1. Metabolic Syndrome as Pathway for Cardiovascular Disease Neil Schneiderman University of Miami Presented at the Pittsburgh Mind-Body Center June 2006

2. MetSyn_PMBC_June2006 2 PATHOGENESIS OF CVD –Genetics –Emotional Stressors Unstable environmentsUnstable environments –Poor Dietary Practices Excess alcohol and caloriesExcess alcohol and calories –Physical Inactivity –Smoking

3. MetSyn_PMBC_June2006 3 Cluster of metabolic conditions thought to represent a pathogenetic pathway for type 2 diabetes and CVD METABOLIC SYNDROME

4. MetSyn_PMBC_June2006 4 According to National Cholesterol Education Program (ATP III) in U.S. and European Guidelines on CVD Prevention, metabolic syndrome is a major risk factor for CVD

5. MetSyn_PMBC_June2006 5 Clinical Criteria for Metabolic Syndrome –Waist circumference: Men: >102cmMen: >102cm Women: > 88 cmWomen: > 88 cm –Serum Triglyceride  150 mg/dL (≥ 1.7 mmol/L) –HDL Cholesterol: Men: < 40 mg/dL (< 1 mmol/L)Men: < 40 mg/dL (< 1 mmol/L) Women: < 50 mg/dL (< 1.3 mmol/L)Women: < 50 mg/dL (< 1.3 mmol/L) –Blood Pressure  130/95 mmHg –Plasma Glucose  110 mg/dL (≥ 6.1 mmol/L) –Waist circumference: Men: >102cmMen: >102cm Women: > 88 cmWomen: > 88 cm –Serum Triglyceride  150 mg/dL (≥ 1.7 mmol/L) –HDL Cholesterol: Men: < 40 mg/dL (< 1 mmol/L)Men: < 40 mg/dL (< 1 mmol/L) Women: < 50 mg/dL (< 1.3 mmol/L)Women: < 50 mg/dL (< 1.3 mmol/L) –Blood Pressure  130/95 mmHg –Plasma Glucose  110 mg/dL (≥ 6.1 mmol/L)

6. MetSyn_PMBC_June2006 6 According to ATP-III guidelines one must have any 3 of 5 risk factors: Large waist circumferenceLarge waist circumference Elevated triglyceridesElevated triglycerides Low HDLLow HDL High blood pressureHigh blood pressure High fasting glucoseHigh fasting glucose Large waist circumferenceLarge waist circumference Elevated triglyceridesElevated triglycerides Low HDLLow HDL High blood pressureHigh blood pressure High fasting glucoseHigh fasting glucose

7. MetSyn_PMBC_June2006 7 Metabolic Syndrome & CHD Mortality (Laaka et al, 2002, JAMA) –1209 Finnish men, 42-60 yrs. Baseline (1984-1989) –Follow-up through 1998 –HR = 4.2 (95% CI, 1.6 – 10.8) for CHD mortality –1209 Finnish men, 42-60 yrs. Baseline (1984-1989) –Follow-up through 1998 –HR = 4.2 (95% CI, 1.6 – 10.8) for CHD mortality

8. MetSyn_PMBC_June2006 8 NCEP (ATPIII) GUIDELINES –Glucose Intolerance –Dyslipidemia –Hypertension –Abdominal Obesity –Glucose Intolerance –Dyslipidemia –Hypertension –Abdominal Obesity WHO Guidelines include either glucose intolerance or insulin resistance

9. MetSyn_PMBC_June2006 9 –Insulin Resistance –Glucose Intolerance –Dyslipidemia –Hypertension –Abdominal Obesity

10. MetSyn_PMBC_June2006 10 Behavioral factors play a major role in the expression of IR, obesity Type 2 diabetes and cardiovascular disease.

