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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