Hot flashes and the heart: an ongoing enigma

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Menopausal vasomotor symptoms are a hallmark of the menopausal transition, with nearly 80% of perimenopausal women and 65% of postmenopausal women reporting hot flashes and/or night sweats.1 Although once thought to be relevant only to quality of life, these symptoms have now emerged as a potential marker of a woman's cardiovascular disease (CVD) risk. In the last decade in particular, several studies investigating their role in CVD have been published, with diverse findings. Early interest in the association of menopausal vasomotor symptoms with CVD risk stemmed from the findings of two large randomized controlled trials—the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI). Although the findings were based on subgroup analyses and small numbers, both trials suggested a more adverse effect of hormone therapy among older and/or high-risk participants with versus without vasomotor symptoms. In HERS, a secondary prevention trial that enrolled older postmenopausal women (mean age = 66.7 y) with prevalent coronary heart disease (CHD), hormone therapy was associated with increased CHD risk (hazard ratio [HR] = 9.01; 95% confidence interval [CI] 1.15-70.35) in the first year among women who reported flushing at baseline but not among those without flushing (P value for interaction of hot flashes with treatment = 0.07).2 Similarly, in the WHI, estrogen alone was linked to elevated CHD risk (HR = 4.34; 95% CI 1.43-13.14) among older postmenopausal women (70-79 y) reporting moderate or severe vasomotor symptoms, but not among women without these symptoms (P value for interaction = 0.04).3 Of note, vasomotor symptoms were not associated with CHD risk among younger women in WHI.3
The notion that hot flashes may serve as a sentinel for CVD risk is biologically plausible given the central role of peripheral vascular reactivity in the development of these symptoms. Although the exact etiology and mechanisms remain largely unknown, it has been speculated that the peripheral “vasomotor instability”4 associated with flushing is also linked to systemic effects on the vasculature. In favor of this hypothesis, hot flashes have been associated in some studies with a significantly higher systolic blood pressure,5 body mass index,6,7 and blood lipid concentrations.7,8 Hot flashes have also been associated with increased intima-media thickness9,10 and greater aortic calcification,11,12 both markers of subclinical CVD. It is important to note that vasomotor changes tend to occur during the same time as the menopausal transition, which is associated with adverse changes in women's CVD risk profiles.
More recently, a growing body of literature has emerged on the timing of onset of vasomotor symptoms in relation to disease risk. The Study of Women's Health Across the Nation, a large multisite community-based cohort of women, found four distinct trajectories of menopausal vasomotor symptoms: early onset with decline in symptoms after menopause; onset near the final menstrual period with later decline; early onset with persistently high frequency; and persistently low frequency. The authors found that women with early onset and persistently high frequency vasomotor symptoms had more adverse health profiles13 suggesting that the relationship between vasomotor symptoms and CVD risk may vary by age or time since the onset of menopause. Consistent with this suggestion, in this issue of Menopause, Thurston et al14 found a significant interaction between age, hot flashes, and endothelial dysfunction in a sample of 304 late perimenopausal and early postmenopausal women (aged 40-53 y) but not in women more distant from menopause (age 54-60 y). Endothelial dysfunction, an indicator of vascular endothelial injury, is not only a marker but a key player in CVD progression and is predictive of future vascular events.

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