11. MetSyn_PMBC_June2006 11 INSULIN RESISTANCE HYPERINSULINEMIAHYPERINSULINEMIA SUGAR/FATS SNS SMOKING INACTIVITY DISTRESS HPAC

12. MetSyn_PMBC_June2006 12 Emotional states that lead to chronic sympathetic arousal result in mobilization of free fatty acids

13. MetSyn_PMBC_June2006 13 –HPA axis dysregulation related to  waist obesity,  cholesterol,  triglycerides,  BP (Rosmond & Bjorntorp, 2000, J Intern Med)

14. MetSyn_PMBC_June2006 14 BEHAVIOR (e.g., smoking, diet, stress & physical inactivity) CONSTITUTIONAL FACTORS (e.g., obesity) SYMPATHETIC NERVOUS SYSTEM ACTIVITY TYPE 2 DIABETES INSULIN RESISTANCE HYPERINSULINEMIA CARDIOVASCULAR DISEASE Cortisol Cortisol

15. MetSyn_PMBC_June2006 15 Women with history of gestational diabetes: Role of insulin metabolism in CV risk Davis et al., J. Diabetes & Complications, 1999

16. MetSyn_PMBC_June2006 16 Women tend to increase insulin resistance during pregnancy, but most don’t become diabetic

17. MetSyn_PMBC_June2006 17 Some women develop diabetes during pregnancy, which resolves postpartum GESTATIONAL DIABETES

18. MetSyn_PMBC_June2006 18 Women who develop gestational diabetes are at increased risk of later getting diabetes, hypertension and CHD. WHY? WHY?

19. MetSyn_PMBC_June2006 19 Is the increased risk related to insulin resistance and/or metabolic syndrome?

20. MetSyn_PMBC_June2006 20 SUBJECTSSUBJECTS –39 Healthy women Prior gestational diabetes (n=21)Prior gestational diabetes (n=21) Uncomplicated pregnancy (n-18)Uncomplicated pregnancy (n-18) –3-18 months postpartum –Not diabetic –Normotensive –Normal HbA 1c –39 Healthy women Prior gestational diabetes (n=21)Prior gestational diabetes (n=21) Uncomplicated pregnancy (n-18)Uncomplicated pregnancy (n-18) –3-18 months postpartum –Not diabetic –Normotensive –Normal HbA 1c

21. MetSyn_PMBC_June2006 21 STUDY PROTOCOL –Day 1 Oral Glucose Tolerance Test (OGTT)Oral Glucose Tolerance Test (OGTT) –Day 2 Euglycemic-Hyperinsulinemic ClampEuglycemic-Hyperinsulinemic Clamp –Day 1 Oral Glucose Tolerance Test (OGTT)Oral Glucose Tolerance Test (OGTT) –Day 2 Euglycemic-Hyperinsulinemic ClampEuglycemic-Hyperinsulinemic Clamp

22. MetSyn_PMBC_June2006 22 EUGLYCEMIC CLAMP TECHNIQUE –Normal glucose level (euglycemia) –Exogenous insulin administered and clamped at 100  U/ml –Rate of glucose infusion (M) needed to maintain euglycemia assessed over 2 hours –Normal glucose level (euglycemia) –Exogenous insulin administered and clamped at 100  U/ml –Rate of glucose infusion (M) needed to maintain euglycemia assessed over 2 hours

23. MetSyn_PMBC_June2006 23 UNIVARIATE COMPARISONS GDControlP M(mg/kg-min)6.29.0.005 G Sum OGTT (G mmol/L) 37.131.4.003 Triglyceride(mg/dL)141.697.4.02 BMI(kg/m2)29.725.9.02 DBP(mm/hg)73.468.3.05

24. MetSyn_PMBC_June2006 24 MANOVA and Univariate Follow-Up Metabolic syndrome Variables=.71.02 Glucose sum F=8.9.01 TriglyceridesF=5.2.03 BMIF=5.6.02 DBPF=3.9.06 GD History vs. no-GD History pp

