¿sirve para algo elevar el hdl?
TRANSCRIPT
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
José R. González Juanatey Área Cardiovascular. Hospital Clínico Universitario de
Santiago de Compostela
1 ¿Sirve para algo elevar el HDL?
J.R.G. JUANATEY
C.H.U.Santiago
HDL y Enfermedad CV
HDL y “Riesgo Residual”
HDL y Riesgo CV. Las implicaciones terapéuticas
¿Qué pasa con los fármacos y el HDL?
HDL y Riesgo CV. Los mecanismos
J.R.G. JUANATEY
C.H.U.Santiago
0,0
1,0
2,0
3,0
100
Framingham Study
Risk of CHD after 4 Years*
25
LDL-C (mg/dL)
160 220 85
65 45
HDL-C (mg/dL)
FUTURE ?
Castelli WP. Can J Cardiol. 1988;4(Suppl A):5A–10A
*Risk of coronary heart disease (CHD) over 4 years of follow-up for men ages 50 to 70
Sachdeva et al, Am Heart J 2009;157:111-7.e2.
LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006
LDLC (mg/dL) 130-160 > 160 < 130
J.R.G. JUANATEY
C.H.U.Santiago
Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325
Biochemical determinants of ACS vs non-ischemic chest pain
HDL: as a main determinant of ACS
ACS
Non-ischemic
chest pain
J.R.G. JUANATEY
C.H.U.Santiago
CV Risk beyond LDL LDL treatment reduces CV Risk
Residual Risk
Overall RR Risk factors
Age Gender
CV disease HT treat
DM Chol T LDL HDL TG
Etc.. TG
Diabetes Physical inact
Diet Obesity
HT HDL
Tobacco
J.R.G. JUANATEY
C.H.U.Santiago
CV Risk beyond LDL
Residual Risk
Etc.. TG
Diabetes Physical inact
Diet Obesity
HT HDL
Tobacco
J.R.G. JUANATEY
C.H.U.Santiago
CV Risk beyond LDL
Residual Risk
Etc.. TG
Diabetes Physical inact
Diet Obesity
HT
HDL Tobacco
J.R.G. JUANATEY
C.H.U.Santiago
Dislipidemias y riesgo global Tablas SCORE con inclusión del c-HDL
No fumadora Fumadora Edad
No fumador Fumador Edad
J.R.G. JUANATEY
C.H.U.Santiago
González-Juanatey J.R, Millán J, Alegría E, Guijarro C, Lozano J.V y Vitale G. Prevalencia y características de la dislipemia en pacientes en prevención primaria y secundaria tratados con estatinas en España. Estudio DYSIS-España. Rev Esp Cardiol 2011; 64(4):286-294
Patients treated with statins in Spain (68,8% GP; 31,2% Inter Med, Cardiology, Endocrinology)
Spain n: 3.617
Dyslipidemia International Study
56%
70%
85%
66%
51%
65%
83%
61%
31%
24%
14%
26%
36%42%
36% 38%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
ECV DM SCORE ≥ 5% Alto RCV
CT > OT c-LDL > OT c-HDL < OT TG > OT
J.R.G. JUANATEY
C.H.U.Santiago
Mecanismos protectores de las HDL
Vasodilatación Antitrombótica HDL
Protección frente a la aterosclerosis
Antinflamatoria Antioxidante
Transporte centrípeto del colesterol
J.R.G. JUANATEY
C.H.U.Santiago
Sorrentino SA et al. Circulation. 2010;121:110-122
Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are
Improved After Extended-Release Niacin Therapy (A), Effect of HDL (50 µ/mL, 60 minutes, 37°C) from healthy subjects (n=10) and diabetic patients (n=33) on endothelial cell NO production as determined by ESR spectroscopy analysis
(A), Endothelium-dependent relaxations of aortic rings of wild-type mice in response to increasing concentrations of HDL isolated from healthy subjects (n=5) or diabetic patients (n=5) are shown
Endo
thel
ial N
O P
rodu
ctio
n (%
of b
uffe
r- tr
eate
d ce
lls)
PBS HDL HDL Healthy Diabetics
P < 0.0001 P < 0.0001 (A)
Endo
thel
ium
-dep
ende
nt
Rel
axat
ion
(%; a
ortic
ring
s)
HDL (µg/ml)
P = 0.007
HDL from Diabetic Patients
HDL from Healthy Subjects
(B)
J.R.G. JUANATEY
C.H.U.Santiago
HDL y Aterosclerosis
Transporte reverso de colesterol
NEJM 2004;350:1491-94
J.R.G. JUANATEY
C.H.U.Santiago
0
5
10
15
20
25
Clinical Significance of High Density Lipoprotein Cholesterol in Patients with Low Low-Density Lipoprotein Cholesterol
DeGoma EM et al JACC 2008;51:49-55
Miocardial injury or IHD hospitalization
All cause mortality
Q1
Q2 Q3 Q4
Unadjusted Rates of the Combined
Primary End Point
Even
t rat
e (%
)
Q1 Q2 Q3 Q4
p 0.04 cHDL categorias 0.007 cHDL continuo
Q1 (n 1,082) Media 28 mg/dl
Q2 (n 1,123) Media 36 mg/dl
Q3 (n 939) Media 43 mg/dl
Q4 (n 1,044) Media 63 mg/dl
4188 sujetos con tratamiento y cLDL <60 mg/dl, seguidos 1 año
J.R.G. JUANATEY
C.H.U.Santiago
Conversion of Anti-Inflammatory and Pro-Inflammatory HDL
Reprinted from Ansell BJ, et al. J Am Coll Cardiol. 2005; 46:1792–1798, with permission from Elsevier Limited.
Myeloperoxidase
Nitrotyrosine
Anti-inflammatory Pro-inflammatory
Apo A1
Chlortyrosine
Apo A1 Paraoxonase, other factors Pro-inflammatory factors, other factors
HDL=high-density lipoprotein
J.R.G. JUANATEY
C.H.U.Santiago
HDL y Enfermedad CV
HDL y “Riesgo Residual”
HDL y Riesgo CV. Las implicaciones terapéuticas
¿Qué pasa con los fármacos y el HDL?
HDL y Riesgo CV. Los mecanismos
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
A-I
Liver
Bile
Nascent HDL
A-I
FCCE
FC
Endothelial NO Production
Anti-oxidant Effects
Anti-inflammatoryEffects
Endothelial Repair
Anti-thromboticEffects
LCATMature HDL
HDL
CETPVLDL/
LDL TGCE
CEFC
PLTPLDL-R
SR-BI Macrophage
ABCA1
ABCG1
SR-BI?
HDL: proposed anti-atherogenic effects
2. Direct HDL-mediated endothelial-protective effects
1. HDL-mediated promotion of RCT(reverse cholesterol transport)
Besler C et al. & Landmesser U. Curr Pharmacol Des 2010, Mar 3. (Epub ahead of print)
J.R.G. JUANATEY
C.H.U.Santiago
Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis
NEJM 2011; 364: 127
Efflux capacity
J.R.G. JUANATEY
C.H.U.Santiago
HDL / Apo A-‐I Pleiotropic Biological
Immuno-‐modulatory
Modula;on of Monocyte/Macrophage
Phenotype Myelopoesis Regula;on
Preserva;on of pancrea;c Beta-‐
cells
An;-‐thrombo;c Pro-‐fibrinoly;c
Improved endothelial health
and func;on
An;-‐inflammatory S;mulate cholesterol efflux and reverse
cholesterol transport
An;-‐oxidant
J.R.G. JUANATEY
C.H.U.Santiago
HDL y Enfermedad CV
HDL y “Riesgo Residual”
HDL y Riesgo CV. Las implicaciones terapéuticas
¿Qué pasa con los fármacos y el HDL?
HDL y Riesgo CV. Los mecanismos
J.R.G. JUANATEY
C.H.U.Santiago
LDL-Cholesterol/HDL-Cholsterol and risk of coronary disease
1% decreasein LDL-C
reduces CHD risk by 1%
1% increasein HDL-C
reduces CHD risk by
2-3%
Statin Therapy
Therapeutic Opportunity ?
LDL-cholesterol / HDL-cholesterol and risk of coronary disease
LDL-cholesterol / HDL-cholesterol and risk of coronary disease!
Statin!Therapy!
Therapeutic Opportunity?!
