LDL Targetsvs

Pleiotropic Effects

Is there more to life than LDL?

LDL Targetsvs

Pleiotropic Effects

Is there more to life than LDL?

Thomas A. Hughes, M.D.

Professor of Medicine - Retired

Division of Endocrinology, Metabolism, and Diabetes

University of Tennessee Health Science Center

HughesEndo.com

Thomas A. Hughes, M.D.

Professor of Medicine - Retired

Division of Endocrinology, Metabolism, and Diabetes

University of Tennessee Health Science Center

HughesEndo.com

LDL Targets vs Pleiotrophic EffectsLDL Targets vs Pleiotrophic Effects

“Treating the number” vs Pleiotropic Effects:

Events directly related to reducing a number:

Lipids - Atherosclerosis (MI, Stroke, PVD)

BP - Stroke, Cardiomyopathy, MI, Nephropathy (Prot)

Glucose - Triopathy, CV events?

Pleio: Those drug effects not related to reducing lipids, BP, Gluc

Direct modulation of enzymes or receptors

Not necessarily class effects

“Treating the number” vs Pleiotropic Effects:

Events directly related to reducing a number:

Lipids - Atherosclerosis (MI, Stroke, PVD)

BP - Stroke, Cardiomyopathy, MI, Nephropathy (Prot)

Glucose - Triopathy, CV events?

Pleio: Those drug effects not related to reducing lipids, BP, Gluc

Direct modulation of enzymes or receptors

Not necessarily class effects

ExperimentalAtherosclerosisExperimental

Atherosclerosis

Rhesis Monkeys(Normal chol 140 mg/dl)

High fat diet 18 mths: chol – 700 mg/dl

followed byLow fat diet 24 mths:

chol – 140 mg/dl

Circ Res 27:59, 1970

Early CVD Disease:

Remodeling of arteries/heart in response to excess

FFA’s, cytokines, lipoproteins, or intravascular pressure

Advanced CVD Disease:

Fibrosis and acute decompensation of a vascular

structure (rupture of an artery or cardiac failure) which

activates coagulation pathway interrupts blood flow

CV event

Early CVD Disease:

Remodeling of arteries/heart in response to excess

FFA’s, cytokines, lipoproteins, or intravascular pressure

Advanced CVD Disease:

Fibrosis and acute decompensation of a vascular

structure (rupture of an artery or cardiac failure) which

activates coagulation pathway interrupts blood flow

CV event

LDL Targets vs Pleiotrophic EffectsLDL Targets vs Pleiotrophic Effects

• Any cardiac event (MI, stroke, angina, TIA, claudication)

• Left ventricular hypertrophy or high pulse pressure

• Type 2 Diabetes or Type 1 DM for 15 years (post-puberty)

• LDL: >160 or >130 for 15 yrs or >100 for 30 yrs

• BP: >160 or >140 mmHg for 10 years

• Smoking > 20 pack-years

• Any cardiac event (MI, stroke, angina, TIA, claudication)

• Left ventricular hypertrophy or high pulse pressure

• Type 2 Diabetes or Type 1 DM for 15 years (post-puberty)

• LDL: >160 or >130 for 15 yrs or >100 for 30 yrs

• BP: >160 or >140 mmHg for 10 years

• Smoking > 20 pack-years

Indicators of Advanced CVD Lesions:Indicators of Advanced CVD Lesions:

LDL Targets vs Pleiotrophic EffectsLDL Targets vs Pleiotrophic Effects

Lipids HBP Insulin Resist

Oxidation

Inflammation

Lipids HBP Insulin Resist

Oxidation

Inflammation

LDL Targets vs Pleiotrophic EffectsLDL Targets vs Pleiotrophic Effects

EndotheliumEndothelium

Medial Smooth Muscle CellsMedial Smooth Muscle Cells

Sub-Endothelial SpaceSub-Endothelial Space

CollagenCollagen

ProteoglycansProteoglycans

Plasma MonocytesPlasma Monocytes

Tissue MonocytesTissue Monocytes

StatinsStatins

“In vivo” statin effect: Dependent on change in LDL

or Pleiotropic?

