Vasomotor Symptoms: Hemostatic and Inflammatory Markers
Objective: Emerging research suggests links between menopausal hot flashes and cardiovascular risk. The mechanisms underlying these associations are unclear due, in part, to the incomplete understanding of the physiology of hot flashes. We aimed to examine the longitudinal associations between hot flashes/night sweats and both inflammatory and hemostatic markers, controlling for cardiovascular risk factors and estradiol concentrations.
Methods: Participants in the Study of Women's Health Across the Nation (n = 3,199), a longitudinal cohort study, were aged 42 to 52 years at cohort entry. Women completed interviews (hot flashes, night sweats: none, 1-5, and ≥6 d in the past 2 weeks), physical measures (blood pressure, height, weight), and a blood draw (high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, factor VIIc, tissue plasminogen activator antigen [tPA-ag], fibrinogen, glucose, serum estradiol) yearly for 8 years. Hot flashes/night sweats were examined in relation to each inflammatory/hemostatic marker in linear mixed models adjusting for demographic factors, cardiovascular risk factors, and medication use, as well as serum estradiol.
Results: Compared with experiencing no flashes, reporting hot flashes was associated with higher tPA-aglog (hot flashes 1-5 d: percent change, or % change [95% CI], 3.88 [2.22-5.58]; P < 0.0001; ≥6 d: % change [95% CI], 4.11 [1.95-6.32]; P < 0.001) and higher factor VIIclog (hot flashes ≥6 d: % change [95% CI], 2.13 [0.80-3.47]; P < 0.01) in multivariable models. Findings persisted after adjusting for estradiol. Findings for night sweats were similar but attenuated with adjustment.
Conclusions: Frequent hot flashes were associated with higher factor VIIc and tPA-ag. Hemostatic pathways may be relevant to understanding hot flash physiology and links between hot flashes and cardiovascular risk.
Vasomotor symptoms (VMS; hot flashes and/or night sweats) are experienced by most women transitioning through menopause. VMS are associated with sleep disturbance, depressed mood, and overall decrements in physical, social, and emotional quality of life. Most women with menopausal symptoms, principally VMS, seek treatment for them.
Despite their prevalence and impact on women's lives, the physiology of VMS is not well understood. Leading etiologic models cite VMS as thermoregulatory heat dissipation events occurring in the context of the menopausal withdrawal of gonadal hormones. However, many other central and peripheral systems have been implicated in VMS, and the need for better understanding of the physiology of VMS has been recognized.
In addition to the quality of life implications of VMS, some evidence, albeit not entirely consistent, links VMS to cardiovascular risk. In the Women's Health Initiative and the Heart and Estrogen/Progestin Replacement Study, older postmenopausal women with moderate-to-severe VMS at the study baseline were at greatest cardiovascular risk with hormone use. Our findings from the Study of Women's Health Across the Nation (SWAN) Heart Study further showed that midlife women with hot flashes had indices of greater subclinical cardiovascular disease (CVD), including poorer endothelial function, greater aortic calcification, and greater intima media thickness, than did women without hot flashes. Others have found similar findings for endothelial function. Associations generally persist with adjustment for standard cardiovascular risk factors.
The reason(s) for the links between VMS and cardiovascular risk is not fully understood. One study has suggested that hot flash severity may be associated with alterations in inflammatory processes. Altered inflammation and hemostasis, two interrelated systems, play key roles in the pathogenesis of CVD. These alterations have been related, in many cases, prospectively, to CVD risk. In fact, the endothelium, dysfunction of which has been linked to VMS, plays a central role in regulating blood coagulation and inflammation.
The primary study aim was to examine the associations between VMS and inflammatory and hemostatic markers in SWAN, a large, longitudinal study of women transitioning through menopause. We assessed the longitudinal relations of VMS to high-sensitivity C-reactive protein (hs-CRP), an acute-phase reactant prospectively associated with CVD risk; the procoagulant/antifibrinolytic hemostatic markers; plasminogen activator inhibitor-1 (PAI-1); tissue plasminogen activator antigen (tPA-ag); and factor VIIc (FVIIc); and the acute-phase reactant protein, fibrinogen, all of which have been linked to CVD risk. We hypothesized that VMS would be associated with adverse alterations in inflammation and hemostasis after adjusting for potential confounding/explanatory factors (eg, smoking, obesity, and educational attainment) as well as serum estradiol (E2), a gonadal hormone associated with both VMS and inflammation/hemostasis. We also evaluated any modification of these associations by menopausal stage and race/ethnicity, given the importance of these factors to VMS and cardiovascular risk.
