Gender Aspects in the Metabolic syndrome Vera Regitz

Gender Aspects in the Metabolic syndrome Vera Regitz. Zagrosek Cardiovascular disease in women & Gender in medicine Charite and German Heart Institute, 1

Issues today: n n n Definition and diagnosis of the Met. S Gender differences in incidence and prevalence Gender differences in the components and their role in cardiovascular risk n Insulin resistance (IR) and diabetes n Hyper-/dyslipidemia n Abdominal obesity, adipokine secretion n Hypertension Met. S and sex hormones Treatment of Met. S 2

Metabolic Syndrome Incidence: Features • Insulin resistance • Abdominal obesity • Dyslipidemia • Hypertension USA in 2000: 47 000 people Rise in obesity 1991 – 2000: 61 % In women: 74 % Complications: • Hypercoagulability • Endothelial Dysfunction • Inflammation • CAD Steinbaum, Progress in Cardiovascular 3

Increase in age- and gender dependent prevalence of the Met. S in the US Regitz-Zagrosek et al. , Clin Res 4

Definitions of the Metabolic syndrome (Met. S) • Insulin resistance • Abdomina l obesity • Dyslipidemia • Hypertension adapted from. Regitz-Zagrosek et al. , Clin Res 5

Gender aspects in the definition of Met. S Biggest difference is the diagnosis of hyperglycemia, Impaired glucose tolerance (IGT) vs elevated fasting glucose (IFG) Regitz-Zagrosek et al. , Clin Res 6

Sex-related differences in glucose metabolism Relation between FG and OGT 2 h glucoe – (GT) women Fasting glucose Women have higher 2 h glucose for each fasting glucose level Williams et al. , Diab Med. 2003 IGT F-G Mechanisms? W Rathmann et al, Diabetologica 2 7

Summary I: Gender aspects in the definition and epidemiology of the Met. S n n n 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 Met. S in women – Epidemiology indicates an increasing prevalence of the Met. S which affects mainly young women – obesity and malnutrition play a major role Gender differences in Met. S/Diabetes related CV risk 8

Interheart: 9 risk factors explain 90 % of myocardial infarctions in the world – 5 are part of the Met. S 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 Relatives Risiko Increase in Relative Risik for death from CAD in female and male patients with diabetes and Hyperglycemia Pan, Am J Epidem, 1986, 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 12 Wome n Men Women with Polyc. ovarian syndr. 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 women 90 90 Non diabetic 80 80 70 70 60 60 50 50 diabetic 20 30 40 50 60 non diabetic 40 40 10 men 70 Months after MI non Diabetics m / f 10 20 30 40 50 60 70 Months after MI Diabetics m / f Haffner SM et al. N Engl J Med. 1998; 339: 229 -234. Sprafka JM et al. Diabetes Care. 13

Mechanisms behind gender differences in dia Myocardial aspects: Female myocardium is more sensitive to the consequences of diabetes than the male Type II diabetes in animal models females + - 40 % - 59 % - 30 % Hypertrophy Ins. Stim- 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 15 Steinberg et al, J Clin Invest. , 1996

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

hormones, kidney function and blood pressure Kidney: Hyperglycemic effects on RVR and FF lead to loss of protection in women Renal sodium retention Insulin resistence Hyperglycemia Hyperinsulinaemia Liver Sympathicus stimulation SHBG Vessels: Proliferation / Migration of smooth muscle cells Vascular contractility Hormonal disturbances Obesity IGF -BP Ovar Anovulation Estroge n modifies RAS acitivity Aogen, ACE, AT 1/2 Receptorexpressio n Androgen Activitity 17

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 E 2 conversion Visceral fat: source of FFA and inflammatory mediators, directly delivered to the liver via the portal vein. 20

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; 20

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 Age 25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 25 - 64 Adapted from C Gasse J Hum Hypertension 2001; 15: 27 -36 Age 23

Prevention of Met. S Life style changes are important in women „Multicenter lifestyle demonstration project“ n Diet - Training - Stress. Management, social support, QL n 440 Pat, 21 % women n Comparable improvements in both sexes n Mortality rates depending on fitness Fitne ss Confirmation: Interheart study JAMA 1995; 1093, Blair et al 24

