Patricio López-Jaramillo MD PhD FACP

Director de Investigaciones y de la

Clínica de Síndrome Metabólico, Prediabetes y Diabetes, FOSCAL

Instituto MASIRA, Facultad de Salud, Universidad de Santander (UDES)

Presidente Sociedad Latinoamericana de Hipertension (LASH)

Bucaramanga-Colombia

RESISTENCIA A LA INSULINA E INFLAMACION

CARDIOMETABOLIC TRIANGLE

METABOLIC SYNDROME/DIABETES / CARDIOVASCULAR DISEASES

HYPERINSULINEMIA/ INSULIN

RESISTANCE

LOW DEGREE INFLAMMATION

ABDOMINAL OBESITY

ET-1

c-GMP

.O -2

ONOO-

AAeNOSO2

Relajación

Control crecimiento

Acc. Antitrombótica

TXA2PGI2

c-AMPCa2+

Pre-pro-ETADMA

Células

Endoteliales

Células Músculo Liso Vascularl (CMLV)

NO.

Angiotensina II

Estimulación

Inhibición

Contracción

Crecimiento

Acc. Pro-trombótica

.

RAS EXPRESSION IN HUMAN ADIPOSE TISSUE

Karlsson C, et al. J Clin Endocrinol Metab. 1998; 83: 3925-3929

Harte et al, Circulation. 2005;111: 1954-1961

RELATIONSHIP BETWEEN CIRCULATING ANGIOTENSIN II LEVELS AND BMI

Harte et al, Circulation. 2005;111: 1954-1961

RELATIONSHIP BETWEEN SUBCUTANEOUS

VENOUS DRAINAGE TNF- AND

ANGIOTENSIN II LEVELS

ANGIOTENSIN II ENHANCES ENDOTHELIAL TNF α PROTEIN

PRODUCTION

Arenas et al, Am J Physiol. Cell Physiol. 2004 ; 286 : C779-C784

ANGIOTENSIN II INDUCES ENDOTHELIAL RELEASE OF MMP-2

Arenas et al, Am J Physiol. Cell Physiol. 2004; 286 : C779-C784

AT1R BUT NOT AT2R ANTAGONISM PREVENTS MMP-2 RELEASE FROM HUVECS

INDUCED BY ANGIOTENSIN II

Arenas et al, Am J Physiol. Cell Physiol. 2004 ; 286 : C779-C784

TUMOR NECROSIS FACTOR ALPHA AND FLOW MEDIATED VASODILATATION

López-Jaramillo et al. Rev Esp Cardiol. 2007;60:168-178

eNOS EXPRESSION IS REDUCED IN WAT OF OBESE RODENTS

Valerio et al. (2006) J. Clin. Invest. 116: 2791-2798

eNOS-/- mice exhibit a markedincrease in visceral fat

INSULIN RESISTANCE: FOCUS ON SIGNALING PATHWAYS

Adapted from Henriksen EJ, Jacob S. J Cell Physiol. 2003;196:171-9.

BK2

receptor

BKNO

NO Glucose transport

GLUT-4 trans-location

GLUT-4 biosynthesis

GLUT-4

Akt1

PI3-KIRS-1

AT1

receptor

Insulin receptor

Insulin

+ +

+

+

+

+

-

-

Ang II

EFFECTS OF ORAL GLUCOSE LOADING ON THE FLOW-MEDIATED DILATION OF THE BRACHIAL

ARTERY

Kawano et al. J Am Coll Cardiol 1999; 34:146-154

2 hours1- hourFasting

0

2

4

6

Flo

w-M

ed

iate

dD

ila

tio

n(%

) NGT

IGT

DM

8

HYPERGLYCEMIA-INDUCED ROS PRODUCTION IN ENDOTHELIAL CELLS

BROWNLEE M. DIABETES 2004; 54:1615-1625

VASCULAR SUPEROXIDE PRODUCTION IN DIABETES MELLITUS

Guzik et al. Circulation 105: 1656-1662, 2002

asasasasasasasasssssasssasasa

sasasassa

adadadadada

A background inflammatory condition,

which is known to occur in

metabolic syndrome, is necessary

for long-lasting elevation of glucose

to be deleterious

D-glucose

(mmol/l)

IL-1b (10 ng/ml)

5.5 8 11 22

iNOS

5.5 8 11 22

50

75

100

125

150

175

200

IL-1b (10 ng/ml)

*

*

*

D-glucose

(mmol/l)

Imm

un

ore

ac

tive

iN

OS

(% 5

.5 m

mo

l/l D

-glu

co

se +

IL

-1b)

B

18 hours

Imm

un

ore

ac

tive

iN

OS

(fo

ld-i

nc

rease

vs 5

.5 m

mo

l/l

D-g

luc

ose w

ith

no

cyto

kin

e)

5.5 8 11 22

D-glucose (mmol/l)

iNOS

5.5 8 11 220

10

20

30

40

D-glucose (mmol/l)

A

18 hours

D-GLUCOSE ENHANCES THE GENERATION

OF iNOS IN THE PRESENCE OF IL-1B

Lafuente et al (2008) J. Hypertens. 26: 478 - 485

VASCULAR REACTIVITY

Rings of internal mamary artery (2 a 3

mm)

Response Curves to:

• Potasium chloride (KCl)

• Acetilcholin (ACh)

• Phelinephrine (PE)

• Sodium nitroprussiate(SNP)

• Angiotensin II (AII)

8,5

5,216,37

18,1

0,75

3,47

0

5

10

15

20

25

30

n= 17 n= 17 n= 17 n= 27 -AO +AO

p=0.04

p=0.04

-AO -AO+AO +AO

-AO: Without Abdominal Obesity

Adiponectin (μg/dL)

Leptin (ng/dL)

Leptin/Adiponectin Ratio

LEPTIN/ADIPONECTIN RATIO IN PATIENTS WITH SEVERE CORONARY ARTERY DISEASE DIVIDED BY

THE PRESENCE OF ABDOMINAL OBESITY.

