1
Vera Regitz-ZagrosekCardiovascular disease in women &Gender in medicine Charite and German Heart Institute, Berlin
Gender Aspects in the Metabolic syndrome
2
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
3
Complications:•Hypercoagulability
•Endothelial Dysfunction•Inflammation
•CAD
Incidence:
USA in 2000:47 000 000 people
Rise in obesity 1991 – 2000: 61 % In women: 74 %
Metabolic Syndrome
Steinbaum, Progress in Cardiovascular Diseases; 2004
Features• Insulin resistance• Abdominal obesity• Dyslipidemia• Hypertension
4
Increase in age- and gender dependent prevalence of the MetS in the US
Regitz-Zagrosek et al., Clin Res Cardiol 2006
5
Definitions of the Metabolic syndrome (MetS)
adapted fromRegitz-Zagrosek et al., Clin Res Cardiol 2006
• Insulin resistance
• Abdominal obesity
• Dyslipid-emia
• Hyper-tension
6
Gender aspects in the definition of MetS
Regitz-Zagrosek et al., Clin Res Cardiol 2006
Biggest difference is the diagnosis of hyperglycemia,
Impaired glucose tolerance (IGT) vs elevated fasting glucose (IFG)
7
Sex-related differences in glucose metabolism
0
5
10
15
20
25
30
35
40
45
50
Known D Unkn D IGT IFG all%
of p
opul
atio
n
womenmen
W Rathmann et al, Diabetologica 2003
2 h
g lu c
o e –
( GT )
Mechanisms?
Fasting glucoseF-GIGT
Women have higher 2 h glucose for each fasting glucose level
Williams et al., Diab Med. 2003
men
women
Relation between FG and OGT
8
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
9
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
10
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
11
Interaction of hyperglycaemia and diabetes with CAD is sex dependent
0
1
2
3
4
5
6
F, Diab M, Diab F, HyGly M, HyGly
Pan, Am J Epidem, 1986, Chicago H S
Rela
tives
Ris i
koIncrease in Relative Risik for death from CAD in female and male patients with diabetes and Hyperglycemia
12
Diabetes has a higher incidence in women, is associated with hormonal disturbances and is a stronger risk factor in women – why?
Lundberg et al, Arch Int Med, 1997
10
12
14
16
0
2
4
6
8
Diabetics Risk for MI Lethality from MI MI due toDiabetes
PCOS
WomenMenWomen with Polyc.ovarian syndr.
Diabetes as risk factor in women and men
13
Survival of women and men after MI dependent on diabetic state
Haffner SM et al. N Engl J Med. 1998;339:229-234. Sprafka JM et al. Diabetes Care. 1991;14:537-543.Haffner SM et al. N Engl J Med. 1998;339:229-234. Sprafka JM et al. Diabetes Care. 1991;14:537-543.
non Diabetics m / f
100men
90
80
70
60
50
40
605040302010
Months after MI70
Months after MI
women100
90
80
70
60
40
605040302010 70
50
Diabetics m / f
diabetic
Non diabetic non diabetic
diabetic
14
Myocardial aspects: Female myocardium is more sensitive to the consequences of diabetes than the male
Desrois M, JMM 2004
Hypertrophy
Type II diabetes in animal modelsmales
recoveryGluc-uptake in ischemia
InsStim- Glucoseuptake
females+ ++
-23 % - 40 % - 59 % =
=- 30 %
Vascular aspects: NO Generation and endothelial function is impaired to a greater degree in diabetic women than in men
Mechanisms behind gender differences in diabetes
15
Insulin increases endothelial NO
Metabolic Syndrome - endothelial Dysfunction
VasodilatationRegulation vascular tone and blood pressureInhibition of smooth muscle cell Proliferation
Inhibition of platelet aggregationReduction of Lipid-Oxidation
Obesity / Insulin resistence
-40-50 % !
