Molecular and Vascular Evidence in Managing Hypertension and Hyperlipidemia (Dr. Hananto Adrianto

7/27/2019 Molecular and Vascular Evidence in Managing Hypertension and Hyperlipidemia (Dr. Hananto Adrianto

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Molecular and Vascular Evidence inMolecular and Vascular Evidence inManaging Hypertension andManaging Hypertension and

HyperlipidemiaHyperlipidemia

HanantoHananto AndriantoroAndriantoro

DivisiDivisi vascular,vascular,Department Cardiology and vascular MedicineDepartment Cardiology and vascular Medicine

Faculty Medicine University of IndonesiaFaculty Medicine University of Indonesia


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Endothelial dysfunctionEndothelial dysfunction

Normal vascular endothelial cells support cardiovascularNormal vascular endothelial cells support cardiovascular

function by promoting vasodilatation and by inhibitingfunction by promoting vasodilatation and by inhibitingplatelet aggregation, white blood cell adhesion, andplatelet aggregation, white blood cell adhesion, and

smooth muscle cell proliferation.smooth muscle cell proliferation.

In contrast, dysfunctional endothelium promotesIn contrast, dysfunctional endothelium promotesvasoconstriction, favors platelet aggregation, white bloodvasoconstriction, favors platelet aggregation, white blood

cell adhesion, and smooth muscle cell proliferation.cell adhesion, and smooth muscle cell proliferation.

Hypercholesterolemia, hyperglycemia, hypertension, andHypercholesterolemia, hyperglycemia, hypertension, andsmoking are the most common risks associated withsmoking are the most common risks associated with

endothelial dysfunction.endothelial dysfunction.


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Integrated Perspective on CV Risk FactorsIntegrated Perspective on CV Risk Factors

and Vascular Diseaseand Vascular Disease

CVDisease

Ross.Ross.NNEnglEnglJ MedJ Med. 1999;340:115. 1999;340:115--126.126.

Oxidative Stress & InflammationOxidative Stress & Inflammation

Endothelial DysfunctionEndothelial Dysfunction




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Cardiovascular deathCardiovascular death

Cause of death of cardiovascular diseaseCause of death of cardiovascular diseaseMyocardial infarctionMyocardial infarction

Heart failureHeart failure

Cerebro Vascular DeseaseCerebro Vascular Desease

Aorta diseaseAorta disease

Pheriperal Vascular diseasPheriperal Vascular diseaseeEnd Stage Renal DiseaseEnd Stage Renal Disease


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EndothelialEndothelial Function inFunction in

HyperlipidemiaHyperlipidemia


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Cholesterol and CHDMultiple Risk Factor Intervention trial( MRFIT)

150 200 250 300 Mg/dl

CH

D

mortality

rate

350

360.000 men, aged 35-57


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LDLLDL--C Oxidation Promotes theC Oxidation Promotes theDevelopment of Atherosclerotic LesionsDevelopment of Atherosclerotic Lesions

OxidativeOxidativestressstress

NativeNative

LDLLDL--CCModifiedModifiedLDLLDL--CC

Meagher EA, FitzGerald GA.Meagher EA, FitzGerald GA. FreeFree RadRadBiolBiolMedMed. 2000;28:1745. 2000;28:1745--1750;1750; ChisolmChisolm GM, Steinberg D.GM, Steinberg D. FreeFree RadRadBiolBiolMedMed. 2000;28:1815. 2000;28:1815--1826;1826; HeineckeHeinecke JW.JW.Am JAm JCardiolCardiol.. 2003;91(suppl):12A2003;91(suppl):12A--16A.16A.

