Rebecca C. Thurston, PhD Departments of Psychiatry, Psychology, and - PowerPoint PPT Presentation

Rebecca C. Thurston, PhD Departments of Psychiatry, Psychology, and Epidemiology University of Pittsburgh

Vas asomotor Sympt ptoms ( (VMS)  Hot flashes, night sweats  Over 70% of women experience during menopausal transition  Can persist for decades (10 years!)

Ho Hot F Fla lashes D Dura ration 100 % US women 50 0 0 10 20 30 40 50 60 70 80 80 51 0 Final Menstrual Period (FMP) Death Birth

VMS MS  Long understood to have important impact on quality of life  Few medical implications?

Is a a Hot F Flas ash Just st a a Hot F Flas ash?  WHI and HERS: women with baseline VMS highest CVD risk with HT use • WHI (older women) Rossouw et al., 2007 • HERS (women with CHD) Huang et al., 2009

VMS and Subclinical CVD

Su Subclinical al C Car ardio iovasc scular ar D Disease isease (CVD) D) M Measu easures es  FMD: Endothelial dysfunction (lower worse)  Early in CVD  Calcification: Calcified plaques  IMT: Thickness of intimal and medial layers

Study o Stu of f Wome men’s ’s H Health A th Across ss the the Na Natio tion ( (SWAN) Subclinical Hot Flashes Cardiovascular Disease (CVD) • Flow mediated dilation (FMD) • Calcification CV Risk • Intima media E2? Factors? thickness (IMT )

Baseline Study o dy of Wom omen en’s ’s Health 1 Acr cros oss t the Nat ation ion (SWAN AN) 2 3 SWAN Heart (N=557) SWAN (N=3302) 4 B Pittsburgh, Chicago Annually: 5 B Baseline Yrs 4-7 • Demographic, 6 F B Health • FMD: Brachial 7 B F behaviors, Affect artery ultrasound 8 F • Hot flashes • Calcification: EBT 9 F aorta • SBP, DBP, BMI 10 • IMT: Carotid artery • Blood Draw: E2, 11 ultrasound lipids, glucose Follow up Yrs 6-9 12 • IMT 13

Hot Fl Flas ashes & & Fl Flow M Med ediat iated Dil Dilat ation ion 12 * FMD (%, M, SD) 10 8 6 4 None Any Hot Flashes Age, site, race, lumen diameter, BMI, education, DBP, HT use, HDL, LDL, triglycerides, glucose, diabetes history, lipid med use, smoking, physical activity, E2, cycle day of blood draw (Thurston et al., 2008, Circulation)

Hot F Flash ashes & es & Aortic ic C Cal alcif ific ication % with Aortic Calcification 80 * 70 60 50 None Any Hot Flashes (Thurston et al., 2008, Circulation) Age, site, race, education, BMI, smoking, SBP, antidepressant use, HT, menopausal status, depressive sx, phys activity, glucose , HDL, LDL, triglycerides, diabetes hx, cycle day, E2

Cross S Sectio ional nal A Associatio ciation b n between n Ho Hot F Flas ashes and I and IMT MT 0.73 * 0.72 IMT (mm) 0.71 0.7 0.69 0.68 None 1-5 Days 6+ Days Hot flashes in past 2 weeks age, site, race, education, BMI, smoking status, SBP, HDL, LDL, triglycerides, glucose, diabetes status/meds, CVD status/meds, HT use, E2, cycle day of blood draw (Thurston et al., 2011, Menopause)

Associat ociation ion b between n Hot Flas ashes es Acr cros oss V Vis isit its and and IM IMT * 0.73 0.72 IMT (mm) 0.71 0.7 0.69 0.68 None One Both Visits with Hot Flashes age, site, race, education, BMI, smoking status, SBP, HDL, LDL, triglycerides, glucose, diabetes status/meds, CVD status/meds, HT use, E2, cycle day of blood draw (Thurston et al., 2011, Menopause)

Mor ore evide idence ce: H : Hot F Flas ashes es an and d Fl Flow Media diated ed Dil Dilat atio ion (Bechlioulis et al 2010, JCEM)

Mo More E Evi vidence: V VMS MS and nd IMT IMT (Ozkaya et al 2011, Int J of Gyn & Obstet)

Su Summa mmary of f Su Subc bclin inic ical CVD CVD fin indin ings  Positive findings  VMS and IMT (Ozkaya et al., 2011; Thurston et al., 2011)  VMS (duration) and aortic calcification (Thurston et al., 2010)  VMS and FMD/aortic calcification (Thurston et al., 2008; Bechlioulis et al 2010 )  Negative findings: Coronary artery calcification  WHI: women with hysterectomy (Allison et al., 2010)  KEEPS: healthy early perimenopausal women (Wolff et al., 2013)

Ho Hot F Fla lashes a and Subcli linical C l CVD  Women with hot flashes may have higher subclinical CVD • Older or with some elevated CVD risk factors?  Not explained by CVD risk factors, E2  Mechanisms?