25. MetSyn_PMBC_June2006 25 MANOVA and Univariate Follow-Up Metabolic syndrome M covaried =.89.45 Glucose sum F=.04.85 TriglyceridesF=3.30.08 BMIF=.01.93 DBPF=.83.37 pp

26. MetSyn_PMBC_June2006 26 CONCLUSIONCONCLUSION GD resolves after pregnancy to clinically nondiabetic status, but subclinical differences in metabolic syndrome variables leave women vulnerable to future CHD

27. MetSyn_PMBC_June2006 27 (Shen et al., 2006, Ann Epidemiol) FACTOR STRUCTURE OF METABOLIC SYNDROME: CONFIRMATORY FACTOR ANALYSIS

28. MetSyn_PMBC_June2006 28 Hierarchical 4-factor model with overarching metabolic syndrome factor tested on 517 healthy adults (24-44 yrs) from Miami Community Health Study.

29. MetSyn_PMBC_June2006 29 SAMPLESAMPLE –Gender 261 women261 women 256 men256 men –Ethnicity 33% African American33% African American 26% Cuban American26% Cuban American 41% Non-Hispanic White41% Non-Hispanic White –Gender 261 women261 women 256 men256 men –Ethnicity 33% African American33% African American 26% Cuban American26% Cuban American 41% Non-Hispanic White41% Non-Hispanic White

30. MetSyn_PMBC_June2006 30 The Metabolic Syndrome Insulin Resistance ObesityObesity LipidsLipids Blood Pressure Fasting Insulin Fasting Glucose Body Mass Index WaistWaist HDL Cholesterol TriglyceridesTriglycerides Systolic BP Diastolic BP 0.87 0.80 0.59 0.72 0.56 0.47 0.85 1.00 -0.60 0.76 0.89 0.83

31. MetSyn_PMBC_June2006 31 The proposed factor structure was well supported (comparative fit index = 0.97) and similar between men and women and across ethnic groups.

32. MetSyn_PMBC_June2006 32 (Klaus, Hurwitz et al., submitted) Structural Equation Model of metabolic syndrome in different sample of 338 healthy adults

33. MetSyn_PMBC_June2006 33 SAMPLESAMPLE –Gender 163 women163 women 175 men175 men –Age 18 to 55 years18 to 55 years

34. MetSyn_PMBC_June2006 34 MEASURESMEASURES –Central Obesity Waist circumferenceWaist circumference –Insulin Sensitivity Euglycemic clampEuglycemic clamp –Inflammation C-reactive proteinC-reactive protein Interleukin 6Interleukin 6 –Fibrinolysis Plasminogen activator inhibitor-Type 1 (PAI-1)Plasminogen activator inhibitor-Type 1 (PAI-1) –Central Obesity Waist circumferenceWaist circumference –Insulin Sensitivity Euglycemic clampEuglycemic clamp –Inflammation C-reactive proteinC-reactive protein Interleukin 6Interleukin 6 –Fibrinolysis Plasminogen activator inhibitor-Type 1 (PAI-1)Plasminogen activator inhibitor-Type 1 (PAI-1)

35. MetSyn_PMBC_June2006 35 MEASURESMEASURES –Lipids TriglycerideTriglyceride High density lipoproteinHigh density lipoprotein Total cholesterol/HDLTotal cholesterol/HDL –Echocardiography (Cardiac Mass) Left ventricular mass indexLeft ventricular mass index Interventricular mass indexInterventricular mass index Left posterior wall thicknessLeft posterior wall thickness –Vascular Endothelial Function Endothelial dependent brachial a. vasodilationEndothelial dependent brachial a. vasodilation –Lipids TriglycerideTriglyceride High density lipoproteinHigh density lipoprotein Total cholesterol/HDLTotal cholesterol/HDL –Echocardiography (Cardiac Mass) Left ventricular mass indexLeft ventricular mass index Interventricular mass indexInterventricular mass index Left posterior wall thicknessLeft posterior wall thickness –Vascular Endothelial Function Endothelial dependent brachial a. vasodilationEndothelial dependent brachial a. vasodilation

