin, and the risk of future disease. There are three known neurotensin receptors, Ntsr1, Ntsr2 and Ntsr3. Neurotensin and Ntsr1 are commonly expressed in human ductal breast cancer tumors while genetic variations of Ntsr3 have been linked to the development of coronary artery disease (CAD) by way of elevated levels of low-density lipoprotein cholesterol.

Mature neurotensin is unstable both in vivo and in vitro, but a precursor, proneurotensin, is produced in stoichiometric amounts relative to mature neurotensin. Researchers measured a stable 117-amino acid fragment on proneurotensin as a marker of neurotensin levels.

The study used a subset of the Malmö Diet and Cancer study, a prospective epidemiologic cohort of 28,449 men (born 1923-1945) and women (born 1923-1950). All of the participants were residents of Malmö at the time of a baseline exam between 1991 and 1996. A subset of 6,103 individuals was randomly selected from the larger cohort for the MDC Cardiovascular Cohort (MDC-CC) that was designed to investigate the epidemiology of carotid artery disease. Fasting plasma samples were available for 4,632 individuals. The final study population included 2,559 women and 1,802 men after eliminating those who had diabetes, CVD or cancer at baseline, as well as individuals for whom complete data on potential covariates was not available.

"Fasting proneurotensin was significantly associated with development of diabetes, cardiovascular disease, breast cancer, and with total and cardiovascular mortality," said lead author Olle Melander, MD, PhD, Lund University, Malmö, Sweden. "The relationships between proneurotensin at all end points were significant in women but not in men; however, because there was only significant interaction between sex and proneurotensin for the outcome of incident cardiovascular disease, it remains to be shown whether the association is specific for women."

"The relationship between proneurotensin and morbidity and mortality was only significant in women," Dr. Melander concluded. "It has been repeatedly shown that estradiol up-regulates expression of neurotensin. Thus, it can be speculated that the association between proneurotensin and adverse outcomes was only significant in women is partially explained by higher lifetime exposure to estrogen in women."

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