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

Rebecca C. Thurston, PhD
Departments of Psychiatry, Psychology, and
Epidemiology
University of Pittsburgh
Outline
 Introduction
to hot flashes
 Hot
flashes and subclinical
cardiovascular disease
 Mechanisms
 Discussion/future
directions
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
Hot Flashes Duration
% US women
100
50
0
0
0
Birth
10
20
30
40
50
60
51
Final Menstrual Period
70
80
80
Death
Hot Flashes
 Associated
with pronounced
impairments quality of life:
 Physical, social, emotional
functioning
 Sleep disruption, irritability,
depressed mood, poorer
cognitive function
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
Physiology of Hot Flashes
Estradiol
(E2)
Follicle
stimulating
hormone
(FSH)
Hot
Flashes
Randolph, J. F. et al. J Clin
Endocrinol Metab
2004;89:1555-1561
Copyright ©2004 The Endocrine Society
Physiology of Hot Flashes
Sweating
Sweating
Thermoneutral zone
Shivering
Thermoneutral zone
Tc
Tc
Shivering
Asymptomatic
Symptomatic
(Freedman, 2001)
Outline
 Introduction
to hot flashes
 Hot
flashes and subclinical
cardiovascular disease
 Mechanisms
 Discussion/future
directions
 Hot
flashes long understood to
have important impact on quality
of life
Few medical implications?
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
Study Questions
Subclinical
Cardiovascular
Disease (CVD)
Hot Flashes
• Flow mediated
dilation (FMD)
• Calcification
CVE2?
Risk
Factors?
Subclinical Cardiovascular Disease
(CVD) Measures
 FMD:
Endothelial
dysfunction (lower worse)
 Early in CVD
 Calcification:
Calcified
plaques in aorta and
coronary arteres
Study of Women’s Health Across the
Nation (SWAN)
Baseline
1
SWAN (N=3302)
2
3
4
B
5
B
6
B
7
B
8
9
10
SWAN Heart (N=557)
Annually:
Pittsburgh, Chicago
• Demographic,
Yrs 4-7
Health behaviors,
• FMD: Brachial
Affect
artery ultrasound
• Hot flashes
• Calcification: EBT
• SBP, DBP, BMI
aorta
• Blood Draw: E2,
lipids, glucose
Hot Flashes & Flow Mediated Dilation
-0.97 (0.44),
B (SE) = -1.01
-0.99
(0.41), p = 0.03
0.02
0.01
+ Covariates
Covariates, E2
FMD (%, M, SD)
12
*
10
8
6
4
None
Any
Hot Flashes
race, lumen diameter, BMI, education, DBP, HT use, HDL,
LDL, status,
Age, site, race
menopausal
triglycerides,
glucose, diabetes
history,
lipidhistory,
med use,
activity,
E2,
LDL, HDL, triglycerides,
glucose,
diabetes
lipidsmoking,
med use,physical
smoking,
physical
(Thurston et al., 2008, Circulation)
cycle
activityday of blood draw