36. MetSyn_PMBC_June2006 36

37. MetSyn_PMBC_June2006 37 Fat/Carb Stress Age Gender Central Obesity  R 2 = 0.12

38. MetSyn_PMBC_June2006 38 SUMMARY IN HEALTHY ADULTS –The model shows direct and indirect pathways, linking cardiac risk factors –Central obesity is a major proximal variable in the pathway –Obesity predicts inflammation, lipidemia and cardiac mass –Stress predicts central obesity, explaining 5% of the variance

39. MetSyn_PMBC_June2006 39 –Overall model in healthy adults indicates CV risk factors predict blood pressure. –Do adolescents with high blood pressure reveal metabolic syndrome? –Overall model in healthy adults indicates CV risk factors predict blood pressure. –Do adolescents with high blood pressure reveal metabolic syndrome?

40. MetSyn_PMBC_June2006 40 Modifying Risk in Youth with Elevated Blood Pressure Patrice Saab, Project Leader

41. MetSyn_PMBC_June2006 41 PARTICIPANTSPARTICIPANTS –10 TH Grade; Mean age, 16.2 yrs –148 Participants 107 boys107 boys 41 girls41 girls –Ethnicity% Hispanic White51Hispanic White51 Black30Black30 Non Hispanic White16Non Hispanic White16 Other3Other3 –10 TH Grade; Mean age, 16.2 yrs –148 Participants 107 boys107 boys 41 girls41 girls –Ethnicity% Hispanic White51Hispanic White51 Black30Black30 Non Hispanic White16Non Hispanic White16 Other3Other3

42. MetSyn_PMBC_June2006 42 –Youth with BP > 90 th percentile on 2 occasions in ELEVATED group –Youth’s friend with BP < 90 th percentile comprised NORMAL group –Youth with BP > 90 th percentile on 2 occasions in ELEVATED group –Youth’s friend with BP < 90 th percentile comprised NORMAL group

43. MetSyn_PMBC_June2006 43 VariableElevatedNormal SBP (mmH g ) * 133117 DBP (mmH g ) * 7769 Parental history HT(%) * 6938 BMI (kg/m 2 ) * 31.426.3 * P <.01

44. MetSyn_PMBC_June2006 44

45. MetSyn_PMBC_June2006 45 VariableElevatedNormal Triglycerides (mg/dL) * 10784 HDL (mg/dL) * 4144 LDL (mg/dL) 10294 Total Cholesterol (mg)dL) 164154 Total Cholesterol / HDL * 4.13.7 * P <.05

46. MetSyn_PMBC_June2006 46 VariableElevatedNormal Fasting Glucose (mg/dL) 8685 Glucose 120 min (mg/dL)* 10293 VO 2 max (ml/kg/min)* 3741 * P <.05

47. MetSyn_PMBC_June2006 47

48. MetSyn_PMBC_June2006 48 VariableElevatedNormal LVM/H 2.7 (g/m 2.7 ) * 41.636.6 Cardiac Index (l/min/m 2 ) * 3.43.1 Stroke Index (ml/m 2 ) * 46.843.9 * P <.01 Echocardiographic Data

49. MetSyn_PMBC_June2006 49 CRITERIA FOR METABOLIC SYNDROME –Blood Pressure  130/85 mmHg –Waist  102 cm (males)  88 cm (females) –HDL  40 mg/dL (males)  50 mg/dL (females –Triglyceride  150 mg/dL –Fasting Glucose  110 mg/dL –Blood Pressure  130/85 mmHg –Waist  102 cm (males)  88 cm (females) –HDL  40 mg/dL (males)  50 mg/dL (females –Triglyceride  150 mg/dL –Fasting Glucose  110 mg/dL (Must meet at least 3 of 5)

