Atherosclerosis – A Systemic Complex Disease

AgendaAgenda

• What is atherosclerosis?

• What is the role of endothelial dysfunction in the atherosclerotic process?

• What is the effect of lipid therapy on atherosclerosis?

AgendaAgenda

• What is atherosclerosis?

• What is the role of endothelial dysfunction in the atherosclerotic process?

• What is the effect of lipid therapy on atherosclerosis?

Atherosclerosis Is a Chronic Inflammatory Disease With LDL-C at the CoreAtherosclerosis Is a Chronic Inflammatory Disease With LDL-C at the Core

•

Libby P. J Intern Med. 2000;247:349-358.

PHASE I: Initiation PHASE II: Progression PHASE III: Complication

Atherosclerosis Starts at a Young AgeAtherosclerosis Starts at a Young Age

0%

20%

40%

60%

80%

100%

<25 25-35 >35Donor Age (yr)

22%

47%

70%

Nissen S. Am J Cardiol. 2001:87(suppl):15A-20A.

Determined by coronary intravascular ultrasound

Pre

vale

nce

of

Ath

ero

scle

rosi

s (%

)

Atherosclerosis Frequently Goes Undetected for YearsAtherosclerosis Frequently Goes Undetected for Years

Lumen size does not change significantly—even in the presence of a large lipid core

Strong JP, et al. JAMA. 1999;281:727-735. Glagov S, et al. N Engl J Med.1987;316:1371-1375.

MediaIntima

MediaIntima

Lumen Lumen

Size of lumendoes not change

dramatically

Vascular wall remodelsto accommodate

lipid core

Kannel WB. Importance of hypertension as a major risk factor in cardiovascular disease. In: Genest J, Koiw E, Kuchel O, Boucher R, Nowaczynski W, Rojo-Ortega JM eds. Hypertension: Physiopathology and Treatment. New York, NY: McGraw-Hill Book Co;1977:888-910.

Risk Factors Can Further Confound Atherosclerosis—and Increase CHD RiskRisk Factors Can Further Confound Atherosclerosis—and Increase CHD Risk

X 16

X 4.5

X 9X 6

X 3

X 4

X 1.6

Framingham Interaction of Risk Factors

Smoking Hypertension SBP >195 mm Hg

CholesterolTC >330 mg/dl(8.53 mmol/L)

Heart Disease: A Textbook of Cardiovascular Disease. 6th ed. Philadelphia, Pa: W.B.Saunders Co; 2001:995-1009. Miller M. Clin Cardiol. 1999;22(suppl II):II-1-II-6.

Hyperlipidemia Initiates the Development of Atherosclerotic PlaqueHyperlipidemia Initiates the Development of Atherosclerotic Plaque

Libby P. Libby P. J Intern Med.J Intern Med. 2000;247:349-358. 2000;247:349-358.

How Do We Interrupt the Disease Cascade?

Stable Plaque Growth Can Lead to Vascular OcclusionStable Plaque Growth Can Lead to Vascular Occlusion

STABLE PLAQUE

Libby P. Lancet. 1996;348:S4-S7.

This high magnification of the atheroma shows numerous foam cells and an occasional cholesterol cleft.

Atheromatous Plaque, Histological ViewAtheromatous Plaque, Histological View

What Characterizes Unstable Plaque?What Characterizes Unstable Plaque?

Libby P. Circulation. 1995;91:2844-2850.

Glagov S, et al. N Engl J Med. 1987;316:1371-1375. Hackett D. Eur Heart J. 1988;9:1317-1323. Libby P. Lancet. 1996;348:S4-S7.

Unstable angina

Stroke

Peripheral ischemia

Unstable Plaque Rupture Can Lead to Serious Complications Including MI, Unstable Angina, Stroke, and Peripheral Ischemia

Unstable Plaque Rupture Can Lead to Serious Complications Including MI, Unstable Angina, Stroke, and Peripheral Ischemia

Myocardial infarction

Stable plaque can cause systemic complications related to vascular narrowing and occlusion, including stable angina, stroke, renal dysfunction, myocardial infarction, and peripheral ischemia

Renal dysfunction

Stroke

Stable anginaMyocardial infarction

Virmani R et al. Arterioscler Thromb Vasc Biol. 2000;20:1262-1275. Libby P. Circulation. 1995;91:2844-2850.

Vascular Occlusion Ultimately Results in Systemic ComplicationsVascular Occlusion Ultimately Results in Systemic Complications

Peripheral ischemia

Atherosclerosis (Summary)Atherosclerosis (Summary)

• Starts at a young age and frequently goes undetected for years

• Multiple risk factors including hyperlipidemia, hypertension, smoking dramatically increase risk for a cardiovascular event

• Therapies that impact plaque progression and stabilization may play an important role in preventing cardiovascular events

AgendaAgenda

• What is atherosclerosis?

• What is the role of endothelial dysfunction in the atherosclerotic process?

• What is the effect of lipid therapy on atherosclerosis?