J.R.G. JUANATEY
C.H.U.Santiago
Pharmacotherapeu,c Targe,ng of HDL
Vascular Protec,ve Effects of HDL and its Apolipoproteins:
An idea whose ,me for tes,ng is here
Recombinant HDL (rAPO A-‐1 milano)
Niacin
Small molecule (APO A-‐1 inducer)
Plasma derived HDL
Apo A-‐I mime,c pep,des (D4F, others) CETP inhibi,on
drugs, vaccine
EL inhibi,on An,sense oligo
LUV (PL)
SR-‐B1 upregula,on
RXR, PPAR and LXR Agonists
Fibrates, glitazones, glitazars
HDL-‐related (Apo A-‐1)
Gene therapy HDL-‐associated an,oxidants
Paraoxonase, PAF-‐ACH Rimonabant Delipida,on
J.R.G. JUANATEY
C.H.U.Santiago
Ejercicio y partículas LDL/HDL STRRIDE
Efecto del nivel de ejercicio e intensidad sobre LDL - HDL STRRIDE: Studies of Targeted Risk Reduction Interventions through Defined Exercise Kraus WE et al. NEJM 2002;347:1483
J.R.G. JUANATEY
C.H.U.Santiago
↓LDL-c (%)
↑HDL-c (%)
↓TG (%)
Cam
bio
desd
e ba
sal(%
)
Estatinas Niacina
Fibratos
-10
-20
-30
-40
-50
+20
+10
0
20
50
30
15 15
55
25 20
+30
18
5 5 7
20
50
5
35
20 10
Hipolipemiantes: efectos
J.R.G. JUANATEY
C.H.U.Santiago
Sorrentino SA et al. Circulation. 2010;121:110-122
Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy
Effect of ER niacin therapy or placebo on endothelial-protective properties of HDL in diabetic patients
Endo
thel
ial N
O P
rodu
ctio
n (%
of b
uffe
r-tr
eate
d ce
lls)
Placebo ER-Niacin
P = 0.008
HDL Diabetics Baseline
HDL Diabetics
3 Months
HDL Diabetics Baseline
HDL Diabetics
3 Months
(A) P = 0.04
NA
DPH
Oxi
dase
Act
ivity
(p
mol
O2.
- / 2
50,0
00 c
ells
/ min
])
Placebo ER-Niacin
HDL Diabetics Baseline
HDL Diabetics
3 Months
HDL Diabetics Baseline
HDL Diabetics
3 Months
(C)
J.R.G. JUANATEY
C.H.U.Santiago
Endo
thel
ium
-dep
ende
nt
Vaso
dila
tion
FDD
[%]
0
5
10
15
DiabeticsBaseline
Diabetics3 Months
Placebo
Diabetics Baseline
Diabetics3 Months
ER-Niacin
P < 0.0001
Niacin therapy improves endothelial function in type-2 diabetics with low HDL
Sorrentino SA et al. & Landmesser U. Circulation 2010; 121:110-22
J.R.G. JUANATEY
C.H.U.Santiago
AIM-HIGH (NEJM 2011)
Unblinded Active Run-In ERN/LRPT 1g/20mg for 4 wks then ERN/LRPT 2g/40mg for 4
wks (On top of Simva 40mg +/- ezetimibe)
ERN/LRPT 2g/40mg (On top of Simva 40mg
+/- ezetimibe)
Simva 40 mg (+/- ezetimibe)
n= ~25,000 2,300 events
4 Year Median Follow-up
High Risk Patients (MI, Peripheral/Cerebrovascular Disease, or Diabetes + Vascular Disease)
Study Design
Composite of non-fatal MI or coronary death; fatal or non-fatal stroke; or any revascularization procedure (including
coronary or non-coronary angioplasty or grafting)
HDL-c: Inhibición de CETP
CETP
Torcetrapid Dalcetrapid Anacetrapid Evacetrapid
CETP inhibitors in Published Studies
Dalcetrapib: CETP modulator vs CETP inhibitors
Beneficial shape change Dalcetrapib binds in the tunnel of CETP inducing a fixed conformational change
CETP shape change prevents interaction with large diameter lipoproteins such as LDL and VLDL
anacetrapib
torcetrapib
CETP inhibitors
Form triple complexes CETP inhibitors bind CETP and HDL together into a triple complex
CETP becomes ‘saturated’ with triple complexes and so, cholesterol transfer activity is fully inhibit CETP
modulator Allows transfer between HDL’s CETP is still able to transfer cholesterol between HDL sub-types
Produces Functional HDL
dalcetrapib
No cholesterol transfer possible Fixed triple complex prevents any cholesterol transfer
dalcetrapid
On Target Differentiation: HDL Composition
0
5000
10000
15000
20000
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47Fractions
RFI
02.551020
0
5000
10000
15000
20000
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47Fractions
RFI
02.551020
0
5000
10000
15000
20000
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47Fractions
RFI
02.551020
0
5000
10000
15000
20000
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47Fractions
RFI
02.551020
Control Dalcetrapib
Torcetrapib (CETPi) Anacetrapib (CETPi)
Pre β HDL Pre β HDL
1Dernick et al. Poster presented at 6th IAS-Sponsored Workshop on HDL. May 17-20, 2010; Whistler, BC, Canada; 2Barter et al. N Engl J Med. 2007;357:2109–2122.
J.R.G. JUANATEY
C.H.U.Santiago
Lipid Changes Following Treatment with CETP Inhibitors
Dalcetrapib
Torcetrapib
Anacetrapib
Evacetrapib
HDL-C
ApoA1
LDL-C
Apo-B
TG
Total Cholesterol
J.R.G. JUANATEY
C.H.U.Santiago
ILLUSTRATE No effect of torcetrapib on atheroma volume assessed by IVUS
1Nissen et al. N Engl J Med 2007;356:1304–1316; 2Barter et al. N Engl J Med. 2007;357:2109–2122.
• No improvement in atheroma burden in the torcetrapib + atorvastatin group despite a 59% increase in HDL-C1
• A significant blood pressure increase was observed with torcetrapib + atorvastatin vs atorvastatin alone (P<0.001)1
0 5
10 15 20 25 30 35 40 45 50
Atorvastatin only (n=446)
Atorvastatin + Torcetrapib (n=464)
Perc
ent A
ther
oma
Vo
lum
e (%
)
P=0.78
Percent atheroma volume change Change in blood pressure
100
80
60
40
20
0 ≤-20 -15 -10 -5 0 5 10 15 20 25
≥26
Torcetrapib plus atorvastatin
Atorvastatin only
Change in systolic blood (mmHg)
Patie
nts
(%)
J.R.G. JUANATEY
C.H.U.Santiago
Torcetrapib’s Failure Due to Off-Target Effects, Not CETP Inhibition
J.R.G. JUANATEY
C.H.U.Santiago
Dal-VESSEL: Change in Blood Pressure
Dalcetrapibb 600 mg
J.R.G. JUANATEY
C.H.U.Santiago
DEFINE: Changes in Blood Pressure Over 18 Months
Anacetrapib
Anacetrapib
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
HDL-c: Inhibición de CETP
J.R.G. JUANATEY
C.H.U.Santiago
• 30,000 patients with occlusive arterial disease in North America, Europe and Asia
• Background LDL-lowering with atorvastatin • Randomized to anacetrapib 100 mg vs. placebo • Scheduled follow-up: 4 years • Primary outcome: Coronary death, myocardial
infarction or coronary revascularization
www.revealtrial.org
J.R.G. JUANATEY
C.H.U.Santiago
HDL y Enfermedad CV
HDL y “Riesgo Residual”
HDL y Riesgo CV. Las implicaciones terapéuticas
¿Qué pasa con los fármacos y el HDL?
HDL y Riesgo CV. Los mecanismos
J.R.G. JUANATEY
C.H.U.Santiago
LDL-Cholesterol/HDL-Cholsterol and risk of coronary disease
1% decreasein LDL-C
reduces CHD risk by 1%
1% increasein HDL-C
reduces CHD risk by
2-3%
Statin Therapy
Therapeutic Opportunity ?
LDL-cholesterol / HDL-cholesterol and risk of coronary disease
LDL-cholesterol / HDL-cholesterol and risk of coronary disease!
Statin!Therapy!
Therapeutic Opportunity?!