H2O2 Vasc prolif& hypertrophy

H2O2 Vasc prolif& hypertrophy

Stimulated by TZDsStimulated by TZDs

Catalase H2OCatalase H2O

Structure of the NAD(P)H OxidaseStructure of the NAD(P)H Oxidase

Reprinted with permission from Griendling KK et al. Circ Res. 2000 86:494–501.Reprinted with permission from Griendling KK et al. Circ Res. 2000 86:494–501.

Nox1

Vasc Oxidase Activated: PK-C, ATII, TNFa, Aldosterone, Thrombin, & Turbulent FlowInhibited: Nitric Oxide - TZD’s, Statins, Spironolactone, (Amlodip scavenger)

Vasc Oxidase Activated: PK-C, ATII, TNFa, Aldosterone, Thrombin, & Turbulent FlowInhibited: Nitric Oxide - TZD’s, Statins, Spironolactone, (Amlodip scavenger)

Always Active

Oxidative Bursts

GlucoseFFA’s

GlucoseFFA’s

Insulin Resistance SyndromeInsulin Resistance Syndrome

FFAFFA

TGTG

TGTG

TGTG

(Free FattyAcids)

(Free FattyAcids)

VLDL-TGVLDL-TG

ATIILeptinTNFaPAI-1

ATIILeptinTNFaPAI-1

AdiponectinAdiponectinXXVisceral

FatVisceral

Fat

PPAR: Peroxisome Proliferator-Activated ReceptorPPAR: Peroxisome Proliferator-Activated Receptor

FFAFFA

PPAR Action(Fibrate + TZD)PPAR Action(Fibrate + TZD)

TGTG

TGTG

TGTG

VLDL-TGVLDL-TG

ATIILeptinTNFa

ATIILeptinTNFa

AdiponectinAdiponectin

XX

Arachidonic

Prosta-Glandins

E2, F2, I2, TXA2

LTC4

Inflammation

Arachidonic

Prosta-Glandins

E2, F2, I2, TXA2

LTC4

Inflammation

Insulin Resistance SyndromeInsulin Resistance Syndrome

FFAFFA

TriglyceridesPhospholipids

Fat Storage

TriglyceridesPhospholipids

Fat Storage

Beta-Oxidation

NADH+

Super Oxide (SO)“Reactive Oxygen

Species”(ROS)

Beta-Oxidation

NADH+

Super Oxide (SO)“Reactive Oxygen

Species”(ROS)

Ceramide - SM

Nitric Oxide

Apoptosis(Islets)

Ceramide - SM

Nitric Oxide

Apoptosis(Islets)

Omega-3Vit E

Omega-3Vit E

Glucose and Fatty Acid OxidationGlucose and Fatty Acid Oxidation

NAD(P)HNAD(P)H

GlucoseGlucose

CO2+

H2O

CO2+

H2O

PyruvatePyruvate

FFAFFA

KrebsKrebs

(electron transport chain)(electron transport chain)

(beta oxidation)(beta oxidation)(glycolysis)(glycolysis)

O2 H2OO2 H2O

H+H+

H+H+

H+H+

ATPATP3H+3H+

e-e-

UCPUCP

CoQ10CoQ10 ROS (SO)ROS (SO)

O2O2

Glucose and Fatty Acid OxidationGlucose and Fatty Acid Oxidation

NAD(P)HNAD(P)H

CO2+

H2O

CO2+

H2O

PyruvatePyruvate

KrebsKrebs

(electron transport chain)(electron transport chain)

(beta oxidation)(beta oxidation)(glycolysis)(glycolysis)

GlucoseGlucose FFAFFA

Super Oxide“Oxidative Stress”

Oxidize CYS in RAS

Protein Kinase CJNK/SAPK, p38 MAPK

(Ser-Thr Kinases)

Super Oxide“Oxidative Stress”

Oxidize CYS in RAS

Protein Kinase CJNK/SAPK, p38 MAPK

(Ser-Thr Kinases)