Steinberg et al,J Clin Invest.,1996
Female sex
16
Decreased Glucose tolerance – Hyperinsulinemia
plasminogen activator inhibitor factor 1 (PAI-1) tissue plasminogen activator antigen (t-PA)
Metabolic Syndrome- Hypercoagulability
decreased Fibrinolysis
Estrogen
Fibrinogen synthesisplatelet function
Thromboses
pulmonary embolism
17
Sympathicus stimulation
Vessels: Proliferation / Migrationof smooth muscle cellsVascular contractility
Interaction between obesity, IR, sexual hormones, kidney function and blood pressure
SHBG
Obesity
Insulin resistence
Hormonal disturbances
Anovu-lation
Hyperinsulinaemia
IGF-BP
Androgen Activitity
IGFLiver Ovar
Estrogen modifies RAS acitivity
Aogen, ACE, AT1/2-Receptor-expression
Kidney: Hyperglycemic effects on RVR and FF lead to loss of protection in womenRenal sodium retention
Hyperglycemia
18
Disturbed glucose utilization in skeletal muscle
glucose liberation from liver cells
increased lipolysis
increased FFA
Components of the Metabolic Syndrome - Hypertriglyceridemia follows insulin resistance
19
Sex hormones and lipid metabolism
Women haveLower TC, LDL, TGLHigher HDLMenopause decreases HDL,Increases LDL and TC and Lp(a), and VLDL, and TGL.
Lpa: procoagulatory
20
Males: visceral fat women: subcutaneous fat!!!
Metabolic Syndrome – role of visceral fat
Tumor necrosis factor α (TNF α)
Resistin
Adiponectin
Leptin
Adipokines:
Testosterone to E2 conversion
Visceral fat: source of FFA and inflammatory mediators, directly delivered to the liver via the portal vein.
21
MetS is more important than obesity alone – effect of visceral versus subcutaneous fat
Kip et al, Circ.2004;109:706
22
Metabolic Syndrome - obesity causes hypertension by gender specific mediators
Hall, Hypertension;2003
23Adapted from C Gasse J Hum Hypertension 2001; 15: 27-36
Risk factor hypertension – steep increase in postmenopausal women
3,0
8,6
19,5
31,1
45,1
14,5
0
10
20
30
40
50
25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 25 - 64Age
% Women
9,2
18,4
26,0
36,5
41,6
21,0
0
10
20
30
40
50
25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 25 - 64Age
% Men
24
Prevention of MetS Life style changes are important in women
„Multicenter lifestyle demonstration project“
Diet - Training - Stress- Management, social support, QL
440 Pat, 21 % women Comparable improvements in
both sexes Mortality rates depending on
fitness 0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
5
Women Men
Mor
talit
y (%
)
none
less
moderate
good
JAMA 1995; 1093, Blair et alConfirmation: Interheart study
Fitness
Fitness
25
0
5
10
15
20
25
30
35
KHK Diabetes KHK + Diab.
FrauenMänner
Metabolic treatment goals are achieved less frequently in women with CAD than in men
Cassens et al, unpubl.
% Z
ielw
erte
rreic
hung
Patients with CAD
Survey on 284000 cases, 110 centers
26
Women with cardiometabolic risk factors are undertreated if compared with men
Comparable diagnosis and risk profile
Bischoff et al, Clin Res Card 2006
27
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
28
Interdisciplinary Gender Research
Innere Medizin Kardiologie
Kulturwissenschaften
Pharmakologie
Biochemie
Humangenetik Allgemeinmedizin
NeonatologieGynäkologie
Psychosomatik, Psychiatrie
NeuroimmunologieAnaesthesie
Unfallchirurgie
Kardiochirurgie
GiM Berlin
Praeventivmedizin
Epidemiologie
Public Health
Molekulare Medizin
29
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
30
69
Prevalence of MetS (WHO and NCEP criteria), Diabetes and CAD in the US population
31
Obesity as a major cause of hypertension
Obesity is the most common cause of hypertension independent on genetic background
10
15
20
25
30
35
22 24 26 28 30
body mass index (kg/sqm)
% H
yper
tens
ion
US
Cameron, urban
Cameron, ruralNigeria
Barbados
Jamaica
