Metabolic Syndrome as Pathway for Cardiovascular Disease Neil Schneiderman University of Miami...

Metabolic Syndrome Metabolic Syndrome as Pathway as Pathway

for Cardiovascular Diseasefor Cardiovascular Disease

Neil SchneidermanNeil Schneiderman

University of MiamiUniversity of Miami

Presented at thePresented at thePittsburgh Mind-Body CenterPittsburgh Mind-Body Center

June 2006June 2006

MetSyn_PMBC_June20062

PATHOGENESIS OF CVDPATHOGENESIS OF CVD

– GeneticsGenetics

– Emotional StressorsEmotional Stressors

• Unstable environmentsUnstable environments

– Poor Dietary PracticesPoor Dietary Practices

• Excess alcohol and caloriesExcess alcohol and calories

– Physical InactivityPhysical Inactivity

– SmokingSmoking


Cluster of metabolic Cluster of metabolic conditions thought to conditions thought to represent a pathogenetic represent a pathogenetic pathway for type 2 diabetes pathway for type 2 diabetes and CVDand CVD

Cluster of metabolic Cluster of metabolic conditions thought to conditions thought to represent a pathogenetic represent a pathogenetic pathway for type 2 diabetes pathway for type 2 diabetes and CVDand CVD

METABOLIC SYNDROMEMETABOLIC SYNDROMEMETABOLIC SYNDROMEMETABOLIC SYNDROME


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


Clinical Criteria for Metabolic Clinical Criteria for Metabolic SyndromeSyndrome

– Waist circumference:Waist circumference:• Men: >102cmMen: >102cm

• Women: > 88 cmWomen: > 88 cm

– Serum Triglyceride Serum Triglyceride 150 mg/dL (150 mg/dL (≥ 1.7 mmol/L)≥ 1.7 mmol/L)

– HDL Cholesterol: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 Blood Pressure 130/95 mmHg 130/95 mmHg

– Plasma Glucose Plasma Glucose 110 mg/dL ( 110 mg/dL (≥ 6.1 mmol/L)≥ 6.1 mmol/L)

– Waist circumference:Waist circumference:• Men: >102cmMen: >102cm

• Women: > 88 cmWomen: > 88 cm

– Serum Triglyceride Serum Triglyceride 150 mg/dL (150 mg/dL (≥ 1.7 mmol/L)≥ 1.7 mmol/L)

– HDL Cholesterol: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 Blood Pressure 130/95 mmHg 130/95 mmHg

– Plasma Glucose Plasma Glucose 110 mg/dL ( 110 mg/dL (≥ 6.1 mmol/L)≥ 6.1 mmol/L)


According to ATP-III guidelines one According to ATP-III guidelines one must have any 3 of 5 risk factors:must have any 3 of 5 risk factors:According to ATP-III guidelines one According to ATP-III guidelines one must have any 3 of 5 risk factors: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


Metabolic Syndrome & CHD MortalityMetabolic Syndrome & CHD Mortality(Laaka et al, 2002, (Laaka et al, 2002, JAMA)JAMA)

Metabolic Syndrome & CHD MortalityMetabolic Syndrome & CHD Mortality(Laaka et al, 2002, (Laaka et al, 2002, JAMA)JAMA)

– 1209 Finnish men, 42-60 yrs. 1209 Finnish men, 42-60 yrs. Baseline (1984-1989)Baseline (1984-1989)

– Follow-up through 1998Follow-up through 1998

– HR = 4.2 (95% CI, 1.6 – 10.8) for CHD HR = 4.2 (95% CI, 1.6 – 10.8) for CHD mortalitymortality

– 1209 Finnish men, 42-60 yrs. 1209 Finnish men, 42-60 yrs. Baseline (1984-1989)Baseline (1984-1989)

– Follow-up through 1998Follow-up through 1998

– HR = 4.2 (95% CI, 1.6 – 10.8) for CHD HR = 4.2 (95% CI, 1.6 – 10.8) for CHD mortalitymortality


NCEP (ATPIII) GUIDELINESNCEP (ATPIII) GUIDELINESNCEP (ATPIII) GUIDELINESNCEP (ATPIII) GUIDELINES– Glucose IntoleranceGlucose Intolerance

– DyslipidemiaDyslipidemia

– HypertensionHypertension

– Abdominal ObesityAbdominal Obesity

– Glucose IntoleranceGlucose Intolerance

– DyslipidemiaDyslipidemia

– HypertensionHypertension

– Abdominal ObesityAbdominal Obesity

WHO Guidelines include either glucose WHO Guidelines include either glucose intolerance or insulin resistanceintolerance or insulin resistanceWHO Guidelines include either glucose WHO Guidelines include either glucose intolerance or insulin resistanceintolerance or insulin resistance


– Insulin ResistanceInsulin Resistance

–Glucose IntoleranceGlucose Intolerance

–DyslipidemiaDyslipidemia

–HypertensionHypertension

–Abdominal ObesityAbdominal Obesity


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


INSULIN INSULIN RESISTANCERESISTANCE

INSULIN INSULIN RESISTANCERESISTANCE

HYPERINSULINEMIAHYPERINSULINEMIAHYPERINSULINEMIAHYPERINSULINEMIA

SUGAR/FATSSUGAR/FATS

SNSSNS

SMOKINGSMOKING

INACTIVITYINACTIVITYDISTRESSDISTRESS

HPACHPAC


Emotional states that lead Emotional states that lead to chronic sympathetic to chronic sympathetic arousal result in arousal result in mobilization of free fatty mobilization of free fatty acidsacids


–HPA axis dysregulation related HPA axis dysregulation related to to waist obesity, waist obesity, cholesterol, cholesterol, triglycerides, triglycerides, BPBP

–HPA axis dysregulation related HPA axis dysregulation related to to waist obesity, waist obesity, cholesterol, cholesterol, triglycerides, triglycerides, BPBP

(Rosmond & Bjorntorp, 2000, J Intern Med)(Rosmond & Bjorntorp, 2000, J Intern Med)


BEHAVIORBEHAVIOR(e.g., smoking, diet, stress &

physical inactivity)

CONSTITUTIONAL CONSTITUTIONAL FACTORSFACTORS(e.g., obesity)

