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Sympathoexcitatory Effect of Tobacco in Premenopausal Women

Institution: University of California, Los Angeles
Investigator(s): Holly Middlekauff,
Award Cycle: 2009 (Cycle 18) Grant #: 18XT-0115 Award: $245,492
Subject Area: Cardiovascular Disease
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Cardiovascular disease is the leading cause of death in women, killing 1of every 3. Heart disease and strokes are largely diseases of older women; the onset of these diseases lags that of men by about 10 years. This lag has been attributed to the protective effects of cyclical female hormones on the heart. However, smoking in young, pre-menopausal women obliterates this gender advantage. Smoking has the greatest adverse impact on cardiovascular health in pre-menopausal women, increasing their risk of heart disease by 7-fold compared with a 3-fold increase in young men who smoke. The cardiovascular risk is even greater, up to 20-fold, in women taking oral contraceptive pills (“The Pill”). We do not know why smoking is particularly lethal in pre-menopausal women, but we suspect disruption of the benefits of cyclical female hormones may be to blame.

Increased adrenaline is associated with increased cardiovascular risk, including risk of heart attack, sudden unexpected death, and heart failure. Adrenaline follows a cyclical pattern in healthy, non-smoking pre-menopausal women; adrenaline levels are lowest during a woman’s period, and highest about a week before her period. We have preliminary evidence that this pattern is disrupted in pre-menopausal women who smoke, and adrenaline levels do not fall during their periods. We hypothesize that exposure to tobacco smoke in young, pre-menopausal women eliminates the normal cyclical pattern of adrenaline, and adrenaline remains elevated throughout the menstrual cycle. Further, we hypothesize that the mechanism underlying this increased adrenaline burden is blunted control of the adrenaline system. Adrenaline is usually controlled by special sensors in blood vessels called “baroreceptors.” Tobacco smoke generates toxic substances in the body that are known to interfere with these important sensors. The overall goal of this proposal is to investigate the abnormalities in the pattern and control of adrenaline release in pre-menopausal women who smoke.

In virtually every heart disease in which adrenaline levels have been studied, a major, harmful role for adrenaline has been uncovered. In fact, medications to block the effects of adrenaline, (“beta-blockers”) are mandatory for prevention and treatment of a variety of heart diseases, including heart attacks, heart failure, cholesterol build up in the arteries feeding the heart, heart rhythm disorders, and chest pains. Even people who have no known heart disease, but who have a high risk for a heart attack, are told by their doctors to take these medications. If our hypothesis that pre-menopausal smokers have a greater adrenaline burden than non-smoking pre-menopausal women is proven true by these experiments, it could lead to large drug trials of beta-blockers in pre-menopausal smokers to reduce heart attack risk in this vulnerable population.