Stevo Julius MD. Sc.D.Active emeritus professor of Medicine and Physiology University Medical Center Ann Arbor Michigan

Sympathetic overdrive and the metabolic syndrome in prehypertension .

Pathophysiology of obesity and insulin resistance.

Tachycardia is reliable and practical marker of

sympathetic overactivity.

20

30

40

50

60

70

80

90

100

Heart Rate Nor-Epi MSNA

Controls

Hypertensives

Obese

CHF

b/m

in p

g/d

Lb

urs

t/m

in

Modified from Grassi G et al, J Hypertens 1998 and 1999

Tecumseh Study Plasma Norepinephrine

in All Normotensives vs. Hyperkinetic

and Normokinetic Hypertensives

Normotensives

(n = 438)

400

350

300

250

200

Pla

sm

a N

E (

pg

/mL

)

Hyperkinetic

Hypertensives

(n = 25)

Normokinetic

Hypertensives

(n = 50)

P < 0.001 P < 0.01

Julius et al., J. Hypertension, 1991

Card. Output

Heart rate

Glucose

Association of tachycardia with other cardiovascular risk factors in the Tecumseh study

Cholesterol

HDLCholesterol Heart Rate

Triglyceride

Hematocrit

BMI

Bloodpressure

Insulin

p<0.0001

p<0.01

p<0.05

Adjusted from Palatini P & Julius S, J Hypertens, 1997

A

A B

B C

C

D

D

Association ??

Causation ??

A PERENIAL SCINETIFIC PROBLEM

RELATIONSHIP OF TACHYCARDIA AND

SYMPATHETIC OVERDRIVE TO OBESITY AND

INSULIN RESISTANCE.

---Is there a plausible mechanism by which

the overdrive could cause metabolic

syndrome?

--- Did the overdrive precede the metabolic

syndrome?

Sympathetic overactivity and

insulin resistance- diabetes

Hyperkinetic state of

tachycardia and high cardiac output

Prehypertensiven=124

Normotensive

n=840

10% 38%

Julius et al J of Hypertension 1991, v 9

Normokinetic

The prevalence of hyperkinetic prehypertension determined by noninvasive

measurement in an unselected general population of the

village of Tecumseh

A large proportion of subjects with prehypertension has

hyperkinetic circulation

Heart rate trends in two subpopulations of

prehypertension in Tecumseh

40

50

60

70

80

90

100

110

7 years 22 years 32 years

Hyperkinetic

+

++

Heart rate

**

Normokinetic

Julius et al., J. Hypertension, 1991

The question:

How could a hemodynamic abnormality (hypertension) be

associated with a metabolic condition (insulin resistance) ??

The answer:

Through changes in microcirculation facilitated

by increased sympathetic tone

HYPOTHESIS

The hemodynamic link between insulin resistance and

hypertension.

S Julius, T Gudbrandsson, K Jamerson, S T Shahab and

O. Andersson Journal of Hypertension 1991, 9

Schematic Presentation

of the Nutritional Blood Flow

Insulin

Resistance

Normal

S. Julius, 2001

Forearm

blood flow

Arterial catheter Venous catheter

Testing the hypothesis Jamerson KA,

Julius S et al. Hypertension

1993;21:618-23

0

20

40

60

80

100

120

140

10 20 40 60 80 100 120 140

p< 0.05

Time (min)

O2 and

Glucose

Utilization

(mg/dl/min)

The Effect of Insulin Infusion and Reflex Vasoconstriction on

Glucose and Oxygen Extraction in the Forearm of 14 Healthy

Volunteers

Baseline Insulin Infusion Insulin Infusion +

Thigh Cuff

Oxygen

extraction

Jamerson KA, Julius S et al. Hypertension 1993;21:618-23.

-40

-30

-20

-10

0

10

20

30

% C

hange

Effects of antihypertensive agents on insulin sensitivity

Index another argument supporting the concept that

vasoconstriction causes insulin resistance*

*Data derived from various double-blind and open

studies Lithell. Diabetes Care 1991; 14: 203-9

Anderson, et al. Am J Hyp 1996; 323-33

FASTING PLASMA INSULIN ADJUSTED FOR CONFOUNDERS

IN THE SUBJECTS CLASSIFIED AS HAVING NORMAL HR

OR HIGH HR ACCORDING TO MIXTURE ANALYSIS

(The Tecumseh Study)

10

12

14

16

18

20

Men Women

High HR

Normal HR

p=0.04p=0.008

mU

/ml

Palatini P et al, Hypertension 1997; 30: 1267

Stratified resting Heart Rate and OR (95% CI)* of developing Metabolic Syndrome in 4 years in

89,860 Chinese People

Jiang X et al. Heart. 2014 Sep 1.