NORMAL ENDOTHELIUM ABNORMAL ENDOTHELIUM

LDL-C HTN Diabetes Smoking

DYSFUNCTION

Vasculartone

Retardplatelet &leukocyteadhesion

InhibitSMCmigration/proliferation

Barrier toLDL-CDegrade VLDL-C& chylotriglyceride(lipase)

Plateletleukocyteadhesion

SMCmigration& growth

Lipiddeposition Clearance

Vasoconstriction

Dysfunction

Endothelial Dysfunction:Imbalance of Normal Vascular Processes Endothelial Dysfunction:Imbalance of Normal Vascular Processes

Vogel RA. Am J Med. 1999;107:479-487. Forgione MA, et al. J Curr Opin Cardiol. 2000;15:409-415.

Methods to Assess Endothelial FunctionMethods to Assess Endothelial Function• Invasive Measures

•Quantitative coronary angiography

–Changes in coronary artery size

–Endothelial-mediated vasodilation with serial intracoronary infusions of increasing dosages of acetylcholine

• Noninvasive Measures•Ultrasound of brachial artery

–Changes in brachial artery size

–Endothelial-mediated vasodilation with reactive hyperemia

• Whether brachial artery endothelial function correlates directly with coronary artery endothelial function is an important question that is currently being studied

Di Mario C, et al. Am Heart J. 1994;127:514-531. Weldinger F, et al. Am J Cardiol. 2002;89:1025-1029. Corretti M, et al. J Am Coll Cardiol. 2002;39:257-265. Fathi R, et al. Am Heart J. 2001;141:694-703. Gokee N, et al. Circulation. 2002;105:1567-1572. Bae J-H. J Cardiol. 2001;37 Suppl:89-92. Deng YB, et al. Clin Cardiol. 2001;24:291-296. Kuvin J, et al. J Am Coll Cardiol. 2001;38:1843-1849. Kuvin J, et al. Am Heart J. 2001;141:327-328.

• 500 asymptomatic subjects composite risk factor score calculated for each subject one point for each of the following:

– Cholesterol 240mg/dl– Current or former smoker– Current smoker with consumption 10 pack-years– Family history of premature vascular disease– Male gender– Age 50 years

0

P<0.001

Flo

w-

Med

iate

d

Dila

tio

n (

%) 20

15

10

5

0

-51 2 3 4 5

Flow-mediated dilation measured by external ultrasound imaging of the brachial or femoral artery

Celermajer DS, et al. J Am Coll Cardiol. 1994;24:1468–1474.

Risk Factor Score

Risk Factors Are Strongly Related to Endothelial DysfunctionRisk Factors Are Strongly Related to Endothelial Dysfunction

• Value taken at 7.7 years follow-up

• 147 patients admitted after routine diagnostic cath or PTCA

• Cardiac events include CV death, unstable angina, MI, PTCA, CABG, ischemic stroke, peripheral artery revascularization

4.3%

12%

25%

Normal(N=23)

Mild–Moderate(N=25)

Severe(N=20)

Flow-dependent Dilation ≥19% 10.3–19%

Worsening Endothelial Dysfunction

Car

dia

c E

ven

t In

cid

ence

(%

)

Adapted from Schachinger V, et al. Circulation. 2000;101:1899–1906.

<10.3%

Endothelial Dysfunction May Be Associated With Adverse Clinical Outcomes

Endothelial Dysfunction May Be Associated With Adverse Clinical Outcomes

FMD = Flow-Mediated Dilation Adapted from Neunteufl T, et al. Am J Cardiol. 2000;86:207–210.

15%

50%

Normal(FMD>10%)

Abnormal(FMD<10%)

Car

dia

c E

ven

t In

cid

ence

(%

)

P = 0.002

• Value taken at 5 years

• 73 patients admitted with angina pectoris who underwent coronary angiography

• FMD evaluated by brachial artery ultrasound examination

• Cardiac events include myocardial infarction, CABG, PTCA

Endothelial Dysfunction May Be Associated With Adverse Clinical Outcomes

Endothelial Dysfunction May Be Associated With Adverse Clinical Outcomes

Potential Mechanisms By Which Statins May Affect Endothelial Dysfunction

Potential Mechanisms By Which Statins May Affect Endothelial Dysfunction

The clinical relevance of these effects has not been established.Data on file, Parke-Davis.

Atorvastatin May Effect Endothelial Dysfunction by Multiple MechanismsAtorvastatin May Effect Endothelial Dysfunction by Multiple Mechanisms

The clinical relevance of these effects has not been established.Data on file, Parke-Davis.

