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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
8/13/2019 Factores de Riesgo Mte Cardiovascular
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MONOCYTES/MACROPHAGES IN ATHEROSCLEROTIC LESIONS
8/13/2019 Factores de Riesgo Mte Cardiovascular
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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
(Fortuo A et al,submitted)
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
(Fortuo A et al,submitted)
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
(Fortuo A et al,submitted)
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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MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN
PATIENTES WITH STAGE 1-2 CKD
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
(Fortuo A et al,submitted)
( *P< 0.05 compared with controls)
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(Fortuo A et al,submitted)
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
(Fortuo A et al,submitted)
0
4
3
2
1
Basal Insulin
Fold
increasecomparedwithbasal
Insulin
Apocynin
Insulin
BIS I
P < 0.05
MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN
8/13/2019 Factores de Riesgo Mte Cardiovascular
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NADPH
gp91 p22
p47
p67
rac
O2-
O2H+
NADP+
EC
IC
MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN
PATIENTES WITH STAGE 1-2 CKD
The molecule itself
Critical subunit
for activity
MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN
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p22phox:-actin
(ADU)
0
15
10
5
Controls Normal Increasedoxidase activity oxidase activity
(Fortuo A et al,submitted)
p22phox
-actin
MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN
PATIENTES WITH STAGE 1-2 CKD
The molecule itself
Patients
P < 0.01
MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN
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(San Jos et al,Hypertension 2004;44:163-169)
MECHANISMS OF PHAGOCYTIC NADPH OXIDASE OVERACTIVTY IN
PATIENTES WITH STAGE 1-2 CKD
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
(Fortuo A et al,submitted)
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
(Fortuo A et al,submitted)
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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VASCULAR PATHOPHYSIOLOGY IN EARLY CHRONIC KIDNEY DISEASE
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
VASCULAR PATHOPHYSIOLOGY IN EARLY CHRONIC KIDNEY DISEASE
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VASCULAR PATHOPHYSIOLOGY IN EARLY CHRONIC KIDNEY DISEASE
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