Hot Flashes & Aortic Calcification
% with Aortic Calcification
OR = 1.63,
1.55,
1.10-2.19,
0.01
1.53, 1.07-2.49,
1.02-2.29, p = 0.02
0.04
80
+ Covariates
Covariates, E2
*
70
60
50
None
Any
Hot Flashes
(Thurston et al., 2008, Circulation)
race, education, BMI, smoking, SBP, antidepressant use, HT, menopausal status,
Age, site, race
depressive sx, phys activity, glucose,
glucose, HDL, LDL, triglycerides, diabetes hx
hx, cycle day, E2
Is a Hot Flash Just a Hot Flash?
 Other
subclinical CVD
measures?
Intima Media Thickness (IMT)
 IMT:
Thickness of medial
and intimal layers of
carotid artery
 Most well-validated and
widely-used measure of
subclinical CVD
Study Questions
Intima media
thickness (IMT)
Hot Flashes
CVE2?
Risk
Factors?
Study of Women’s Health Across the
Nation (SWAN)
Baseline
1
SWAN (N=3302) SWAN Heart (N=557)
2
3
4
B
5
B
6
B
F
7
B
F
8
F
9
F
10
Pittsburgh, Chicago
Annually:
• Demographic,
Baseline Yrs 4-7
Health behaviors, • IMT: Carotid artery
Affect
ultrasound
• Hot flashes
Follow up Yrs 6-9
• SBP, DBP, BMI
• IMT
• Blood Draw: E2,
lipids, glucose
Cross Sectional Association between
Hot Flashes and IMT
B (SE)
= 0.03
(0.01),
= 0.02+E2
B (SE)
= 0.03
(0.01),
p = p0.03
*
age, site, race, education, BMI, smoking status, SBP, HDL, LDL, triglycerides, glucose,
diabetes status/meds, CVD status/meds, HT use, menopausal
E2, cycle daystatus
of blood draw
(Thurston et al., 2011, Menopause)
Association between Hot Flashes
Across Visits and IMT
BB
(SE)
(SE)
= 0.02
= 0.03
(0.01),
(0.01),
p=
p 0.04
= 0.03
+E2
*
age, site, race, education, BMI, smoking status, SBP, HDL, LDL, triglycerides, glucose,
diabetes status/meds, CVD status/meds, HT use, menopausal
E2, cycle daystatus
of blood draw
(Thurston et al., 2011, Menopause)
Relation between hot flashes and
IMT by obesity status
Hot flashes
*BMI p<0.01
0.76
0.74
IMT (mm)
0.72
0.7
Normal
Overweight
Obese
0.68
0.66
0.64
0.62
0.6
None
One
Both
Study Visits with Hot Flashes
Hot Flashes and Subclinical CVD
 Women
with hot flashes had higher
subclinical CVD (FMD, calcification, IMT)
 Persist
 Most
 Hot
controlling for CVD risk factors, E2
pronounced with high BMI
flashes mark something more?
 Consider
role of the vasculature in hot
flashes
 Mechanisms?
Outline
 Introduction
to hot flashes
 Hot
flashes and subclinical
cardiovascular disease
 Mechanisms
 Discussion/future
directions
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
Physiologic Measurement of Hot
Flashes
Hot Flash Diary

