Linear thinking

1
Linear thinking
A
B
C








Does Not Apply to Circular Phenomena
A
B
C
2
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.
3
Nevertheless I will argue that in some
individuals -- 1. High blood pressure and
sympathetic over activity precede the metabolic
syndrome. -- 2. That sympathetic overactivity
may be the linchpin between insulin resistance,
overweight and hypertension -- 3. The ensuing
metabolic syndrome, independent of the BP
elevation, negatively affects vascular health.
4
BLOOD PRESSURE TRENDS INTECUMSEH, MI






Plt .01
Hypertensive Normotensive

S. Julius, et al JAMA 264354-358, 1990
Plt.001

5
Arm Girth 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
6
Elevated heart rate is a reliable marker of
sympathetic over activity. Sympathetic
overactivity is seen in early phases of
hypertension
7
Heart rate trends in subjects diagnosed as
hyperkinetic hypertensives at 30 years of age
Heart rate




From the Tecumseh Study
8
Elevated HR Sympathetic and Parasympathetic
Abnormalities in Borderline Hypertension
Borderline Hypertension Control Subjects

• The cardiac pacemaker
• is normal
• gt Sympathetic drive and
• lt parasympathetic inhibition
• abnormality in the integration
• of autonomic control

120 110 100 90 80 70 60
50 45 40 35 30 25 20
Cardiac Index (I/min/m2)
Heart Rate (bpm)
Rest Propranolol Atropine
Rest Propranolol Atropine
Julius et al, Circulation 1971
9
Norepinephrine and renin in mild hypertension
Plasma Norepinephrine Concentration (ng/l)
300 200 100 0

Normal Subjects
High Renin
Normal Renin
plt0.01
Essential Hypertension
Esler et al. N Engl J Med 1977296-405
10
Sympathetic overactivity is seen in early phases
of hypertension and this might precede insulin
resistance
11
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
12
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 Matsuo et al, Am J Hypertension 1997
13
Insulin and Heart Rate at Baseline and after a
High Fat Diet in a Group of Dogs Treated with
Clonidine and a Group of Dogs of Control
Insulin
Heart Rate
Plt0.001
Plt0.001
Pmol/L
bpm
n.s.
n.s.
Baseline
Diet
Adapted from Rocchini AP et al, Hypertension
199933548
14
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
15
Patient Characteristics - Tecumseh BP Study
Julius S, et al JAMA 1990, 264354-358.
16
Tecumseh Study Plasma Norepinephrine in All
Normotensives vs. Hyperkinetic and Normokinetic
Hypertensives
400 350 300 250 200
P lt 0.001
P lt 0.01
Plasma NE (pg/mL)
Normotensives (n 438)
Hyperkinetic Hypertensives (n 25)
Normokinetic Hypertensives (n 50)
Julius et al., J. Hypertension, 1991
17
Risk Factors - Tecumseh BP Study
Julius S, et al JAMA 1990 264 354-358.
18
Mechanism of insulin resistance
19
Why is high BP intimately associated with insulin
resistance?
How could a hemodynamic condition (hypertension)
be associated with the metabolic syndrome of
insulin resistance?
20
Schematic Presentation of the Nutritional Blood
Flow
Insulin Resistance
Normal
S. Julius, 2001
21
(No Transcript)
22
(No Transcript)
23
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.
24
Mechanism of weight gain
25
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.
26
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
27
CHANGE IN HEART RATE RESPONSE TO ISOPROTERENOL (3
µg/min IV) FROM RESTING MEASUREMENT
Heart Rate (BPM)
You never know what will happen in research. 30
years later this old finding became very Important
N 18
N 25
Julius et al, Cir Research 1975 36-37 (suppl)
199.
28
Increased through beta receptor stimulation
29
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.
30
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.
31
Energy expenditure response to isoproterenolol
is decreased in hypertension.

EE increase (Kcal/Kg/24h)
Isoproterenol i.v. Infusion Rate (ng/Kg/min)
Valentini, Julius, Palatini et al J. Hypertension
2004
32
Valentini M, Julius S, Palatini P, et al. J
Hypertens 2004 22 1999-2006.
Valentini M, Julius S, Palatini P, et al. J
Hypertens 2004 22 1999-2006.
33
HR Skinfold Thickness trends in Subjects
Defined at age 30 y as Pure Hyperkinetic
Borderline Hypertensives The Tecumseh Study
HR (beats/min)
SBP (mmHg)
Skinfold Thickness (mm)


110 110 90 80 70
160 150 140 130 120
18 16 14



P lt 0.0001

7 22 30
7 22 30
7 22 30
Age
Normotensive (N 787)
Hyperkinetic BL HT (N 24)
Julius S. et al. J. Hypertens. 199412495-502.
34
2- and 3-Adrenergic Receptor Polymorphisms Are
Related to the Onset of Weight Gain and Blood
PressureElevation Over 5 Years Kazuko Masuo, MD,
PhD Tomohiro Katsuya, MD, PhD Yuxiao Fu, MD et
al Methods and ResultsTo longitudinally
clarify the relevance to alterations in
-adrenergic receptor polymorphisms related to
weight gain, blood pressure (BP) elevation, and
sympathetic nerve activity as measured by plasma
norepinephrine level, we studied 160 young,
nonobese, normotensive men. Changes in body
weight, BP, plasma norepinephrine levels, and
2-adrenergic (Arg16Gly, Gln27Glu) and
3-adrenergic (Trp64Arg) receptor polymorphisms
were measured periodically over a 5-year period.
Weight gain and BP elevation were defined as 10
increases from entry levels over 5 years in body
mass index or mean BP. The presence of the Gly16
allele of Arg16Gly was associated with a higher
frequency of weight gain and BP elevation over
the 5-year period. The subjects carrying the
Glu27 allele of Gln27Glu and the Trp64 allele of
Trp64Arg had a higher frequency of BP elevation.
Significantly higher levels of plasma
norepinephrine at entry and at year 5 were
observed in the subjects with the Gly16 allele of
Arg16Gly and the Glu27 allele of Gln27Glu
compared with those without the Gly16 or the
Glu27 alleles. ConclusionsThese results
demonstrate that the Gly16 allele is related to
greater weight gain and BP elevation.
Additionally, Glu27 and Trp64 alleles are linked
to BP elevation. The subjects carrying the
2-polymorphisms linked to weight gain and BP
elevation also have higher plasma norepinephrine
levels that are present at entry before weight
gain and BP elevation. These findings suggest
that 2-adrenergic receptor polymorphisms in
association with a heightened sympathetic nerve
activity could predict the future onset of
obesity and hypertension, as shown in the 5-year
longitudinal study. (Circulation.
20051113429-3434.)
35
Beta 2 receptor polymorphism and heart rate
response of young healthy subjects to infusions
(8 min) of increasing doses of beta agonist.
N 11 N 15
increase in heart rate
of salbutamol
AA arginine 16 arginine 16 A/G arginine 16
glycine 16
Adapted from Gratze et al Hypertension 1999.