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

2. Outline  Introduction to hot flashes  Hot flashes and subclinical cardiovascular disease  Mechanisms  Discussion/future directions

3. Hot Flashes  Sensation of intense heat, sweating, flushing  Hot flashes, night sweats (vasomotor symptoms)  Over 70% of women experience during menopausal transition  Can persist for decades

4. Hot Flashes Duration 0 80 51 Birth Death Final Menstrual Period % US women

5. Hot Flashes  Associated with pronounced impairments quality of life: Physical, social, emotional functioning Sleep disruption, irritability, depressed mood, poorer cognitive function

6. Hot Flashes  Leading cause of treatment seeking among midlife women  Findings of risk associated with hormone therapy (HT) Most effective treatment for hot flashes  Increased interest in physiology of and nonhormonal treatments for hot flashes  Underlying physiology not well-understood

7. Physiology of Hot Flashes Copyright ©2004 The Endocrine Society Randolph, J. F. et al. J Clin Endocrinol Metab 2004;89:1555-1561 Estradiol (E2) Follicle stimulating hormone (FSH) Hot Flashes

8. Physiology of Hot Flashes Sweating Shivering Thermoneutral zone TcTc TcTc AsymptomaticSymptomatic Shivering Sweating (Freedman, 2001)

9. Outline  Introduction to hot flashes  Hot flashes and subclinical cardiovascular disease  Mechanisms  Discussion/future directions

10.  Hot flashes long understood to have important impact on quality of life  Few medical implications?

11. Is a Hot Flash Just a Hot Flash?  WHI & HERS: Women with hot flashes at highest cardiovascular risk with HT use  Cardiovascular risk factors (smoking) also risk factors for hot flashes  E2 widespread cardiovascular impact  Potent vasodilator associated with hot flashes, not other types of sweating

12. Study Questions Hot Flashes Subclinical Cardiovascular Disease (CVD) Flow mediated dilation (FMD) Calcification CV Risk Factors? E2?

13. Subclinical Cardiovascular Disease (CVD) Measures  FMD: Endothelial dysfunction (lower worse) Early in CVD  Calcification: Calcified plaques in aorta and coronary arteres

14. Study of Women’s Health Across the Nation (SWAN) Baseline Yrs 4-7 FMD: Brachial artery ultrasound Calcification: EBT aorta SWAN Heart (N=557) Pittsburgh, Chicago SWAN (N=3302) Annually: Demographic, Health behaviors, Affect Hot flashes SBP, DBP, BMI Blood Draw: E2, lipids, glucose 10 B B B B 2 3 4 5 6 7 8 9 1

15. Hot Flashes & Flow Mediated Dilation B (SE) = -0.99 (0.41), p = 0.02 B (SE) = - 0.97 (0.44), p = 0.03 B (SE) = -1.01 (0.41), p = 0.01 + Covariates + Covariates, E2 Age, site, race, lumen diameter, BMI, education, DBP, HT use, menopausal status, LDL, HDL, triglycerides, glucose, diabetes history, lipid med use, smoking, physical activity 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) Age, site, race *

16. Age, site, race, education, BMI, smoking, SBP, antidepressant use, HT, menopausal status, depressive sx, phys activity, glucose, HDL, LDL, triglycerides, diabetes hx Hot Flashes & Aortic Calcification OR = 1.55, 1.10-2.19, p = 0.01 + Covariates, E2 OR = 1.63, 1.07-2.49, p = 0.02 + Covariates OR = 1.53, 1.02-2.29, p = 0.04 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 Age, site, race (Thurston et al., 2008, Circulation) *

17. Is a Hot Flash Just a Hot Flash?  Other subclinical CVD measures?

18. Intima Media Thickness (IMT)  IMT: Thickness of medial and intimal layers of carotid artery  Most well-validated and widely-used measure of subclinical CVD

19. Study Questions Hot Flashes Intima media thickness (IMT) CV Risk Factors? E2?

20. Study of Women’s Health Across the Nation (SWAN) Baseline Baseline Yrs 4-7 IMT: Carotid artery ultrasound SWAN Heart (N=557) Pittsburgh, Chicago SWAN (N=3302) Annually: Demographic, Health behaviors, Affect Hot flashes SBP, DBP, BMI Blood Draw: E2, lipids, glucose 10 B B B B 2 3 4 5 6 7 8 9 F F F F 1 Follow up Yrs 6-9 IMT