Cooper, 1997Am J Hypert
32
Direct relationship between BMI and blood pressure
22354 Korean subjects
707274767880828486
16 18 20 22 24 26 28 30 32
Body Mass Index (kg/sqm)
Dia
stol
ic B
lood
Pre
ssur
e (m
m H
g)
Jones DW,
33
Insulin
MAPK PI 3 Kinase AKT
HypertrophyGlucose transportProliferation Glycogen-synthesis
Lipid metabolismAnti inflammationVasodilatation/NORe-endothelialisationProgenitor cells
Interaction insulin signalling - Sexual hormones
CRP, IL6, TNFPAI1
Monocyte adhesionPlaque formation
Endothelial dysfunction
Estrogen Insulin resistance
+Renal Na reabs.+SNS+Hypertension
34
Mechanisms behind the gender related risk of metabolic Syndrome - Insulin resistance
Physiological effects of Insulin
Regulation of Energy metabolism
Endothelial vasodilatation
Antiinflammatory
Insulin resistance
Insulin sensitive cells in target organs
NO- liberation- and NO Synthase Expression in Endothelial cells
NF-kB, ICAM 1, MCP1, CRP
Dandona et Aljyda, Am J Cardiol, 2002
35
Sex dependent fasting glucose (FG) and glucose tolerance (IGT) in the RIAD study
Hanefeld M, Diab care, 2003
DiabetesAtherosclerose
WomenMen
IGT
Atherosclerose, Diabetes
Insulin resistance DisturbedInsulin secretion
IFG
Elev. FFA
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
36
Sex and/or gender in the MetS ????
Insulin and Estradiol in STZ rats Effect of E2 on myocardial metabolism in rodents
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
Sex
Gen-der
37
Obesity and insulin resistance (IR) inhibit myocardial substrate metabolism and efficiency in young women
Peterson L R, Circ 2004
Obesity, IR Plasma FFA
Increased MFAUp mismatch FA – accumulation Ceramide Apoptosis
oxidative stress LV damage increase MFAO 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, p<0.06LV-mass 121 + 23 154 + 24 p<0.001CO, 4.1 + 0.6 4.9 + 0.9 p<0.005 MVO2 2.24 + 0.492.72+ 0.65 p<0.05 BMI, r= 0.58efficiency%, 18.5 + 7.3 13.3+5.2 p<0.05 BMI, r=0.4
38
CRPInflammation
Fat
Sexual hormones affect many organs
39
Oestrogen receptors and isoforms
Brzozowski et al.,Nature 1999
40
E2
Metabolites
HO
OHE2
G-Proteinrasraf
MEK
ER
E2
Src
X
PI3K AktNOER
E2
NOS
GF
SRCa2+
Ca2+
Ca2+
SERCA
ER
E2
ER
ER
E2
MAPK
GSK3
DNA
PPARNR ER
E2
ERE
Regitz-Zagrosek, Nat Rev Drug Dev, 2006,
AP1 SP1E2
5
Protein complexes
41ER a, Human myocardium
Oestrogen receptors in human coronary arteries
42
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
43
Adipositas, metabolisches Syndrom - Assoziation mit CRP bei Frauen
Kip et al, Circ.2004;109:706
44
Männer (braun) vs Frauen (grün) AP = Angina pectoris; DM = Diabetes mellitus; HTN = Hypertension; LVH = links ventrikuläre Hypertrophie; MI = Myokardinfarkt; VHD = valvuläre HerzerkrankungLevy et al. JAMA 275: 1557-1562, 1996
Risk of CHF for selected risk factors
Framingham Heart Study: Risk factors in women
45
Insulineffekte als Grundlage des Risikos II
46
Perspectives in therapy
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?
Postmenopausale HT reduziert Diabetesinzidenz.
Margolis et al., 2004
47
Metabolic Syndrome – obesity causes hypertension
Rahmouni et al,Hypertension;2005
48
viszerale Adipozyten
TNF- α insulin resistance liberation of FFA reduction in gluc uptake
Resistin: endothelial dysfunction in pigs Increase in Insulin resistence Inflammation
Adiponectin higher concentr. in women protective hormone Proliferation smooth muscle cells foam cell formation
Leptin inhibits food intake by central mech. low leptin secretion from visceral fat
in women mainly from subcut. fat
InsulinresistenzAdipositas
Overexpression
Reduced Expression
Overexpression
Overexpression
Metabolic Syndrome – role of visceral fatVisceral fat: source of FFA and inflammatory mediators, directly delivered to the liver via the portal vein.