VMS and the Autonomic Nervous System

VMS a S and A nd Aut uton onomic N Nervou ous Syste tem  Etiology of VMS: Role of autonomic nervous system speculated  Reduced parasympathetic (vagal) control of heart rate linked to elevated CVD risk  High frequency heart rate variability (HF-HRV)

Study Q y Quest stion Cardiac vagal Hot Flashes control (HF- HRV)

VMS a S and th nd the A Aut utonomic N Nervous Syste tem  Controlled laboratory studies  “Real world” ambulatory studies

Physio ysiologic Measure urement nt of of Hot Fl Flashe hes

Hot Flash Diar Flash Diary  Occurrence  Severity  Bothersome  Emotions  …

Redu duce ced C Car ardiac diac Vagal Con ontrol ol Dur During ing Ho Hot F Flashe hes: L Labora boratory Flash Flash Period Period Pre-Flash Post-Flash Period Period * p < 0.05 vs. minute zero (Thurston et al. 2010, Menopause )

Redu duce ced C Car ardiac diac Vagal Con ontrol ol Dur During ing Hot Fl Flas ashes: A : Ambulat atory y (24 hrs) Hot Flash HF-HRV (lnmsec 2 ) Pre-flash Post-flash p<0.0001 p<0.0001 (Thurston et al., 2012, Minutes surrounding hot flash Menopause )

Autonomic ic Ne Nervous Syst System m and Ho Hot F Fla lashes  Others similar findings: Freedman et al., 2011; deZambotti et al., 2013; Hoikkala et al., 2010  Mechanism linking hot flashes to CVD risk?  Insight into etiology of hot flashes  Autonomic nervous system?

VMS and CVD risk factors (traditional and novel)

Hot Flash Flashes an and S Syst ystolic B Blo lood Pressu essure (Gerber e et al. . 2007, M , Menop opause)

Hot F Ho Fla lashes a and LDL C Chole olesterol p<0.001 130 125 LDL, mg/dL 120 115 110 None 1-5 Days 6+ Days 105 100 0 1 3 4 5 6 7 SWAN Visit (Thurston et al., 2012, Obstet Gynecol ) Hot flashes in past two weeks Covariates: age, site, race, education, menopausal status, alcohol use, physical activity, smoking, anxiety, BMI, CVD status/medication, lipid lowering medication

Hot Fl Flashes a and nd HOMA OMA p<0.0001 2.5 HOMA (median) 2.3 2.1 1.9 None 1-5 days >=6 days 1.7 1.5 0 1 3 4 5 6 7 SWAN Study Visit (Thurston et al., JCEM , 2012) Hot flashes in past two weeks Covariates: Age, site, race, education, menopausal status, alcohol, smoking, physical activity, smoking, anxiety, BMI, heart, BP or lipid lowering med

Hot Flash Flashes an and T TPA-antig antigen 10 p<0.001 TPA-antigen (log) 9 8 7 None 1-5 Days 6+ Days 6 5 0 1 3 4 5 6 7 SWAN Visit (Thurston et al., 2011, Hot flashes in past two weeks Menopause ) Covariates: education, menopausal status, alcohol, parity smoking, exercise, affect, BMI, CV meds, diabetes/insulin, steroids, pain med, antidepressants

Ho Hot Flashes a and P nd P-selectin ctin (Bechlioulis et al 2012, JCEM)

VMS a S and C nd CVD Ris Risk  Subclinical CVD  Autonomic nervous system  Blood pressure  Lipids  Insulin resistance  Inflammatory/hemostatic factors

Stu Studie ies o of f CVD CVD events: V ts: Very y few  VMS in context of HT use elevated risk (older women): WHI & HERS (Rossouw et al., 2007; Huang et al., 2009)  Early VMS reduced risk, Later VMS higher risk: WHI-OS (Szmuilowicz et al., 2011)  Night sweats increased CHD events: EPOS (Gast et al., 2011)

Consi sider erat atio ions  Age of onset: older? (see poster 107)  Duration or burden of VMS: More persistent/ frequent/ severe?  Existing CVD risk profile: Women with elevated CVD risk factors?  VMS measures: Brief, self-report measures, recall and reporting biases  Post-hoc analyses

Hot F Flas ashes and and CVD Risk  Study designed to address relations between hot flashes and CVD risk  Comprehensively study mechanisms linking hot flashes and CVD risk: R01HL105647, N=300 (PI: Thurston)

Women, Menopause, Heart Disease Heart Disease 30000 Thousands 20000 Deaths in 10000 0 0 10 20 30 40 50 60 70 80 Hot Flashes 100 % 50 0 0 10 20 30 40 50 60 70 80 0 51 80 Birth Menopause Death (Dennerstein et al., 2000; Kronenberg, 1999; Mosca, 1997; Tunstall-Pedoe, 1998)

Implicat ications ns?  Possibly……midlife marker of CVD risk  Aggressive risk factor reduction among women with hot flashes?  Improve health of midlife women

Acknowledgements Karen Matthews, PhD Emma Barinas-Mitchell, PhD Kim Sutton-Tyrrell, DrPH Samar El Khoudary, PhD Faith Selzer, PhD Rachel Hess, MD, MSc Carolyn Crandall, MD, MS Barbara Sternfeld, PhD Susan Everson-Rose, PhD, MPH Ellen Gold, PhD Imke Janssen, PhD Lynda Powell, PhD