50. MetSyn_PMBC_June2006 50 Waist ≥ 102 cm in boys ≥ 88 cm in girls LDL > 110 mg/dL LVM/ht 2.7  95 th percentile (38.6 g/m 2.7 ) Risk Factor Cut Points Prevalence (%) BMI  95 th percentile TRIG  150 mg/dL HDL  40 mg/dL in boys & 50 mg/dL in girls Normal Elevated Normal All p’s significant at p <.05

51. MetSyn_PMBC_June2006 51 – 31% of Elevated BP group and 5% of Normal BP group met adult criteria for metabolic syndrome – Elevated blood pressure predicts adult metabolic syndrome in adolescents (p<.001) – 31% of Elevated BP group and 5% of Normal BP group met adult criteria for metabolic syndrome – Elevated blood pressure predicts adult metabolic syndrome in adolescents (p<.001) Metabolic Syndrome

52. MetSyn_PMBC_June2006 52 Structural Equation Modeling in 205 adolescents (150 boys, 55 girls) –Half with elevated blood pressure –Half with normal blood pressure –Half with elevated blood pressure –Half with normal blood pressure

53. MetSyn_PMBC_June2006 53.37 * CHOL FIT BMI LDL TG HDL PA % POLY FAT % TOT FAT % SAT FAT DIET -.43 *.15 *.02 * -.20 *.70 * *

54. MetSyn_PMBC_June2006 54 CONCLUSIONSCONCLUSIONS –Abdominal obesity is a key feature of metabolic syndrome in youth. –Diet and poor fitness predict abdominal obesity in youth. –Abdominal obesity is a key feature of metabolic syndrome in youth. –Diet and poor fitness predict abdominal obesity in youth.

55. MetSyn_PMBC_June2006 55 COMMENTCOMMENT –The adolescents with metabolic syndrome seem destined to develop premature cardiovascular disease unless the syndrome itself is treated –Weight reduction is Tx of choice –The adolescents with metabolic syndrome seem destined to develop premature cardiovascular disease unless the syndrome itself is treated –Weight reduction is Tx of choice

56. MetSyn_PMBC_June2006 56 STRUCTURAL EQUATION MODEL FOR METABOLIC SYNDROME IN POST-MI PATIENTS (Schneiderman, Gellman et al., in preparation)

57. MetSyn_PMBC_June2006 57 PARTICIPANTSPARTICIPANTS Mean age: 53 yrs Mean time since index MI: 61 days Number of patients: 174 –Gender 55 Women 55 Women 119 Men 119 Men –Ethnicity 136 (78%) Hispanic White136 (78%) Hispanic White 29 (17%) Black 29 (17%) Black 6 (3%) Non Hispanic White 6 (3%) Non Hispanic White 3 (2%) Other 3 (2%) Other Mean age: 53 yrs Mean time since index MI: 61 days Number of patients: 174 –Gender 55 Women 55 Women 119 Men 119 Men –Ethnicity 136 (78%) Hispanic White136 (78%) Hispanic White 29 (17%) Black 29 (17%) Black 6 (3%) Non Hispanic White 6 (3%) Non Hispanic White 3 (2%) Other 3 (2%) Other

58. MetSyn_PMBC_June2006 58 WEIGHT and METABOLISM –Weight Normal 15%Normal 15% Overweight (BMI >25 25 <30) 44% Obese (BMI  30) 41%Obese (BMI  30) 41% –Metabolic syndrome88% –Diabetes (FG  126 mg/dL)21% –Impaired Glucose (FG 111-125 mg/dL)14% –Normal Glucose 65% –Weight Normal 15%Normal 15% Overweight (BMI >25 25 <30) 44% Obese (BMI  30) 41%Obese (BMI  30) 41% –Metabolic syndrome88% –Diabetes (FG  126 mg/dL)21% –Impaired Glucose (FG 111-125 mg/dL)14% –Normal Glucose 65%