Patients with CAD Survey on 284000 cases, 110 centers % Zielwerterreichung Metabolic treatment goals are achieved less frequently in women with CAD than in men Cassens et al, unpubl. 25

Women with cardiometabolic risk factors are undertreated if compared with men Comparable diagnosis and risk profile 26 Bischoff et al, Clin Res Card 2006

Summary n n n Definition of the metabolic syndrome determines gender distribution Met. S 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 Pharmakologi e Humangenetik Biochem ie Praeventivmedizi n Public Health Epidemiologie Kulturwissenschafte n Gi. M Molekulare Medizin Kardiochirurgie Allgemeinmedizin Gynäkologie Neonatologie Unfallchirur gie Anaesthesi e Neuroimmunolog ie Psychosomatik, Psychiatrie Berlin 28

Summary I : Sex and gender differences in IR and Diabetes n n n 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 Met. S (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 US Barbados Jamaica Cameron, urban Nigeria Cameron, rural Cooper, 199 Am J Hypert 31

Direct relationship between BMI and blood pressure 22354 Korean subjects Jones DW, 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 CRP, IL 6, TNF Anti inflammation PAI 1 Vasodilatation/NO Monocyte adhesion Re-endothelialisation Plaque formation Progenitor cells Endothelial dysfunction 33

risk of metabolic Syndrome - Insulin resistance Physiological effects of Insulin sensitive cells in target organs NO- liberation- and NO Synthase Expression in Endothelial cells NF-k. B, ICAM 1, MCP 1, CRP Regulation of Energy metabolism Endothelial vasodilatation Antiinflammatory Insulin resistance 34 Dandona et Aljyda, Am J Cardiol, 2002

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, Diabetes Hanefeld M, Diab care, 2003 35

Sex and/or gender in the Met. S ? ? n n n n n Insulin and Estradiol in STZ rats Sex Effect of E 2 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 Gen. Higher mortality of women after coronary artery surgery der Undertreatment of women with coronary risk factors 36

Obesity and insulin resistance (IR) inhibit myocardial substrate metabolism and efficiency in young women Obesity, IR Plasma FFA Increased MFAUp mismatch increase MFAO FA – accumulation Ceramide Apoptosis oxidative stress LV damage Increase MVO 2 (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. 06 LV-mass 121 + 23 154 + 24 p<0. 001 CO, 4. 1 + 0. 6 4. 9 + 0. 9 p<0. 005 MVO 2 2. 24 + 0. 49 2. 72+ 0. 65 p<0. 05 BMI, r= 0. 58 efficiency%, 18. 5 + 7. 3 13. 3+5. 2 p<0. 05 BMI, r=0. 4 37 Peterson L R, Circ 2004

Sexual hormones affect many organs Inflammation Fat CRP 38

Oestrogen receptors and isoforms Brzozowski et al. , Nature 1999 39

E 2 Ca 2+ OH G-Protein HO E 2 ER X E 2 raf ER MEK Src NO Ca 2+ ER NOS SR Protein complexes E 2 MAPK PI 3 K Akt GSK 3 b E 2 ras Ca 2+ SERCA ER E 2 Metabolites GF ER AP 1 SP 1 E 2 5 NR ER ERE Regitz-Zagrosek, Nat Rev Drug Dev, 2006, PPAR DNA 40

Oestrogen receptors in human coronary arteries ER a, Human myocardium 41

Rehabilitation and Sekundärprävention Nur ca 25 % Frauen in Kv Reha! n n Motivation? Aerobic Exercise? Smoking habits n 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 44 Levy et al. JAMA 275: 1557 -1562,

Insulineffekte als Grundlage des Risikos II 45

Perspectives in therapy Postmenopausale HT reduziert Diabetesinzidenz. n n n 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; 2

Metabolic Syndrome – role of visceral fat Visceral fat: source of FFA and inflammatory mediators, directly delivered to the liver via the portal vein. Overexpression. TNF- α Insulinresistenz Adipositas insulin resistance liberation of FFA reduction in gluc uptake Reduced Expression Adiponectin higher concentr. in women protective hormone Proliferation smooth muscle foam cell formation Overexpression Resistin: endothelial dysfunction in pigs Increase in Insulin Overexpression resistence Inflammation viszerale Adipozyten Leptin inhibits food intake by central mec low leptin secretion from visceral fa in women mainly from subcu 48