SYMPATHETICSYMPATHETIC

NERVOUS SYSTEMNERVOUS SYSTEM

ACTIVITYACTIVITY

TYPE 2 DIABETESTYPE 2 DIABETES

INSULIN RESISTANCEINSULIN RESISTANCE

HYPERINSULINEMIAHYPERINSULINEMIA

CARDIOVASCULAR DISEASECARDIOVASCULAR DISEASE

CortisolCortisol


Women with history of Women with history of gestational diabetes: Role of gestational diabetes: Role of insulin metabolism in CV riskinsulin metabolism in CV risk

Women with history of Women with history of gestational diabetes: Role of gestational diabetes: Role of insulin metabolism in CV riskinsulin metabolism in CV risk

Davis et al., J. Diabetes & Complications, 1999Davis et al., J. Diabetes & Complications, 1999


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

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


Some women develop Some women develop diabetes during pregnancy, diabetes during pregnancy, which resolves postpartumwhich resolves postpartum

Some women develop Some women develop diabetes during pregnancy, diabetes during pregnancy, which resolves postpartumwhich resolves postpartum

GESTATIONAL DIABETESGESTATIONAL DIABETESGESTATIONAL DIABETESGESTATIONAL DIABETES


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

WHY?WHY?

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

WHY?WHY?


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

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


SUBJECTSSUBJECTSSUBJECTSSUBJECTS– 39 Healthy women39 Healthy women

• Prior gestational diabetes (n=21)Prior gestational diabetes (n=21)

• Uncomplicated pregnancy (n-18)Uncomplicated pregnancy (n-18)

– 3-18 months postpartum3-18 months postpartum

– Not diabeticNot diabetic

– NormotensiveNormotensive

– Normal HbANormal HbA1c1c

– 39 Healthy women39 Healthy women

• Prior gestational diabetes (n=21)Prior gestational diabetes (n=21)

• Uncomplicated pregnancy (n-18)Uncomplicated pregnancy (n-18)

– 3-18 months postpartum3-18 months postpartum

– Not diabeticNot diabetic

– NormotensiveNormotensive

– Normal HbANormal HbA1c1c


STUDY PROTOCOLSTUDY PROTOCOLSTUDY PROTOCOLSTUDY PROTOCOL

– Day 1Day 1

• Oral Glucose Tolerance Test (OGTT)Oral Glucose Tolerance Test (OGTT)

– Day 2Day 2

• Euglycemic-Hyperinsulinemic ClampEuglycemic-Hyperinsulinemic Clamp

– Day 1Day 1

• Oral Glucose Tolerance Test (OGTT)Oral Glucose Tolerance Test (OGTT)

– Day 2Day 2

• Euglycemic-Hyperinsulinemic ClampEuglycemic-Hyperinsulinemic Clamp


EUGLYCEMIC CLAMP TECHNIQUEEUGLYCEMIC CLAMP TECHNIQUEEUGLYCEMIC CLAMP TECHNIQUEEUGLYCEMIC CLAMP TECHNIQUE

– Normal glucose level (euglycemia)Normal glucose level (euglycemia)

– Exogenous insulin administered and Exogenous insulin administered and clamped at 100clamped at 100 U/ml U/ml

– Rate of glucose infusion (M) needed Rate of glucose infusion (M) needed to maintain euglycemia assessed to maintain euglycemia assessed over 2 hoursover 2 hours

– Normal glucose level (euglycemia)Normal glucose level (euglycemia)

– Exogenous insulin administered and Exogenous insulin administered and clamped at 100clamped at 100 U/ml U/ml

– Rate of glucose infusion (M) needed Rate of glucose infusion (M) needed to maintain euglycemia assessed to maintain euglycemia assessed over 2 hoursover 2 hours


UNIVARIATE COMPARISONSUNIVARIATE COMPARISONSUNIVARIATE COMPARISONSUNIVARIATE COMPARISONS

GDGD ControlControl PP

MM (mg/kg-min)(mg/kg-min) 6.26.2 9.09.0 .005.005

G Sum OGTTG Sum OGTT (G mmol/L)(G mmol/L) 37.137.1 31.431.4 .003.003

TriglycerideTriglyceride (mg/dL)(mg/dL) 141.6141.6 97.497.4 .02.02

BMIBMI (kg/m2)(kg/m2) 29.729.7 25.925.9 .02.02

DBPDBP (mm/hg)(mm/hg) 73.473.4 68.368.3 .05.05


MANOVA MANOVA andand Univariate Univariate Follow-UpFollow-UpMANOVA MANOVA andand Univariate Univariate Follow-UpFollow-Up

Metabolic syndromeMetabolic syndrome

VariablesVariables ==.71.71

.02.02

Glucose sumGlucose sum FF == 8.98.9 .01.01

TriglyceridesTriglycerides FF == 5.25.2 .03.03

BMIBMI FF == 5.65.6 .02.02

DBPDBP FF == 3.93.9 .06.06

GD History vs. no-GD HistoryGD History vs. no-GD HistoryGD History vs. no-GD HistoryGD History vs. no-GD History

pppp


MANOVA and MANOVA and Univariate Follow-UpUnivariate Follow-UpMANOVA and MANOVA and Univariate Follow-UpUnivariate Follow-Up

Metabolic syndromeMetabolic syndrome

M covariedM covaried ==.89.89

.45.45

Glucose sumGlucose sum FF ==.04.04

.85.85

TriglyceridesTriglycerides FF ==3.303.30

.08.08

BMIBMI FF ==.01.01

.93.93

DBPDBP FF ==.83.83

.37.37

pppp


CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION

GD resolves after pregnancy to GD resolves after pregnancy to clinically nondiabetic status, but clinically nondiabetic status, but subclinical differences in subclinical differences in metabolic syndrome variables metabolic syndrome variables leave women vulnerable to future leave women vulnerable to future CHDCHD

GD resolves after pregnancy to GD resolves after pregnancy to clinically nondiabetic status, but clinically nondiabetic status, but subclinical differences in subclinical differences in metabolic syndrome variables metabolic syndrome variables leave women vulnerable to future leave women vulnerable to future CHDCHD


(Shen et al., 2006, (Shen et al., 2006, Ann Epidemiol)Ann Epidemiol)(Shen et al., 2006, (Shen et al., 2006, Ann Epidemiol)Ann Epidemiol)

