Gender Aspects in the
Metabolic syndrome
Vera Regitz-Zagrosek
Cardiovascular disease
in women &
Gender in medicine
Charite and German
Heart Institute, Berlin
1
Issues today:





Definition and diagnosis of the MetS
Gender differences in incidence and prevalence
Gender differences in the components and their role in
cardiovascular risk
 Insulin resistance (IR) and diabetes
 Hyper-/dyslipidemia
 Abdominal obesity, adipokine secretion
 Hypertension
MetS and sex hormones
Treatment of MetS
2
Metabolic Syndrome
Incidence:
Features
• Insulin resistance
• Abdominal obesity
• Dyslipidemia
• Hypertension
USA in 2000:
47 000 000 people
Rise in obesity
1991 – 2000: 61 %
In women: 74 %
Complications:
•Hypercoagulability
•Endothelial Dysfunction
•Inflammation
•CAD
Steinbaum, Progress in Cardiovascular Diseases; 2004
3
Increase in age- and gender dependent prevalence of
the MetS in the US
Regitz-Zagrosek et al., Clin Res Cardiol 2006
4
Definitions of the Metabolic syndrome (MetS)
• Insulin
resistance
• Abdominal
obesity
• Dyslipidemia
• Hypertension
adapted fromRegitz-Zagrosek et al., Clin Res Cardiol 2006
5
Gender aspects in the definition of MetS
Biggest
difference is the
diagnosis of
hyperglycemia,
Impaired glucose
tolerance (IGT)
vs elevated
fasting glucose
(IFG)
Regitz-Zagrosek et al., Clin Res Cardiol 2006
6
Sex-related differences in glucose metabolism
Relation between FG and OGT
50
45
women
40
men
% of population
35
30
women
men
25
20
15
10
5
0
Fasting glucose
Women have higher 2 h glucose for
each fasting glucose level
Williams et al., Diab Med. 2003
Known D
Unkn D
IGT
IGT
IFG
F-G
all
Mechanisms?
W Rathmann et al, Diabetologica 2003
7
Summary I: Gender aspects in the definition and
epidemiology of the MetS