J.R.G. JUANATEY
C.H.U.Santiago
Effect of HDL on endothelial cell nitric oxide production ?
HDL from Healthy subject
HDL from Patient with CAD
30 minutes
J.R.G. JUANATEY
C.H.U.Santiago
Vascular effects of HDL in patients with coronary disease
(ESR spectroscopy measurement)
HDL Healthy
HDLStable CAD
HDLACS -20
-15
-10
-5
0
5
10
15
20
25N
itric
oxi
de p
rodu
ctio
n (c
hang
es v
s. P
BS
-trea
ted
cells
, in
%)
P < 0.05 n.s.
P < 0.05
-150000
-100000
-50000
0
50000
100000
3450 3455 3460 3465 3470 3475 3480 3485
Magnetic field (G)
Arb
itrar
y U
nits
-150000
-100000
-50000
0
50000
100000
3450 3455 3460 3465 3470 3475 3480 3485
Magnetic field (G)
Arbi
trary
Uni
ts
-150000
-100000
-50000
0
50000
100000
3450 3455 3460 3465 3470 3475 3480 3485
Magnetic field (G)
AU
Besler C et al., In revisionBesler et al 2011
J.R.G. JUANATEY
C.H.U.Santiago
Sorrentino SA et al. Circulation. 2010;121:110-122
Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are
Improved After Extended-Release Niacin Therapy (A), Effect of HDL (50 µ/mL, 60 minutes, 37°C) from healthy subjects (n=10) and diabetic patients (n=33) on endothelial cell NO production as determined by ESR spectroscopy analysis
(A), Endothelium-dependent relaxations of aortic rings of wild-type mice in response to increasing concentrations of HDL isolated from healthy subjects (n=5) or diabetic patients (n=5) are shown
Endo
thel
ial N
O P
rodu
ctio
n (%
of b
uffe
r- tr
eate
d ce
lls)
PBS HDL HDL Healthy Diabetics
P < 0.0001 P < 0.0001 (A)
Endo
thel
ium
-dep
ende
nt
Rel
axat
ion
(%; a
ortic
ring
s)
HDL (µg/ml)
P = 0.007
HDL from Diabetic Patients
HDL from Healthy Subjects
(B)
J.R.G. JUANATEY
C.H.U.Santiago
Conversion of Anti-Inflammatory and Pro-Inflammatory HDL “quality vs quantity”
Ansell BJ, et al. J Am Coll Cardiol. 2005; 46:1792–1798.
Myeloperoxidase
Nitrotyrosine
Anti-inflammatory Pro-inflammatory
Apo A1
Chlortyrosine
Apo A1 Paraoxonase, other factors Pro-inflammatory factors, other factors
HDL=high-density lipoprotein
J.R.G. JUANATEY
C.H.U.Santiago
HDL y Enfermedad CV
HDL y “Riesgo Residual”
HDL y Riesgo CV. Las implicaciones terapéuticas
¿Qué pasa con los fármacos y el HDL?
HDL y Riesgo CV. Los mecanismos
Lipid Abnormalities - Predictors -
LDL-C at goal LDL-C at goal + Low HDL-C
LDL-C at goal + High TG
LDL-C at goal + Low HDL-C +
High TG OR (95%-CI) OR (95%-CI) OR (95%-CI) OR (95%-CI)
Age ≥70 years 1.22 (1.14-1.30) n.s. 0.86 (0.79-0.93) 0.77 (0.69-0.87) Female Gender 0.77 (0.73-0.83) 0.55 (0.50-0.60) 0.80 (0.74-0.87) 0.70 (0.62-0.79) Family Hx of premature CHD 0.92 (0.86-0.98) 1.09 (1.00-1.19) n.s. n.s. Current smoker 0.86 (0.79-0.94) 1.15 (1.03-1.28) n.s. 1.32 (1.15-1.51) Sedentary lifestyle 0.86 (0.81-0.91) n.s. n.s. n.s. Alcohol > 2 units/week 0.83 (0.78-0.88) 0.62 (0.57-0.68) n.s. 0.73 (0.65-0.82) BMI ≥30 kg/m² (obesity) 1.26 (1.18-1.34) 1.40 (1.27-1.53) 1.44 (1.32-1.57) 1.47 (1.31-1.66) Waist circumference n.s. 1.42 (1.28-1.56) 1.36 (1.24-1.49) 1.59 (1.40-1.82) Hypertension 1.25 (1.16-1.34) 1.28 (1.16-1.42) 1.32 (1.20-1.46) 1.37 (1.19-1.57) Diabetes mellitus 1.53 (1.43-1.63) 1.76 (1.62-1.91) 1.67 (1.54-1.80) 1.98 (1.77-2.20)
Ischemic heart disease 1.60 (1.50-1.71)
1.59 (1.46-1.72)
1.27 (1.17-1.38)
1.54 (1.38-1.72)
Cerebrovascular disease 1.18 (1.06-1.31) n.s. n.s. n.s. Heart failure 0.78 (0.70-0.87) n.s. n.s. n.s. Peripheral artery disease 0.85 (0.77-0.95) n.s. n.s. n.s. BP ≥140/90 mmHG 0.65 (0.61-0.70) 0.81 (0.74-0.88) 0.89 (0.82-0.96) 0.88 (0.79-0.98) 20-40 vs 10 mg Simva equ. 1.75 (1.59-1.92) 1.71 (1.46-1.99) 1.73 (1.50-2.00) 1.77 (1.43-2.19) ≥ 80 vs 10 mg Simva equ. 2.67 (2.36-3.02) 2.85 (2.39-3.39) 2.29 (1.93-2.71) 2.69 (2.12-3.41) Ezetimibe 1.21 (1.09-1.34) 1.13 (1.00-1.28) 1.26 (1.12-1.42) n.s. Specialist (Card/Endo/Dia/Int) 1.19 (1.12-1.27) 1.19 (1.09-1.29) n.s. n.s.
All High risk patient
Diabetes CVD ESC-score <5%
(n=21,264) (n=17,036) (n=4,486) (n=10,108) (n=4,228)
TC not at goal [%]* 52.8 50.5 49.6 45.2 62.2
LDL-c not at goal [%]† 48.0 46.2 44.2 41.4 55.2
LDL-c at goal (%) 52.0 53.8 55.8 58.6 44.8
Low HDL-c (<40 men/45 women) [%]‡ 26.5 28.4 29.9 30.9 18.7
Elevated TG (>150 mg/dL) [%]§ 37.8 38.7 43.0 37.9 34.1
Dyslipidemia International Study - Lipid Parameters -
Defined as CVD and diabetes mellitus and/or ESC Score ≥5%; *Total cholesterol ≥190 mg/dL in patients with ESC-Score <5%, and total cholesterol ≥175 mg/dL in patients with ESC-Score ≥5%, diabetes and/or CVD; †LDL-cholesterol ≥115 mg/dL in patients with ESC-Score <5%, and LDL-cholesterol ≥100 mg/dL in patients with ESC-Score ≥5%, diabetes and/or CVD, data on 21,550 patients were available; † Data on 20,385 patients were available, ‡Data on 20,388 patients were available, §Data on 20,489 patients were available
J.R.G. JUANATEY
C.H.U.Santiago
Biochemical determinants of ACS vs non-ischemic chest pain
Variables OR IC 95% p
Female 0,36 0,23 - 0,57 <0,01
Atrial fibrillation 0,27 0,14 - 0,52 <0,01
Age 1,05 1,03 - 1,06 <0,01
Active smoking 1,73 1,00 - 2,99 0,05
Diabetes 1,75 1,10 - 2,80 0,02
Glucose >100 mg/dl 1,89 1,22 - 2,94 <0,01
HDL < 40 mg/dl 2,99 1,95 - 4,59 <0,01
HDL: as a main determinant of ACS
Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325
J.R.G. JUANATEY
C.H.U.Santiago
Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325
Biochemical determinants of ACS vs non-ischemic chest pain
HDL: as a main determinant of ACS
ACS
Non-ischemic
chest pain
J.R.G. JUANATEY
C.H.U.Santiago
Residual Risk in ACS
“Residual Risk” in ACS. Role of HDL
HDL and CV Risk. The therapeutic implications
The Future
HDL and CV Risk. The mechanisms
J.R.G. JUANATEY
C.H.U.Santiago
Determinantes bioquímicos de SCA vs. DT no isquémico
HDL: principal determinante del SCA
Cordero A, et al. Rev Esp Cardiol; 2012; 65: 319-325
J.R.G. JUANATEY
C.H.U.Santiago
HDL promotes endothelial repair 1. HDL s;mulates endothelial cell prolifera;on in culture
(physiologic levels of LDL are toxic) Tauber 1980, 1981
2.HDL s;mulates endothelial cell migra;on independent of prolifera;on; effects addi;ve to bFGF and mediated by different signaling pathways Murugesan 1994, Shaul 1997
3.HDL s;mulates endothelial cell progenitor cells (EPC) Seetharam 2006, Sumi 2007
4.Intramiocardial injec;on of EPC improves refractory angina Losordo 2011
J.R.G. JUANATEY
C.H.U.Santiago
The HDL-C paradox Low HDL-‐C without increased atherosclerosis risk Apo A-‐I milano carriers SRB-‐1 overexpressing mice
High HDL-‐C without reduced atherosclerosis risk Human subjects with high HDL-‐C and CAD/AMI Carriers of certain CETP muta,ons SRB-‐1 gene dele,on in animals LCAT overexpression Torcetrapib in humans Niacin ?