AtherogenicAtherogenic effectseffects FoamFoam--cell formationcell formation

MonocyteMonocyte mobilitymobility

ChemoattractionChemoattraction

Endothelial adhesionEndothelial adhesion

FreeFree--radical productionradical production


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Acute Elevations of Plasma AsymmetricAcute Elevations of Plasma Asymmetric DimethylarginineDimethylarginine

and Impaired Endothelial Function in Response to aand Impaired Endothelial Function in Response to aHighHigh--Fat Meal in Patients With Type 2 DiabetesFat Meal in Patients With Type 2 Diabetes

Percentage of flowPercentage of flow--induced dilation of the brachial arteryinduced dilation of the brachial artery

(A; n550, *(A; n550, *PP,0.0001) and plasma level of ADMA,0.0001) and plasma level of ADMA

(B; n550, **(B; n550, **PP,0.0005) before (PRE,0.0005) before (PRE--) and 5 hours after (POST) and 5 hours after (POST--) ingestion of the) ingestion of the

highhigh--fat meal.fat meal.((ArteriosclerArteriosclerThrombThromb VascVascBiolBiol. 2000;20:2039. 2000;20:2039--2044.)2044.)


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LDL CholesterolLDL Cholesterol UpregulatesUpregulates Synthesis of AsymmetricalSynthesis of Asymmetrical

DimethylarginineDimethylarginine in Human Endothelial Cellsin Human Endothelial Cells

((Circ ResCirc Res. 2000;87:99. 2000;87:99--105.)105.)

This increase in ADMA production was significantly inhibited byThis increase in ADMA production was significantly inhibited by thethe

intracellular antioxidantintracellular antioxidantpyrrollidinepyrrollidine dithiocarbamatedithiocarbamate (PDTC)(PDTC)Tanah lot 2008Tanah lot 2008


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ADMA endogenous inhibitors of NOSADMA endogenous inhibitors of NOS

AsymmetricAsymmetric dimethylargininedimethylarginine (ADMA) is(ADMA) is synthesisedsynthesised from Lfrom L--argininearginineby proteinby protein

methylasemethylase I and subsequently metabolized byI and subsequently metabolized by dimethylargininedimethylarginine dimethylaminohydrolasedimethylaminohydrolase

(DDAH) yielding(DDAH) yielding citrullinecitrulline. ADMA acts as an endogenous inhibitor of nitric oxide (NO). ADMA acts as an endogenous inhibitor of nitric oxide (NO)

synthesis and its concentration is increased in certain diseasesynthesis and its concentration is increased in certain disease states, possibly as a result ofstates, possibly as a result of

decreased DDAH actionsdecreased DDAH actions

HeartHeart2001;85:3422001;85:342350350


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TetrahydrobiopterinTetrahydrobiopterin (BH 4)(BH 4)Am JAm JPhysiolPhysiolHeart CircHeart CircPhysiolPhysiol, 2001, 2001 ;;280: H2484280: H2484H2488.H2488.


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Effects ofEffects ofTetrahydrobiopterinTetrahydrobiopterin onon

Endothelial DysfunctionEndothelial DysfunctionJ Am SocJ Am Soc NephrolNephrol 11: 30111: 301309, 2000309, 2000

Renal Perfusion Pressure : RPPRenal Perfusion Pressure : RPP


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CaveolinCaveolin

The principal protein component of caveolae isThe principal protein component of caveolae iscaveolincaveolin

Interacts with various signaling, including GInteracts with various signaling, including G

proteins and calcium regulating protein.proteins and calcium regulating protein.

Caveolin is also inhibitor of endCaveolin is also inhibitor of endoothelial nitricthelial nitric

oxide synthase (eNOS)oxide synthase (eNOS)

Razani, Undergraduate research,2002;1:44Razani, Undergraduate research,2002;1:44--5050

Razani, pharmacol Rev.2002;54:431Razani, pharmacol Rev.2002;54:431--467467


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CaveolaeCaveolae

PharmacolPharmacolRevRev , 2002, 2002 54:43154:431467467


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Lipid Rafts

CaveolaeCaveolae

CaveolinCaveolin

Phospholipid

SpingolipidSpingolipid

CholesterolCholesterol



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EndothelialEndothelial Function inFunction in

HyperHypertensiontension


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Endothelial Dysfunction andEndothelial Dysfunction and

HypertensionHypertension

the defect in the endotheliumthe defect in the endothelium--derived NO system inderived NO system in

hypertensive vessels is likely not due to decreasedhypertensive vessels is likely not due to decreasedavailability of its precursor, Lavailability of its precursor, L--argininearginine

MuscarinicMuscarinic receptor defect with abnormal responsesreceptor defect with abnormal responses

to acetylcholineto acetylcholine

the cause of endothelial dysfunction in patients withthe cause of endothelial dysfunction in patients with

hypertension is not limited to a defect at thehypertension is not limited to a defect at the

muscarinicmuscarinic receptor level, but is related to a broaderreceptor level, but is related to a broaderabnormality of endothelial cells.abnormality of endothelial cells.

