Metabolic Syndrome

1
Metabolic Syndrome Clinical Importance

• Insulin resistance diabetes
• - Coronary heart disease in hypertension

2
CHD Risk Accordingto Plasma Insulin Levels
(Quintiles)

25 20 15 10 5 0

P 0.085
P 0.002
P 0.016

CHD incidence rate per 1,000 patients/9.5 years
1 2 3 4 5
1 2 3 4 5
1 2 3 4 5
Fasting plasma insulin
1-hour plasma insulin
2-hour plasma insulin
top quintile has been divided into two deciles
n982 CHD-free men
Pyöräiä et alActa Med Scand 1985701(suppl)38-52
3
Association of SBP and CV Mortalityin Type 2
Diabetes
Nondiabetic Diabetic
CVmortalityrate/10,000 person-yr
SBP (mm Hg)
Stamler J et al. Diabetes Care. 199316434-444.
4
14 antihypertensive trialsPredicted versus
observed outcomes
Stroke reduction
CHD reduction
observed
predicted
predicted
observed
42
40
14
25
Collins et al Lancet 1990, 335 827-838
5
Metabolic Syndrome Natural History
6
The Tecumseh Blood Pressure StudyN 946

• A prospective epidemiologic study of antecedents
  of hypertension in a general population of young
  adults.

Lake Huron
Lake Michigan
Ann Arbor
CHICAGO

DETROIT

Tecumseh
7
Patient Characteristics - Tecumseh BP Study
Julius S, et al JAMA 1990, 264354-358.
8
Risk Factors - Tecumseh BP Study
Julius S, et al JAMA 1990 264 354-358.
9
Blood pressure and risk factors
Correlations are adjusted for sex
Cholesterol


Triglycerides
Hematocrit



DBP




Insulin
Overweight



Heart Rate
plt0.001 plt0.01 plt0.05
Tecumseh BP Study, 1990.
10
Metabolic variables in white coat (WC) and
sustained (SUST) borderline hypertension Tecumseh
study
plt.001
n.s.
plt.001
26
22
Insulin Level
18
14
N34
N28
N621
10
NORMAL WC SUST
Julius et al., Hypertension 16, 1990. Tecumseh
11
Blood pressure trends in Tecumseh, MI


Hypertensive

Normotensive



Age in years
plt0.01
plt0.001
Julius S, et al JAMA 264354-358, 1990
12
Arm Grith and Subscapular Skin folds in
Normotensives ( ) and Borderline
Hypertensives ( )


Sub-scapular Skin Fold (cm)
Arm Girth (cm)
Plt0.0015 Plt0.001 Julius
et al, JAMA 1990264354-358
13
Pathophysiology of the metabolic syndrome. Role
of sympathetic over activity

• In insulin resistance
• - In overweight - obesity

14
Night-time heart rate correlates with insulin
insensitivity
R 0.51 P lt 0.001
(µU/ml ? hr)
Heart Rate (beats/min)
Facchini FS et al. AJH 1996 91013-17
15
A comparison of normotensive subjects whose BP
did or did not increase after 10 years
AFTER 10 YEARS
BASELINE

600

PLASMA NOREPHINEPHRINE (pg/ml)
PLASMA NOREPHINEPHRINE (pg/ml)
400
200
No BP Increase
? BP Increase
No BP Increase
? BP Increase
Adapted from Matsuo et al, Am J Hypertension 1997
16
A comparison of normotensive subjects whose BP
did or did not increase after 10 years
AFTER 10 YEARS
BASELINE
10