Does the HDL func,onality ma_er: Quan,ty vs Quality?
J.R.G. JUANATEY
C.H.U.Santiago
HDL Becomes Pro-inflammatory During Acute Phase Response
Van Lenten et al JCI 1995
Normal HDL Acute Phase HDL
Apo A-‐I
PON SAA Acute illness
Inhibits ox-‐LDL induced subendothelial monocyte recruitment in-‐vivo
(an,-‐inflammatory)
Promotes ox-‐LDL induced subendothelial monocyte recruitment
in-‐vivo (Pro-‐inflammatory)
A high propor,on of CAD pa,ents have dysfunc,onal HDL Circula,on 2003
J.R.G. JUANATEY
C.H.U.Santiago
Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with CAD
Besler C al JCI 2011
HDL of CAD pa,ents and ACS pa,ents lacks endothelial repair and an,-‐inflammatory ac,vity
HDL of CAD ac,vated endothelial lec,n-‐like oxidized LDL receptor (LOX 1), triggering endotehlial PKCBII ac,va,on, whicvh in turn inhibited eNOS-‐ac,va,ng
pathways and eNOS-‐dependent NO produc,on
Reduced HDL-‐associated paraoxonase 1 (PON 1) ac,vity as one molecular mechanism leading to the genera,on of HDL with endothelial PKCBII-‐ac,va,ng proper,es, at least in part due to increased forma,on of malondialdehyde in HDL
J.R.G. JUANATEY
C.H.U.Santiago
•Anti-atherogenic functions of HDL ?
•“HDL dysfunction“ in cardiovascular disease
•Impact of HDL-targeted therapies on HDL dysfunction
HDL dysfunction –the true therapeutic target ?HDL dysfunction –
The true therapeutic target?
J.R.G. JUANATEY
C.H.U.Santiago
0 0,1 0,2 0,3 0,4 0,5 0,6
Phosphatidylinositol-glycan-specific …
Endosialin OS=Homo sapiens GN=CD248
Aminopeptidase N OS=Homo sapiens …
Sonic hedgehog protein OS=Homo sapiens …
Beta-1A of Integrin beta-1 OS=Homo sapiens …
IGK@ protein OS=Homo sapiens GN=IGK@
Integrin alpha-2 OS=Homo sapiens GN=ITGA2
Apolipoprotein F (APOF), mRNA OS=Homo …
Angiotensinogen OS=Homo sapiens GN=AGT
Serum paraoxonase/arylesterase 1 OS=Homo …
Serum paraoxonase/lactonase 3 OS=Homo …
Prenylcysteine oxidase 1 OS=Homo sapiens …
Apolipoprotein D OS=Homo sapiens GN=APOD
Cathelicidin antimicrobial peptide OS=Homo …
Apolipoprotein A-II OS=Homo sapiens …
DPI of Desmoplakin OS=Homo sapiens GN=DSP
Hemoglobin subunit alpha OS=Homo sapiens …
Antithrombin-III OS=Homo sapiens …
Apolipoprotein L1 OS=Homo sapiens …
Alpha-2-macroglobulin OS=Homo sapiens …Reduced in
ACS patients
0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9
Pulmonary surfactant-associated protein B OS=Homo sapiens …Apolipoprotein A-V OS=Homo sapiens GN=APOA5
Heparin cofactor 2 OS=Homo sapiens GN=SERPIND1Serotransferrin OS=Homo sapiens GN=TF
Lipopolysaccharide-binding protein OS=Homo sapiens GN=LBPPlatelet-activating factor acetylhydrolase OS=Homo sapiens …
Serum amyloid A protein OS=Homo sapiens GN=SAA1C4b-binding protein alpha chain OS=Homo sapiens GN=C4BPA
Haptoglobin OS=Homo sapiens GN=HPAdipocyte plasma membrane-associated protein OS=Homo …
Vitronectin OS=Homo sapiens GN=VTNLong palate, lung and nasal epithelium carcinoma-associated …
Alpha-2-HS-glycoprotein OS=Homo sapiens GN=AHSGAlpha-1-acid glycoprotein 2 OS=Homo sapiens GN=ORM2
Alpha-1-antichymotrypsin OS=Homo sapiens GN=SERPINA3Cholesteryl ester transfer protein OS=Homo sapiens GN=CETP
Apolipoprotein C-IV OS=Homo sapiens GN=APOC4Beta-2-glycoprotein 1 OS=Homo sapiens GN=APOH
Anthrax toxin receptor 1 OS=Homo sapiens GN=ANTXR1Apolipoprotein B-100 OS=Homo sapiens GN=APOB
Complement component C9 OS=Homo sapiens GN=C9Complement C3 OS=Homo sapiens GN=C3
HLA class I histocompatibility antigen, A-24 alpha chain …Protein AMBP OS=Homo sapiens GN=AMBP
Haptoglobin-related protein OS=Homo sapiens GN=HPRComplement component 4B (Childo blood group) OS=Homo …
Anthrax toxin receptor 2 OS=Homo sapiens GN=ANTXR2Alpha-2-antiplasmin OS=Homo sapiens GN=SERPINF2
GTP-binding protein SAR1a OS=Homo sapiens GN=SAR1AApolipoprotein(a) OS=Homo sapiens GN=LPA
Inter-alpha-trypsin inhibitor heavy chain H4 OS=Homo …Vesicular integral-membrane protein VIP36 OS=Homo sapiens …
Apolipoprotein A-IV OS=Homo sapiens GN=APOA4Serum albumin OS=Homo sapiens GN=ALB
Serum amyloid A-4 protein OS=Homo sapiens GN=SAA4Apolipoprotein C-III OS=Homo sapiens GN=APOC3
Increased in ACS patients
Changes of HDL proteome in coronary disease
Riwnato M, Besler C et al. (submitted)
J.R.G. JUANATEY
C.H.U.Santiago
HDL characterisation:Functionally relevant changes
Mechanisms of altered function of HDL ?
R.Laaksonen/A.von Eckardstein
“Lipidomics“ “Proteomics”
Functional genomis
Analysis of changes in HDL-associated
lipids
Analysis of changes in HDL-associated
proteins
HDL-cargo
J.R.G. JUANATEY
C.H.U.Santiago
Atherosclerosis development results fromdysbalance of increased foam cell formation
and impaired HDL-dependent cholesterol efflux from lipid-laden macrophages
Heinecke J, New Engl J Med 2011
J.R.G. JUANATEY
C.H.U.Santiago
Cholesterol efflux capacity of ApoB-depleted serum and coronary disease
Khera AV et al.; N Engl J Med. 2011; 364(2):127-35
J.R.G. JUANATEY
C.H.U.Santiago
Vascular effects of HDL in coronary disease -Study setup
Isolation of HDL2/3(by sequential ultracentrifugation)
Endothelial Function
(Endothelial cell NO production and vasoreactivity)
ESR spectroscopyOrgan chamber
ESR spectroscopy
Patients with acute coronary syndrome (n=25)Patients with stable coronary disease (n=25)
Healthy control subjects (n=25)
Vascular effects
Anti-oxidanteffects
(Endothelial cell superoxide production)
Anti-inflammatoryeffects
(Endothelial cell inflammatory activation)
Monocyte adhesion VCAM-1 expression
Effects on Re-Endothelialization
Carotid artery injury model in nude mice
Anti-thromboticeffects
Tissue factor Arterial thrombosis
J.R.G. JUANATEY
C.H.U.Santiago
Effect of HDL on endothelial cell nitric oxide production ?