FACTOR STRUCTURE OFFACTOR STRUCTURE OFMETABOLIC SYNDROME:METABOLIC SYNDROME:CONFIRMATORY FACTOR CONFIRMATORY FACTOR

ANALYSISANALYSIS

FACTOR STRUCTURE OFFACTOR STRUCTURE OFMETABOLIC SYNDROME:METABOLIC SYNDROME:CONFIRMATORY FACTOR CONFIRMATORY FACTOR

ANALYSISANALYSIS


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

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


SAMPLESAMPLESAMPLESAMPLE– GenderGender

• 261 women261 women

• 256 men256 men

– EthnicityEthnicity

• 33% African American33% African American

• 26% Cuban American26% Cuban American

• 41% Non-Hispanic White41% Non-Hispanic White

– GenderGender


• 256 men256 men

– EthnicityEthnicity

• 33% African American33% African American

• 26% Cuban American26% Cuban American

• 41% Non-Hispanic White41% Non-Hispanic White


The The Metabolic Metabolic SyndromeSyndrome

The The Metabolic Metabolic SyndromeSyndrome

Insulin Insulin ResistanceResistance

Insulin Insulin ResistanceResistance

ObesityObesityObesityObesity

LipidsLipidsLipidsLipids

Blood Blood PressurePressure

Blood Blood PressurePressure

Fasting InsulinFasting InsulinFasting InsulinFasting Insulin

Fasting GlucoseFasting GlucoseFasting GlucoseFasting Glucose

Body Mass IndexBody Mass IndexBody Mass IndexBody Mass Index

WaistWaistWaistWaist

HDL CholesterolHDL CholesterolHDL CholesterolHDL Cholesterol

TriglyceridesTriglyceridesTriglyceridesTriglycerides

Systolic BPSystolic BPSystolic BPSystolic BP

Diastolic BPDiastolic BPDiastolic BPDiastolic BP

0.870.87

0.800.80

0.590.59

0.720.72

0.560.56

0.470.47

0.850.85

1.001.00

-0.60-0.60

0.760.76

0.890.89

0.830.83


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

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


(Klaus, Hurwitz et al., (Klaus, Hurwitz et al., submittedsubmitted))(Klaus, Hurwitz et al., (Klaus, Hurwitz et al., submittedsubmitted))

Structural Equation Model of Structural Equation Model of metabolic syndrome in different metabolic syndrome in different sample of 338 healthy adultssample of 338 healthy adults

Structural Equation Model of Structural Equation Model of metabolic syndrome in different metabolic syndrome in different sample of 338 healthy adultssample of 338 healthy adults


SAMPLESAMPLESAMPLESAMPLE– GenderGender


• 175 men175 men

– AgeAge

• 18 to 55 years18 to 55 years


MEASURESMEASURESMEASURESMEASURES– Central ObesityCentral Obesity• Waist circumferenceWaist circumference

– Insulin SensitivityInsulin Sensitivity• Euglycemic clampEuglycemic clamp

– InflammationInflammation• C-reactive proteinC-reactive protein

• Interleukin 6Interleukin 6

– FibrinolysisFibrinolysis• Plasminogen activator inhibitor-Type 1 (PAI-1)Plasminogen activator inhibitor-Type 1 (PAI-1)

– Central ObesityCentral Obesity• Waist circumferenceWaist circumference

– Insulin SensitivityInsulin Sensitivity• Euglycemic clampEuglycemic clamp

– InflammationInflammation• C-reactive proteinC-reactive protein

• Interleukin 6Interleukin 6

– FibrinolysisFibrinolysis• Plasminogen activator inhibitor-Type 1 (PAI-1)Plasminogen activator inhibitor-Type 1 (PAI-1)


MEASURESMEASURESMEASURESMEASURES– LipidsLipids

• TriglycerideTriglyceride

• High density lipoproteinHigh density lipoprotein

• Total cholesterol/HDLTotal cholesterol/HDL

– Echocardiography (Cardiac Mass)Echocardiography (Cardiac Mass)• Left ventricular mass indexLeft ventricular mass index

• Interventricular mass indexInterventricular mass index

• Left posterior wall thicknessLeft posterior wall thickness

– Vascular Endothelial FunctionVascular Endothelial Function• Endothelial dependent brachial a. vasodilationEndothelial dependent brachial a. vasodilation

– LipidsLipids• TriglycerideTriglyceride

• High density lipoproteinHigh density lipoprotein

• Total cholesterol/HDLTotal cholesterol/HDL

– Echocardiography (Cardiac Mass)Echocardiography (Cardiac Mass)• Left ventricular mass indexLeft ventricular mass index

• Interventricular mass indexInterventricular mass index

• Left posterior wall thicknessLeft posterior wall thickness

– Vascular Endothelial FunctionVascular Endothelial Function• Endothelial dependent brachial a. vasodilationEndothelial dependent brachial a. vasodilation


Fibrinolysis

0.40

0.76

-0.54

-0.24

-0.29

-0.28

-0.24

-0.43

InflammationR 2=0.57

CentralObesity

LipidemiaR 2=0.16

0.20

0.65

0.23

0.16

0.11

-0.30

0.27

-0.22

-0.19-0.19

0.16

InsulinSensitivity

R 2=0.42

GlucoseTolerance

R 2=0.30

R 2=0.34

CardiacContractility

R 2=0.11

Cardiac Compliance

R 2=0.10

CardiacMassR 2=0.42

-0.18

0.27

Diastolic Blood

PressureR 2=0.34

MyocardialOxygen Demand

R 2=0.30

Endothelial -dependent

FMDR 2=0.13

0.35

0.18

-0.15

FibrinolysisFibrinolysis

0.400.40

0.760.76

-- 0.540.54

-- 0.240.24

-- 0.290.29

-- 0.280.28

--0.240.24

-- 0.430.43

InflammationR 2=0.57

InflammationInflammationRR 22==0.570.57

CentralCentralObesityObesity

LipidemiaR 2=0.16

LipidemiaLipidemiaRR 22 =0.16=0.16

0.200.20

0.650.65

0.230.23

0.16

0.110.11

--0.300.30

0.270.27

-- 0.220.22

--0.190.19--0.190.19

0.160.16

InsulinInsulinSensitivitySensitivity

RR 22 =0.42=0.42

GlucoseGlucoseToleranceTolerance

RR 22 =0.30=0.30

RR 22 =0.34=0.34

CardiacCardiacContractilityContractility

RR 22 =0.11=0.11

CardiacCardiac ComplianceCompliance

RR 22 =0.10=0.10

CardiacCardiacMassMassRR 22=0.42=0.42

--0.180.18

0.270.27

Diastolic Blood

PressureR 2=0.34


R 2=0.30


FMDR 2=0.13

Diastolic Blood

PressureR 2=0.34

Diastolic Blood

PressureR 2=0.34

DiastolicDiastolic BloodBlood

PressurePressureRR 22=0.34=0.34


R 2=0.30

MyocardialMyocardialOxygenOxygen DemandDemand

RR 22=0.300.30


FMDR 2=0.13


FMDR 2=0.13

EndothelialEndothelial -dependentdependent

FMDFMDRR 22=0.13=0.13

0.350.35

0.180.18

-- 0.150.15


Fat/CarbFat/Carb

StressStress

AgeAge

GenderGender

CentralCentralObesityObesity

RR22 = 0.12 = 0.12


SUMMARY IN HEALTHY ADULTSSUMMARY IN HEALTHY ADULTSSUMMARY IN HEALTHY ADULTSSUMMARY IN HEALTHY ADULTS

– The model shows direct and indirect The model shows direct and indirect pathways, linking cardiac risk factorspathways, linking cardiac risk factors