8
Plasma Insulin (mU/ml)
6
4
2
No BP Increase
No BP Increase
BP Increased
BP Increased
Adapted from Masno et al, Am J Hypertension 1997
17
Why is high BP intimately associated with insulin
resistance?
How could a hemodynamic condition (hypertension)
be associated with the metabolic syndrome of
insulin resistance?
18
Schematic Presentation of the Nutritional Blood
Flow
Insulin Resistance
Normal
S. Julius, 2001
19
(No Transcript)
20
(No Transcript)
21
The Effect of Insulin Infusion and Reflex
Vasoconstriction on Glucose and Oxygen Extraction
in the Forearm of 14 Healthy Volunteers
Insulin Infusion Thigh Cuff
Insulin Infusion
Baseline
plt 0.05
Insulin
O2 and Glucose Utilization (mg/dl/min)
Oxygen extraction
Time (min)
Jamerson KA, Julius S et al. Hypertension
199321618-23.
22
Results of current long term outcome studies
support the hemodynamic concept of
insulin resistance in hypertension
23
VALUE Incidence of New-onset Diabetes
23 Risk Reduction With Valsartan
18
P lt 0.0001
16
14
12
10
New-Onset Diabetes ( of patients in treatment
group)
16.4
8
13.1
6
4
2
0
Valsartan-based Regimen (n 5254)
Amlodipine-based Regimen (n 5168)
Julius S et al. Lancet. June 2004363.
24
New onset diabetes in studies of hypertension
(Adapted from Opie and Schall J.Hyperts
221453-1458, 2004
( p 0.001)
ACEI, ARB vs Conventional

LIFE
CAPPP

NS
ALLHAT (ACEI)

CCB vs Conventional
NORDIL INSIGHT ALLHAT INVEST
NS
0.023

NS
0.004
CCB vs ARB

VALUE
0.5
2
1
Favors New drugs Favors conventional RX

25
Pathophysiology of the metabolic syndrome. Role
of sympathetic over activity

• In insulin resistance
• - In overweight - obesity

26
Overweight and HypertensionA Two Way
Street? S.Julius, M. Valentini and P.
Palatini. Hypertension 2000 35 807-813.
27
RISK OF DEVELOPING OBESITY IN 10 YEARS ACCORDING
TO BP STATUS (AT THE OUTSET SUBJECTS WERE WEIGHT
MATCHED)
Men
Women
Observed v.s. Predicted obesity
Blood Pressure Status
From Kannel WB et al. Ann Intern Med.
6748-59,1967.
28
Weight gender -matched children with higher BP
gain more weight. (The Tecumseh BP study)

Controls at age 6 ys. SBP 106 mm Hg (N49)
Skin fold thickness mm.
Upper Quintile at age 6ys. SBP 127 mm Hg (N49)
P lt 0.01
Age (years)
Julius, Valentini, Palatini Hypertension
200035807-813
29
Components of energy output
Increased through beta receptor stimulation
30
CHANGE IN HEART RATE RESPONSE TO ISOPROTERENOL (3
µg/min IV) FROM RESTING MEASUREMENT
Heart Rate (BPM)
N 18
N 25
Julius et al, Cir Research 1975 36-37 (suppl)
199.
31
Metabolic Beta-Adrenergic Responsiveness to
adrenaline infusion is Decreased in Hypertension


? HR (beats/min)
? Glucose (mg )
Hypertensives (n13) Normotensives (n13)
p lt 0.05

? Phoshate (mg )
Kjeldsen SE, et al. Blood Pressure 5, 1996.
32
HYPOTHESIS
If in addition to cardiovascular responses, the
metabolic responses were also decreased in
hypertension, the patients ability to dissipate
calories would be diminished and they would gain
more weight.
33
Heart rate response to isoproterenolol bolus is
decreased in hypertension

Delta HR (beats/min)
Isoproterenol Bolus Dose (µg/m2)
Valentini M, Julius S, et al, J of Hypertension
221999-2006, 2004
34
Energy expenditure response to isoproterenolol
is decreased in hypertension.

EE increase (Kcal/Kg/24h)
Isoproterenol i.v. Infusion Rate (ng/Kg/min)
Valentini M, Julius S, et al, J of Hypertension
221999-2006, 2004