HDL from Healthy subject
HDL from Patient with CAD
30 minutes
J.R.G. JUANATEY
C.H.U.Santiago
Vascular effects of HDL in patients with coronary disease
(ESR spectroscopy measurement)
HDL Healthy
HDLStable CAD
HDLACS -20
-15
-10
-5
0
5
10
15
20
25N
itric
oxi
de p
rodu
ctio
n (c
hang
es v
s. P
BS
-trea
ted
cells
, in
%)
P < 0.05 n.s.
P < 0.05
-150000
-100000
-50000
0
50000
100000
3450 3455 3460 3465 3470 3475 3480 3485
Magnetic field (G)
Arb
itrar
y U
nits
-150000
-100000
-50000
0
50000
100000
3450 3455 3460 3465 3470 3475 3480 3485
Magnetic field (G)
Arbi
trary
Uni
ts
-150000
-100000
-50000
0
50000
100000
3450 3455 3460 3465 3470 3475 3480 3485
Magnetic field (G)
AU
Besler C et al., In revisionBesler et al 2011
J.R.G. JUANATEY
C.H.U.Santiago
Baseline TNFαTNFα + HealthyHDL
TNFα +Stable CAD
HDL
TNFα +ACS
HDL
0
5
10
15
20
25
30
35
Num
ber o
f GC
SF-la
bele
d m
onoc
ytes
pe
r hig
h po
wer
fiel
d
P < 0.05 P < 0.05n.s.
P < 0.05
Effects of HDL on vascular inflammation:monocyte adhesion on TNFα-stimulated
endothelial cells
Besler C et al., In revisionBesler et al 2011
J.R.G. JUANATEY
C.H.U.Santiago
Endothelial binding of HDL in patients with coronary disease
HDLHealthy
HDLsCAD
HDLACS
Spec
ific
bind
ing
of 1
25I-H
DL
[in %
HD
L H
ealth
y]
0
20
40
60
80
100
P<0.01
P<0.01120
Besler C et al., In revisionBesler et al 2011
J.R.G. JUANATEY
C.H.U.Santiago
Ulf LandmesserZurich Univ.
Altered endothelial effects of HDL in cardiovascular
disease
Alan FogelmanUCLA
Novel approaches to stimulateHDL functions
Alan Tall Columbia Univ., New York
Molecular mechanisms of vascular effects of HDL
John DeanfieldUCL,London
Clinical implications of HDL dysfunction
Bart StaelsLille, Inserm
Novel molecular targets stimu-lating HDL functions
Jan A. KuivenhovenAmsterdam Univ.
Effects of HDL-genes on HDL functions
Thomas LüscherZurich Univ.
Vasculareffects of HDL and
its alterations
Stanley Hazen Cleveland Clinic
Molecular mechanisms of HDL dysfunction
Leducq Transatlantic Network:HDL dysfunction in the pathophysiology in
cardiovascular disease and as a novel treatment target
Network Project Managment: Michaela Keel
J.R.G. JUANATEY
C.H.U.Santiago
Residual Risk in ACS
“Residual Risk” in ACS. Role of HDL
HDL and CV Risk. The therapeutic implications
The Future
HDL and CV Risk. The mechanisms
J.R.G. JUANATEY
C.H.U.Santiago
LaRosa JC et al. N Engl J Med. 2005;352:1425-35
Major CVevents
(%)
CHD death, MI, resuscitation after cardiac arrest, fatal/nonfatal stroke
Follow-up (years)
65421 3
Atorvastatin 80 mg (n = 4995)
00.00
0.05
0.10
0.15
22% Risk reductionHR = 0.78 (0.69–0.89)P < 0.001
Treating to New TargetsN = 10,001
The forgotten majority
Intense statin therapy improves outcome –but still a substantial “residual” risk
Moderate Statin Therapie (n = 4995)
J.R.G. JUANATEY
C.H.U.Santiago
Pharmacotherapeu,c Targe,ng of HDL
Vascular Protec,ve Effects of HDL and its Apolipoproteins:
An idea whose ,me for tes,ng is here
Recombinant HDL (rAPO A-‐1 milano)
Niacin
Small molecule (APO A-‐1 inducer)
Plasma derived HDL
Apo A-‐I mime,c pep,des (D4F, others) CETP inhibi,on
drugs, vaccine
EL inhibi,on An,sense oligo
LUV (PL)
SR-‐B1 upregula,on
RXR, PPAR and LXR Agonists
Fibrates, glitazones, glitazars
HDL-‐related (Apo A-‐1)
Gene therapy HDL-‐associated an,oxidants
Paraoxonase, PAF-‐ACH Rimonabant Delipida,on
J.R.G. JUANATEY
C.H.U.Santiago
Seven Weekly Reinfusions of ex-‐vivo Delipidated HDL in ACS Pa,ents
Normalize average Preβ-‐HDL
Undelipidated Plasma
Delipidated Plasma
% Change in Atheroma Volume (IVUS)
Control (n=12)
Ac,ve Rx (n=14)
Waksman R et al JACC 2010
3 + 21
12 + 37
J.R.G. JUANATEY
C.H.U.Santiago
Effects of HDL from healthy subjects and type-2 diabetics with metabolic syndrome (low HDL) on endothelial NO-Production
HDL Healthy
En
do
thelial
NO
Pro
du
ctio
n
[% o
f bu
ffer
-tr
eate
d ce
lls]
PBS HDLDiabetics
0
50
100
150
200
P < 0.0001 P < 0.0001
Sorrentino SA et al. & Landmesser U. Circulation 2010; 121:110-22
J.R.G. JUANATEY
C.H.U.Santiago
CETP Inhibition and Lipoprotein Metabolism
Adopted from Brewer 2004Adapted from Brewer 2004
J.R.G. JUANATEY
C.H.U.Santiago
Residual Risk in ACS
“Residual Risk” in ACS. Role of HDL
HDL and CV Risk. The therapeutic implications
The Future
HDL and CV Risk. The mechanisms
J.R.G. JUANATEY
C.H.U.Santiago
A Poten,al New Therapeu,c Paradigm for Atherosclerosis
Acute/Subacute Therapy
Rou,ne Rx
IV HDL/Apo A-‐I mime,c pep,des
Rapid Plaque Remodeling Regression Stabiliza,on
Lipid deple,on Reduced Plaque Inflamma,on
Oral HDL based Rx ¿ HDL gene therapy?
Long term Therapy
Sustained plaque remodeling regresion stabiliza,on
J.R.G. JUANATEY
C.H.U.Santiago
Residual Risk in ACS
“Residual Risk” in ACS. Role of HDL
HDL and CV Risk. The therapeutic implications
The Future
HDL and CV Risk. The mechanisms
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
↓LDL-c (%)
↑HDL-c (%)
↓TG (%)
Cam
bio
desd
e ba
sal(%
)
Estatinas
Niacina
Fibratos
-10
-20
-30
-40
-50
+20
+10
0
20
50
30
15 15
55
25 20
+30
18
5 5 7
20
50
5
35
20 10
Hipolipemiantes: efectos
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
25% Buen control
5,7%
Solo LDL>100 mg/dl
Solo HDL<40 mg/dl
Solo TG>150 mg/dl
15,8%
8,8%
7,2%
7,11% 14,0%
16,2%
Riesgo residual: 29,9%
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
Riesgo residual lipídico en ICP-Bypass
J.R.G. JUANATEY
C.H.U.Santiago
Actual contribution of each risk factor in improving the UKPDS CHD risk
score for Steno-2 intensive treatment arm
Smoking3%
SBP11%
HbA1c13%
Total cholesterol48%
Lipids73%
HDL cholesterol25%
J.R.G. JUANATEY
C.H.U.Santiago
Riesgo residual lipídico en diabéticos
Pacientes no diabéticos Pacientes no diabéticos
J.R.G. JUANATEY
C.H.U.Santiago
Riesgo residual lipídico en diabéticos
J.R.G. JUANATEY
C.H.U.Santiago
Riesgo residual lipídico en diabéticos
47,0 (17,5) mg/dl
43,9 (14,8) mg/dl
p<0,01
J.R.G. JUANATEY
C.H.U.Santiago
HDL Biology: What is New Lipid Transport
Individuals with similar HDL-‐C levels but higher total
macrophage efflux capacity had significantly higher ABCA1-‐mediated efflux
Higher ABCA1-‐mediated efflux was directly
correlated with the level of pre-‐b-‐1 HDL in serum
J.R.G. JUANATEY
C.H.U.Santiago
A-I
Bile
Nascent HDL
A-I
FCCE
FCLCATMature
HDL
HDL
CETPVLDL/
LDL TGCE
CEFC
PLTPLDL-R
SR-BI Macrophage
ABCA1
ABCG1
SR-BI ?