– Central obesity is a major proximal Central obesity is a major proximal variable in the pathwayvariable in the pathway

– Obesity predicts inflammation, Obesity predicts inflammation, lipidemia and cardiac masslipidemia and cardiac mass

– Stress predicts central obesity, Stress predicts central obesity, explaining 5% of the varianceexplaining 5% of the variance


– Overall model in healthy adults Overall model in healthy adults indicates CV risk factors predict indicates CV risk factors predict blood pressure.blood pressure.

– Do adolescents with high blood Do adolescents with high blood pressure reveal metabolic pressure reveal metabolic syndrome?syndrome?

– Overall model in healthy adults Overall model in healthy adults indicates CV risk factors predict indicates CV risk factors predict blood pressure.blood pressure.

– Do adolescents with high blood Do adolescents with high blood pressure reveal metabolic pressure reveal metabolic syndrome?syndrome?


Modifying Risk in Youth with Modifying Risk in Youth with Elevated Blood PressureElevated Blood PressureModifying Risk in Youth with Modifying Risk in Youth with Elevated Blood PressureElevated Blood Pressure

Patrice Saab, Project LeaderPatrice Saab, Project Leader


PARTICIPANTSPARTICIPANTSPARTICIPANTSPARTICIPANTS– 1010THTH Grade; Mean age, 16.2 yrs Grade; Mean age, 16.2 yrs

– 148 Participants148 Participants

• 107 boys107 boys

• 41 girls41 girls

– EthnicityEthnicity %%

• Hispanic WhiteHispanic White 5151

• BlackBlack 3030

• Non Hispanic WhiteNon Hispanic White 1616

• OtherOther 33

– 1010THTH Grade; Mean age, 16.2 yrs Grade; Mean age, 16.2 yrs

– 148 Participants148 Participants

• 107 boys107 boys

• 41 girls41 girls

– EthnicityEthnicity %%

• Hispanic WhiteHispanic White 5151

• BlackBlack 3030

• Non Hispanic WhiteNon Hispanic White 1616

• OtherOther 33


– Youth with BP > 90Youth with BP > 90thth percentile on percentile on 2 occasions in ELEVATED group2 occasions in ELEVATED group

– Youth’s friend with BP < 90Youth’s friend with BP < 90thth percentile comprised NORMAL percentile comprised NORMAL groupgroup

– Youth with BP > 90Youth with BP > 90thth percentile on percentile on 2 occasions in ELEVATED group2 occasions in ELEVATED group

– Youth’s friend with BP < 90Youth’s friend with BP < 90thth percentile comprised NORMAL percentile comprised NORMAL groupgroup


VariableVariable ElevatedElevated NormalNormal

SBP (mmHSBP (mmHgg) ) ** 133133 117117

DBP (mmHDBP (mmHgg) ) ** 7777 6969

Parental history HT(%) Parental history HT(%) ** 6969 3838

BMI (kg/mBMI (kg/m22) ) ** 31.431.4 26.326.3

* P < .01* P < .01




Triglycerides (mg/dL) Triglycerides (mg/dL) ** 107107 8484

HDL (mg/dL) HDL (mg/dL) ** 4141 4444

LDL (mg/dL)LDL (mg/dL) 102102 9494

Total Cholesterol (mg)dL)Total Cholesterol (mg)dL) 164164 154154

Total Cholesterol / HDL Total Cholesterol / HDL ** 4.14.1 3.73.7* P < .05* P < .05



Fasting Glucose (mg/dL)Fasting Glucose (mg/dL) 8686 8585

Glucose 120 min (mg/dL)Glucose 120 min (mg/dL)** 102102 9393

VOVO2 max2 max (ml/kg/min) (ml/kg/min)** 3737 4141

* P < .05* P < .05




LVM/HLVM/H2.72.7 (g/m (g/m2.72.7) ) ** 41.641.6 36.636.6

Cardiac Index (l/min/mCardiac Index (l/min/m22) ) ** 3.43.4 3.13.1

Stroke Index (ml/mStroke Index (ml/m22) ) ** 46.846.8 43.943.9

* P < .01* P < .01

Echocardiographic DataEchocardiographic DataEchocardiographic DataEchocardiographic Data


CRITERIA FOR METABOLIC CRITERIA FOR METABOLIC SYNDROMESYNDROME

CRITERIA FOR METABOLIC CRITERIA FOR METABOLIC SYNDROMESYNDROME

– Blood PressureBlood Pressure 130/85 mmHg130/85 mmHg

– WaistWaist 102 cm (males)102 cm (males) 88 cm (females)88 cm (females)

– HDLHDL 40 mg/dL (males)40 mg/dL (males) 50 mg/dL (females50 mg/dL (females

– Triglyceride Triglyceride 150 mg/dL150 mg/dL

– Fasting Glucose Fasting Glucose 110 mg/dL110 mg/dL

– Blood PressureBlood Pressure 130/85 mmHg130/85 mmHg

– WaistWaist 102 cm (males)102 cm (males) 88 cm (females)88 cm (females)

– HDLHDL 40 mg/dL (males)40 mg/dL (males) 50 mg/dL (females50 mg/dL (females

– Triglyceride Triglyceride 150 mg/dL150 mg/dL

– Fasting Glucose Fasting Glucose 110 mg/dL110 mg/dL

(Must meet at least 3 of 5)(Must meet at least 3 of 5)


Waist Waist ≥ 102 ≥ 102 cm in boyscm in boys ≥ 88 cm in ≥ 88 cm in

girlsgirls

LDLLDL>>

110 mg/dL110 mg/dL

LVM/htLVM/ht2.72.7 9595thth

percentilepercentile(38.6 g/m(38.6 g/m2.72.7))