Monocyteadherence

LDLPlatelet

aggregation

LDL

HDL

Ox-LDL

Macrophage

CE

N

N

CE

CE

CE

Foam cellENDOTHELIUMNitric oxide(Endothelial

function)Oxidation

MATRIX

BLO

OD

Activation

(MMP)

Smooth muscle cells(proliferation and

migration)

3 months

220patients

Patient population Patients with CHD

Atorvastatin 80 mg

Pravastatin 40 mg

REVERSAL SubstudyREVERSing Atherosclerosis with Aggressive Lipid Lowering

REVERSAL SubstudyREVERSing Atherosclerosis with Aggressive Lipid Lowering

Brachialreactivity

Brachialreactivity

Brachial Artery Reactivity Trial (BART)Brachial Artery Reactivity Trial (BART)

Endothelial DysfunctionEndothelial Dysfunction

• Endothelial dysfunction reflects an imbalanceof normal vascular processes

• Risk factors including hyperlipidemia, hypertension, diabetes and smoking may contribute to endothelial dysfunction and may have an cumulative effect

• Endothelial dysfunction may be correlated with clinical outcomes

• Statin therapy may improve endothelial dysfunction

AgendaAgenda

• What is atherosclerosis?

• What is the role of endothelial dysfunction in the atherosclerotic process?

• What is the effect of lipid therapy on atherosclerosis?

Statin Coronary Angiographic Studies Suggest Better Outcomes Due to Plaque Stabilization and Composition

Statin Coronary Angiographic Studies Suggest Better Outcomes Due to Plaque Stabilization and Composition

Duration Drug/dose in % % in Study n (years) (mg/day) stenosis CV events

CCAIT 165 2 L 36† 1.7* -28

MAAS 144 4 S 20 2.1* —

PLAC I 206 2 P 40 — -60*

LCAS 171 2.5 F 40 + C 0.6* -33

Post-CABG 676 5.4 L 76 + C 7.9* -29*

*Statistically significant. †Average daily dose. C, cholestyramine; Cp, colestipol; CV, cardiovascular; F, fluvastatin; L, lovastatin; P, pravastatin; S, simvastatin.

Blankenhorn DH, et al. Ann Intern Med. 1993;119:969-976. Brown G, et al. N Engl J Med. 1990;323:1289-1298. Herd JA, et al. Am J Cardiol. 1997;80:278-286. Pitt B, et al. J Am Cardiol. 1995;26:1133-1139. The Post Coronary Artery Bypass Graft Trial Investigators, N Engl J Med. 1997;336:153-162. Vos J, et al. Eur Heart J. 1997;18:1081-1089. Waters D, et al. Circulation.1995;92:2404-2410.

New Diagnostic Techniques Are More Sensitive in Determining the True Extent of the DiseaseNew Diagnostic Techniques Are More Sensitive in Determining the True Extent of the Disease

Nissen S. Am J Cardiol. 2001;87(suppl):15A-20A.

ASAP Study Demonstrated IMT Regression with Atorvastatin 80 mg in FH PatientsASAP Study Demonstrated IMT Regression with Atorvastatin 80 mg in FH Patients

-0.04 -0.02 0 0.02 0.04

Mean change (mm)

Atorvastatin 80 mg Simvastatin 40 mg

Reduction

Increase

Change in carotid intima media thickness (IMT) over 2 years

p=0.0017

p=0.0005

Smilde TJ, et al. Lancet. 2001;357:577-581.

Marchesi S, et al. J Cardiovasc Pharmacol. 2000: 36:617-621.

0

2

4

6

8

10

12

% C

han

ge

FM

V

baseline week 1 week 2 week 4 week 8

AtorvastatinDiet

*p<0.05 vs diet

Changes in brachial artery flow-mediated vasodilation (FMV) over time

*

**

Statin Therapy Improved Flow-mediated Vasodilation in Hyperlipidemic WomenStatin Therapy Improved Flow-mediated Vasodilation in Hyperlipidemic Women

Effects of Lipid TherapyEffects of Lipid Therapy

• Research suggests that changes in plaque stability and composition, in response to lipid-lowering therapy, may be responsible for reductions of coronary events

• Statin therapy improved flow-mediated vasodilation in hyperlipidemic women

• ASAP study demonstrated IMT regressionwith atorvastatin 80 mg in FH patients compared with FH patients on simvastatin 40 mg

Blankenhorn DH, et al. Ann Intern Med. 1993;119:969-976. Brown G, et al. N Engl J Med. 1990;323:1289-1298. Herd JA, et al. Am J Cardiol. 1997;80:278-286. Pitt B, et al. J Am Cardiol. 1995;26:1133-1139. The Post Coronary Artery Bypass Graft Trial Investigators, N Engl J Med. 1997;336:153-162. Vos J, et al. Eur Heart J. 1997;18:1081-1089. Waters D, et al. Circulation.1995;92:2404-2410. Smilde TJ et al. Lancet. 2001;357:577-581. Marchesi S et al. J Cardiovasc Pharmacol 2000: 36:617-621

ConclusionConclusion

• Atherosclerosis is a complex systemic disease involving LDL deposition, endothelial dysfunction, and inflammation that may drive the progression of disease

• Endothelial dysfunction may be predictive of CVD risk

• Besides their lipid-lowering efficacy statins may provide additional vascular benefits

Libby P. J Intern Med. 2000;247:349-358 . Schachinger V, et al. Circulation. 2000;101:1899–1906.Marchesi S, et al. J Cardiovasc Pharmacol. 2000: 36:617-621.