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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.