21. Cross Sectional Association between Hot Flashes and IMT age, site, race, education, BMI, smoking status, SBP, HDL, LDL, triglycerides, glucose, diabetes status/meds, CVD status/meds, HT use, menopausal status 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 +E2B (SE) = 0.03 (0.01), p = 0.03 B (SE) = 0.03 (0.01), p = 0.02 (Thurston et al., 2011, Menopause) *

22. Association between Hot Flashes Across Visits and IMT B (SE) = 0.03 (0.01), p = 0.03B (SE) = 0.02 (0.01), p = 0.04 +E2 age, site, race, education, BMI, smoking status, SBP, HDL, LDL, triglycerides, glucose, diabetes status/meds, CVD status/meds, HT use, menopausal status 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) *

23. Relation between hot flashes and IMT by obesity status Study Visits with Hot Flashes IMT (mm) Hot flashes *BMI p<0.01

24. Hot Flashes and Subclinical CVD  Women with hot flashes had higher subclinical CVD (FMD, calcification, IMT)  Persist controlling for CVD risk factors, E2  Most pronounced with high BMI  Hot flashes mark something more?  Consider role of the vasculature in hot flashes  Mechanisms?

25. Outline  Introduction to hot flashes  Hot flashes and subclinical cardiovascular disease  Mechanisms  Discussion/future directions

26. A Note about Measurement  Epidemiologic studies use questionnaire measures of hot flashes  Crude, memory and reporting influences  Physiologic, diary measures of hot flashes  Data in “real time”  More precise  Insight into reporting influences

27. Physiologic Measurement of Hot Flashes

28. Hot Flash Diary  Occurrence  Severity  Bothersome  Location on body  Aura  Emotions  Health behaviors…

29. “False Positive” Hot Flash Reporting Physiologic Reported (Diary) YesNo Yes347208 No394--

30. Psychological Factors Associated with False Positive Hot Flashes (Thurston et al., 2005, Psychosom Med) * * † † p < 0.1 * p < 0.05

31. Emotional Antecedents of “False Positive” Hot Flashes Frustration Sadness StressTiredHappyRelaxed In Control * * * p < 0.05 (Thurston et al., 2005, Psychosom Med)

32. A Note about Measurement  Mood and emotions can impact hot flashes  When using self-report measures only, consider the role of emotion  Best to have physiologic + diary measures (laboratory/clinical studies)

33. Hot Flashes and Autonomic Nervous System  Etiology of hot flashes: Role of autonomic nervous system speculated Sympathetic, parasympathetic (vagus)  Reduced parasympathetic (vagal) control of heart rate linked to elevated CVD risk  High frequency heart rate variability (HF-HRV) index of cardiac vagal control

34. Study Question Hot Flashes Cardiac vagal control (HF- HRV)

35. PMBC FLASHES Study 30 peri and postmenopausal women, aged 40-60, >4 hot flashes/day, no HT, SSRI/SNRIs Lab procedures to induce hot flashes Continuous ECG (HF-HRV) and sternal skin conductance Hot flashes physiologically measured and self-reported Observation 30 min Stress 5 min Heat 30 min Cold Pressor 1 min

36. Data Reduction & Analysis  Spectral analysis of heart rate time series  Linear mixed models Minutes during flash compared to non-flash pre and post flash periods Covariates: Age, task, race, menopausal status, education, smoking, anxiety, BMI, diabetes, use of cardiovascular meds/HTN, physical activity

37. FlashPre-flashPost-flash Hot Flash Data Reduction & Analysis Minute -10Minute +10

38. Reduced Cardiac Vagal Control During Hot Flashes: Laboratory * p < 0.05 vs. minute zero Pre-Flash Period Post-Flash Period Flash Period (Thurston et al. 2010, Menopause) Flash Period

39. Ambulatory Study: During Daily Life 42 peri and postmenopausal women, aged 40-60, >4 hot flashes/day, no HT, SSRI/SNRIs, or CV medications Wore ambulatory monitor for 24 hours o Hot flashes o ECG o Respiration Hot flashes physiologically measured and self-reported

40. Reduced Cardiac Vagal Control During Hot Flashes: Ambulatory (24 hrs) Pre-flashPost-flash p<0.0001 Minutes surrounding hot flash HF-HRV (lnmsec 2 ) (Thurston et al., 2012, Menopause) Hot Flash

41. Autonomic nervous system and hot flashes  Reduced HF-HRV during hot flashes Laboratory and ambulatory settings  Insight into etiology of hot flashes Reproductive hormonal Thermoregulatory  Autonomic nervous system?  Mechanism linking hot flashes to CVD risk?

