Factores de Riesgo Mte Cardiovascular

8/13/2019 Factores de Riesgo Mte Cardiovascular

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ADVANCED CKD AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE

(Foley RN et al,Am J Kidney Dis1998;32:S112-S119)


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EARLY CKD AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE

(Manjunath G et al,J Am Coll Cardiol

2003;41:47-65)

(Manjunath G et al,Kidney Int

2003;63:1121-1129)


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(Vanholder R et al,Nephrol Dial Transplant2005;20:1048-1056)

EARLY CKD AS A RISK FACTOR FOR CARDIOVASCULAR DISEASE

0 0


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VASCULAR PATHOPHYSIOLOGY IN CHRONIC KIDNEY DISEASE

Increased CV risk

Cardiac damage

Oxidative

stress

Genes

CKD

Ambient

Microinflammation

Atherosclerosis

Increased CV risk

Metabolic

alterations

Hemodynamic

disturbances


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MONOCYTES/MACROPHAGES IN ATHEROSCLEROTIC LESIONS


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NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (NADPH)

OXIDASE IN MONOCYTES/MACROPHAGES

NADPH

gp91 p22

p47

p67

rac

O2-

O2H+

NADP+

EC

IC

Cathcart MK

Regulation of superoxide anion production

by NADPH oxidase in monocytes/macrophages.

Contributions to atherosclerosis.

Ar ter ioscler Thromb Vasc Biol2004;24:23-28


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EXPRESSION OF NADPH OXIDASE IN HUMAN CORONARY ARTERIES

Nonatherosclerotic

arteries

Atherosclerotic

arteries

Advancedatherosclerotic

lesions

Hematoxylin-eosin Anti-p22phox Negative controls

(Azumi H et al, Circulation1999;100:1494-1498)


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PHAGOCYTIC NADPH OXIDASE ACTIVITY AND ATHEROSCLEROSIS

IN ASYMPTOMATIC SUBJECTS

(Zalba G et al,Arterioscler Thromb Vasc Biol2005;APP April 28)

O

2- production

(counts/s)

Carotid IMT quartiles

0

25

20

15

10

5

30

P < 0.05

q1 q2 q3 q4


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HYPOTHESIS AND GOALS

Early stages of CKD are associated with

phagocytic NADPH oxidase overactivity

To assess NADPH oxidase-mediated O2-

production in peripheral blood monocytes

and lymphocytes from patients with stage

1-2 and 3 CKD

&

To assess associations of NADPH oxidase

activity with systemic oxidative parameters

and atherosclerosis in the same patients


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SUBJECTS AND DESIGN

Subjects who attended for routine medical examination

No known history of renal disease and atherosclerosis

Complete medical work-up

after informed consent

21 healthy 42 patients with CKD

subjects (22 stage 1-2, 20 stage 3)

Carotid Measurement of Biochemical

arteries NADPH oxidase & hormonal

ultrasonography in PMN cells determinations


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DEMOGRAPHIC AND RENAL CHARACTERISTICS OF STUDIED SUBJECTS

(Fortuo A et al,submitted)

Controls Patients with CKD

stage 1-2 stage 3

Gender, m/f 14/7 19/3 16/4

Age, years 483 572 * 6310 *

GFR, ml/min/1.73 m2 904 914 508 * U alb. : U creat., mg/g 3.60.4 33.82.4 * 46.64.7 *

( *P< 0.05 compared with controls, P< 0.05 compared with stage 1+2)


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DETERMINATION OF NADPH OXIDASE ACTIVITY IN

HUMAN PHAGOCYTIC CELLS

(Fortuo A et al,J Hypertens2004;22:2169-2175)

Lucigenin-enhanced

luminescence(

RLU/s)

PMA

0

25

20

15

10

5

30

P < 0.05

Basal Control DPI Apocynin SOD

35


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BASAL NADPH OXIDASE ACTIVITY IN PHAGOCYTIC CELLS

FROM PATIENTS WITH CKD


O2

- production(RLU/s)

Controls Stage 1-2 Stage 30

2.5

2.0

1.5

1.0

0.5

3.0

N.S.


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PMA-STIMULATED NADPH OXIDASE ACTIVITY IN PHAGOCYTIC

CELLS FROM PATIENTS WITH CKD


O2

- production(R

LU/s)

Controls Stage 1-2 Stage 30

10.0

8.0

6.0

4.0

2.0

12.0

P < 0.02

(NADPH oxidase overactivitywas not associated with age)


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Abnormally high activity

Normal activity (Fortuo A et al,submitted)

PMA-STIMULATED NADPH OXIDASE ACTIVITY IN PHAGOCYTIC

CELLS FROM PATIENTS WITH CKD

5%

48% 52%

53% 47%

95%Controls

Stage 1-2 CKD

Stage 3 CKD

P< 0.05


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MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN

PATIENTES WITH STAGE 1-2 CKD

The clinical context

(Fortuo A et al,J Hypertens2004;22:2169-2175)

O2- production(RL

U/s)

Basal PMA Basal PMA0

15.0

12.0

9.0

6.0

3.0

18.0

P < 0.05

P < 0.02 P < 0.01

Normotensive Hypertensive


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HEMODYNAMIC CHARACTERISTICS OF PATIENTS WITH STAGE 1-2 CKD


Controls Patients with stage

1-2 CKD

SBP, mmHg 1102 1414 *DBP, mmHg 722 893 *MAP, mm Hg 843 1065 *

PP, mm Hg 302 514 *

Hypertensive, % 0 82

( *P< 0.05 compared with controls)


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Environmental factors

(Lassgue B,Am J Physiol Regul Integr Comp Physiol2003;285:R277-R297)

NAD(P)Hox

HORMONESAng II, ET-1,Insulin...