ClinClin.. CardiolCardiol. 1997; 20 (. 1997; 20 (SupplSuppl. II), II. II), II--2626IIII--3333


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Endothelial dysfunction in hypertensionEndothelial dysfunction in hypertension

ClinClin CardiolCardiol 1997;20:suppl II, II261997;20:suppl II, II26--II33II33


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Endothelial dysfunction in hypertensionEndothelial dysfunction in hypertension

ClinClin CardiolCardiol 1997;20:suppl II, II261997;20:suppl II, II26--II33II33


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Statintatin

NEW TREATMENT APPROACH

Vascular and cardiac biology alteredascular and cardiac biology altered

Hypertension /ypertension / hyperlipidemiayperlipidemia

Treat the Endotheliumreat the Endothelium

Therapeutic optionsherapeutic options

ACECEInhibitorsnhibitors

Ca Channela Channelblockerslockers

* Minimal evidence of effects on endothelial function* Minimal evidence of effects on endothelial functionHan 2005Han 2005


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AtorvastatinAtorvastatinandand

endothelial nitric oxideendothelial nitric oxidesynthetasesynthetase


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Caveolin and hypercholesterolCaveolin and hypercholesterol

The expression of caveolin is markedly elevatedThe expression of caveolin is markedly elevated

under conditions of hypercholesterolemiaunder conditions of hypercholesterolemia

CaveolinCaveolin--1 Inhibits NO1 Inhibits NO SynthaseSynthase ActivityActivity

Atherosclerosis , lipid rafts have been shown toAtherosclerosis , lipid rafts have been shown toplay an important role in other disease processes,play an important role in other disease processes,

includingincluding hypertensionhypertension

J Clin Invest.2002;110:597J Clin Invest.2002;110:597--603603

Circulation.2003;107:2270Circulation.2003;107:2270--22732273


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CARDSCARDSCollaborationCollaborationAtorvastatinAtorvastatin Diabetes StudyDiabetes Study

Atorvastatin provided impressive benefits in patients with type

2 diabetes with no history of CVD and with normal to mildly-

elevated cholesterol levels 37% reduction in major CVD events (P= .001)

48% reduction in stroke (P = .016)

27% reduction in all-cause mortality (P= .059) Consistent effect regardless of baseline lipids, gender, or age

Safety profile of atorvastatin 10 mg was excellent and

comparable to placebo

CARDS became the second atorvastatin trial to end early

because of observed treatment benefit

AtorvastatinAtorvastatin provided impressive benefits in patients with typeprovided impressive benefits in patients with type

2 diabetes with no history of CVD and with normal to mildly2 diabetes with no history of CVD and with normal to mildly--

elevated cholesterol levelselevated cholesterol levels 37% reduction in major CVD events (37% reduction in major CVD events (PP= .001)= .001)

48% reduction in stroke (48% reduction in stroke (PP = .016)= .016)

27% reduction in all27% reduction in all--cause mortality (cause mortality (PP= .059)= .059) Consistent effect regardless of baseline lipids, gender, or ageConsistent effect regardless of baseline lipids, gender, or age

Safety profile ofSafety profile ofatorvastatinatorvastatin 10 mg was excellent and10 mg was excellent and

comparable to placebocomparable to placebo

CARDS became the secondCARDS became the second atorvastatinatorvastatin trial to end earlytrial to end early

because of observed treatment benefitbecause of observed treatment benefit

Colhounolhoun HM,M, Betteridgeetteridge DJ,J, Durringtonurrington PN, et al.N, et al. Lancetancet. 2004;364:6852004;364:685-696.96.