Risk Factor Cut PointsRisk Factor Cut PointsRisk Factor Cut PointsRisk Factor Cut Points

Pre

vale

nce

Pre

vale

nce

(%

)(%

)P

reva

len

ceP

reva

len

ce (

%)

(%)

BMI BMI

9595thth percentilepercentile

TRIGTRIG

150 150 mg/dLmg/dL

HDL HDL 40 mg/dL in 40 mg/dL in

boys & 50 boys & 50 mg/dL in girlsmg/dL in girls

Elevated NormalNormalElevated NormalNormal

All p’s significant at p < .05All p’s significant at p < .05

0

10

20

30

40

50

60

70

80

90


– 31% of Elevated BP group and 5% 31% of Elevated BP group and 5% of Normal BP group met adult of Normal BP group met adult criteria for metabolic syndromecriteria for metabolic syndrome

– Elevated blood pressure predicts Elevated blood pressure predicts adult metabolic syndrome in adult metabolic syndrome in adolescents (p<.001)adolescents (p<.001)

– 31% of Elevated BP group and 5% 31% of Elevated BP group and 5% of Normal BP group met adult of Normal BP group met adult criteria for metabolic syndromecriteria for metabolic syndrome

– Elevated blood pressure predicts Elevated blood pressure predicts adult metabolic syndrome in adult metabolic syndrome in adolescents (p<.001)adolescents (p<.001)

Metabolic SyndromeMetabolic SyndromeMetabolic SyndromeMetabolic Syndrome


Structural Equation Modeling Structural Equation Modeling in 205 adolescents in 205 adolescents (150 boys, 55 girls)(150 boys, 55 girls)

Structural Equation Modeling Structural Equation Modeling in 205 adolescents in 205 adolescents (150 boys, 55 girls)(150 boys, 55 girls)

– Half with elevated blood pressureHalf with elevated blood pressure

– Half with normal blood pressureHalf with normal blood pressure

– Half with elevated blood pressureHalf with elevated blood pressure

– Half with normal blood pressureHalf with normal blood pressure


.37 *.37 *

CHOLCHOL

FITFIT

BMIBMI

LDLLDL

TGTG

HDLHDL

PAPA

% % POLY POLY FATFAT

% % POLY POLY FATFAT

% % TOT TOT FATFAT

% % TOT TOT FATFAT

% SAT FAT

% SAT FAT

DIET

-.43 *-.43 *

.15 *.15 *

.02 .02 **

-.20 *-.20 *

.70 *.70 *

**


CONCLUSIONSCONCLUSIONSCONCLUSIONSCONCLUSIONS

– Abdominal obesity is a key feature Abdominal obesity is a key feature of metabolic syndrome in youth.of metabolic syndrome in youth.

– Diet and poor fitness predict Diet and poor fitness predict abdominal obesity in youth.abdominal obesity in youth.

– Abdominal obesity is a key feature Abdominal obesity is a key feature of metabolic syndrome in youth.of metabolic syndrome in youth.

– Diet and poor fitness predict Diet and poor fitness predict abdominal obesity in youth.abdominal obesity in youth.


COMMENTCOMMENTCOMMENTCOMMENT

– The adolescents with metabolic The adolescents with metabolic syndrome seem destined to syndrome seem destined to develop premature develop premature cardiovascular disease unless cardiovascular disease unless the syndrome itself is treatedthe syndrome itself is treated

– Weight reduction is Tx of choiceWeight reduction is Tx of choice

– The adolescents with metabolic The adolescents with metabolic syndrome seem destined to syndrome seem destined to develop premature develop premature cardiovascular disease unless cardiovascular disease unless the syndrome itself is treatedthe syndrome itself is treated

– Weight reduction is Tx of choiceWeight reduction is Tx of choice


STRUCTURAL EQUATION STRUCTURAL EQUATION MODEL FOR METABOLIC MODEL FOR METABOLIC SYNDROME IN POST-MI SYNDROME IN POST-MI PATIENTSPATIENTS

STRUCTURAL EQUATION STRUCTURAL EQUATION MODEL FOR METABOLIC MODEL FOR METABOLIC SYNDROME IN POST-MI SYNDROME IN POST-MI PATIENTSPATIENTS

(Schneiderman, Gellman et al., in preparation)(Schneiderman, Gellman et al., in preparation)


PARTICIPANTSPARTICIPANTSPARTICIPANTSPARTICIPANTSMean age: 53 yrsMean age: 53 yrs

Mean time since index MI: 61 daysMean time since index MI: 61 days

Number of patients: 174Number of patients: 174

– GenderGender• 55 Women55 Women

• 119 Men119 Men

– EthnicityEthnicity• 136 (78%) Hispanic White136 (78%) Hispanic White

• 29 (17%) Black29 (17%) Black

• 6 (3%) Non Hispanic White6 (3%) Non Hispanic White

• 3 (2%) Other3 (2%) Other

Mean age: 53 yrsMean age: 53 yrs

Mean time since index MI: 61 daysMean time since index MI: 61 days

Number of patients: 174Number of patients: 174

– GenderGender• 55 Women55 Women

• 119 Men119 Men

– EthnicityEthnicity• 136 (78%) Hispanic White136 (78%) Hispanic White

• 29 (17%) Black29 (17%) Black

• 6 (3%) Non Hispanic White6 (3%) Non Hispanic White

• 3 (2%) Other3 (2%) Other


WEIGHT and METABOLISMWEIGHT and METABOLISMWEIGHT and METABOLISMWEIGHT and METABOLISM– WeightWeight

• NormalNormal 15%15%

• Overweight (BMI >25 <30)Overweight (BMI >25 <30) 44%44%

• Obese (BMI Obese (BMI 30) 30) 41%41%

– Metabolic syndromeMetabolic syndrome 88%88%

– Diabetes (FG Diabetes (FG 126 mg/dL) 126 mg/dL) 21%21%

– Impaired Glucose (FG 111-125 mg/dL)Impaired Glucose (FG 111-125 mg/dL) 14%14%

– Normal Glucose Normal Glucose 65%65%

– WeightWeight

• NormalNormal 15%15%

• Overweight (BMI >25 <30)Overweight (BMI >25 <30) 44%44%

• Obese (BMI Obese (BMI 30) 30) 41%41%

– Metabolic syndromeMetabolic syndrome 88%88%

– Diabetes (FG Diabetes (FG 126 mg/dL) 126 mg/dL) 21%21%

– Impaired Glucose (FG 111-125 mg/dL)Impaired Glucose (FG 111-125 mg/dL) 14%14%

– Normal Glucose Normal Glucose 65%65%


PRESCRIBED MEDICATIONSPRESCRIBED MEDICATIONSPRESCRIBED MEDICATIONSPRESCRIBED MEDICATIONS

%%

– AntihypertensivesAntihypertensives 9999

– StatinsStatins 8989

– Anticoagulants Anticoagulants (including aspirin: 89%)(including aspirin: 89%) 9393