59. MetSyn_PMBC_June2006 59 PRESCRIBED MEDICATIONS % –Antihypertensives99 –Statins89 –Anticoagulants (including aspirin: 89%) 93 % –Antihypertensives99 –Statins89 –Anticoagulants (including aspirin: 89%) 93

60. MetSyn_PMBC_June2006 60 Χ 2 (19) = 20.398 (p =.37) CFI =.996 RMSEA =.020 SRMR =.047 Χ 2 (19) = 20.398 (p =.37) CFI =.996 RMSEA =.020 SRMR =.047 PAI-1 Insulin Sensitivity Index CRP LV Mass Glucose AUC HDL Waist Circumference EthnicityEthnicity GenderGender AgeAge.75.32 -.33 -.87 -.32 -.17 -.19 -.27.32 -.45

61. MetSyn_PMBC_June2006 61 CONCLUSIONSCONCLUSIONS –Waist circumference predicts inflammation, insulin resistance, lipids, blood glucose, coagulation and LV mass. –Differences in structural models between healthy young adults and post-MI patients (in BP and lipids) is attributable to antihypertensive medication and statins. –Waist circumference predicts inflammation, insulin resistance, lipids, blood glucose, coagulation and LV mass. –Differences in structural models between healthy young adults and post-MI patients (in BP and lipids) is attributable to antihypertensive medication and statins.

62. MetSyn_PMBC_June2006 62 COMMENTCOMMENT –Because abdominal obesity is proximal, weight loss should be a high priority in overweight post-MI patients in order to reduce standard cardiac risk factors

63. MetSyn_PMBC_June2006 63 Weight loss, of course, should also be a high priority in preclinical, overweight people, particularly in those at high risk for diabetes or CVD.

64. MetSyn_PMBC_June2006 64 –Two randomized clinical trials showed that lifestyle intervention can postpone Type 2 diabetes –DPP, 2002, N. Eng. J. Med., USA –Tuomilehto, 2001, N. Eng. J. Med., Finland

65. MetSyn_PMBC_June2006 65 Tuomilehto (2001) randomized 522 middle- aged, overweight people with IGT to lifestyle intervention or control

66. MetSyn_PMBC_June2006 66 Tuomilehto (2001) –Mean weight lost in year 1 Intervention: 4.2 ± 5.1 KgIntervention: 4.2 ± 5.1 Kg Control: 0.8 ± 3.7 KgControl: 0.8 ± 3.7 Kg –Cumulative incidence of diabetes after 4 years: Intervention: 11%Intervention: 11% Control: 23%Control: 23% –Risk of diabetes reduced 58% (p <.001)

67. MetSyn_PMBC_June2006 67 –RCT of 3234 nondiabetics with elevated glucose randomized to: Lifestyle modificationsLifestyle modifications MetforminMetformin PlacbeoPlacbeo –Average follow-up 2.8 years –RCT of 3234 nondiabetics with elevated glucose randomized to: Lifestyle modificationsLifestyle modifications MetforminMetformin PlacbeoPlacbeo –Average follow-up 2.8 years DIABETES PREVENTION PROGRAM — (DPP 2002, N Eng J Med)

68. MetSyn_PMBC_June2006 68 16-lesson curriculum covering diet, exercise and behavior modification DIABETES PREVENTION PROGRAM

69. MetSyn_PMBC_June2006 69 DIABETES PREVENTION PROGRAM –Cumulative Incidence of Diabetes Placebo28.9%Placebo28.9% Metformin21.7%Metformin21.7% Behavior14.4%Behavior14.4% –Changes in weight and physical activity differed among groups (p <.001 for each comparison) –Cumulative Incidence of Diabetes Placebo28.9%Placebo28.9% Metformin21.7%Metformin21.7% Behavior14.4%Behavior14.4% –Changes in weight and physical activity differed among groups (p <.001 for each comparison)

70. MetSyn_PMBC_June2006 70 COMMENTCOMMENT –When compared with high cost of treating individual risk factors (hyperlipidemia, hyertension) and difficulties in managing diabetes complications, a program of diet and exercise would seem cost- effective.