Different definitions of the metabolic syndrome lead to the
inclusions of more or less women – gender is of major
relevance for this syndrome
Obesity and insulin resistance are significant contributors to
the MetS in women –
Epidemiology indicates an increasing prevalence of the MetS
which affects mainly young women – obesity and malnutrition
play a major role
Gender differences in MetS/Diabetes
related CV risk
8
Interheart: 9 risk factors explain 90 % of myocardial
infarctions in the world – 5 are part of the MetS and
some are gender specific
Diabetes
Hypertension
Exercise
9
Risk factors don‘t just add, they potentiate
Additional risk factors in women:
Polymorphisms in the coagulation
system: 80 fold risk with HRT in pts with
mutations in coag factors (Herrington D,
2001)
LVH: develops more slowly,
but carries greater risk in women (Lia Y,
Circ 1995), Thrainsdottir I, J Int Med
2003
10
Interaction of hyperglycaemia and diabetes with
CAD is sex dependent
Increase in Relative Risik for death from CAD in female and
male patients with diabetes and Hyperglycemia
6
5
4
3
2
1
0
F, Diab
M, Diab
F, HyGly
M, HyGly
Pan, Am J Epidem, 1986, Chicago H S
11
Diabetes as risk factor in women and men
Diabetes has a higher incidence in women, is associated with
hormonal disturbances and is a stronger risk factor in women – why?
16
14
Women
Men
Women with Polyc.ovarian syndr.
12
10
8
6
4
2
0
Diabetics
Lundberg et al, Arch Int Med, 1997
PCOS
Risk for MI
Lethality from MI
MI due to
Diabetes
12
Survival of women and men after MI dependent on
diabetic state
100
100
women
90
90
Non diabetic
80
men
non diabetic
80
70
70
60
60
50
50
diabetic
diabetic
40
40
10
20 30 40 50 60
70
Months after MI
non Diabetics m / f
10 20 30 40 50 60
70
Months after MI
Diabetics m / f
13
Haffner SM et al. N Engl J Med. 1998;339:229-234. Sprafka JM et al. Diabetes Care. 1991;14:537-543.
Mechanisms behind gender differences in diabetes
Myocardial aspects:
Female myocardium is more sensitive to the
consequences of diabetes than the male
Type II diabetes in animal models
females
males
+
- 40 %
- 59 %
- 30 %
Hypertrophy
InsStim- Glucoseuptake
Gluc-uptake in ischemia
recovery
++
-23 %
=
=
Vascular aspects:
NO Generation and endothelial function is impaired to
a greater degree in diabetic women than in men
Desrois M, JMM 2004
14
Metabolic Syndrome - endothelial Dysfunction
Insulin
-40-50 % !
Female sex
increases endothelial NO
Vasodilatation
Regulation vascular tone and blood pressure
Inhibition of smooth muscle cell Proliferation
Inhibition of platelet aggregation
Reduction of Lipid-Oxidation
Obesity / Insulin resistence
Steinberg et al,J Clin Invest.,1996 15
Metabolic Syndrome- Hypercoagulability
Decreased Glucose tolerance – Hyperinsulinemia
 plasminogen activator inhibitor factor 1 (PAI-1)
 tissue plasminogen activator antigen (t-PA)
decreased Fibrinolysis
Fibrinogen synthesis
platelet function
Thromboses
pulmonary
embolism
Estrogen
16
Interaction between obesity, IR, sexual hormones,
kidney function and blood pressure
Kidney:
Hyperglycemic effects
on RVR and FF lead to
loss of protection in
women
Renal sodium retention
Obesity
Insulin resistence
Hyperglycemia
Hyperinsulinaemia
Liver
Sympathicus stimulation
SHBG
Vessels:
Proliferation / Migration
of smooth muscle cells
Vascular contractility
Hormonal
disturbances
IGF
IGF
-BP
Ovar
Anovulation
Estrogen
modifies
RAS
acitivity
Aogen, ACE,
AT1/2Receptorexpression
Androgen Activitity
17
Components of the Metabolic Syndrome Hypertriglyceridemia follows insulin resistance
Disturbed glucose utilization in
skeletal muscle
 glucose liberation from
liver cells
 increased lipolysis
 increased FFA
18
Sex hormones and lipid metabolism
Women have
Lower TC, LDL, TGL
Higher HDL
Menopause
decreases HDL,
Increases LDL and
TC and Lp(a), and
VLDL, and TGL.
Lpa: procoagulatory
19
Metabolic Syndrome – role of visceral fat
Males: visceral fat
women: subcutaneous fat!!!
Adipokines:
Tumor necrosis factor α (TNF α)
Adiponectin
Resistin
Leptin
Testosterone to E2 conversion
Visceral fat: source of FFA and inflammatory mediators,
directly delivered to the liver via the portal vein.
20
MetS is more important than obesity alone – effect
of visceral versus subcutaneous fat
Kip et al, Circ.2004;109:706
21
Metabolic Syndrome - obesity causes hypertension by
gender specific mediators
22
Hall, Hypertension;2003
Risk factor hypertension – steep increase in
postmenopausal women
% 50
Women
% 50
45,1
Men
41,6
40
40
36,5
31,1
30
30
19,5
20
14,5
8,6
10
26,0
18,4
20
10
21,0
9,2
3,0
0
0
25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 25 - 64
25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 25 - 64
Age
Adapted from C Gasse J Hum Hypertension 2001; 15: 27-36
Age
23
Prevention of MetS Life style changes are important
in women
5
none
less
4,5
moderate
4
„Multicenter lifestyle
demonstration project“
3,5
 Diet - Training - Stress3
Management,
2,5
social support, QL
2
 440 Pat, 21 % women
1,5
 Comparable improvements in
1
both sexes
 Mortality rates depending on 0,5
fitness
0
good
Fitness
Mortality (%)
Fitness
Women
Men
Confirmation: Interheart study
JAMA 1995; 1093, Blair et al
24
Metabolic treatment goals are achieved less
frequently in women with CAD than in men
Survey on 284000
cases, 110 centers
% Zielwerterreichung
Patients with CAD
35
30
25
20
Frauen
Männer
15
10
5
0
KHK
Diabetes
KHK + Diab.
Cassens et al, unpubl.
25
Women with cardiometabolic risk factors are
undertreated if compared with men
Comparable
diagnosis and risk
profile
26
Summary





