Vera Regitz-Zagrosek Cardiovascular disease in women & Gender in medicine

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

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. Metabolic Syndrome Incidence: USA in 2000: 47 000 000 people Rise in obesity 1991 – 2000: 61 % In women: 74 % • Features • Insulin resistance • Abdominal obesity • Dyslipidemia • Hypertension • Complications: • Hypercoagulability • Endothelial Dysfunction • Inflammation • CAD Steinbaum, Progress in Cardiovascular Diseases; 2004

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) • Insulin resistance • Abdominal obesity • Dyslipid-emia • Hyper-tension adapted fromRegitz-Zagrosek et al., Clin Res Cardiol 2006

6. 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

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

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 Increase in Relative Risik for death from CAD in female and male patients with diabetes and Hyperglycemia Relatives Risiko Pan, Am J Epidem, 1986, Chicago H S

12. 16 14 12 10 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? Women Men Women with Polyc.ovarian syndr. 8 6 4 2 0 PCOS Diabetics Risk for MI Lethality from MI MI due to Diabetes Lundberg et al, Arch Int Med, 1997

13. Survival of women and men after MI dependent on diabetic state 70 10 20 30 40 50 60 30 10 20 40 50 60 100 100 women men 90 90 Non diabetic 80 80 non diabetic 70 70 60 60 diabetic 50 50 diabetic 40 40 70 Months after MI Months after MI non Diabeticsm / f Diabetics m / f Haffner SM et al. N Engl J Med. 1998;339:229-234. Sprafka JM et al. Diabetes Care. 1991;14:537-543.

14. Type II diabetes in animal models females males + Hypertrophy ++ InsStim- Glucoseuptake -23 % - 40 % - 59 % Gluc-uptake in ischemia = recovery = - 30 % Mechanisms behind gender differences in diabetes Myocardial aspects:Female myocardium is more sensitive to the consequences of diabetes than the male Vascular aspects:NO Generation and endothelial function is impaired to a greater degree in diabetic women than in men Desrois M, JMM 2004

15. Metabolic Syndrome - endothelial Dysfunction Female sex Insulin increases endothelial NO Vasodilatation Regulation vascular tone and blood pressure Inhibition of smooth muscle cell Proliferation Inhibition of platelet aggregation Reduction of Lipid-Oxidation -40-50 % ! Obesity / Insulin resistence Steinberg et al,J Clin Invest.,1996

16. Metabolic Syndrome- Hypercoagulability Decreased Glucose tolerance – Hyperinsulinemia plasminogen activator inhibitor factor 1 (PAI-1) tissue plasminogen activator antigen (t-PA) Thromboses pulmonary embolism decreased Fibrinolysis Fibrinogen synthesis platelet function Estrogen

17. 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 Hormonal disturbances Obesity Estrogen modifies RAS acitivity Aogen, ACE, AT1/2-Receptor- expression Insulin resistence Hyperglycemia Hyperinsulinaemia Ovar Liver IGF Sympathicus stimulation IGF-BP SHBG Anovu- lation Vessels: Proliferation / Migration of smooth muscle cells Vascular contractility Androgen Activitity

18. Components of the Metabolic Syndrome - Hypertriglyceridemia follows insulin resistance Disturbed glucose utilization in skeletal muscle  glucose liberation from liver cells increased lipolysis increased FFA

19. 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

20. 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.

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

23. % % 50 50 Women Men 45,1 41,6 40 40 36,5 31,1 30 30 26,0 21,0 19,5 18,4 20 20 14,5 9,2 8,6 10 10 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 Age Risk factor hypertension – steep increase in postmenopausal women Adapted from C Gasse J Hum Hypertension 2001; 15: 27-36

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 Fitness Fitness Confirmation: Interheart study JAMA 1995; 1093, Blair et al

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

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. GiM Interdisciplinary Gender Research Innere Medizin Kardiologie Molekulare Medizin Kardiochirurgie Pharmakologie Humangenetik Allgemeinmedizin Gynäkologie Biochemie Neonatologie Praeventivmedizin Unfallchirurgie Public Health Anaesthesie Neuroimmunologie Epidemiologie Psychosomatik, Psychiatrie Kulturwissenschaften Berlin

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. Prevalence of MetS (WHO and NCEP criteria), Diabetes and CAD in the US population 69

31. 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, 1997 Am J Hypert

32. Direct relationship between BMI and blood pressure 22354 Korean subjects Jones DW,

33. Interaction insulin signalling - Sexual hormones Insulin MAPK PI 3 Kinase AKT Hypertrophy Glucose transport Proliferation Glycogen-synthesis Lipid metabolism Anti inflammation Vasodilatation/NO Re-endothelialisation Progenitor cells Insulin resistance Estrogen CRP, IL6, TNF PAI1 Monocyte adhesion Plaque formation Endothelial dysfunction +Renal Na reabs. +SNS +Hypertension

34. Mechanisms behind the gender related risk of metabolic Syndrome - Insulin resistance Physiological effects of Insulin Insulin sensitive cells in target organs Regulation of Energy metabolism  NO- liberation- and NO Synthase Expression in Endothelial cells Endothelial vasodilatation  NF-kB, ICAM 1,  MCP1, CRP Antiinflammatory Insulin resistance Dandona et Aljyda, Am J Cardiol, 2002

35. 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

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 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<0.06 LV-mass 121 + 23 154 + 24 p<0.001 CO, 4.1 + 0.6 4.9 + 0.9 p<0.005 MVO2 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 Peterson L R, Circ 2004

38. Inflammation CRP Fat Sexual hormones affect many organs

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

40. ER ER ER OH E2 HO E2 SP1 AP1 E2 Ca2+ E2 ras G-Protein ER raf X MEK E2 Src E2 NO MAPK ER PI3K Akt Ca2+ NOS GSK3b SR SERCA Protein complexes E2 E2 Ca2+ Metabolites GF 5 ER NR PPAR ERE DNA Regitz-Zagrosek, Nat Rev Drug Dev, 2006,

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

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. 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, 1996

45. Insulineffekte als Grundlage des Risikos II

46. 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? Perspectives in therapy Postmenopausale HT reduziert Diabetesinzidenz. Margolis et al., 2004

47. Metabolic Syndrome – obesity causes hypertension Rahmouni et al,Hypertension;2005

48. 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 insulin resistance  liberation of FFA  reduction in gluc uptake Insulinresistenz Adipositas Adiponectin higher concentr. in women  protective hormone Proliferation smooth muscle cells foam cell formation Reduced Expression Overexpression Resistin: endothelial dysfunction in pigs Increase in Insulin resistence Inflammation Overexpression viszerale Adipozyten Leptin  inhibits food intake by central mech. low leptin secretion from visceral fat in women mainly from subcut. fat

49. 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

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!