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Cumulative incidence for primary end point of non fatalCumulative incidence for primary end point of non fatal

myocardial infarction and fatal coronary artery diseasemyocardial infarction and fatal coronary artery disease


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Cumulative incidence for primary end point ofCumulative incidence for primary end point ofnon fatalnon fatal

andand fatalfatal strokestroke (ASCOT(ASCOT--LLA)LLA)


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AmlodipineAmlodipine besylatebesylate

andand

endothelial nitric oxideendothelial nitric oxidesynthetasesynthetase


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Nitric Oxide ReleaseNitric Oxide Release

P t l t d Eff t f Diff t A tP t l t d Eff t f Diff t A t


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LokeLoke et al.et al. Hypertension.Hypertension. 1999;34:5631999;34:563--567;567; LokeLoke.. CirculationCirculation. 1999;100:1291. 1999;100:1291--12971297

LaufsLaufs et al.et al. Circulation.Circulation. 1998;97:11291998;97:1129--1135.1135.

Postulated Effects of Different Agents onPostulated Effects of Different Agents on

Endothelial Cell NO ProductionEndothelial Cell NO Production

Endothelial CellEndothelial Cell

eNOSeNOS

LL--ArginineArginine NO +NO + LL--CitrullineCitrulline

BKBK22

eNOSeNOS mRNAmRNA

BH4BH4

GG

KininsKinins

CCBCCBCCB


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AmlodipinAmlodipin Releases Nitric Oxide From CanineReleases Nitric Oxide From Canine


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CoronaryCoronary MicrovesselsMicrovesselsAnAn UnexpextectedUnexpextected Mechanism of action of Calcium ChanelMechanism of action of Calcium Chanel--BlockingBlockingAgentAgent

Circulation 1998;97:576Circulation 1998;97:576--580580

0

10

20

30

40

50

60

70

80

-10M -9M -8M -7M -6M -5M ( log )

ChangeinNitrite(pmol/mg)

Amlodipine Ramipril Diltiazem



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-20

0

20

4060

80

100

120140

-10M -9M -8M -7M -6M -5M (Log)

ChangeinNitrite(pmol/mg

)

Amlodipine Enalapril Nifedipine


CoronaryCoronary MicrovesselsMicrovesselsAnAn UnexpextectedUnexpextected Mechanism of action of Calcium ChanelMechanism of action of Calcium Chanel--BlockingBlockingAgentAgent

Circulation 1998;97:576Circulation 1998;97:576--580580



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-10

0

10

20

30

40

50

60

-10M -9M -8M -7M -6M -5M ( log )

Cha

ngeinnitrite

(pmol/mg)

Microvessels

Large Coronary Artery

Aorta


CoronaryCoronary MicrovesselsMicrovesselsAnAn UnexpextectedUnexpextected Mechanism of action of Calcium ChanelMechanism of action of Calcium Chanel--BlockingBlocking

AgentAgentCirculation 1998;97:576Circulation 1998;97:576--580580

A l di iA l di i P tP t Ki iKi i M di t d Nit i idM di t d Nit i id


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AmlodipinAmlodipin PromotesPromotes KininKinin--Mediated Nitric oxideMediated Nitric oxide

Production in CoronaryProduction in Coronary MicrovesselsMicrovessels of Failing Humanof Failing HumanHeartsHearts

Am JAm J CardiolCardiol 1999;84:27L1999;84:27L--33L33L

0

10

20

30

40

50

60

70

-10mol/L -9 mol/L -8mol/L -7mol/L -6mol/L -5mol/L ( Log )

changeinNitri

te(pmol/mg

)Amlodipine

Ramiprilat

Bradykinin


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Antioxidant effectsAntioxidant effects

Membrane Antioxidant Activity ofMembrane Antioxidant Activity of AmlodipineAmlodipine


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Membrane Antioxidant Activity ofMembrane Antioxidant Activity ofAmlodipineAmlodipine

LOOH = lipid peroxide.