42.  In SWAN, hot flashes associated with elevated subclinical CVD  Mechanisms? Autonomic nervous system (Thurston et al., 2010, Thurston et al., 2012) Inflammation/hemostasis (Thurston et al., 2011) Hot Flashes and CVD risk

43. Other mechanisms: Inflammation/hemostasis  Inflammation/hemostasis and hot flashes? Regulated in part by vascular endothelium One study: IL-8 elevated among women with hot flashes (Yasui et al., 2006) Sensitive to reproductive hormones

44. CV risk factors? Study Questions Hot Flashes E2? Inflammation/ hemostasis CRP, PAI-1, Factor VIIc, TPA-antigen, fibrinogen

45. B Study of Women’s Health Across the Nation (SWAN) SWAN (N = 3302) Annually: Demographic, Health behaviors, Medications/Health status, Affect Hot flashes, night sweats SBP, DBP, BMI Blood Draw: E2, lipids, glucose 7 6 5 4 2 3 4 5 6 7 8 9 1 3 1 B Inflammatory/hemostatic markers: CRP, PAI-1, and tPA-ag Fibrinogen and FVIIc 10

46. Hot Flashes and TPA-antigen Hot flashes in past two weeks Covariates: education, menopausal status, alcohol, parity smoking, exercise, affect, BMI, CV meds, diabetes/insulin, steroids, pain med, antidepressants p<0.001 (Thurston et al., 2011)

47. Hot Flashes and Factor VIIc p<0.01 Hot flashes in past two weeks Covariates: education, menopausal status, alcohol, parity smoking, exercise, affect, BMI, CV meds, diabetes/insulin, steroids, pain med, antidepressants (Thurston et al., 2011)

48.  In SWAN, hot flashes associated with elevated subclinical CVD  Mechanisms? Autonomic nervous system (Thurston et al., 2010, Thurston et al., 2012) Inflammation/hemostasis (Thurston et al., 2011) Lipids (Thurston et al., 2012) Hot Flashes and CVD risk

49. What about lipids?  Well known CV risk factor  Some research suggestive of adverse lipid profile among women with hot flashes

50. CV risk factors? Study Questions Hot Flashes E2? Adverse lipid profile? LDL, HDL, Triglycerides, ApoB, ApoA1

51. B 7 6 5 4 2 3 4 5 6 7 8 9 1 3 1 B Lipids: LDL, HDL, triglycerides, ApoB, ApoA1 10 Study of Women’s Health Across the Nation (SWAN) SWAN (N = 3302) Annually: Demographic, Health behaviors, Medications/Health status, Affect Hot flashes, night sweats SBP, DBP, BMI Blood Draw: E2, FSH, glucose

52. Hot Flashes and LDL Cholesterol 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 p<0.001 (Thurston et al., 2012)

53. Hot Flashes and ApoB p<0.0001 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 (Thurston et al., 2012)

54. Hot Flashes and Triglycerides p<0.0001 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 (Thurston et al., 2012)

55.  In SWAN, hot flashes associated with elevated subclinical CVD  Mechanisms? Autonomic nervous system (Thurston et al., 2010, Thurston et al., 2012) Inflammation/hemostasis (Thurston et al., 2011) Lipids (Thurston et al., 2012) Hot Flashes and CVD risk

56. Outline  Introduction to hot flashes  Hot flashes and subclinical cardiovascular disease  Mechanisms  Discussion/future directions

57. Hot Flashes and CVD risk  Hot flashes associated with elevated subclinical CVD  Multiple mechanisms  Subtypes of hot flashes?  Synergize with other CV risk factors?  Physiologic, diary measures of hot flashes?

58. Next Steps: CVD Risk and Hot Flashes  New study designed to address CVD risk and hot flashes R01HL105647: N=300 with and without hot flashes, 5 years Detailed physiologic, psychological mechanisms Physiologic, diary hot flash measures

59. Implications?  Better understand physiology of hot flashes  Midlife marker of CVD risk?  Aggressive risk factor reduction among women with hot flashes?  Improve health of midlife women

60. SWAN has grant support from the NIH, DHHS, through the NIA, NINR, NHLBI, ORWH (NR004061; AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495, HL065581, HL06551) Thurston: K23AG029216 University of Pittsburgh Institute on Aging The content of this presentation is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH. Karen Matthews, PhD Kim Sutton-Tyrrell, DrPH Rachel Hess, MD, MSc Samar El Khoudary, PhD Faith Selzer, PhD Susan Everson-Rose, PhD, MPH Ellen Gold, PhD Imke Janssen, PhD Lynda Powell, PhD Israel Christie, PhD Carolyn Crandall, MD, MS Barbara Sternfeld, PhD Acknowledgements

61. Thank you!

62. Questions?