%%

– AntihypertensivesAntihypertensives 9999

– StatinsStatins 8989

– Anticoagulants Anticoagulants (including aspirin: 89%)(including aspirin: 89%) 9393


ΧΧ22(19) (19) = 20.398 (p = = 20.398 (p =

.37).37)

CFI = .996CFI = .996

RMSEA = .020RMSEA = .020

SRMR = .047SRMR = .047

ΧΧ22(19) (19) = 20.398 (p = = 20.398 (p =

.37).37)

CFI = .996CFI = .996

RMSEA = .020RMSEA = .020

SRMR = .047SRMR = .047

PAI-1PAI-1

Insulin Insulin Sensitivity Sensitivity

IndexIndex

CRPCRP

LV MassLV Mass

Glucose AUCGlucose AUC

HDLHDL

Waist Waist CircumferenCircumferen

cece

EthnicityEthnicityEthnicityEthnicity

GenderGenderGenderGender

AgeAgeAgeAge

.75.75

.32.32

-.33-.33

-.87-.87

-.32-.32

-.17-.17

-.19-.19

-.27-.27

.32.32

-.45-.45



– Waist circumference predicts Waist circumference predicts inflammation, insulin resistance, inflammation, insulin resistance, lipids, blood glucose, coagulation and lipids, blood glucose, coagulation and LV mass.LV mass.

– Differences in structural models Differences in structural models between healthy young adults and between healthy young adults and post-MI patients (in BP and lipids) is post-MI patients (in BP and lipids) is attributable to antihypertensive attributable to antihypertensive medication and statins.medication and statins.

– Waist circumference predicts Waist circumference predicts inflammation, insulin resistance, inflammation, insulin resistance, lipids, blood glucose, coagulation and lipids, blood glucose, coagulation and LV mass.LV mass.

– Differences in structural models Differences in structural models between healthy young adults and between healthy young adults and post-MI patients (in BP and lipids) is post-MI patients (in BP and lipids) is attributable to antihypertensive attributable to antihypertensive medication and statins.medication and statins.



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

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


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


–Two randomized clinical Two randomized clinical trials showed that lifestyle trials showed that lifestyle intervention can postpone intervention can postpone Type 2 diabetesType 2 diabetes

– DPP, 2002, DPP, 2002, N. Eng. J. MedN. Eng. J. Med., USA., USA– Tuomilehto, 2001, Tuomilehto, 2001, N. Eng. J. Med.N. Eng. J. Med., Finland, Finland


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


Tuomilehto (2001)Tuomilehto (2001)

– Mean weight lost in year 1Mean weight lost in year 1• Intervention: 4.2 Intervention: 4.2 ± 5.1 Kg± 5.1 Kg

• Control: 0.8 ± 3.7 KgControl: 0.8 ± 3.7 Kg

– Cumulative incidence of diabetes after Cumulative incidence of diabetes after 4 years:4 years:• Intervention: 11%Intervention: 11%

• Control: 23%Control: 23%

– Risk of diabetes reduced 58% (p < .001)Risk of diabetes reduced 58% (p < .001)


– RCT of 3234 nondiabetics with RCT of 3234 nondiabetics with elevated glucose randomized to:elevated glucose randomized to:

• Lifestyle modificationsLifestyle modifications

• MetforminMetformin

• PlacbeoPlacbeo

– Average follow-up 2.8 yearsAverage follow-up 2.8 years

– RCT of 3234 nondiabetics with RCT of 3234 nondiabetics with elevated glucose randomized to:elevated glucose randomized to:

• Lifestyle modificationsLifestyle modifications

• MetforminMetformin

• PlacbeoPlacbeo

– Average follow-up 2.8 yearsAverage follow-up 2.8 years

DIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAM

— (DPP 2002, (DPP 2002, N Eng J Med)N Eng J Med)— (DPP 2002, (DPP 2002, N Eng J Med)N Eng J Med)


16-lesson curriculum 16-lesson curriculum covering diet, exercise and covering diet, exercise and behavior modificationbehavior modification

16-lesson curriculum 16-lesson curriculum covering diet, exercise and covering diet, exercise and behavior modificationbehavior modification

DIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAM


DIABETES PREVENTION PROGRAMDIABETES PREVENTION PROGRAM

–Cumulative Incidence of DiabetesCumulative Incidence of Diabetes

• PlaceboPlacebo 28.9%28.9%

• MetforminMetformin 21.7%21.7%

• BehaviorBehavior 14.4%14.4%

–Changes in weight and physical Changes in weight and physical activity differed among groupsactivity differed among groups(p < .001 for each comparison)(p < .001 for each comparison)

–Cumulative Incidence of DiabetesCumulative Incidence of Diabetes

• PlaceboPlacebo 28.9%28.9%

• MetforminMetformin 21.7%21.7%

• BehaviorBehavior 14.4%14.4%

–Changes in weight and physical Changes in weight and physical activity differed among groupsactivity differed among groups(p < .001 for each comparison)(p < .001 for each comparison)



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

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


– Diabetes Prevention Project (2002) Diabetes Prevention Project (2002) showed lifestyle intervention (diet and showed lifestyle intervention (diet and exercise) can delay the onset of type 2 exercise) can delay the onset of type 2 diabetesdiabetes

• Our behavior change pathway is Our behavior change pathway is consistent with the RCT resultsconsistent with the RCT results

– Project LOOK AHEAD is now examining Project LOOK AHEAD is now examining long term (up to 11.5 yrs) effects of long term (up to 11.5 yrs) effects of weight loss upon CVD event rates in weight loss upon CVD event rates in overweight and obese type 2 diabeticsoverweight and obese type 2 diabetics

– Diabetes Prevention Project (2002) Diabetes Prevention Project (2002) showed lifestyle intervention (diet and showed lifestyle intervention (diet and exercise) can delay the onset of type 2 exercise) can delay the onset of type 2 diabetesdiabetes