*p


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Antioxidant Properties of CalciumAntioxidant Properties of Calcium

Antagonists Related to MembraneAntagonists Related to MembraneBiophysical InteractionsBiophysical Interactions

Am JAm J CardiolCardiol 1999;84:16L1999;84:16L--22L22L

0

10

20

30

40

50

60

70

80

90

20 60 200

Drug Concentration (micro mol/L)

Inhib

itionofMDA

Formation(%)

Amlodipine

Verapamil

Ditiazem

CCB Inhibition of LipidCCB Inhibition of Lipid PeroxidationPeroxidation


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00

1010

2020

3030

4040

AmlodipineAmlodipine

BesylateBesylateFelodipineFelodipine VerapamilVerapamil DiltiazemDiltiazem

**

%

Inhibition

ofLipidPeroxide

%

Inhibition

ofLipidPeroxide

FormationbyDrug(1.0

FormationbyDrug(1.0M)M)

**PP


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Calcium AntagonistCalcium Antagonist--induced NO release may contribute toinduced NO release may contribute to

the pharmacologic profile of this class of drugsthe pharmacologic profile of this class of drugs (Klaus W et al,(Klaus W et al,1997)1997)

AmlodipineAmlodipine BesylateBesylate

NONO

VasodilatingVasodilating AntithromboticAntithrombotic

AntiartheroscleroticAntiartherosclerotic

AntiproliferativeAntiproliferative

Fatal and nonFatal and non fatal strokefatal stroke


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Fatal and nonFatal and non--fatal strokefatal stroke

Number at riskNumber at risk

AmlodipineAmlodipine perindoprilperindopril 96399639 94839483 93319331 91569156 89728972 78637863

AtenololAtenolol thiazidethiazide 96189618 94619461 92749274 90599059 88438843 77207720

0.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0 YearsYears0.00.0

1.01.0

2.02.0

3.03.0

4.04.0

5.05.0

AmlodipineAmlodipine perindoprilperindopril(No. of events 327)(No. of events 327)

AtenololAtenolol thiazidethiazide(No. of events 422)(No. of events 422)

HR = 0.77 (0.66HR = 0.77 (0.66--0.89)0.89)

p = 0.0003p = 0.0003

%%

23%23%

Unstable anginaUnstable angina


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Unstable anginaUnstable angina




0.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.00.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

1.21.2

HR = 0.68 (0.51HR = 0.68 (0.51--0.92)0.92)

p = 0.0115p = 0.0115

%%

AmlodipineAmlodipine perindoprilperindopril(No. of events 73)(No. of events 73)


YearsYears

32%32%

P i h l t i l diP i h l t i l di


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Peripheral arterial diseasePeripheral arterial disease

0.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0

0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

HR = 0.65 (0.52HR = 0.65 (0.52--0.81)0.81)

p = 0.0001p = 0.0001




%%

YearsYears

AmlodipineAmlodipine perindoprilperindopril(No. of events = 133)(No. of events = 133)

AtenololAtenolol thiazidethiazide(No. of events = 202)(No. of events = 202)

35%35%

Cardiovascular MortalityCardiovascular Mortality


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Cardiovascular MortalityCardiovascular Mortality




0.00.0 1.01.0 2.02.0 3.03.0 4.04.0 5.05.0 YearsYears0.00.0

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

AmlodipineAmlodipine

perindoprilperindopril(No. of events 263)(No. of events 263)


HR = 0.76 (0.65HR = 0.76 (0.65--0.90)0.90)

p = 0.0010p = 0.0010

%%24%24%


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Amlodipine andAmlodipine andAtorvastatinAtorvastatin

CombinationCombination

Multiple CV Risk Management Results in Dramatic


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Reductions in CVD

10%10%

ReductionReduction

in BPin BP

10%10%

ReductionReduction

in TCin TC+

45%45%

ReductionReductionin CVDin CVD=

Attention should be moved from knowing ones BP and

cholesterol concentrations to knowing ones absolute CV risk

and its determinants. J. Emberson et al

and Jackson et al

Emberson J et al.Eur Heart J. 2004;25:484-491. Jackson R et al.Lancet. 2005;365:434-441.