O2 H2OO2 H2O

H+H+

H+H+

H+H+

e-e-

UCPUCP

ATPATP3H+3H+

ROS (SO)ROS (SO)CoQ10CoQ10

H+H+TZD’sTZD’s

O2O2

Protein Kinase C ActivationProtein Kinase C Activation

TGF-

Collagen Fibronectin

TGF-

Collagen Fibronectin

PAI-1

Fibrinolysis

PAI-1

Fibrinolysis

IL-1, TNFaHypertension, PTH

Advanced Glycosylation EndproductsAldose reductase pathway

IL-1, TNFaHypertension, PTH

Advanced Glycosylation EndproductsAldose reductase pathway Hyperglycemia

ROSROS

oxLDL

ROS

oxLDL

ROS

DAG ( Glycolysis)DAG ( Glycolysis)

PKC

eNOS ET-1

VasoconstrictionHypoxia

eNOS ET-1

VasoconstrictionHypoxia

Adapted from: Brownlee. Nature 2001; 414:813-820; Way KJ et al. Diabetic Med 2001;18:945-959

Adapted from: Brownlee. Nature 2001; 414:813-820; Way KJ et al. Diabetic Med 2001;18:945-959

Vitamin EVitamin ExxVEGF

Vascular Permeability, Angiogenesis

(Neovascularization)

VEGF

Vascular Permeability, Angiogenesis

(Neovascularization)

(NAD(P)H Oxidase)(NAD(P)H Oxidase)

LOX-1RASLOX-1RAS

NF-kBNF-kBIRS-1

InsulinResist

IRS-1

InsulinResist

Endothelial Dysfunction

LOX-1LOX-1

TNFaTNFa

Statin effect not dependenton change in LDL

(Pleiotropic)

“In vivo” statin effect: Dependent on change in LDL

or Pleiotropic?

Collins T , Cybulsky M: JCI 107:255, 2001Collins T , Cybulsky M: JCI 107:255, 2001

Nuclear Factor kB (NF-kB) ActivationNuclear Factor kB (NF-kB) ActivationIL-1 TNFaIL-1 TNFa

Super OxideProtein Kinase C

Super OxideProtein Kinase C

InsulinStatinsTZDs

InflammatoryReaction

Primary Medicatorof TNFa effects

HypertensionLOX-1

Collins T , Cybulsky M: JCI 107:255, 2001Collins T , Cybulsky M: JCI 107:255, 2001

Nuclear Factor kB (NF-kB) ActivationNuclear Factor kB (NF-kB) ActivationIL-1 TNFaIL-1 TNFa

Super OxideProtein Kinase C

Super OxideProtein Kinase C

InsulinStatinsTZDs

InflammatoryReaction

DAGMAPKDAGMAPK

PK-CPK-C

HypertensionLOX-1

L-ARGL-ARG

NOSNADPH

NOSNADPH

L-Citrullin + NOL-Citrullin + NO

L-Citrullin + SOL-Citrullin + SO

NOSNADPH

NOSNADPH

ONOO-

(peroxynitrite)ONOO-

(peroxynitrite)

Nitric Oxide and Super OxideNitric Oxide and Super Oxide

Nitric Oxide Synthase (NOS) activated by bradykinin (ACE-I, Amlo), acetylcholine, histamine, serotonin, thrombin, estrogen, substance P, shear stress, and insulin

Inhibited by asym dimethylarginine (Prot ADMA DDAH (-S.Ox) & Urine)

Nitric Oxide Synthase (NOS) activated by bradykinin (ACE-I, Amlo), acetylcholine, histamine, serotonin, thrombin, estrogen, substance P, shear stress, and insulin

Inhibited by asym dimethylarginine (Prot ADMA DDAH (-S.Ox) & Urine)

BH4BH4

BH2BH2

BH4 is a required cofactor for NOSSO converts Tetrahydrobiopterin (BH4) to Dihydrobiopterin (BH2) BH4 deficiency

BH4 is a required cofactor for NOSSO converts Tetrahydrobiopterin (BH4) to Dihydrobiopterin (BH2) BH4 deficiency

Super Oxide (SO = O2o)Super Oxide (SO = O2o)

