THE METABOLIC SYNDROME A Reversible LifeThreatening Condition

1
THE METABOLICSYNDROMEA Reversible
Life-ThreateningCondition

• Defusing The MetabolicTime Bomb

2
Defusing The Metabolic Time Bomb Outline of
Module 3

• From basic science to treatment
• Intra-abdominal obesity
• Atherogenic dyslipidaemia
• Inflammation / Atherosclerosis
• Hypertension
• Glucose intolerance
• PPARs modulators of the metabolic syndrome
• Endocrine function of visceral fat
• Future research objectives
• Clinicians and the metabolic syndrome

3
Visceral Fat Associates with Atherogenic
Dyslipidaemia
Adapted from Pouliot MC, et al. Diabetes
199241826-834.

4
Visceral Fat Associates with Insulin Resistance
Adapted from Pouliot MC, et al. Diabetes
199241826-834.
5

Atherogenic Dyslipidaemia Commonly Present
withMetabolic Syndrome

• Atherogenic Dyslipidaemia
• ? Triglycerides
• ? VLDL
• ? apo CIII
• ? Small, dense LDL particles
• ? Apo B
• ? HDL
• ? Apo A-I

6
Atherogenic Dyslipidaemia
??-oxydation pathway
FFA
Glycerol
ApoB
LPL
LPL
TG
VLDL
IDL
HDL
TG
TG
EC
EC
TG
EC
cholesterol
Remnants
VLDL
EC
TG
FFA
LPL
FFA
LPL HS
EC
FFA
Chylomicrons
LPL
TG
FFA
7
Insulin Resistance and Atherogenic Dyslipidaemia
A Common Association

• Most patients with atherogenic dyslipidaemia are
  insulin resistant
• High triglycerides correlated with insulin
  resistance
• Low HDL-C and insulin resistance commonly
  co-exist
• A TG/HDL-C ratio gt 4 is suggestive of insulin
  resistance
• Many patients with insulin resistance and
  atherogenic dyslipidaemia have a fatty liver.

8
Abnormal Lipid Levels in Men With Type 2 Diabetes
Adapted from Garg A, Grundy SM. Diabetes Care.
199913153-169.
9
Abnormal Lipid levels in WomenWith Type 2
Diabetes
Adapted from Garg A, Grundy SM. Diabetes Care.
199913153-169.
10
Anti-atherogenic Properties of HDL
HDL and reverse cholesterol transport
11
Anti-atherogenic Properties of HDL

• Mechanisms other than reverse cholesterol
  transport by which HDL may be anti-atherogenic
• Anti-oxidant effects
• Inhibition of adhesion molecule expression
• Inhibition of platelet activation
• Prostacyclin stabilisation
• Promotion of NO production

12
Low HDL-C Predicts CHD Risk
Low HDL-C is an independent predictor of CHD
riskeven when LDL-C is low
Castelli WP. Can J Cardiol. 19984 (suppl
A)5A-10A.
13
Patients with Elevated Triglycerides are at
IncreasedRisk for CHD
High TG associates with higher relative risk for
CHD in the Framingham Heart Study
Castelli WP. Can J Cardiol. 19984 (suppl
A)5A-10A.
14
LDL Size and CHD risk
LDL size divergent findings on CHD risk
15
Small, Dense, LDL Particles were an
IndependentRisk Factor for CAD in Quebec
Cardiovascular Study
St Pierre, et al. Circulation. 20011042295.
16
Joint Evaluation of TG and LDL Size As Predictors
of First MI TG not LDL size is an independent
predictor
US Physicians Health Study
Sacks F, Campos H. J Clin Endocrin Metab. Oct.
2003.
17
Large LDL Size is an Independent Predictor of CHD
Death and MI in the Placebo but not Pravastatin
Group The CARE trial, 416 cases
Campos H, et al. JAMA 20012861468-1474.
18
LDL Size and CHD Summary of Epidemiological
Studies

• 8 Prospective Studies
• Univariate analysis
• Small LDL univariate predictor in 5 studies
• Large LDL univariate predictor in 1 study
• Multivariate analysis including HDL and TG
• Small LDL predictor in 1 study
• Large LDL predictor in 2 studies
• LDL size not a predictor in 4 studies
• Cholesterol, HDL, LDL, TG were usual predictors

Sacks F Campos H. J Clin Endocrin Metab, Oct
2003
19
Metabolic Syndrome is a Proinflammatory State

• In individuals with the metabolic syndrome,
  overproduction of proinflammatory cytokines by
  the expanded adipose tissue mass results in
• ? IL-6
• ? C-reactive protein (CRP)
• ? TNFa
• ? Resistin
• ? Adiponectin