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GEMINI: Real-World Experience with the Utility of

CADUET ( l di i b l t / t t ti l i )

GEMINI: RealGEMINI: Real--World Experience with the Utility ofWorld Experience with the Utility of

CADUETCADUET (amlodipine besylate/atorvastatin calcium)(amlodipine besylate/atorvastatin calcium)


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CADUET (amlodipine besylate/atorvastatin calcium)CADUETCADUET (amlodipine besylate/atorvastatin calcium)(amlodipine besylate/atorvastatin calcium)

Evaluated the realEvaluated the real--world utility of singleworld utility of single--pill CADUETpill CADUET

Uncontrolled, 14Uncontrolled, 14--week, officeweek, office--based, prospective, openbased, prospective, open--label study of 1220label study of 1220

patientspatients

Broad range of severity of concomitant hypertension and dyslipidBroad range of severity of concomitant hypertension and dyslipidaemiaaemia

No washout periodNo washout period

CADUET was used in a variety of treatment situationsCADUET was used in a variety of treatment situations

Added to existing treatmentAdded to existing treatment Substituted for amlodipine and atorvastatinSubstituted for amlodipine and atorvastatin

Initial drug therapy with diet and exerciseInitial drug therapy with diet and exercise

Dosing and titration were at the discretion of the investigatorDosing and titration were at the discretion of the investigator

Primary objective: assess percentage of patients at BP and lipidPrimary objective: assess percentage of patients at BP and lipid goals at 14goals at 14weeksweeks

GEMINI was an openGEMINI was an open--label, uncontrolled clinical study; no conclusions about efficaclabel, uncontrolled clinical study; no conclusions about efficacy or safety can be madey or safety can be made

Blank R et al.Blank R et al.J Clin Hypertens.J Clin Hypertens. 2005;7:2642005;7:264--273.273.

GEMINI: Baseline LDL-C and BP LevelsGEMINI: Baseline LDLGEMINI: Baseline LDL--C and BP LevelsC and BP Levels


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Group IGroup I Group IIGroup II Group IIIGroup III

SBP (mm Hg)SBP (mm Hg)

CV Risk Group 1:CV Risk Group 1:

Patients with HTN, DYS,Patients with HTN, DYS,and no additional CV riskand no additional CV risk

factorsfactors


Patients with HTN, DYS, andPatients with HTN, DYS, and1 additional CV risk factor (not1 additional CV risk factor (not

DM or CHD)DM or CHD)


Patients with HTN, DYS,Patients with HTN, DYS,and CHD or CHD riskand CHD or CHD risk

equivalentequivalent

Patients at increasing CV riskPatients at increasing CV risk

LDLLDL--C and BP Levels at Baseline, by CV Risk GroupC and BP Levels at Baseline, by CV Risk Group

LDL

LDL--C(mg/dL)

C(mg/dL)

Shaded quadrant represents joint BP and LDLShaded quadrant represents joint BP and LDL--C goal attainment for each CV risk group.C goal attainment for each CV risk group.

DYS=dyslipidaemia; DM=diabetes mellitus.DYS=dyslipidaemia; DM=diabetes mellitus.

Blank R et al.Blank R et al.J Clin Hypertens.J Clin Hypertens. 2005;7:2642005;7:264--273.273.

200140100120 160180 200140100120 160180 200140100120 160180

50

100

150

200

250

300

50

100

150

200

250

300

50

100

150

200

250

300

GEMINI: Number of Patients Reaching BP and

LDL-C Goals at End Point Increased from Baseline

GEMINI: Number of Patients Reaching BP and

LDL-C Goals at End Point Increased from Baseline


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LDL-C Goals at End Point Increased from BaselineLDL C Goals at End Point Increased from Baseline

Group I Group II Group III

CV Risk Group 1:Patients with HTN, DYS,

and no additional CV risk

factors

CV Risk Group 2:Patients with HTN, DYS, and

1 additional CV risk factor (not

DM or CHD)

CV Risk Group 3:

Patients with HTN, DYS,

and CHD or CHD risk

equivalent

Patients at increasing CV risk

Shaded quadrant represents joint BP and LDL-C goal attainment for each CV risk group.