Lopez-Jaramillo et al. Hormone Molecular Biology and Clinical Investigation 2013. DOI 10.1515/hmbci-2013-0053

http://www.springerlink.com/content/j3tj16543664/

Published online: 17 May 2006

BLOOD PRESSURE AND C REACTIVE PROTEIN IN A HISPANIC PEDIATRIC

POPULATION

López-Jaramillo et al. Am J Hypertens 2008; 21: 527-532

MODIFICACIONES EPIGENETICAS

Gluckman P et al. N Eng J Med 2008; 359: 61-73.

MATERNAL MALNUTRITION AND FETAL PROGRAMMING ASSOCIATED WITH GREATER CV

RISK IN ADULT LIFE

HANDGRIP STRENGTH: CV AND MORTALITY OUTCOMES

Cohen et al. PLoS One 2014 Apr 8;9(4):e93150. doi: 10.1371/journal.pone.0093150. eCollection 2014

Cohen et al. PLoS One 2014 Apr 8;9(4):e93150. doi: 10.1371/journal.pone.0093150. eCollection 2014.

LOW MUSCLE STRENGH IS ASSOCIATED WITH METABOLIC RISK FACTORS IN COLOMBIAN

CHILDREN: THE ACFIES STUDY

Years of Follow-up

Pro

po

rtio

n w

ith

e

ve

nts

0.0

0.1

0.2

0.3

0.4

0 1 2 3 4 5 6 7

1st2nd3rd4th5th

# at Risk 1 2 3 4 5 6 7

1st

2nd

3rd

4th

5th

1627 1538 1451 1351 1252 1150 783 170

1627 1561 1497 1431 1365 1287 928 199

1627 1570 1528 1481 1414 1345 957 236

1624 1572 1515 1461 1411 1365 1016 247

1630 1583 1537 1495 1440 1389 1015 219

Log rank test P:

1st vs. 5th: <0.0001

2nd vs. 5th: <0.0001

3rd vs. 5th: 0.0466

4th vs. 5th: 0.9924

Males: Time to Adjudicated Primary Outcome 1 - CV Death MI Stroke

Years of Follow-up

Pro

po

rtio

n w

ith

eve

nts

0.0

0.1

0.2

0.3

0.4

0 1 2 3 4 5 6 7

1st

2nd

3rd

4th

5th

# at Risk 1 2 3 4 5 6 7

1st

2nd

3rd

4th

5th

875 836 791 736 703 658 426 75

877 849 830 797 763 716 477 95

876 850 832 811 787 767 505 87

876 858 842 827 810 790 528 93

877 862 849 841 830 815 554 108

Log rank test P:

1st vs. 5th: <0.0001

2nd vs. 5th: <0.0001

3rd vs. 5th: 0.0002

4th vs. 5th: 0.2990

Females: Time to Adjudicated Primary Outcome 1 - CV Death MI Stroke

HAZARD RATIOS: MEN AND WOMEN

Adj HR (95%CI) P Events

Per 1 Kg Increase N (%) Rate

Composite 0.91 (0.90, 0.93) <0.001 1471 (18.1) 3.2

CV Death 0.88 (0.86, 0.90) <0.001 811 (10.0) 1.7

MI 0.97 (0.94, 1.00) 0.04 509 (6.3) 1.1

Stroke 0.90 (0.87, 0.93) <0.001 442 (5.4) 0.9

Revascularization 0.99 (0.97, 1.01) 0.16 1415 (17.4) 3.3

Heart Failure 0.89 (0.86, 0.91) <0.001 474 (5.8) 1.0

Death 0.87 (0.85, 0.88) <0.001 1347 (16.6) 2.8

Hazard Ratio

Reduced Risk

10.8

Increased Risk

Lopez-Jaramillo et al. Int J Cardiol 2014; 172; 458-461

Hazard Ratio

Reduced Risk

0.6 1.21

Increased Risk

Adj HR (95%CI) P Events

Per 1 Kg Increase N (%) Rate

Composite 0.76 (0.72, 0.80) <0.001 578 (13.2) 2.3

CV Death 0.70 (0.66, 0.75) <0.001 343 (7.8) 1.3

MI 0.79 (0.72, 0.86) <0.001 151 (3.4) 0.6

Stroke 0.84 (0.77, 0.90) <0.001 206 (4.7) 0.8

Revascularization 0.90 (0.85, 0.96) <0.001 349 (8.0) 1.4

Heart Failure 0.70 (0.64, 0.76) <0.001 176 (4.0) 0.7

Death 0.70 (0.67, 0.73) <0.001 566 (12.9) 2.2

FOSCAL/FOSCAL INTERNACIONAL:

A VUESTRAS ORDENESinvestigaciones@foscal.com.co

jplopezj@gmail.comGRACIAS