20
CRP Increases Number of Metabolic Syndrome
Components (IRAS)
Mean values of CRP versus the number of metabolic
syndrome components dyslipidaemia, upper body
obesity, insulin resistance, hypertension
Festa A, et al. Circulation. 200110242-47.
21
High CRP Levels Predict CVD in Patients with and
without Metabolic Disorders
Malik S, et al. (NHANES 1999-2000). Diabetes
Care. 200528690-93.
22
High CRP Adds More Predictive Power for CHD
inPatients with the Metabolic Syndrome (WOSCOPS)
Sattar N, et al. WOSCOPS. Circulation.
2003108414-9.
23
The Number of Metabolic Syndrome
ComponentsCorrelate with Carotid Intimal Medial
Thickness
Composite carotid intimal medial thickness
(CIMT) with metabolic syndrome in young adults
Tzou WS, et al. J Am Coll Cardiol.
200546457-463.
24
Atherosclerosis Is An Inflammatory Disease

• Initial step of atherosclerosis leukocyte
  recruitment by the dysfunctional endothelium,
  facilitated by chemo-attractants and adhesion
  molecules (VCAM-1, ICAM-1)
• In the intima, maturation of the mononuclear
  phagocyte towards the foam cell (capture of
  modified lipoproteins)
• Activated foam cells
• express the procoagulant tissue factor
• generate reactive oxygen species and
  pro-inflammatory cytokines (CRP, IL-6)
• can also be the source of enzymes that alter the
  metabolism of the extracellular matrix
• Death of the mononuclear phagocyte by either
  oncosis or apoptosis leads to formation of the
  lipid core of the atherosclerotic plaque

25
Atherosclerosis Is An Inflammatory Disease

• The endothelium and smooth muscle vascular cells
  can themselves elaborate pro-inflammatory
  cytokines.
• In the initial phase of inflammation, elaboration
  of pro-inflammatory cytokines and the cross talk
  between leukocytes and intrinsic vascular wall
  cells play a key role in the initiation of the
  progression phase.

26
Atherosclerosis Is An Inflammatory Disease

• Alterations in the metabolism of the
  extracellular matrix under the plaque
  arterial remodelling
• Suppression of new collagen synthesis by smooth
  muscle cells
• Overproduction of collagen-degrading proteinases
  that attack the collagen within the fibrous cap
• Inflammatory mediators tightly control the
  biosynthesis of tissue factor (a procoagulant)
• Weakening of the fibrous cap thrombosis
  of a disrupted atheroma

27
Some Patients have Predominant Visceral Fat
Moderate Visceral Obesity with little Abdominal
Subcutaneous Fat
Severe Visceral Obesity with little Abdominal
Subcutaneous Fat
Fujimoto, et al. Obes Res. 19942364-371.
28
Obesity Is An Inflammatory Stimulus

• Metabolic syndrome is a proinflammatory,
  proatherogenic condition
• Many adipose tissue products can cause insulin
  resistance and inflammation
• Cytokines (e.g., TNF-a, IL-6)
• Chemokines
• Growth factors
• Procoagulants (e.g., PAI-1)
• Free fatty acids
• Resistin
• Reduced adiponectin
• Reduced nitric oxide synthase

29
Obesity Is Proinflammatory State
Serum C-reactive protein rises with increasing
BMIin both men and women
Visser, et al. JAMA. 19992822131-2135.
30
CRP Predicts Incident Hypertension
Sesso HD, et al. JAMA. 20032902945-2951.
31
The Metabolic Syndrome Worsens the Prognosis
ofPatients with Essential Hypertension
Schillaci G, et al. (PIUMA study). J Am Coll
Cardiol 2004431817-22.
32
The Metabolic Syndrome Associates with Greater
Left Ventricular Hypertrophy in Patients with
Hypertension
C Cuspidi et al. (PIUMA). J Hypertens
2004221991-8.
33
Adiponectin Levels are Significantly Lower in
Hypertensive Subjects
Iwashima Y, et al. Hypertension 2004431318-1323.
34
Patients with Coronary Heart Disease Have a High
Prevalence of Dysglycaemia
Euro Heart Survey
Glucose testing during acute admissions for
coronary heart disease Glucose testing done
electively in patients with coronary disease
Bartnik M, et al (Euro Heart Survey on diabetes).
Eur Heart J 2004251880-90.
35
Abnormal Glucose Tolerance Predicts Mortalityin
Patients with Acute Myocardial Infarction
Bartnik M, et al. Eur Heart J 2004251990-7.
36
From Basic Science to TreatmentPPARS Modulators
of the Metabolic Syndrome
PPARs