Blank R et al.J Clin Hypertens. 2005;7:264-273.

LDL-C and BP Levels for all CV Risk Groups at Baseline (in Yellow) and at End Point (in Blue)

200140100120 160180 200140100120 160180 200140100120 160180

50

100

150

200250

300

50

100

150

200250

300

50

100

150

200250

300

SBP (mm Hg)

LDL

LDL--C(mg/dL)

C(mg/dL)


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SoftSoft endend--pointspoints include indicesinclude indicesof atherosclerosis such as a change in the thickness of theof atherosclerosis such as a change in the thickness of the

arterial wall or in the volume of atherosclerotic tissuearterial wall or in the volume of atherosclerotic tissue

within the arteries.within the arteries.

Evidence Based MedicineEvidence Based MedicineClinical endClinical end--points can be divided into two groups.points can be divided into two groups.

HardHard endend--pointspoints are the numberare the number

of cardiovascular events such as myocardial infarction orof cardiovascular events such as myocardial infarction orstroke, orstroke, orthe hardest endthe hardest end--point of allpoint of all -- the mortality ratethe mortality rate

from cardiovascular disease.from cardiovascular disease.

Preston Mason, P Libby, Gerd Assmann, International Task Force fPreston Mason, P Libby, Gerd Assmann, International Task Force for the Prevention ofor the Prevention of

Coronary Heart Disease, March 2004Coronary Heart Disease, March 2004


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Cumulative incidence for nonCumulative incidence for non--fatalfatal


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myocardial infarction and fatal coronarymyocardial infarction and fatal coronaryheart disease.heart disease.

Cumulative incidence for total cardiovascularCumulative incidence for total cardiovascular


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events and procedures in the two blood pressureevents and procedures in the two blood pressuretreatment groupstreatment groups

CARPE: CADUET (amlodipine besylate/atorvastatin calcium) TherapyResults in More Patients Achieving Adherence Compared to

CARPE: CADUETCARPE: CADUET (amlodipine besylate/atorvastatin calcium)(amlodipine besylate/atorvastatin calcium) TherapyTherapy

Results in More Patients Achieving Adherence Compared toResults in More Patients Achieving Adherence Compared to


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Concomitant CCB and Statin TherapiesConcomitant CCB and Statin TherapiesConcomitant CCB and Statin Therapies

67,7%

49,9%

40,4%37,4%

46,9%

0%

10%

20%

30%40%

50%

60%

70%

80%

90%

100%

CADUET Atorvastatin +

Amlodipine

Amlodipine + Other

Statin

Other CCB +

Atorvastatin

Other CCB + Other

Statin

All comparison cohorts significantly lower than CADUET,P


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ConclusionConclusion The results of thisThe results of thispresentationpresentation indicate thatindicate that

amlodipine andamlodipine and atorvastatin produced aatorvastatin produced asynergistic effect on endothelialsynergistic effect on endothelial dependentdependent

mechanismsmechanisms of NO biosynthesis.of NO biosynthesis.

The basis forThe basis forthis cellular activity is attributed tothis cellular activity is attributed to

changes in eNOS expression,changes in eNOS expression, increased couplingincreased coupling

efficiency of eNOS and a decrease inefficiency of eNOS and a decrease in cytotoxiccytotoxicONOOONOO..


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Take Home MessageTake Home MessageEndothelial dysfunction in hypertension andEndothelial dysfunction in hypertension and

hyperlipidemia may lead to the development ofhyperlipidemia may lead to the development ofnovel therapeutic strategies to reduce thenovel therapeutic strategies to reduce the

vascular complications associated with thevascular complications associated with the

hypertensive and hyperlipidemia process.hypertensive and hyperlipidemia process.

Documents

Molecular and Vascular Evidence in Managing Hypertension and Hyperlipidemia (Dr. Hananto Adrianto