HDL: proposed anti-atherogenic effects
1. HDL-mediated promotion of RCT(reverse cholesterol transport)
Besler C et al. & Landmesser U. Curr Pharmacol Des 2010, 16: 1480-93
J.R.G. JUANATEY
C.H.U.Santiago
Increased atherosclerosis in ABCA-1 /ABCG1 bone-marrow-deficient mice
Yvan-Charvet L et al.; J Clin Invest. 2007;117(12):3900-8
No significant differences in HDL plasma levels
J.R.G. JUANATEY
C.H.U.Santiago
Endothelial NO production –Anti-atherogenic effects
Vascular smooth muscle cell
Monocyt
Inhibition of Leukocyte adhesion und -infiltration
Inhibition of VSMC proliferation
NO
Platelets
Inhibition of Thrombocyte adhesion and -aggregation
Endothel
Landmesser et al.; Circulation 2004Landmesser et al., Curr Opinion Cardiol 2005; 20:547-51
J.R.G. JUANATEY
C.H.U.Santiago
-20
-10
0
10
20
30
25 g/ml 50 g/ml 100 g/mlHDL HDL HDL
Healthy
sCAD
ACS
P<0.025
En
doth
elia
l nitr
ic o
xide
prod
uctio
n[in
% o
f buf
fer-
treat
ed c
ells
]
HDL –effects on endothelial cell nitric oxide production in patients with CAD
Besler C et al. J Clin Invest (accept minor)
J.R.G. JUANATEY
C.H.U.Santiago
Effects of HDL on endothelial repair after arterial injury
PBS HDLHealthy
HDLStable CAD
HDLACS
0
5
10
15
20
25
30
Re-e
ndot
helia
lized
are
a [in
%] P < 0.0001
P < 0.05
Quantification of re-endothelialized area 3 days after induction of carotid injury by Evan`s blue staining
Besler C et al. J Clin Invest (accept minor)
J.R.G. JUANATEY
C.H.U.Santiago
HDL function(vascular effects)
Which changes of HDL are mediatingdifferences in HDL‘s
vascular effects ?
J.R.G. JUANATEY
C.H.U.Santiago
Correlation between apoB-deficient serum cholesterol efflux and HDL cholesterol
Khera AV et al.; N Engl J Med. 2011; 364(2):127-35
J.R.G. JUANATEY
C.H.U.Santiago
1. HDL from healthy subjects exerts several important anti-atherogenic effects beyond „reverse cholesterol transport“, i.e. stimulation of endothelial NO production, anti-inflammatory and anti-thrombotic effects.
2. In patients with coronary disease or diabetes with low HDL, HDL becomes „dysfunctional“, i.e. loses anti-atherogenic properties.
3. HDL-targeted treatment strategies should therefore be examined for their effect on vasoproetctive properties of HDL. ER-niacin therapy improves endothelial-protective effects of HDL in patients with diabetes and low HDL.
Summary
J.R.G. JUANATEY
C.H.U.Santiago
HDL function(vascular effects)
- The true therapeutic target ?
HDL function (vascular effects)
J.R.G. JUANATEY
C.H.U.Santiago
Endo
thel
ium
-dep
ende
nt
Vaso
dila
tion
FDD
[%]
0
5
10
15
DiabeticsBaseline
Diabetics3 Months
Placebo
Diabetics Baseline
Diabetics3 Months
ER-Niacin
P < 0.0001
Niacin therapy improves endothelial function in type-2 diabetics with low HDL
Sorrentino SA et al. & Landmesser U. Circulation 2010; 121:110-22
J.R.G. JUANATEY
C.H.U.Santiago
Riesgo residual lipídico en pacientes con antecedentes de
revascularización coronaria: Estudio ICP-Bypass
Alberto Cordero Servicio de Cardiología Hospital Universitario San Juan
J.R.G. JUANATEY
C.H.U.Santiago
Departamento de Cardiología Clínica Universitaria de Navarra
J.R.G. JUANATEY
C.H.U.Santiago
LDL-c y cardiopatía isquémica
Colesterol LDL alcanzado, en mg/dl (mmol/l)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - Placebo AFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Placebo
CARE - Rx
LIPID - Placebo CARE - Placebo
HPS - Rx
0
5
10
15
20
25
30
40 (1,0)
60 (1,6)
80 (2,1)
100 (2,6)
120 (3,1)
140 (3,6)
160 (4,1)
180 (4,7)
Tasa
de
epis
odio
s (%
)
6
Prevención secundaria
Prevención primaria
Rx - Tratamiento con estatinas PRA - Pravastatina ATV - Atorvastatina
200 (5,2)
PROVE-IT - PRA PROVE-IT – ATV
TNT – ATV10 TNT – ATV80
CORONA - Rx CORONA - Placebo
Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-79 LaRosa JC, et al. N Engl J Med 2005;352:1425-35
J.R.G. JUANATEY
C.H.U.Santiago Kannel W, et al. Am J Cardiol 1987;59:80
Rie
sgo
rela
tivo
para
IAM
0
0.5
1.0
1.5
2.0
3.0
2.5
1,2
1,9
2,9
0,6 0,9
1,5
0,3 0,4 0,7
0,1 0,2 0,3
c-LDL
100 mg/dl 160 mg/dl 220 mg/dl 85 mg/dl 66 mg/dl
46 mg/dl 23 mg/dl
c-HDL
LDL-c, HDL-c y cardiopatía isquémica
J.R.G. JUANATEY
C.H.U.Santiago
LDL-c, HDL-c y cardiopatía isquémica 21% pacientes presentan progresión de placas
a pesar de LDL-c <70 mg/dl
Bayturan O, et al. JACC 2010;55:2736-42
J.R.G. JUANATEY
C.H.U.Santiago Barter P, et al. NEJM 2007;357:1301-10
LDL-c, HDL-c y cardiopatía isquémica
J.R.G. JUANATEY
C.H.U.Santiago Reiner, et al. E Heart J 2011;32:1769-1818
Guías de dislipemia ESC 2011
J.R.G. JUANATEY
C.H.U.Santiago Hsia J, et al. J Am Coll Cardiol 2011;57:1666-75
LDL-c, HDL-c y cardiopatía isquémica
J.R.G. JUANATEY
C.H.U.Santiago Arós F, et al. Rev Esp Cardiol 2011;64:972-80
LDL-c, HDL-c y cardiopatía isquémica
Evolución en el perfil clínico de los pacientes con SCA
J.R.G. JUANATEY
C.H.U.Santiago
LDL-c, HDL-c y cardiopatía isquémica
Stone G, et al. NEJM 2011;364:226-35
J.R.G. JUANATEY
C.H.U.Santiago
Riesgo residual
Fruchart JC, et al. Am J Cardiol 2008;102:1K-34K
22% Reducción relativa de riesgo
RIESGO RESIDUAL
J.R.G. JUANATEY
C.H.U.Santiago
Introducción
González-Juanatey J.R, et al. Rev Esp Cardiol 2011; 2011;64:286-294
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia de la resistencia insulínica
Cordero A, et al. Med Clin 2006;127:705-08
AGLibres VLDL
Quilomicrones
Insulina Neoglucogénesis LPL
Lipolisis de TG
ADIPOCITOS
Músculo liso
Obesidad Genética
Dieta
Glucosa
↑TG ↓HDL VLDL
CETP
+
LDL fenotipo B
+