Regulators of energy homeostasis, lipid and
glucose metabolism and inflammation
Modulators of the metabolic syndrome and its
cardiovascular complications
37
PPARs Regulate Lipid and Glucose Metabolism
38
Control of Gene Expression by PPARs
PPAR agonists (fatty acids, fibrates, glitazones,
glitazars)
RXR
PPAR
PPAR
p65
p50
Fos
Jun
STAT1
STAT3
RXR
PPAR
GGGGACTTTCCC
TGAGTCA
CTGGGA
Target gene
AGGTCA (N) 1, 2 AGGTCA
NF-kB-RE
TRE
ISGF-RE
PPRE
Trans- activation
Trans-repression
Lipid homeostasis Glucose homeostasis
Anti-inflammatory properties
39
PPARg Agonists Modulate Adipocyte Function
40
PPARg Activation Improves Glucose Metabolism
Adipocyte (PPARg)
? Insulin signaling
?Cytokine production
?FFA levels
Improved Glucose homeostasis
41
PPARg Activation Improves Glucose Metabolism
Adipocyte (PPARg)
? Adiponectin
Inflammatory cytokines (IL-6, TNFa,)
?
Improved Glucose homeostasis Endothelial
function
42
PPARg Agonists Reduce Plasma Free Fatty Acids
Lonnqvist F, et al. Diabetologia 1999 42 (Suppl
1) A231. Abstract (poster) 869.
43
Excess FFA are linked to both Insulin Resistance
and Inflammation
FFA
FA CoA
DAG
IkB
P
--SerIRS1
PKC
NFkB
Inflammation
Insulin Resistance
Inoguchi et al. Diabetes 2000491939-45. Yu et
al. Diabetologia 200144614-20 Lu et al.
Circ.Res. 199679611-8.
44
PPARa Agonists Fibrates(fenofibrate,
gemfibrozil,)

• Major actions
• Reduce atherogenic dyslipidaemia
• Lower triglycerides
• Lower apo B
• Lower apo CIII
• Lower small LDL
• Raise HDL
• Reduces proinflammatory state

45
PPARa Modulates Triglyceride Metabolism
PPARa agonists
Liver
PPARa
apo A-V production
apo C-III production
m
i
t
o
c
h
o
n
d
r
i
a
l

F
A
b
-
o
x
i
d
a
t
i
o
n
VLDL-TG clearance

VLDL-TG secretion
Apo CIII, Plasma TG
small LDL
46
PPARa Agonists Induce the Transcription of HDL
Apolipoproteins apo A-I and apo A-II
PPARa agonists
Liver
Transcription of apo A-I gene
Transcription of apo A-II gene
HDL particles
47
PPAR Agonists Interrupt the Inflammatory Cycle
48
PPARs May Inhibit the NFkB Signaling Pathway at
Multiple Steps (1-6)
49
PPAR Agonists May Block Inflammatory
Atherogenesis at Several Steps
50
Specialized Laboratory Testing Can Provide
Incremental Information in Some Patients with
Metabolic Syndrome

• Dysglycaemia
• OGTT
• Insulin resistance
• Fasting insulin/proinsulin levels
• HOMA-IR
• Insulin resistance by Bergman Minimal Model
• Elevated free fatty acids (fasting and during
  OGTT)
• Atherogenic dyslipidaemia
• Apolipoproteins B and A-II
• Lipoprotein subfractions

51
Specialized Laboratory Testing Can Provide
Incremental Information in Some Patients with
Metabolic Syndrome

• Vascular dysregulation
• Measurement of endothelial dysfunction
• Microalbuminuria
• Proinflammatory state
• Elevated high sensitivity C-reactive protein
  (SAA)
• Elevated inflammatory cytokines (eg TNF-alpha,
  IL-6)
• Decrease in adiponectin plasma levels

52
Lifestyle Therapies First-Line Interventions to
Reduce Metabolic Risk Factors

• The major lifestyle interventions include
• Weight loss in overweight or obese subjects
• Increased physical activity
• Modification of an atherogenic diet
• These changes will produce a reduction in all of
  the metabolic risk factors simultaneously
• In the long run, the greatest benefit for those
  with the metabolic syndrome will be derived from
  effective lifestyle intervention

53
The NutritionistThe DASH Dietary Pattern Foods

• Emphasizes fruits, vegetables, low-fat dairy
  foods
• Includes whole grains, nuts, poultry, fish
• Reduced in fats (27), red meat, sweets, and
  sugar-containing beverages
• Low sodium 65 mmol (1.5 g)

54
The DASH Diet reduces blood pressure
Vollmer WM, et al. Ann Intern Med
20011351019-18.
55
Dietary Fats Effects on Lipoproteins
Predicted changes in plasma HDL cholesterol and
triglyceride concentrations caused by low-fat or
Mediterranean diets
Sacks and Katan. Am J Med 2002113(9B)13s.
56
Polyunsaturated Fat-enriched Diets Reduce
Riskfor Cardiovascular Disease
Randomised dietary clinical trials of
polyunsaturated fats versus saturated fats
Linoleic was the major fat that replaced
saturated, but alpha-linolenic acid also
increased.
Plt0.05
Sacks and Katan. Am J Med 2002 Dec 30
supplement.
57
Diet Type and Weight Loss

• How do low-fat diets compare with
• reduced calorie moderate-fat diets?

