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