L-ARGL-ARG

NOSNADPH

NOSNADPH

L-Citrullin + NOL-Citrullin + NO

L-Citrullin + SOL-Citrullin + SO

NOSNADPH

NOSNADPH

ONOO-

(peroxynitrite)ONOO-

(peroxynitrite)

Nitric Oxide and Super OxideNitric Oxide and Super Oxide

Nitric Oxide Synthase (NOS) activated by bradykinin (ACEI, Amlo), acetylcholine, histamine, serotonin, thrombin, estrogen, substance P, shear stress, and insulin

Inhibited by asymmetric dimethylarginine (ADMA - CRI)

Nitric Oxide Synthase (NOS) activated by bradykinin (ACEI, Amlo), acetylcholine, histamine, serotonin, thrombin, estrogen, substance P, shear stress, and insulin

Inhibited by asymmetric dimethylarginine (ADMA - CRI)

BH4BH4

BH2BH2

BH4 is a required cofactor for NOSSO converts Tetrahydrobiopterin (BH4) to Dihydrobiopterin (BH2) BH4 deficiency

BH4 is a required cofactor for NOSSO converts Tetrahydrobiopterin (BH4) to Dihydrobiopterin (BH2) BH4 deficiency

Super Oxide (SO = O2o)Super Oxide (SO = O2o)

Protein Kinase C

CCB

“In vivo” statin effect: Dependent on change in LDL

or Pleiotropic?

Hyperlipidemia HBPStatins lower BP

Flow-Mediated Vasodilation (FMD)in the Brachial ArteryFlow-Mediated Vasodilation (FMD)in the Brachial Artery

Baseline Diameter Hyperemic Flow Nitroglycerin

3.02 mm 3.34 mm 3.57 mm

Francois Charbonneau, 1996.

10.6%10.6% 18.2%18.2%RestingResting

SurrogateMeasure

Atorvastatin: Rapid & Prolonged ActionAtorvastatin: Rapid & Prolonged Action

Healthy MenAtorva 80 mg

Max at 8 days-38%

Amer J Card 88:1306, 2001

LDL = 95

Endothelial Dysfunction

LOX-1LOX-1

TNFaTNFa

Amlo ------|Amlo ------|

TGFbTGFb

Super OxideSuper OxideNAD(P)HOxidaseNAD(P)HOxidase

NF-kBNF-kB

AT-IIAT-II

AdhesionMoleculesAdhesionMolecules

TNFaTNFa

ProteinKinase CProtein

Kinase C

IL-1IL-1

InsulinResistance

InsulinResistance

IL-1, IL-6IL-8, MCPIL-1, IL-6IL-8, MCP

oxLDLVLDL, IDL

oxLDLVLDL, IDL

HyperglycemiaHyperglycemiaNitric OxideHDL

Nitric OxideHDL

TGFbTGFb

Super OxideSuper OxideNAD(P)HOxidaseNAD(P)HOxidase

NF-kBNF-kB

AT-IIAT-II

AdhesionMoleculesAdhesionMolecules

TNFaTNFa

ProteinKinase CProtein

Kinase C

IL-1IL-1

InsulinResistance

InsulinResistance

IL-1, IL-6IL-8, MCPIL-1, IL-6IL-8, MCP

oxLDLVLDL, IDL

oxLDLVLDL, IDL

HyperglycemiaHyperglycemiaDeficiency:Nitric Oxide

HDL

Deficiency:Nitric Oxide

HDL xx

Early LesionsFatty Streaks

Events generally controlled by endotheliumACE-I should be very effective

Estradiol, Statins

Atherosclerosis:Atherosclerosis: Plaque Rupture ThrombosisPlaque Rupture Thrombosis

Intramural

Intraluminal

Occlusive Infarct

Atherosclerosis:Atherosclerosis: Smooth Muscle Cell RecruitmentSmooth Muscle Cell Recruitment

SMCs attempt to contain the inflammatory response:activated by: Endothelin, PDGF, TGFb inhibited by: IL-1

SMCs attempt to contain the inflammatory response:activated by: Endothelin, PDGF, TGFb inhibited by: IL-1