Interheart Study – Lancet 2004 Weltweite Fall – Kontroll- Studie zum akuten Infarkt, n 9 Risikofaktoren erklären weltweit > 90 % der Infarkte bei Frauen und > 80 % bei Männern n Diabetes, Hypertonie: höheres Risiko bei Frauen n Körperliche Belastung; mässiger Alkoholkonsum: bessere Protektion bei Frauen n Lipidstörung, psychosoziale Faktoren, Rauchen, Übergewicht, Ernährungsverhalten: bei Männern und Frauen vergleichbare RF Yusuf, Lancet 2004 49

Diabetesreduktion durch Hormonersatztherapi (HRT) in HERS n n n 734: Diabetes 218 : erhöhte Nüchternglucose 1811: Normoglycaemie Diabetesinzidenz über 4. 1 Jahre: n Placebo: 9, 5 % n Hormonsubstitution: 6, 2 % n Relatives Risiko 0. 65 (0. 480. 89) n Vorsicht: Progression der KHE bei Diabetikerinnen unter HRT! 50

Inflammatory mechanisms in the Met. S Estrogens Dyslipidemia Hypertension ßVLDL activate Ang II: ROS, Inflammation Cytokines: IL 6, MCP-1 HDL transports VCAM Antioxidant enzymes Obesity Diabetes FFA AGE, RAGE: VLDL Cytokines Adipoc: ROS TNF, IL 6 Inflammation Libby et al, Circ. 51

Insulineffekte als Grundlage des Risikos I 52

Buntes bild vorhanden? Regitz-Zagrosek et al. , Clin Res 53

Metabolisches Syndrom low HDL Physiologisch HDL modulates metabolic pathways from triglyzerides and synthesis of VLDL in hepatozytes n 45 -75 % genetische Veranlagung n 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 von. Triglyzeriden 54

Modulation of the RAS by estrogens contributes to gender specificity of risk Estrogens: Down. Regulation of RAS Hypertension Inflammation Metabolic Syndrome Insulin resistance Impaired glucose tol. II/006 Up-Regulation - CV risks Hypertension Hyperinsulinemia Hypercholesterinemia RAS s. ACE levels, t. ACE activity Renal ACE m. RNA Renal disease and effects of ACEI Cardiovascular and renal events 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 Percentage of women, Mortality of women * p<0. 05 for interaction JACC, 2004 57

Which risk factors in contribute to female overmortality in CABG patients? CRF don‘t explain overmortality in young women in multivariate an Dyspnoea DHZB, JACC, 2004 58

H Regitz-Zagrosek et al. , Clin Res Cardiol 2006 59

Plasma leptins in patients with essential hypertension Leptin: product of obese gen secreted by AC in proportion to adipo reduces appetite increase energy expe sympathetic stimulati Adamczak, 2000, J Hum Hypertension 60

Obesity and plasma leptinsgender differences Adamczak, M, 2000, J Hum Hypertension 61

Insulin resistance and diabetes – are there gender differences? n Continous changes from Insulin resistance to diabetes mellitus Typ II Years from Diagnosis Goldstein, Am J Cardiol, 2002 62

4. Gi. M-Symposium: 11. u. 12. Okt 2007 im Deutschen Herzzentrum Berlin u. Charite Pharmakolo gie Humangenet ik Biochemi e Praeventivmedi zin Public Health Epidemiologi e Kulturwissenschaf ten Innere Medizin Kardiologie Kardiochirurgi e Allgemeinmedizin Gynäkologie Neonatologi e Unfallchirur gie Anaesthes ie Neuroimmunolo gie Psychosomatik, Psychiatrie Quellen: V Regitz-Zagrosek; Nature Reviews 2006 Geschlechterforschung in der Medizin; Eds V Regitz-Zagrosek, J Fuchs, Peter Lang Verlag, Stuttgart, 20 63