58
Caloric Restriction with Moderate Unsaturated Fat
is Superior to Low-fat Diets for Long-term Weight
Reduction
McManus, Antinoro, Sacks. Int J Obesity.
2001251503-11.
59
Caloric Restriction with a Low-carbohydrate diet
is Superior to a Low-fat Diet for 12-month Weight
Reduction
Stern L, et al. Ann Intern Med. 2004140778-785.
60
OMNIHEARTOptimal Macronutrient Intake Trial to
Prevent Heart Disease

• OmniHeart is a controlled feeding study of
  DASH-type diets in 164 adults with hypertension
  or high normal BP.
• The original high carbohydrate, low fat DASH diet
  was modified to reduce carbohydrate and increase
  either protein or unsaturated fat.
• The goal was to improve blood pressure, serum
  lipids, and estimated CHD risk.
• Each diet was provided to the participants for 6
  weeks in crossover design.
• Body weight was kept constant.

Appel LJ, et al. JAMA 20052942455-2464.
61
Blood Pressure Results (mmHg)
Mean change from baseline in each diet
62
Lipid Results (mg/dL)
Mean Change from Baseline in Each Diet
63
Estimated 10-Year CHD Risk
from PROCAM Risk Equation Men from Framingham
Risk Equation Women
Appel LJ, et al. JAMA 20052942455-2464.
64
Conclusions

• All three diets were healthy and had beneficial
  effects on CVD risk factors and CHD risk
• Currently recommended diets, typically rich in
  carbohydrate, can be improved by shifting some
  calories to protein or monounsaturated fat

Appel LJ, et al. JAMA 20052942455-2464.
65
Approximately Half of Patients with Acute
MyocardialInfarction Have Metabolic Syndrome
(RICO AMI France)

• Metabolic syndrome defined
• by NCEP ATP III criteria
• 633 patients with confirmed
• myocardial infarction

Zeller M, et al (RICO). Arch Intern Med.
20051651192-1198.
66
Metabolic Syndrome Worsens Outcomes in Patients
with Acute Myocardial Infarction (RICO AMI
France)
Zeller M, et al (RICO). Arch Intern Med.
20051651192-1198.
67
Predictive Value of the Metabolic Syndrome
forHeart Failure in Patients with Acute MI
Zeller M, et al (RICO). Arch Intern Med.
20051651192-1198.
68
Diabetes and Metabolic Syndrome Worsen Long-term
Prognosis in Patients with Acute Myocardial
Infarction
G Levantesi G, et al. (GISSI-Prevenzione). J Am
Coll Cardiol 200546277-283.
69
Patients With the Metabolic Syndrome Have an
Increased Prevalence of Peripheral Arterial
Disease
VU JD, et al. (NHANES 1999-2000) Am J Cardiol
200596655-8.
70
Severity and Incidence of Carotid
Atherosclerosis are Higher With the Metabolic
Syndrome
Bonora E, et al. (Bruneck study). Diabetes Care
2003261251-7.
71
Young Adults with Metabolic Syndrome Have an
Increased Arterial Stiffness with Reduced
Distensibility and Compliance
Ferreira I, et al. (AGHLS) Arch Intern Med
2005165875-82.
72
The Metabolic Syndrome Associates with a History
of Myocardial Infarction Greater than any of its
Individual Components
Ninomiya JK, et al. (NHANES III). Circulation
200410942-6.
73
The Metabolic Syndrome Associates with a History
of Stroke Greater than any of its Individual
Components
Ninomiya JK, et al. (NHANES III). Circulation
200410942-6.
74
The Metabolic Syndrome is Significantly
Associated with the Prevalence of CHD in the ARIC
Study
McNeill AM, et al. Am J Cardiol
2004941249-1254.
75
There Is No Standard Pediatric Definition For
Metabolic Syndrome !
76
Multiple linear regression shows that waist
circumference and systolic blood pressure were
significant independant predictors for insulin
resistance
Conclusion Waist circumference is a predictor of
insulin resistance syndrome in children and
adolescents and could be included in clinical
practice as a simple tool to help identify
children at risk.
77
Different Definitions of Metabolic Syndrome for
Adolescents
78
Different Definitions for Metabolic Syndrome for
Adolescents
Cook, et al. Arch Pediatr Adolesc
Med 2003157821-827. De Ferranti SD, et al.
Circulation 20041102494-2497.
79
Physical Activity is Inversely Related to Waist
Circumference in Adolescents
Brage S, et al. Int J Obes Relat Metab Discord.
2004 Nov281503-8.
80
Kids Food pyramid