IL-1 ICAM, VCAM, LOX-1, VEGF, collagenase (MMP), apoptosis

AT-II superoxide, PAI-1, matrix synthesis (fibrosis)

Amlodip ----| Migration, prolif, pro-collagen, MMP-1, E-apoptosis, S.Ox

Amer J Med 91 (suppl 1B) 3S-9S, 1991

SMCs begin to take control of plaque metabolism(Dominate pathology in HT CVD)

BKBK

Atorvastatin reduces PAI-1 & Factor VII

SurvivalSurvival

Miettinen H et al. Stroke. 1996;27:2033-2039.Miettinen H et al. Stroke. 1996;27:2033-2039.

<150 mg/L<150 mg/L >300 mg/L>300 mg/L150-300 mg/L150-300 mg/LUrinary proteinUrinary protein

All-cause mortalityAll-cause mortality

MonthsMonths

CVD mortalityCVD mortality

MonthsMonths

A:A: B:B: C:C:

II.17II.17

11

0.60.6

0.50.5

0.40.4

00

0.70.7

0.80.8

0.90.9

3030 4040 5050 6060 7070 8080 90902020101000

AA

BB

CC

Overall <0.001A vs B <0.001A vs C <0.001B vs C <0.001

Overall <0.001A vs B <0.001A vs C <0.001B vs C <0.001

003030 4040 5050 6060 7070 8080 90902020101000

AA

BB

CC

11

0.60.6

0.50.5

0.40.4

0.70.7

0.80.8

0.90.9

Overall <0.001A vs B 0.013A vs C <0.001B vs C <0.001

Overall <0.001A vs B 0.013A vs C <0.001B vs C <0.001

CC

Effect of Proteinuria on All-Cause and CVD Mortality in Patients With Type 2 DiabetesEffect of Proteinuria on All-Cause and CVD Mortality in Patients With Type 2 Diabetes

©1998 PPS©1998 PPS

Effects of Atorvastatin on Proteinurea & Progression of Renal D.Effects of Atorvastatin on Proteinurea & Progression of Renal D.

Bianchi et al; Amer J Kid D 41:565-570, 2003Bianchi et al; Amer J Kid D 41:565-570, 2003

Glomerulonephritis (n = 56)

Age 55.6 yrsCrCl 50.4 ml/minUPE 2.2 g/dayLDL 198 mg/dl 121HDL 36 mg/dlTrig 174 mg/dl 132Album 3.3 g/dl

One year Rx HBPACEI 96%CCB 45%ASA 66%

Goal:LDL < 120 mg/dl or 40%Dose: 10 - 40 mg/d

Glomerulonephritis (n = 56)

Age 55.6 yrsCrCl 50.4 ml/minUPE 2.2 g/dayLDL 198 mg/dl 121HDL 36 mg/dlTrig 174 mg/dl 132Album 3.3 g/dl

One year Rx HBPACEI 96%CCB 45%ASA 66%

Goal:LDL < 120 mg/dl or 40%Dose: 10 - 40 mg/d Atorvastatin

Proteinurea

LDL oxLDL

NADH oxMito SO

V. FatPK-CATII

TNFaAldost

LOX-1Recept

PK-C NF-kBNADH ox

ET-1- eNOSTGFbVEGFIRS-1PAI-1

- G-cyclase

LDL

NF-kB

ROSDAGAT-IIIL-1

TNFaAGE-PRAS

VEGFSorbitol

PTH

IL-1TNFaIL-8

MCP-1E-selectin

ICAMVCAM

MonocyteActivation

SOScav R

Lipid Accum

MonocyteInvasion

AT-IIET-1

SO

IL-1mCSFAT-II

FoamCells

&Necrosis

AtherogenesisAtherogenesis

PlaqueRupture

Clot Lysis

TPA- PAI-1

AT-IITNFa

AGE-PoxLDLInsulin

MMPIL-1AT-II

SMC

ET-1TGFb

IL-1TissueFactorF-VIIF-XII

Endothelial Dysfunctionloss of Nitric Oxideexcess AT-II & ET-1

Atherosclerosis

HDL NO

CardiovascularEvent

SurrogateMeasure