¿Sirve para algo elevar el HDL?

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

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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

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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


Diet Obesity

HT HDL

Tobacco

J.R.G. JUANATEY

C.H.U.Santiago

CV Risk beyond LDL

Residual Risk

Etc.. TG


Diet Obesity

HT

HDL Tobacco

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C.H.U.Santiago

Dislipidemias y riesgo global Tablas SCORE con inclusión del c-HDL

No fumadora Fumadora Edad

No fumador Fumador Edad

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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

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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


Q3 (n 939) Media 43 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





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

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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





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


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

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

3 Months


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.

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Lipid Changes Following Treatment with CETP Inhibitors

Dalcetrapib

Torcetrapib

Anacetrapib

Evacetrapib

HDL-C

ApoA1

LDL-C

Apo-B

TG

Total Cholesterol

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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

(%)

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Torcetrapib’s Failure Due to Off-Target Effects, Not CETP Inhibition

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Dal-VESSEL: Change in Blood Pressure

Dalcetrapibb 600 mg

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DEFINE: Changes in Blood Pressure Over 18 Months

Anacetrapib

Anacetrapib

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C.H.U.Santiago

J.R.G. JUANATEY

C.H.U.Santiago

HDL-c: Inhibición de CETP

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•  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

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HDL y Enfermedad CV





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


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





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

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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



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ACS

Non-ischemic

chest pain

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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

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Determinantes bioquímicos de SCA vs. DT no isquémico

HDL: principal determinante del SCA


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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

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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?

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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

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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


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


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


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




The Future


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


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




The Future


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




The Future


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

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


J.R.G. JUANATEY

C.H.U.Santiago


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


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


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


J.R.G. JUANATEY

C.H.U.Santiago Arós F, et al. Rev Esp Cardiol 2011;64:972-80


Evolución en el perfil clínico de los pacientes con SCA

J.R.G. JUANATEY

C.H.U.Santiago


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


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


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


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


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


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%



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



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



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



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



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


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


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


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


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


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


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

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


Keane WF, et al. Contrib Nephrol. 2011;171:135-42

J.R.G. JUANATEY

C.H.U.Santiago



Receptor periférico

Receptor hepático

J.R.G. JUANATEY

C.H.U.Santiago



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



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

¿Sirve para algo elevar el HDL?

Health & Medicine

Transcript of ¿Sirve para algo elevar el HDL?