Occurrence

Severity

Bothersome

Location on body

Aura

Emotions

Health behaviors…
“False Positive” Hot Flash Reporting
Physiologic
Reported
(Diary)
Yes
No
Yes
347
208
No
394
--
Psychological Factors Associated with
False Positive Hot Flashes
False positive reporting rate
0.7
0.6
0.5
Depressive sx
State anxiety
Trait anxiety
*
*
†
0.4
0.3
0.2
0.1
0
Low
Medium
Level of Negative Affect
(Thurston et al., 2005, Psychosom Med)
High
† p < 0.1
* p < 0.05
Emotional Antecedents of “False
Positive” Hot Flashes
1.5
*
1
In
Control
Relaxed
Happy
Tired
* p < 0.05
(Thurston et al., 2005, Psychosom Med)
Stress
0
*
Sadness
0.5
Frustration
OR False Positive Hot Flash
2
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)
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
Study Question
Hot Flashes
Cardiac vagal
control (HFHRV)
PMBC FLASHES Study
Observation
30 min
Stress
5 min
Heat
30 min
Cold Pressor
1 min
• 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
Data Reduction & Analysis
 Spectral
 Linear
analysis of heart rate time series
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
Data Reduction & Analysis
Hot Flash
Pre-flash
Minute -10
Flash
Post-flash
Minute +10
Reduced Cardiac Vagal Control During
Hot Flashes: Laboratory
Flash
Flash
Period
Period
Pre-Flash
Period
* p < 0.05 vs. minute zero
Post-Flash
Period
(Thurston et al. 2010, Menopause)
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
HF-HRV (lnmsec2)
Reduced Cardiac Vagal Control During
Hot Flashes: Ambulatory (24 hrs)
Hot
Flash
Pre-flash
p<0.0001
Post-flash
p<0.0001
Minutes surrounding hot flash
(Thurston et
al., 2012,
Menopause)
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
risk?
linking hot flashes to CVD
Hot Flashes and CVD risk
 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)
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
Study Questions
Inflammation/
hemostasis
Hot Flashes
CVE2?
risk
factors?
CRP, PAI-1, Factor
VIIc, TPA-antigen,
fibrinogen
Study of Women’s Health Across
the Nation (SWAN)
B
B
1
1
2
3
3
4
4
5
5
6
6
7
7
8
9
10
SWAN (N = 3302)
Annually:
• Demographic, Health behaviors,
Medications/Health status, Affect
• Hot flashes, night sweats
• SBP, DBP, BMI
• Blood Draw: E2, lipids, glucose
Inflammatory/hemostatic markers:
• CRP, PAI-1, and tPA-ag
• Fibrinogen and FVIIc
Hot Flashes and TPA-antigen
TPA-antigen (log)
10
p<0.001
9
8
7
None
6
1-5 Days
6+ Days
5
0
1
Hot flashes in past two weeks
3
4
SWAN Visit
5
6
7
(Thurston et al., 2011)
Covariates: education, menopausal status, alcohol, parity smoking, exercise, affect,
BMI, CV meds, diabetes/insulin, steroids, pain med, antidepressants
Hot Flashes and Factor VIIc
p<0.01
140
Factor VIIc (log)
135
130
125
120
115
110
None
105
1-5 Days
6+ Days
100
0
1
3
SWAN Visit
5
7
(Thurston et al., 2011)
Hot flashes in past two weeks
Covariates: education, menopausal status, alcohol, parity smoking, exercise, affect,
BMI, CV meds, diabetes/insulin, steroids, pain med, antidepressants
Hot Flashes and CVD risk
 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)
What about lipids?
 Well
known CV risk factor
 Some
research suggestive of adverse
lipid profile among women with hot
flashes
Study Questions
Adverse lipid
profile?
Hot Flashes
CVE2?
risk
factors?
LDL, HDL,
Triglycerides, ApoB,
ApoA1
Study of Women’s Health Across
the Nation (SWAN)
B
B
1
1
2
3
3
4
4
5
5
6
6
7
7
8
9
10
SWAN (N = 3302)
Annually:
• Demographic, Health behaviors,
Medications/Health status, Affect
• Hot flashes, night sweats
• SBP, DBP, BMI
• Blood Draw: E2, FSH, glucose
Lipids:
• LDL, HDL, triglycerides, ApoB, ApoA1
Hot Flashes and LDL Cholesterol
p<0.001
130
LDL, mg/dL
125
120
115
110
None
105
1-5 Days
6+ Days
100
0
1
Hot flashes in past two weeks
3
4
SWAN Visit
5
6
7
(Thurston et al., 2012)
Covariates: age, site, race, education, menopausal status, alcohol use, physical
activity, smoking, anxiety, BMI, CVD status/medication, lipid lowering medication
Hot Flashes and ApoB
p<0.0001
ApoB, mg/Dl
120
115
110
105
100
None
1-5 Days
6+ Days
95
0
1
Hot flashes in past two weeks
3
4
SWAN Visit
5
6
7
(Thurston et al., 2012)
Covariates: age, site, race, education, menopausal status, alcohol use, physical
activity, smoking, anxiety, BMI, CVD status/medication, lipid lowering medication
Hot Flashes and Triglycerides
Triglycerides, mg/Dl
160
p<0.0001
150
140
130
120
110
100
None
90
1-5 Days
6+ Days
80
0
1
Hot flashes in past two weeks
3
4
SWAN Visit
5
6
7
(Thurston et al., 2012)
Covariates: age, site, race, education, menopausal status, alcohol use, physical
activity, smoking, anxiety, BMI, CVD status/medication, lipid lowering medication
Hot Flashes and CVD risk
 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)
Outline
 Introduction
to hot flashes
 Hot
flashes and subclinical
cardiovascular disease
 Mechanisms
 Discussion/future
directions
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,
flashes?
diary measures of hot
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
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
Acknowledgements
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
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.
Thank you!
Questions?