Definition of the metabolic syndrome determines gender
distribution
MetS and its Components (hypertension, diabetes) are stronger
cardiovascular risk factors in women than in men
Hyperglycaemia, hyperinsulinemia, IR and Diabetes leads to the
loss of protection from CAD in women
Prevention is effective in both genders
Treatment of related risks is gender dependent
27
Interdisciplinary Gender Research
Innere Medizin
Kardiologie
Pharmakologie
Humangenetik
Molekulare
Medizin
Kardiochirurgie
Allgemeinmedizin
Gynäkologie
Neonatologie
Biochemie
Praeventivmedizin
Unfallchirurgie
Public Health
Anaesthesie
Neuroimmunologie
Epidemiologie
Kulturwissenschaften
GiM
Psychosomatik, Psychiatrie
Berlin
28
Summary I : Sex and gender differences in IR and
Diabetes





Major risk factors in women,
Interaction with sexual hormones
Effects on myocardial substrate metabolism and
efficiency
More severe predictor for CAD and lethality after
AMI
Increased predisposition to endothelial
dysfunction, thromboses and embolism, heart
failure
29
Prevalence of MetS (WHO and NCEP criteria),
Diabetes and CAD in the US population
69
30
Obesity as a major cause of hypertension
Obesity is the most common cause of hypertension
independent on genetic background
% Hypertension
35
US
30
Barbados
25
Jamaica
20
Cameron, urban
15
Nigeria
Cameron, rural
10
22
24
26
28
body mass index (kg/sqm)
30
Cooper, 1997
Am J Hypert
31
Direct relationship between BMI and blood pressure
86
84
82
80
78
76
74
72
70
16
18
20
22
24
26
28
30
32
Body Mass Index (kg/sqm)
Jones DW,
Diastolic Blood Pressure
(mm Hg)
22354 Korean subjects
32
Interaction insulin signalling - Sexual hormones
Insulin
Estrogen
MAPK
Hypertrophy
Proliferation
+Renal Na reabs.
+SNS
+Hypertension
Insulin resistance
PI 3 Kinase
AKT
Glucose transport
Glycogen-synthesis
Lipid metabolism
Anti inflammation
Vasodilatation/NO
Re-endothelialisation
Progenitor cells
CRP, IL6, TNF
PAI1
Monocyte adhesion
Plaque formation
Endothelial dysfunction
33
Mechanisms behind the gender related risk of
metabolic Syndrome - Insulin resistance
Physiological effects of Insulin
Insulin sensitive cells in target organs
 NO- liberation- and
NO Synthase Expression in Endothelial cells
 NF-kB,  ICAM 1,  MCP1,  CRP
Regulation of Energy metabolism
Endothelial vasodilatation
Antiinflammatory
Insulin resistance
Dandona et Aljyda, Am J Cardiol, 2002
34
Sex dependent fasting glucose (FG) and glucose
tolerance (IGT) in the RIAD study
RIAD
(risk in adipositas and diabetes)
667 persons with FH of Dm II, obesity and or metabolic syndrome
367:
NGT
90:
IFG
(men: women = 1.4)
101:
IGT
(women: men = 1.7)
106:
CGT
IFG
IGT
Men
Women
Elev. FFA
Insulin resistance
Disturbed
Insulin secretion
Diabetes
Atherosclerose
Atherosclerose,
Diabetes
Hanefeld M, Diab care, 2003 35
Sex and/or gender in the MetS ????
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

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

Insulin and Estradiol in STZ rats
Effect of E2 on myocardial metabolism in rodents
Sex
Stress and catecholamines in rodents
Aggressive behaviour in rodents
Stress and metabolic effects in rodents
Insulin and estradiol in myocardial metabolism in women
Myocardial hypertrophy in aortic stenosis in women
Higher mortality of women after coronary artery surgery
Undertreatment of women with coronary risk factors
Gender
36
Obesity and insulin resistance (IR) inhibit myocardial
substrate metabolism and efficiency in young women
Obesity, IR
Plasma FFA
Increased MFAUp
mismatch
MFAO
FA – accumulation Ceramide
oxidative stress
Increase MVO2 (decrease in M eff)
Clinical confirmation:
31 women, 19-37 y, echocardiography, PET imaging
12 non-obese:
19 obese:
BMI
23 + 3
38 + 7,
MFA-up
0.36+ 0.06
0.36 + 0.06,
LV-mass
121 + 23
154 + 24
CO,
4.1 + 0.6
4.9 + 0.9
MVO2
2.24 + 0.49
2.72+ 0.65
efficiency%,
18.5 + 7.3
13.3+5.2
Apoptosis
LV damage increase
p<0.06
p<0.001
p<0.005
p<0.05 BMI, r= 0.58
p<0.05 BMI, r=0.4
Peterson L R, Circ 2004
37
Sexual hormones affect many organs
Inflammation
Fat
CRP
38
Oestrogen receptors and isoforms
Brzozowski et al.,
Nature 1999
39
E2
Ca2+
OH
G-Protein
HO
X
E2
ER
E2
raf
ER
MEK
Src
NO
Ca2+
ER
NOS
Protein complexes
E2
E2
MAPK
PI3K Akt
GSK3b
E2
ras
SR
Ca2+
SERCA
ER
Metabolites
GF
ER
5
Regitz-Zagrosek, Nat Rev Drug Dev, 2006,
40
Oestrogen receptors in human coronary arteries
ER a, Human myocardium
41
Rehabilitation and Sekundärprävention
Nur ca 25 % Frauen in Kv Reha!