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia de la resistencia insulínica
Tamaño de las partículas LDL colesterol
Hanak V, et al. Am J Cardiol 2004;94:219-22
Varones Mujeres
Fenotipo B Fenotipo A
Fenotipo B Fenotipo A
Frec
uenc
ia (%
)
Frec
uenc
ia (%
) TG/HDL TG/HDL
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia de la resistencia insulínica Partículas LDL pequeñas y densas = permeables y aterogénicas
Libby P, Nature 2002;420:868-874
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia de la resistencia insulínica
Cordero A, et al. Am J Cardiol 2008;102:424-28
Distribución del TG/HDL y presencia de Sd. Metabólico
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia de la resistencia insulínica
Cordero A, et al. Am J Cardiol 2008;102:424-28
Distribución del TG/HDL en la población
J.R.G. JUANATEY
C.H.U.Santiago
ESC YIA 2009 Cordero A, et al. J Am Cardiol 2009; 104:1393-1397
Valor predictivo de IAM de TG/HDL
Dislipemia de la resistencia insulínica
J.R.G. JUANATEY
C.H.U.Santiago Badimon JJ, et al Rev Esp Cardiol 2010;63:323-33
Aterosclerosis: desequilibrio LDL y HDL
J.R.G. JUANATEY
C.H.U.Santiago
Riesgo residual lipídico (RRL) definido como: LDL <100 mg/dl
• y HDL <40 mg/dl • y/o TG >150 mg/dl
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
J.R.G. JUANATEY
C.H.U.Santiago
25% Buen control
5,7%
Solo LDL>100 mg/dl
Solo HDL<40 mg/dl
Solo TG>150 mg/dl
15,8%
8,8%
7,2%
7,11% 14,0%
16,2%
Riesgo residual: 29,9%
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
Riesgo residual lipídico en ICP-Bypass
J.R.G. JUANATEY
C.H.U.Santiago
Total No RRL RRL p N (%) 2292 1.606 (70,1%) 686 (29,9%)
Edad 65,5 ±12,4 66,1 ±12,2 64,1 ±12,7 <0,01
Varones (%) 78,2% 76,5% 82,0% <0,01
Años evolución 3,3 ±4,2 3,4 ±4,3 3,0 ±3,9 0,03
ICP (%) 76,6% 74,6% 81,2% <0,01
PA sistólica 132,3 ±18,6 133,1 ±18,5 130,3 ±18,6 0,01
PA diastólica 75,9 ±10,9 76,2 (10,9 75,1 ±10,9 0,02
IMC (kg/m2) 28,5 ±4,1 28,4 ±4,1 28,5 ±4,0 0,54
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
Riesgo residual lipídico en ICP-Bypass
J.R.G. JUANATEY
C.H.U.Santiago
Total No RRL RRL p Sobrepeso (%) 49,3% 50,4% 46,8% 0,12
Obesidad (%) 29,1% 28,3% 30,9% 0,21
Obesidad abdominal 44,3% 43,9% 45,0% 0,66
Dislipemia (%) 71,7% 72,7% 69,3% 0,16
Diabetes (%) 33,2% 31,6% 37,0% 0,01
Hipertensión (%) 60,8% 61,1% 60,1% 0,65
Fumadores (%) 48,8% 47,5% 51,8% 0,06
Sedentarismo 42,4% 43,0% 41,1% 0,41
Consumo alcohol 28,6% 29,1% 27,4% 0,42
FG <60 22,8% 22,8% 22,6% 0,41
Otra ECV (%) 6,2% 5,7% 7,5% 0,12
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
Riesgo residual lipídico en ICP-Bypass
J.R.G. JUANATEY
C.H.U.Santiago
Total No RRL RRL p
Colesterol total (mg/dl) 169,4 ±40,2 181,2 ±39,6 144,3 ±27,9 <0,01
LDL (mg/dl) 95,6 ±33,5 106,7 ±34,2 73,8 ±17,5 <0,01
HDL (mg/dl) 46,0 ±16,7 49,5 ±15,0 39,0 ±17,9 0,14
Triglicéridos (mg/dl) 122,0 (93,0-167,0)
112,0 (88,0-149,8)
151,0 (106,2-188,8)
<0,01
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
Riesgo residual lipídico en ICP-Bypass
J.R.G. JUANATEY
C.H.U.Santiago
Total No RRL RRL p Glucemia (mg/dl) 123,8 ±3,9 122,5 ±44,2 126,5 ±43,2 0,12
HbA1c (%) en diabéticos 7,5 ±6,2 7,6 ±7,0 7,4 ±4,5 0,73
Creatinina (mg/dl) 1,1 ±0,5 1,0 ±0,4 1,2 ±0,7 0,04
F. glomerular (ml/min/1,72 m2) 76,9 ±27,4 77,0 ±28,7 76,7 ±24,4 0,80
ALT (UI/L) 31,0 ±22,1 30,6 ±19,1 31,7 ±27,7 0,33
AST (UI/L) 29,4 ±20,3 30,0 ±22,0 28,1 ±15,8 0,07
GGT (UI/L) 48,7 ±54,8 49,1 ±53,4 47,8 ±57,9 0,66
CK (mg(dl) 103,7 ±76,3 103,7 ±69,7 103,8 ±89,1 0,97
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
Riesgo residual lipídico en ICP-Bypass
J.R.G. JUANATEY
C.H.U.Santiago
Resultados: Control de FR
p=0,07
en diabéticos
p=0,68
p<0,01
p<0,01
p<0,01
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
J.R.G. JUANATEY
C.H.U.Santiago
Resultados: hipolipemiantes Total No RRL RRL p Atorvastatina 57,8% 56,1% 61,7% 0,01
dosis (mg/dl) 40,0 ±21,8 39,5 ±22,0 41,2 ±21,4 0,18
Sinvastatina 22,7% 23,0% 22,0% 0,61
dosis (mg/dl) 27,4 ±11,9 27,4 ±12,3 27,3 ±11,1 0,88
Pravastatina 6,2% 6,4% 6,0% 0,73
dosis (mg/dl) 28,9 ±10,7 28,7 ±10,6 29,5 ±11,2 0,70
Lovastatina 0,4% 0,4% 0,6% 0,49
dosis (mg/dl) 30,0 ±19,4 33,3 ±24,2 25,0 ±10,0 0,54
Fluvastatina 6,4% 6,9% 5,1% 0,10
dosis (mg/dl) 75,5 ±14,5 74,9 ±15,7 77,7 ±9,6 0,33
Ezetimibe 18,3% 19,7% 15,0% <0,01
Fibratos 3,7% 3,2% 4,8% 0,06
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
J.R.G. JUANATEY
C.H.U.Santiago
Factores asociados a la presencia de RRL
Variables HDL <40 mg/dl TG>150 mg/dl RRL Edad 0,98 (0,98-0,99); p<0,01 0,98 (0,98-,99); p<0,01 0,99 (0,98-0,99); p=0,02
Sexo masculino 1,81 (1,39-2,34); p<0,01 1,14 (0,89-1,46); p=0,30 1,52(1,16-1,98); p<0,01
Tabaquismo 1,57 (1,14-2,15); p<0,01 1,39 (1,01-1,92); p=0,04 1,18 (0,85-1,63); p=0,33
Diabetes 1,32 (1,07-1,63); p<0,01 1,46 (1,19-1,80); p<0,01 1,35 (1,09-1,68); p<0,01
IMC > 30kg/m2 1,11 (0,87-1,41); p=0,40 1,22 (0,96-1,54); p=0,10 1,09 (0,85-1,40); p=0,48
Obesidad abdominal 1,07 (0,85-1,34); p=0,59 1,33 (1,06-1,68); p=0,01 1,07 (0,84-1,36); p=0,61
Sedentarismo 1,14 (0,93-1,40); p=0,22 1,06 (0,87-1,31); p=0,55 0,91 (0,73-1,13); p=0,38
ICP 1,18 (0,93-1,49); p=0,18 1,26 (1,00-1,60); p=0,05 1,40 (1,09-1,80); p<0,01
Ezetimibe 0,99 (0,97-1,02); p=0,44 1,02 (0,99-1,04); p=0,19 0,97 (0,94-0,99); p<0,01
Fibratos 1,25 (1,13-1,38); p<0,01 1,39 (1,24-1,57); p<0,01 1,04 (0,94-1,15); p=0,43
G-Juanatey JR, Cordero A, et al. Rev Esp Cardiol 2011;64:862-868
J.R.G. JUANATEY
C.H.U.Santiago