49
Interheart Study – Lancet 2004
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
Weltweite Fall – Kontroll- Studie zum akuten Infarkt,
Yusuf, Lancet 2004
50
Diabetesreduktion durch Hormonersatztherapie (HRT) in HERS
734: Diabetes 218 : erhöhte Nüchternglucose 1811: 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!
51
Inflammatory mechanisms in the MetS
Libby et al, Circ. 2002;105:1135
Estrogens
Obesity
FFA VLDLAdipoc:TNF, IL6
Hypertension
Ang II: ROS, Cytokines: IL6, MCP-1VCAM
Dyslipidemia
ßVLDL activateInflammation
HDL transportsAntioxidant enzymes
Diabetes
AGE, RAGE:CytokinesROS
Inflammation
52
Insulineffekte als Grundlage des Risikos I
53
Buntes bild vorhanden?
Regitz-Zagrosek et al., Clin Res Cardiol 2006
54
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
Metabolisches Syndromlow HDL
55
Modulation of the RAS by estrogens contributes to gender specificity of risk
Hypertension
Inflammation
Up-Regulation - CV risks
RASs. ACE levels, t. ACE activity
Renal ACE mRNA
Renal disease and effects of ACEI
II/006
Metabolic SyndromeInsulin resistanceImpaired glucose tol.
Estrogens: Down-Regulation of RAS
HypertensionHyperinsulinemia
Hypercholesterinemia
Cardiovascular and renal events
56Barter, P. J. et al. Arterioscler Thromb Vasc Biol 2003;23:160-167
Role of CETP in plasma lipid transport
57
Early overmortality of young women after CABG
JACC, 2004
0
0,5
1
1,5
2
2,5
<50 50-59 60-69 70-79 >80 allage groups
mor
talit
y ra
tes
of w
omen
, men
(=1)
womenmen
0
10
20
30
40
50
60
70
80
90
100
< 50 50-60 60-70 70-80 >80age groups
% o
f pat
ient
s
womenmen
Percentage of women, Mortality of women
* p<0.05 for interaction
DHZB, n= 17528
58
0
10
20
30
40
50
60
70
80
90
Female,all,n=4278Male,all,n=13250
Which risk factors in contribute to female overmortality in CABG patients?
DHZB, JACC, 2004
Dyspnoea
CRF don‘t explain overmortality in young women in multivariate analysis
59
H
Regitz-Zagrosek et al., Clin Res Cardiol 2006
60
Plasma leptins in patients with essential hypertension
0
5
10
15
20
25
lept
in (n
g/m
l)
Ess Hypertens Normotens
Low RenNorm Renhigh Ren
Adamczak, 2000, J Hum Hypertension
Leptin:
product of obese genesecreted by AC in
proportion to adiposreduces appetiteincrease energy expend.sympathetic stimulation
61
Obesity and plasma leptins- gender differences
0
5
10
15
20
25
30le
ptin
(ng/
ml)
Low Renin Normal R High R
All patsMalesFemales
Adamczak, M, 2000, J Hum Hypertension
62
Continous changes from Insulin resistance to diabetes mellitus Typ II
Components of the Metabolic Syndrome – Insulin resistance and diabetes – are there gender differences?
Years from Diagnosis
Goldstein, Am J Cardiol, 2002
63
Innere Medizin Kardiologie
Kulturwissenschaften
Pharmakologie
Biochemie
Humangenetik Allgemeinmedizin
NeonatologieGynäkologie
Psychosomatik, Psychiatrie
NeuroimmunologieAnaesthesie
Unfallchirurgie
Kardiochirurgie
Praeventivmedizin
Epidemiologie
Public Health
4. GiM-Symposium: 11. u. 12. Okt 2007 im Deutschen Herzzentrum Berlin u. Charite
Quellen: V Regitz-Zagrosek; Nature Reviews 2006Geschlechterforschung in der Medizin; Eds V Regitz-Zagrosek, J Fuchs, Peter Lang Verlag, Stuttgart, 2006