Motivation?
Aerobic Exercise?
Smoking habits
 70 % of women are smokers
before a bypass surgery
Lack of support in partnership
42
Adipositas, metabolisches Syndrom - Assoziation
mit CRP bei Frauen
Kip et al, Circ.2004;109:706
43
Framingham Heart Study: Risk factors in women
Risk of CHF for
selected risk factors
Männer (braun) vs Frauen (grün)
AP = Angina pectoris; DM = Diabetes mellitus; HTN = Hypertension; LVH =
links ventrikuläre Hypertrophie; MI = Myokardinfarkt; VHD = valvuläre
Herzerkrankung
Levy et al. JAMA 275: 1557-1562, 199644
Insulineffekte als Grundlage des Risikos II
45
Perspectives in therapy
Postmenopausale HT reduziert
Diabetesinzidenz.





PPAR Agonisten und Östrogene
interagieren - Geschlechtsspez.
Wirkungen von Glitazonen; bei
Diabetes, Adipositas?
Geschlechtsspezifik im
Arzneimittelstoffwechsel?
Hemmung des Renin Angiotensin
Systems - spezielle Wirkungen bei
postmenopausalen Frauen?
Ca-Stoffwechsel – kardiale
Ionenkanäle – Unterschiede in der
Antiarrhythmikawirkung?
Partielle ER Agonisten –
entwicklunsfähig bei Männern?
Margolis et al., 2004
46
Metabolic Syndrome – obesity causes hypertension
47
Rahmouni et al,Hypertension;2005
Metabolic Syndrome – role of visceral fat
Visceral fat: source of FFA and inflammatory mediators,
directly delivered to the liver via the portal vein.
Overexpression
Insulinresistenz
Adipositas
TNF- α
Reduced Expression
Overexpression
Overexpression
viszerale Adipozyten
 insulin resistance
 liberation of FFA
 reduction in gluc uptake
Adiponectin higher concentr. in women
 protective hormone
Proliferation smooth muscle cells
foam cell formation
Resistin:  endothelial dysfunction in pigs
Increase in Insulin resistence
Inflammation
Leptin
 inhibits food intake by central mech.
low leptin secretion from visceral fat
in women mainly from subcut. fat
48
Interheart Study – Lancet 2004
Weltweite Fall – Kontroll- Studie zum akuten Infarkt,
 9 Risikofaktoren erklären weltweit > 90 % der Infarkte bei Frauen
und > 80 % bei Männern
 Diabetes, Hypertonie: höheres Risiko bei Frauen
 Körperliche Belastung; mässiger Alkoholkonsum: bessere
Protektion bei Frauen
 Lipidstörung, psychosoziale Faktoren, Rauchen,
Übergewicht, Ernährungsverhalten: bei Männern und Frauen
vergleichbare RF
Yusuf, Lancet 2004
49
Diabetesreduktion durch Hormonersatztherapie (HRT) in
HERS



734:
218 :
1811:
Diabetes
erhöhte Nüchternglucose
Normoglycaemie
Diabetesinzidenz über 4.1 Jahre:
 Placebo: 9,5 %
 Hormonsubstitution: 6,2 %
 Relatives Risiko 0.65 (0.48-0.89)