71. MetSyn_PMBC_June2006 71 –Diabetes Prevention Project (2002) showed lifestyle intervention (diet and exercise) can delay the onset of type 2 diabetes Our behavior change pathway is consistent with the RCT resultsOur behavior change pathway is consistent with the RCT results –Project LOOK AHEAD is now examining long term (up to 11.5 yrs) effects of weight loss upon CVD event rates in overweight and obese type 2 diabetics –Diabetes Prevention Project (2002) showed lifestyle intervention (diet and exercise) can delay the onset of type 2 diabetes Our behavior change pathway is consistent with the RCT resultsOur behavior change pathway is consistent with the RCT results –Project LOOK AHEAD is now examining long term (up to 11.5 yrs) effects of weight loss upon CVD event rates in overweight and obese type 2 diabetics

72. MetSyn_PMBC_June2006 72 Psychosocial Intervention 1 o or 2 o CVD PREVENTION BehaviorsBehaviors HormonesHormones     MoodMood StressStress     - Adherence - Lifestyle

73. MetSyn_PMBC_June2006 73 – Interaction of diet, social status and unstable environment can promote atherosclerosis in monkeys – Chronic administration of beta blocker can reduce the effects – Interaction of diet, social status and unstable environment can promote atherosclerosis in monkeys – Chronic administration of beta blocker can reduce the effects Kaplan and Manuck

74. MetSyn_PMBC_June2006 74 –Reducing sympathetic nervous system arousal and hypothalamic pituitary adrenocortical activity thought to be cardioprotective Consequences of Stress at Issue

75. MetSyn_PMBC_June2006 75 –Using Watanabe rabbits we have provided evidence that positive contact and social support can attenuate progression of atherosclerosis

76. MetSyn_PMBC_June2006 76 Social Environment, Endocrines & Vascular Mechanisms in Progression of Atherosclerosis (Phil McCabe, Project Leader)

77. MetSyn_PMBC_June2006 77 Watanabe Heritable Hyperlipidemic Rabbit (WHHL) –Model for human familial hypercholesterolemia –Spontaneous genetic mutation in LDL receptor synthesis –Extremely high plasma lipids from birth –Aortic atherosclerosis begins at 2 months, severe in all animals by 7 months, CHD develops by 8-10 months, death occurs after 1 year

78. MetSyn_PMBC_June2006 78 CRP measured early in the disease process (3 and 5 mos) significantly predicts future atherosclerosis (7 mos) in Watanabe hyperlipidemic rabbits Brooks et al., 2006 SBM

79. MetSyn_PMBC_June2006 79 Social Environment and Progression of Atherosclerosis in the WHHL (McCabe et al., 2002, Circulation) –33 male WHHLs, 3 months of age –Assigned to one of 3 social conditions: Unstable (paired with unfamiliar rabbit 4hrs/day, pairing rearranged each week)Unstable (paired with unfamiliar rabbit 4hrs/day, pairing rearranged each week) Stable (paired with littermate 4hrs/day, pairing maintained throughout study)Stable (paired with littermate 4hrs/day, pairing maintained throughout study) Individually-caged (housed alone, no contact with other animals)Individually-caged (housed alone, no contact with other animals) –Study ran from 3 to 7 months of age

80. MetSyn_PMBC_June2006 80 Percent Time in Behavior as a Function of Group (Mean ± SEM) Agonistic Behavior 45.0 ( ± 9.7)* 23.5 (±8.8) n/a n/a Affiliative Behavior 13.9 (±4.6) 21.3 (±7.2)† n/a n/a Other Nonagonistic Behavior 18.0 (±4.1)* 27.9 (±7.1)* 37.7 (±2.7)* Inactivity 23.1 (±1.3) 27.3 (±1.7)‡ 62.3 (±0.8)* Unstable Stable Individually- caged Individually- caged * p<.0001 vs other groups † p<.01 vs unstable ‡ p<.05 vs unstable