Control de LDL-c y disfunción renal 4D=Die Deutsche Diabetes Dialyse Studie
Inci
denc
ia a
cum
ulad
a de
end
-po
ints
prim
ario
s (%
)
Atorvastatina
Placebo 60
50
40
30
20
10
0 6 0 1 2 3 4 5
Placebo
Inci
denc
ia a
cum
ulad
a
Rosuvastatina 10 mgs
HR=0.96 (95% CI 0.84–1.11) p=0.59
0
5
10
15
20
25
30
35
40 Estudio AURORA
Años desde randomización 0 1 2 3 4 5
Años desde randomización
0 1 2 3 4 5 Años de seguimiento
0
5
10
15
20
25
Porcen
taje de even
tos (%)
Ra;o de riesgo 0.83 (0.74 – 0.94) Logrank 2P=0.0022
Placebo
Eze/simv
SHARP trial
J.R.G. JUANATEY
C.H.U.Santiago Cordero A, et al. submitted
Control de LDL-c y disfunción renal Total GFR >60 GFR <60 p
N (%) 2,037 1573 (77.2%) 464 (22.8%)
Age 66.0 (11.0) 63.9 (10.8) 73.1 (8.3) <0.01
Males 77.8% 83.3% 59.2% <0.01
Systolic BP (mmHg) 132.4 (18.3) 131.9 (18.0) 134.1 (19.1) 0.03
Diastolic BP (mmHg) 75.8 (10.8) 75.9 (10.5) 75.6 (11.7) 0.55
Diabetes 33.9% 30.2% 46.6% <0.01
Hypertension 33.9% 30.2% 46.6% <0.01
Dyslipidemia 72.5% 71.5% 76.4% 0.08
Current smokers 10.5% 11.8% 5.8% <0.01
Obesity 30.2% 29.7% 31.9% 0.36
Abdominal obesity 44.4% 42.0% 53.0% <0.01
Sedentary lifestyle 42.4% 37.5% 59.1% <0.01
Alcohol consumption 29.2% 32.0% 19.8% <0.01
J.R.G. JUANATEY
C.H.U.Santiago
Total GFR >60 GFR <60 p
Creatinine (mg/dl) 1.08 (0.52) 0.94 (0.17) 1.57 (0.88) <0.01
GFR (ml/min/1.71m2) 76.9 (27.4) 85.9 (24.2) 46.4 (10.8) <0.01
Total cholesterol (mg/dl) 169.2 (40.3) 169.5 (40.3) 168.2 (40.6) 0.53
LDL (mg/dl) 95.4 (33.6) 96.1 (33.8) 93.2 (32.7) 0.13
HDL (mg/dl) 46.0 (16.9) 45.9 (16.7) 46.4 (17.6) 0.64
Triglycerides (mg/dl) 121.0 (93.0-167.0)
120.0 (93.0-165.0)
124.0 (94.0-174.0)
0.19
Glycemia (mg/dl) 123.2 (43.3) 121.2 (42.7) 129.0 (44.4) <0.01
HbA1c (%)* 7.1 (1.3) 7.1 (1.3) 7.1 (1.4) 0.98
GGT (IU/L) 49.0 (55.4) 48.2 (55.5) 51.9 (55.1) 0.29
ALT (IU/L) 31.0 (22.3) 31.4 (23.4) 29.5 (178.0) 0.15
AST (IU/L) 29.3 (20.5) 29.6 (21.6) 28.6 (16.2) 0.41
Cordero A, et al. submitted
Control de LDL-c y disfunción renal
J.R.G. JUANATEY
C.H.U.Santiago
Total GFR >60 GFR <60 p
Any statin 94.2% 94.9% 91.8% 0.01
Atorvastatin 58.8% 59.8% 55.2% 0.07
Simvastatin 21.7% 21.2% 23.3% 0.35
Pravastatin 6.0% 6.0% 6.0% 0.99
Lovastatin 0.4% 0.3% 0.5% 0.83
Fluvastatin 6.7% 6.8% 6.3% 0.67
Fibrates 3.9% 3.4% 5.8% 0.02
Ezetimibe 18.9% 19.4% 17.2% 0.30
Statins+ezetimibe 17.5% 18.1% 15.3% 0.16
Cordero A, et al. submitted
Control de LDL-c y disfunción renal
J.R.G. JUANATEY
C.H.U.Santiago
p=0.20 p=0.99 p=0.19 p=0.02
Cordero A, et al. submitted
Control de LDL-c y disfunción renal LDL <100 mg/dl
p=0.25 p=0.52 p=0.37 p=0.05
LDL <70 mg/dl
J.R.G. JUANATEY
C.H.U.Santiago Cordero A, et al. submitted
Control de LDL-c y disfunción renal Interacción de FG <60 ml/min/1,72m2 y Tto estatina+ezetimiba
para la presencia de LDL-c <100 mg/dl
p=0.02
J.R.G. JUANATEY
C.H.U.Santiago
Total GFR>60 ml/min/1.72m2 GFR<60 ml/min/1.72m2
Diabetes 1.26 (0.97-1.63);
p=0.08 1.27 (0.95-1.71); p=0.11 1.19 (0.69-2.04); p=0.53
Dislipemia 0.58 (0.44-0.78);
p<0.01 0.61 (0.44-0.84); p<0.01 0.46 (0.24-0.88); p=0.02
Estatina+Ezetimibe 0.93 (0.69-1.26);
p=0.66 0.75 (0.54-1.06); p=0.10 2.44 (1.18-5.10); p=0.02
Sedentarismo 0.80 (0.62-1.02);
p=0.07 0.76 (0.55-0.99); p=0.04 1.01 (0.58-1.77); p=0.97
Cordero A, et al. submitted
Control de LDL-c y disfunción renal Factores asociados independientemente a LDL-c <100 mg/dl
J.R.G. JUANATEY
C.H.U.Santiago Lazaro A, et al. Rev Esp Cardiol 2010;63:1428-37
Control de LDL-c e inercia terapéutica
J.R.G. JUANATEY
C.H.U.Santiago Lazaro A, et al. Rev Esp Cardiol 2010;63:1428-37
Control de LDL-c e inercia terapéutica
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia en la disfunción renal
Ghandehari H, et al. Am Heart J 2008;156:112-9
J.R.G. JUANATEY
C.H.U.Santiago Martín A Cordero A, et al. Med Clin 2007;128:705-10
DISFUNCIÓN RENAL
CARDIOPATÍA ISQUEMICA
EDAD
FACTORES RIESGO
Hipertrofia VI Homocisteína Proteína-C reactiva
Anemia Microalbuminuria
Disfunción renal y Enf. cardiovascular
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia en la disfunción renal
Keane WF, et al. Contrib Nephrol. 2011;171:135-42
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia en la disfunción renal
Keane WF, et al. Contrib Nephrol. 2011;171:135-42
Receptor periférico
Receptor hepático
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia en la disfunción renal
Keane WF, et al. Contrib Nephrol. 2011;171:135-42
DISFUNCIÓN RENAL
• captación hepática de quilomicrones • actividad LPL hepática • actividad LPL tisular • actividad LPL hepática • expresión del receptor hepático de LDL • absorción intestinal de colesterol
J.R.G. JUANATEY
C.H.U.Santiago
Dislipemia en la disfunción renal
Keane WF, et al. Contrib Nephrol. 2011;171:135-42
Filtrado Glomerular
LDL-c Diálisis
LDL pequeñas y densas
Triglicéridos
HDL-c
J.R.G. JUANATEY
C.H.U.Santiago
Conclusiones 1. El 30% de los pacientes con C. Isquémica tienen un Riesgo Residual lipídico y son, fundamentalmente varones con diabetes. 2. Además, el 25 % de los pacientes con C. Isquémica tienen disfunción renal, especialmente los enfermos con más factores de riesgo y enf. Cardiovascular.
3. Existe una interacción entre la disfunción renal y la asociación del tratamiento de estatina+ezetimibe y la presencia de LDL-c <100 mg/dl.
J.R.G. JUANATEY
C.H.U.Santiago
Riesgo residual lipídico en pacientes con antecedentes de
revascularización coronaria: Estudio ICP-Bypass
Alberto Cordero Servicio de Cardiología Hospital Universitario San Juan