CYTOKINES

TNF,IFN

METABOLITES

Glucose,LDL, oxLDL...

GROWTH FACTORS

TGF-b1,PDGF

PPARs

,

-

+

+

+

+


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Controls Patients with stage1-2 CKD

BMI, kg/m2 25.50.6 29.50.9 *Glucose, mg/dL 912 992 *Total Cholesterol, mg/dL 22012 23011LDL-cholesterol, mg/dL 1 5111 1549HDL-cholesterol, mg/dL 522 4510 *Triglycerides, mg/dL 834 13010 *

Obesity

Diabetes % 0 36Met. Synd.

HOMA 1.60.1 4.50.5 *

METABOLIC CHARACTERISTICS OF PATIENTS WITH STAGE 1-2 CKD


( *P< 0.05 compared with controls)


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Plasma insulin(U/L)

50403020100

30

20

10

0O

2-production(RLU/s)

25

15

5

r = 0.441P< 0.05

Plasmainsulin

(U/L)

Controls Stage 1-2

0

20

15

10

5

P< 0.05

INSULIN AND PMA-STIMULATED NADPH OXIDASE ACTIVITY

IN PHAGOCYTIC CELLS


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EFFECT OF INSULIN ON HUMAN PHAGOCYTIC NADPH OXIDASE


0

4

3

2

1

Basal Insulin

Fold

increasecomparedwithbasal

Insulin

Apocynin

Insulin

BIS I

P < 0.05



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NADPH

gp91 p22

p47

p67

rac

O2-

O2H+

NADP+

EC

IC



The molecule itself

Critical subunit

for activity



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p22phox:-actin

(ADU)

0

15

10

5

Controls Normal Increasedoxidase activity oxidase activity


p22phox

-actin



The molecule itself

Patients

P < 0.01



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(San Jos et al,Hypertension 2004;44:163-169)



The molecule itself *

*The -930 A/G polymorphismof the human p22phox gene


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ATHEROGENIC MECHANISMS IN CHRONIC KIDNEY DISEASE

The role of oxidative stress

(Locatelly F et al,Nephrol Dial Transplant2003;18:1272-1280; Moldinger PS et al, Semin Nephrol2004;24:354-365)

Reduced

anti-oxidant

systems

Increased

phagocytic-

mediated

pro-oxidant

activity

Renal disease

< NO availability LDL oxidation VSMC apoptosis

Endothelial Plaque Rupture &

activation formation thrombosis

Oxidative stress


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LDL OXIDATION AND CAROTID ATHEROSCLEROSIS IN PATIENTS

WITH STAGE 1+2 CKD


OxidizedLDL(U/L)

0

80

60

40

20

Controls Patients

P< 0.05

CarotidIMT(mm)

0

0.80

0.60

0.40

0.20

Controls Patients

P< 0.05

ASSOCIATIONS OF PHAGOCYTIC NADPH OXIDASE ACTIVITY


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ASSOCIATIONS OF PHAGOCYTIC NADPH OXIDASE ACTIVITY,

OXIDIZED LDL AND CAROTID INTIMA-MEDIA THICKNESS


Oxidized LDL(U/L)

1209060300

CarotidIMT(mm)

0.90

0.85

0.80

0.75

0.70

0.65

0.60

r = 0.393

P < 0.005

OxidizedLDL

(U/L)

O2-production(RLU/s)

r = 0.349

P < 0.005

100806040200

140

120

100

80

60

40

20

VASCULAR PATHOPHYSIOLOGY IN EARLY CHRONIC KIDNEY DISEASE


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Proposal

Increased CV risk

Oxidative

stress

Genes

Early

CKD

Ambient

Microinflammation

Atherosclerosis

Increased CV risk

Metabolic

alterations

Hemodynamic

disturbances

Oxidant stress is aresult of NADPH

oxidase-mediated

O2-overproduction

by phagocytic cel ls

Cardiac damage



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Consequence

Increased CV risk

Oxidative

stress

Genes

Early

CKD

Ambient

Microinflammation

Atherosclerosis

Increased CV risk

Metabolic

alterations

Hemodynamic

disturbances

I t i s necessaryto explore the

benefi cial eff ects

of antioxidant

measures with

proven eff icacy

Cardiac damage


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Universidad deNavarra

Cliniciens (CUN)

Oscar Beloqui

Alberto Benito

Inmaculada Colina

Biochemists (CIMA)

Ana Fortuo

Uju Moreno

Gorka San Jos

Guillermo Zalba

Techniciens (CIMA)

Ana Montoya

Raquel Ros

Factores de Riesgo Mte Cardiovascular

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