• Our behavior change pathway is Our behavior change pathway is consistent with the RCT resultsconsistent with the RCT results

– Project LOOK AHEAD is now examining Project LOOK AHEAD is now examining long term (up to 11.5 yrs) effects of long term (up to 11.5 yrs) effects of weight loss upon CVD event rates in weight loss upon CVD event rates in overweight and obese type 2 diabeticsoverweight and obese type 2 diabetics


PsychosocialPsychosocialInterventionIntervention

PsychosocialPsychosocialInterventionIntervention

11o o or 2or 2oo

CVD PREVENTIONCVD PREVENTION11o o or 2or 2oo

CVD PREVENTIONCVD PREVENTION

BehaviorsBehaviorsBehaviorsBehaviors

HormonesHormonesHormonesHormones

MoodMoodMoodMood

StressStressStressStress

- Adherence- Adherence- Adherence- Adherence- Lifestyle- Lifestyle- Lifestyle- Lifestyle


– Interaction of diet, social status Interaction of diet, social status and unstable environment can and unstable environment can promote atherosclerosis in promote atherosclerosis in monkeysmonkeys

– Chronic administration of beta Chronic administration of beta blocker can reduce the effectsblocker can reduce the effects

– Interaction of diet, social status Interaction of diet, social status and unstable environment can and unstable environment can promote atherosclerosis in promote atherosclerosis in monkeysmonkeys

– Chronic administration of beta Chronic administration of beta blocker can reduce the effectsblocker can reduce the effects

Kaplan and ManuckKaplan and ManuckKaplan and ManuckKaplan and Manuck


– Reducing sympathetic nervous Reducing sympathetic nervous system arousal and system arousal and hypothalamic pituitary hypothalamic pituitary adrenocortical activity thought adrenocortical activity thought to be cardioprotectiveto be cardioprotective

– Reducing sympathetic nervous Reducing sympathetic nervous system arousal and system arousal and hypothalamic pituitary hypothalamic pituitary adrenocortical activity thought adrenocortical activity thought to be cardioprotectiveto be cardioprotective

Consequences of Stress at IssueConsequences of Stress at IssueConsequences of Stress at IssueConsequences of Stress at Issue


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

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


Social Environment, Social Environment, Endocrines & Vascular Endocrines & Vascular Mechanisms in Progression Mechanisms in Progression of Atherosclerosisof Atherosclerosis

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


Watanabe Heritable Watanabe Heritable Hyperlipidemic Rabbit (WHHL)Hyperlipidemic Rabbit (WHHL)

– Model for human familial Model for human familial hypercholesterolemiahypercholesterolemia

– Spontaneous genetic mutation in LDL Spontaneous genetic mutation in LDL receptor synthesisreceptor synthesis

– Extremely high plasma lipids from birthExtremely high plasma lipids from birth

– Aortic atherosclerosis begins at 2 months, Aortic atherosclerosis begins at 2 months, severe in all animals by 7 months, CHD severe in all animals by 7 months, CHD develops by 8-10 months, death occurs after develops by 8-10 months, death occurs after 1 year1 year


CRP measured early in the CRP measured early in the disease process (3 and 5 disease process (3 and 5 mos) significantly predicts mos) significantly predicts future atherosclerosis (7 future atherosclerosis (7 mos) in Watanabe mos) in Watanabe hyperlipidemic rabbitshyperlipidemic rabbits

CRP measured early in the CRP measured early in the disease process (3 and 5 disease process (3 and 5 mos) significantly predicts mos) significantly predicts future atherosclerosis (7 future atherosclerosis (7 mos) in Watanabe mos) in Watanabe hyperlipidemic rabbitshyperlipidemic rabbits

Brooks et al., 2006 SBMBrooks et al., 2006 SBM


Social Environment and Progression of Social Environment and Progression of Atherosclerosis in the WHHLAtherosclerosis in the WHHL

(McCabe et al., 2002, (McCabe et al., 2002, CirculationCirculation))

– 33 male WHHLs, 3 months of age33 male WHHLs, 3 months of age

– Assigned to one of 3 social conditions:Assigned to one of 3 social conditions:• Unstable (paired with unfamiliar rabbit 4hrs/day, Unstable (paired with unfamiliar rabbit 4hrs/day,

pairing rearranged each week)pairing rearranged each week)

• Stable (paired with littermate 4hrs/day, pairing Stable (paired with littermate 4hrs/day, pairing maintained throughout study)maintained throughout study)

• Individually-caged (housed alone, no contact with Individually-caged (housed alone, no contact with other animals)other animals)

– Study ran from 3 to 7 months of ageStudy ran from 3 to 7 months of age


Percent Time in Behavior as a Percent Time in Behavior as a Function of Group (Mean ± SEM)Function of Group (Mean ± SEM)

Percent Time in Behavior as a Percent Time in Behavior as a Function of Group (Mean ± SEM)Function of Group (Mean ± SEM)

Agonistic BehaviorAgonistic Behavior 45.0 (45.0 (±±9.7)*9.7)* 23.5 (±8.8)23.5 (±8.8) n/an/a

Affiliative BehaviorAffiliative Behavior 13.9 (±4.6)13.9 (±4.6) 21.3 (±7.2)†21.3 (±7.2)† n/an/a

Other Nonagonistic Other Nonagonistic BehaviorBehavior

18.0 (±4.1)*18.0 (±4.1)* 27.9 (±7.1)*27.9 (±7.1)* 37.7 (±2.7)*37.7 (±2.7)*

InactivityInactivity 23.1 (±1.3)23.1 (±1.3) 27.3 (±1.7)‡27.3 (±1.7)‡ 62.3 (±0.8)*62.3 (±0.8)*

UnstableUnstable StableStableIndividually-

caged

Individually-caged

* p<.0001 vs other groups* p<.0001 vs other groups† † p<.01 vs unstablep<.01 vs unstable‡ ‡ p<.05 vs unstablep<.05 vs unstable


Area of Atherosclerosis as a Area of Atherosclerosis as a Function of Social EnvironmentFunction of Social Environment

0

100

200

300

400

500

600

700

800

Unstable Stable Individually-caged

Are

a o

f A

the

ros

cle

ros

is (

mm

2)


– Stable social environment, characterized by Stable social environment, characterized by increased affiliative behavior and decreased increased affiliative behavior and decreased agonistic behavior, slows the progression of agonistic behavior, slows the progression of atherosclerosis by approximately 50% in atherosclerosis by approximately 50% in animals genetically predisposed to diseaseanimals genetically predisposed to disease