Copyright © BMJ Publishing Group Ltd & British Cardiovascular Society. All rights reserved.

*adjusted for other risk factors and confounders

Sympathetic overactivity and

overweight- obesity

Indices of Body Size at 32 years of age

in the Tecumseh Study

Julius S, et al: JAMA 1990-264:354-358

* P<0.001; ** P<0.005

Normotension Borderline Hypertension

90

85

80

75

70

22

21

20

19

18

17

16

15

Triceps Skin Folds (mm)Weight (kg)

n = 801 n = 123 N = 756 n = 112

*** 35

30

25

20

15

10

Overweight (%)

n = 799 n = 123

*

Heart rate trends in “pure hyperkinetic

prehypertension” (n= 24, &) and normotensives (n =

787) in the Tecumseh study

60

70

80

90

100

110

7 years 22 years 32 years

Heart

rate

beats

/ m

in

S. Julius .K. Jamerson , J. Hypertension, 1994

& Prehypertensive with elevated Li –Na counter-transport eliminated

Prehypertension Normotension

P<0.0001

P<0.0001P<0.0001

Arm Girth and Subscapular Skin folds at 6 years of age and 21 years

in subjects classified at 32 ys. of age as normotensives ( ) and

Borderline hypertensives ( )

10

15

20

25

30

35

40

6.4 21.5

Arm

Girth

(cm)

0.5

0.75

1

1.25

1.5

1.75

2

6.4 21.5

Sub-

scapular

skin

fold (cm)

Age (years) Age (years)

*P<0.0015; † P<0.001

*

†

Julius S, et al, JAMA 1990;264:354-358.

High BP and tachycardia first obesity later. How come?

Increased through

beta receptor stimulation

Over a period of 30 years the Ann Arbor group investigate the

heart rate response to beta adrenergic agonist in 3 separate

experiments on 3 different hypertensive populations.

Kjeldsen SE, et al. Blood Pressure 5, 1996.

Julius et al, Cir Research 1975; 36-37 (suppl): 199.

Valentini, Julius, Palatini et al J. Hypertension 2004

HYPOTHESIS:

If in addition to cardiovascular responses, metabolic responses

to isoproterenol were also decreased in hypertension, patient’s

ability to dissipate calories would be diminished.

In each study hypertensive patients had a suppressed

heart rate increase to beta adrenergic agonists.

Material.

13 patients with stage I hypertension

25 normal controls (similar age and gender)

Design.

Day one. Lab tests, Heart rate response to

increasing doses of isoproterenol (bolus)

Day two: Hemodynamic, electrolyte, glucose

and energy expenditure responses to

increasing doses of isoproterenol (infusion)

Valentini, Julius, Palatini et al J. Hypertension 2004

Isoproterenol Bolus Dose (µg/m2)

* * *

Valentini, Julius, Palatini et al J. Hypertension 2004

0

10

20

30

40

50

0,1 0,25 0,5 1 2

Controls

Hypertensives

Heart rate response to graded increase

of beta adrenergic stimulation

0

2

4

6

8

10

10 20 40

Controls

Hypertensives

EE

incre

ase (

Kcal/K

g/2

4h

)

Isoproterenol i.v. Infusion Rate (ng/Kg/min)

* *

Energy expenditure response to isoproterenol is

decreased in hypertension.

Valentini, Julius, Palatini et al J. Hypertension 2004

1

1,5

2

2,5

1,5 3 4,5 6

24-h urinary NE (pg/ml)

r= -0.51

P= 0.0352

3

4

5

1,5 3 4,5 6

Lo

g H

R c

ha

ng

e (

beats

/min

)

r= -0.52

P= 0.016

24-h urinary NE (pg/ml)

Isoproterenol Bolus Isoproterenol Infusion

Lo

g E

E c

ha

ng

e (

Kca

l/K

g/m

in)

Valentini, Julius, Palatini et al, J Hypertens 2004;22:1999

Correlations of 24h Urinary Norepinephrine With Heart Rate Responsiveness and

Energy Expenditure (EE) Responsiveness at the Highest Isoproterenol Dose in

the Whole Study Population

Long term sympathetic stimulation in hypertension

elicits down regulation of beta adrenergic receptors.

This decreases patients ability to “burn off” excessive calories

and favors gain of weight.

In most patients the weight gain is not due to insufficient

willpower or lack of motivation for life style modification; rather

it reflects a physiologic imperative.