Abstract and Introduction
Abstract
Objective: Emerging research suggests links between menopausal hot flashes and cardiovascular risk. The mechanisms underlying these associations are unclear due, in part, to the incomplete understanding of the physiology of hot flashes. We aimed to examine the longitudinal associations between hot flashes/night sweats and both inflammatory and hemostatic markers, controlling for cardiovascular risk factors and estradiol concentrations.
Methods: Participants in the Study of Women's Health Across the Nation (n = 3,199), a longitudinal cohort study, were aged 42 to 52 years at cohort entry. Women completed interviews (hot flashes, night sweats: none, 1-5, and ≥6 d in the past 2 weeks), physical measures (blood pressure, height, weight), and a blood draw (high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, factor VIIc, tissue plasminogen activator antigen [tPA-ag], fibrinogen, glucose, serum estradiol) yearly for 8 years. Hot flashes/night sweats were examined in relation to each inflammatory/hemostatic marker in linear mixed models adjusting for demographic factors, cardiovascular risk factors, and medication use, as well as serum estradiol.
Results: Compared with experiencing no flashes, reporting hot flashes was associated with higher tPA-aglog (hot flashes 1-5 d: percent change, or % change [95% CI], 3.88 [2.22-5.58]; P < 0.0001; ≥6 d: % change [95% CI], 4.11 [1.95-6.32]; P < 0.001) and higher factor VIIclog (hot flashes ≥6 d: % change [95% CI], 2.13 [0.80-3.47]; P < 0.01) in multivariable models. Findings persisted after adjusting for estradiol. Findings for night sweats were similar but attenuated with adjustment.
Conclusions: Frequent hot flashes were associated with higher factor VIIc and tPA-ag. Hemostatic pathways may be relevant to understanding hot flash physiology and links between hot flashes and cardiovascular risk.
Introduction
Vasomotor symptoms (VMS; hot flashes and/or night sweats) are experienced by most women transitioning through menopause. VMS are associated with sleep disturbance, depressed mood, and overall decrements in physical, social, and emotional quality of life. Most women with menopausal symptoms, principally VMS, seek treatment for them.
Despite their prevalence and impact on women's lives, the physiology of VMS is not well understood. Leading etiologic models cite VMS as thermoregulatory heat dissipation events occurring in the context of the menopausal withdrawal of gonadal hormones. However, many other central and peripheral systems have been implicated in VMS, and the need for better understanding of the physiology of VMS has been recognized.
In addition to the quality of life implications of VMS, some evidence, albeit not entirely consistent, links VMS to cardiovascular risk. In the Women's Health Initiative and the Heart and Estrogen/Progestin Replacement Study, older postmenopausal women with moderate-to-severe VMS at the study baseline were at greatest cardiovascular risk with hormone use. Our findings from the Study of Women's Health Across the Nation (SWAN) Heart Study further showed that midlife women with hot flashes had indices of greater subclinical cardiovascular disease (CVD), including poorer endothelial function, greater aortic calcification, and greater intima media thickness, than did women without hot flashes. Others have found similar findings for endothelial function. Associations generally persist with adjustment for standard cardiovascular risk factors.
The reason(s) for the links between VMS and cardiovascular risk is not fully understood. One study has suggested that hot flash severity may be associated with alterations in inflammatory processes. Altered inflammation and hemostasis, two interrelated systems, play key roles in the pathogenesis of CVD. These alterations have been related, in many cases, prospectively, to CVD risk. In fact, the endothelium, dysfunction of which has been linked to VMS, plays a central role in regulating blood coagulation and inflammation.
The primary study aim was to examine the associations between VMS and inflammatory and hemostatic markers in SWAN, a large, longitudinal study of women transitioning through menopause. We assessed the longitudinal relations of VMS to high-sensitivity C-reactive protein (hs-CRP), an acute-phase reactant prospectively associated with CVD risk; the procoagulant/antifibrinolytic hemostatic markers; plasminogen activator inhibitor-1 (PAI-1); tissue plasminogen activator antigen (tPA-ag); and factor VIIc (FVIIc); and the acute-phase reactant protein, fibrinogen, all of which have been linked to CVD risk. We hypothesized that VMS would be associated with adverse alterations in inflammation and hemostasis after adjusting for potential confounding/explanatory factors (eg, smoking, obesity, and educational attainment) as well as serum estradiol (E2), a gonadal hormone associated with both VMS and inflammation/hemostasis. We also evaluated any modification of these associations by menopausal stage and race/ethnicity, given the importance of these factors to VMS and cardiovascular risk.
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