– Unstable group exhibited more advanced Unstable group exhibited more advanced lesions than the other groupslesions than the other groups

– Group differences in disease could not be Group differences in disease could not be explained by differences in lipids, explained by differences in lipids, glucocorticoids, or gonadal steroidsglucocorticoids, or gonadal steroids



– Stable social environment, characterized by Stable social environment, characterized by increased affiliative behavior & less agonistic increased affiliative behavior & less agonistic behavior, slows the progression of behavior, slows the progression of atherosclerosis in animals genetically atherosclerosis in animals genetically predisposed to diseasepredisposed to disease

– Stable environment is accompanied by Stable environment is accompanied by increased plasma oxytocinincreased plasma oxytocin

• Note that affiliative interaction between human Note that affiliative interaction between human partners releases oxytocinpartners releases oxytocin(Grewen, Girdler, Amico, & Light, 2005)(Grewen, Girdler, Amico, & Light, 2005)



Pathophysiology of AtherosclerosisPathophysiology of Atherosclerosis

Endothelium

Vessel Lumen

MCP-1

E-Selectin

Intima

VCAM-1ICAM-1

StickingMonocyte Rolling

Transmigration

From Charo. Current Opinion in Lipidology 1992


Pathophysiology of AtherosclerosisPathophysiology of Atherosclerosis

Endothelium

Vessel Lumen

IntimaFoam Cell

Monocyte

Cytokines

Growth FactorsMetalloproteinases

Cell ProliferationMatrix Degradation Macrophage

Ox-LDLOx-LDLOx-LDLOx-LDL

LDLLDL

NAD(P)HOxidase


Oxytocin and Vascular Cells:Oxytocin and Vascular Cells:In VitroIn Vitro studies studies

Oxytocin and Vascular Cells:Oxytocin and Vascular Cells:In VitroIn Vitro studies studies

– We have cultured human aortic We have cultured human aortic endothelial cells, monocytes, and endothelial cells, monocytes, and vascular smooth muscle cellsvascular smooth muscle cells

– Incubated cells with physiological Incubated cells with physiological concentrations of oxytocinconcentrations of oxytocin

– Assessed the influence of oxytocin on Assessed the influence of oxytocin on oxidative stress (via NAD[P]H oxidase oxidative stress (via NAD[P]H oxidase activity) and inflammation (via cell activity) and inflammation (via cell adhesion molecule expression) adhesion molecule expression)

– We have cultured human aortic We have cultured human aortic endothelial cells, monocytes, and endothelial cells, monocytes, and vascular smooth muscle cellsvascular smooth muscle cells

– Incubated cells with physiological Incubated cells with physiological concentrations of oxytocinconcentrations of oxytocin

– Assessed the influence of oxytocin on Assessed the influence of oxytocin on oxidative stress (via NAD[P]H oxidase oxidative stress (via NAD[P]H oxidase activity) and inflammation (via cell activity) and inflammation (via cell adhesion molecule expression) adhesion molecule expression)


Vascular Cells Express Vascular Cells Express Oxytocin ReceptorsOxytocin Receptors

Vascular Cells Express Vascular Cells Express Oxytocin ReceptorsOxytocin Receptors


Oxytocin Inhibits Vascular Oxytocin Inhibits Vascular Oxidative StressOxidative Stress

Oxytocin Inhibits Vascular Oxytocin Inhibits Vascular Oxidative StressOxidative Stress


Oxytocin inhibits Early Vascular Oxytocin inhibits Early Vascular Inflammatory ProcessesInflammatory Processes

Oxytocin inhibits Early Vascular Oxytocin inhibits Early Vascular Inflammatory ProcessesInflammatory Processes

0

500

1000

1500

2000

0 2 4 6 8

Time (h)

Me

an

Flu

ore

sc

en

ce

In

ten

sit

y

Time course of TNF-alpha-stimulatedTime course of TNF-alpha-stimulated cell surface expression of ICAM-1 in HAEC cell surface expression of ICAM-1 in HAEC

Time course of TNF-alpha-stimulatedTime course of TNF-alpha-stimulated cell surface expression of ICAM-1 in HAEC cell surface expression of ICAM-1 in HAEC

TNF

TNF + OT

ControlOxytocin


– Vascular cells express oxytocin receptorsVascular cells express oxytocin receptors

– Oxytocin inhibits oxidative stress and Oxytocin inhibits oxidative stress and inflammation in cultured vascular cellsinflammation in cultured vascular cells

– It is proposed that the beneficial effects of a It is proposed that the beneficial effects of a prosocial environment on disease prosocial environment on disease progression may be mediated through the progression may be mediated through the direct effect of peripheral oxytocin on direct effect of peripheral oxytocin on pathophysiological mechanisms occuring in pathophysiological mechanisms occuring in vascular wallvascular wall



– Behavioral (lifestyle) pathways leading Behavioral (lifestyle) pathways leading from psychosocial/behavioral from psychosocial/behavioral interventions and CVD prevention are interventions and CVD prevention are reasonably well understood.reasonably well understood.

– The hormonal/stress reduction The hormonal/stress reduction pathways between our psychosocial pathways between our psychosocial interventions and CVD prevention are interventions and CVD prevention are less well understood but are being less well understood but are being studied in appropriate models.studied in appropriate models.

– Behavioral (lifestyle) pathways leading Behavioral (lifestyle) pathways leading from psychosocial/behavioral from psychosocial/behavioral interventions and CVD prevention are interventions and CVD prevention are reasonably well understood.reasonably well understood.

– The hormonal/stress reduction The hormonal/stress reduction pathways between our psychosocial pathways between our psychosocial interventions and CVD prevention are interventions and CVD prevention are less well understood but are being less well understood but are being studied in appropriate models.studied in appropriate models.



↓ HDL ↑ LDL

Inflammation

CentralObesity

↑ IR

↓ Glucose tolerance

Hypertension

Type 2 diabetes

Endothelial dysfunction

CHD

Acute Coronary Syndrome

Dyslipidemia

↑ Cardiac mass

CRP IL-6

↑ Fibrinolysis

Summary: Why we need to decrease central obesitySummary: Why we need to decrease central obesitySummary: Why we need to decrease central obesitySummary: Why we need to decrease central obesity

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Metabolic Syndrome as Pathway for Cardiovascular Disease Neil Schneiderman University of Miami...

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