Vorsicht: Progression der KHE bei
Diabetikerinnen unter HRT!
50
Inflammatory mechanisms in the MetS
Estrogens
Dyslipidemia
Hypertension
Obesity
Diabetes
ßVLDL activate
Inflammation
Ang II: ROS,
Cytokines:
IL6, MCP-1
VCAM
FFA
VLDL
Adipoc:
TNF, IL6
AGE, RAGE:
Cytokines
ROS
HDL transports
Antioxidant
enzymes
Inflammation
Libby et al, Circ. 2002;105:1135
51
Insulineffekte als Grundlage des Risikos I
52
Buntes bild vorhanden?
Regitz-Zagrosek et al., Clin Res Cardiol 2006
53
Metabolisches Syndrom
low HDL
Physiologisch  HDL modulates metabolic pathways from triglyzerides and
synthesis of VLDL in hepatozytes

45-75 % genetische Veranlagung

Folge von Stoffwechselstörungen
Insulinresistenz
 Austausch der Cholesterinester von HDL und LDL zu VLDL und
Triglyzeriden
 HDL ineffektiv in peripherer Cholesterinclearance
 Entwicklung noch kleinerer LDL Partikel
 Zunahme der Insulinresistenz, Anstieg vonTriglyzeriden
54
Modulation of the RAS by estrogens contributes to
gender specificity of risk
Estrogens: DownRegulation of RAS
Hypertension
Inflammation
Metabolic Syndrome
Insulin resistance
Impaired glucose tol.
Up-Regulation - CV risks
Hypertension
Hyperinsulinemia
Hypercholesterinemia
RAS
s. ACE levels,
t. ACE activity
Renal ACE
mRNA
Renal disease and effects of
ACEI
Cardiovascular and renal events
II/006
55
Role of CETP in plasma lipid transport
Barter, P. J. et al. Arterioscler Thromb Vasc Biol 2003;23:160-167
56
Early overmortality of young women after CABG
DHZB, n= 17528
Mortality of women
Percentage of women,
100
90
80
% of patients
70
60
50
40
30
20
10
2,5
mortality rates of women, men (=1)
women
men
* p<0.05 for interaction
women
men
2
1,5
1
0,5
0
0
< 50
JACC, 2004
50-60
60-70
age groups
70-80
>80
<50
50-59
60-69
70-79
>80
all
age groups
57
Which risk factors in contribute to female overmortality
in CABG patients?
CRF don‘t explain overmortality in young women in multivariate analysis
90
80
Female,all,n=4278
Male,all,n=13250
70
Dyspnoea
60
50
40
30
20
10
He
ar
tf
ai
lu
Re
re
na
li
m
pa
irm
Ad
d.
ca
rd
.s
ur
g
PT
CA
BG
CA
I
Di
ab
et
es
Em
er
ge
nc
y
M
di
so
rd
Li
pi
d
Hy
pe
rte
ns
io
n
0
DHZB, JACC, 2004
58
H
Regitz-Zagrosek et al., Clin Res Cardiol 2006
59
leptin (ng/ml)
Plasma leptins in patients with essential hypertension
25
Leptin:
20
product of obese gene
secreted by AC in
proportion to adipos
reduces appetite
increase energy expend.
sympathetic stimulation
15
Low Ren
Norm Ren
high Ren
10
5
0
Ess Hypertens
Normotens
Adamczak, 2000, J Hum Hypertension
60
Obesity and plasma leptinsgender differences
30
leptin (ng/ml)
25
20
All pats
Males
Females
15
10
5
0
Low Renin
Normal R
High R
Adamczak, M, 2000, J Hum Hypertension
61
Components of the Metabolic Syndrome – Insulin
resistance and diabetes – are there gender differences?

Continous changes from Insulin resistance to diabetes mellitus
Typ II
Years from Diagnosis
Goldstein, Am J Cardiol, 2002
62
4. GiM-Symposium: 11. u. 12. Okt 2007 im Deutschen
Herzzentrum Berlin u. Charite
Innere Medizin
Kardiologie
Pharmakologie
Humangenetik
Biochemie
Praeventivmedizin
Public Health
Epidemiologie
Kulturwissenschaften
Kardiochirurgie
Allgemeinmedizin
Gynäkologie
Neonatologie
Unfallchirurgie
Anaesthesie
Neuroimmunologie
Psychosomatik, Psychiatrie
Quellen:
V Regitz-Zagrosek; Nature Reviews 2006
Geschlechterforschung in der Medizin;
Eds V Regitz-Zagrosek, J Fuchs, Peter Lang Verlag, Stuttgart, 2006
63