81. MetSyn_PMBC_June2006 81 Area of Atherosclerosis as a Function of Social Environment

82. MetSyn_PMBC_June2006 82 –Stable social environment, characterized by increased affiliative behavior and decreased agonistic behavior, slows the progression of atherosclerosis by approximately 50% in animals genetically predisposed to disease –Unstable group exhibited more advanced lesions than the other groups –Group differences in disease could not be explained by differences in lipids, glucocorticoids, or gonadal steroids CONCLUSIONSCONCLUSIONS

83. MetSyn_PMBC_June2006 83 –Stable social environment, characterized by increased affiliative behavior & less agonistic behavior, slows the progression of atherosclerosis in animals genetically predisposed to disease –Stable environment is accompanied by increased plasma oxytocin Note that affiliative interaction between human partners releases oxytocin (Grewen, Girdler, Amico, & Light, 2005)Note that affiliative interaction between human partners releases oxytocin (Grewen, Girdler, Amico, & Light, 2005) CONCLUSIONSCONCLUSIONS

84. MetSyn_PMBC_June2006 84 Pathophysiology of Atherosclerosis From Charo. Current Opinion in Lipidology 1992

85. MetSyn_PMBC_June2006 85 Pathophysiology of Atherosclerosis Ox-LDLOx-LDL LDL NAD(P)H Oxidase

86. MetSyn_PMBC_June2006 86 Oxytocin and Vascular Cells: In Vitro studies –We have cultured human aortic endothelial cells, monocytes, and vascular smooth muscle cells –Incubated cells with physiological concentrations of oxytocin –Assessed the influence of oxytocin on oxidative stress (via NAD[P]H oxidase activity) and inflammation (via cell adhesion molecule expression) –We have cultured human aortic endothelial cells, monocytes, and vascular smooth muscle cells –Incubated cells with physiological concentrations of oxytocin –Assessed the influence of oxytocin on oxidative stress (via NAD[P]H oxidase activity) and inflammation (via cell adhesion molecule expression)

87. MetSyn_PMBC_June2006 87 Vascular Cells Express Oxytocin Receptors

88. MetSyn_PMBC_June2006 88 Oxytocin Inhibits Vascular Oxidative Stress

89. MetSyn_PMBC_June2006 89 Oxytocin inhibits Early Vascular Inflammatory Processes Time course of TNF-alpha-stimulated cell surface expression of ICAM-1 in HAEC TNF  TNF  + OT Control Oxytocin

90. MetSyn_PMBC_June2006 90 –Vascular cells express oxytocin receptors –Oxytocin inhibits oxidative stress and inflammation in cultured vascular cells –It is proposed that the beneficial effects of a prosocial environment on disease progression may be mediated through the direct effect of peripheral oxytocin on pathophysiological mechanisms occuring in vascular wall CONCLUSIONSCONCLUSIONS

91. MetSyn_PMBC_June2006 91 –Behavioral (lifestyle) pathways leading from psychosocial/behavioral interventions and CVD prevention are reasonably well understood. –The hormonal/stress reduction pathways between our psychosocial interventions and CVD prevention are less well understood but are being studied in appropriate models. –Behavioral (lifestyle) pathways leading from psychosocial/behavioral interventions and CVD prevention are reasonably well understood. –The hormonal/stress reduction pathways between our psychosocial interventions and CVD prevention are less well understood but are being studied in appropriate models. CONCLUSIONSCONCLUSIONS

92. MetSyn_PMBC_June2006 92 ↓ HDL ↑ LDL Inflammation Central Obesity ↑ IR ↓ Glucose tolerance Hypertension Type 2 diabetes Endothelial dysfunction CHD Acute Coronary Syndrome Dyslipidemia ↑ Cardiac mass CRPIL-6 ↑ Fibrinolysis Summary: Why we need to decrease central obesity