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Aortic and Carotid Magnetic
Resonance Image (MRI) Imaging
• Can identify plaque components such as fibrous cap, lipid core, calcium,
hemorrhage, and thrombosis (vunerable plaques have thin fibrous cap and
large lipid core)
• Non-invasive and no radiation
• Computerized morphometric analysis involves following edge of
significant contrast, providing measures of total vascular and lumen area,
the difference being the vessel wall area (Image Pro-Plus, Media
Cybernetics).
• Image-specific error of 2.6% for aortic and 3.5% for carotid plaques allows
accurate measurement of changes in plaque size of >5.2% for aortic lesions
and >7% for carotid lesions (Corti et al., 2001)


MRI Assessment of Thoracic Aorta
Plaque
• Challenges include obtaining sufficient sensitivity for
sub-mm imaging and exclusion of artifacts from
respiratory motion and blood flow.
• Multicontrast approaches include performing T1-,PD-,
and T2-weighted images with high resolution “black
blood” spin used to visualize adjacent vessel wall.
• Matched MRI and TEE cross-sectional aortic images
show strong correlation for plaque composition and
maximum plaque thickness.


In Vivo MRI imaging of Coronary
Artery Plaque
• Difficulties include cardiac and respiratory motion, nonlinear

course of coronary arteries, and small size and location of
coronary arteries.
• Inter- and intraobserver variability assessed by intraclass
correlation ranged from 0.96-0.99.
• Wall thickness in human coronaries can be differentiated
between normal and >40% stenosis; breathholding can
minimize respiratory motion.
• Fayad and Fuster, Am J Cardiol 2001; 88 (suppl): 42E-45E.


Lipid-Lowering by Simvastatin and
Reduction in MRI Vessel Wall Area
• 18 asymptomatic hypercholesterolemic patients studied,
with a total of 35 aortic and 25 carotid plaques measured
• Serial black-blood MRI of aorta and carotid artery
performed at baseline, 6, and 12 months
• At 12 months (but not 6 months), significant reductions
in vessel wall thickness and area (8% reduction in aorta
and 15% reduction in carotid artery vessel wall area),
without lumen area changes, were observed.


MRI Serial T2-Weighted Images During
Simvastatin Treatment: Coronary vessels
(top) and descending aorta (bottom)
(Corti et al., Circulation 2001; 104: 249-52)


Changes in MRI vessel wall and lumen area and wall
thickness after 6 and 12 months of simvastatin treatment

Click for la
rger picture


High-frequency Brachial
Ultrasonography
• The endothelium regulates vascular tone through release of
vasodilators and vasoconstrictors.
• Brachial artery flow-mediated vasodilation (FMD) is
assessed by high-frequency ultrasound assessment of
changes in brachial artery diameter after 5-minute blood
pressure cuff arterial occlusion.
• Endothelial dysfunction demonstrated as reduced FMD, and
associated with coronary risk factors.
• Brachial artery FMD correlates with coronary artery FMD.


Brachial Ultrasonography (cont.)
• Brachial or coronary artery flow mediated vasodilation
(FMD) predict long-term cardiovascular events.
• Clinical applicability not well-established, but measures
frequently used to measure endothelial function.
• FMD decreases after age 40 in men and 50 in women,
reduced at SBP>100 mmHg, LDL > 75 mg/dl, and in
diabetics
• Cholesterol reduction rapidly improves FMD.


Brachial Artery Images Pre-Post Pressure Cuff Occlusion

Click for larger picture


Intravascular Ultrasound (IVUS)
Assessment of Atherosclerosis
• Detects plaque changes resulting from compensatory
expansion that remodels the external elastic membrane;
lumen not often narrowed until late in the process
• Invasive, expensive, normally reserved for persons with
established coronary disease
• Volume of plaque obtained by measuring external
elastic membrane, lumen area, and plaque and repeating
every mm for at least 25-50 mm of artery.


IVUS: Clinical studies involving
progression/regression of plaque
• 25 patients randomized to 10 mg pravastatin vs.
placebo for 3 years showed a 41% increase in
atheroma volume in the placebo patients vs. a 7%
decrease in the pravastatin patients (p=0.0005)
• REVERSAL prospective, randomized, double-blind
multicenter trial will examine changes in volume of
plaque in patients treated with either 80 mg
atorvastatin or 40 mg pravastatin;
• Nissen S, Am J Cardiol 2001; 87 (suppl): 15A-20A


Atheroma “regression” (reverse remodeling

maintaining similar lumen area) seen by IVUS


Multivariate Relative Risks of CHD/Mortality
Associated with Composite *Subclinical Disease
Men and
Women

Men Only

Women Only

Total CHD

1.99
(1.33-3.00)

1.84
(1.09-3.09)

2.41
(1.26-4.62)

Total MI

1.32
(0.75-2.32)

0.93
(0.47-1.84)

2.54
(0.87-7.43)

Total
Mortality

1.82
(1.08-3.08)

2.52
(1.18-5.37)

1.21
(0.57-2.57)

as ABI <=0.9, Internal or common carotid wall thickness >80th
%tile, carotid diameter stenosis >25%, major Minnesota ECG
abnormalities or abnormal LVEF, abnormal wall motion on
echocardiogram, or positive Rose questionnaire for claudication or
angina pectoris
* Defined


Use of Surrogate Endpoints:
Considerations in Drug Development

• Burden of sponsor is to provide evidence that the drug
is safe and effective, and often studies to achieve
clinical endpoints take longer.

• Surrogate endpoint studies can change labeling and
indications depending on results.
• But surrogate endpoints are sometimes a “leap of faith”
and an endpoint study is often still required to validate
assumptions made regarding clinical benefit. Hard
endpoint studies may not always parallel results of
surrogate endpoint studies.


LDL Cholesterol Goals and Cutpoints for
Therapeutic Lifestyle Changes (TLC)
and Drug Therapy in Different Risk Categories
Risk Category
CHD or CHD Risk
Equivalents
(10-year risk >20%)

2+ Risk Factors
(10-year risk
20%)
0–1 Risk Factor

LDL Goal
(mg/dL)

<100

<130

<160

LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes (TLC)
(mg/dL)

100

LDL Level at Which
to Consider
Drug Therapy
(mg/dL)

130
(100–129: drug
optional)
10-year risk 10–20%:
130

130

160

10-year risk <10%:
160
190
(160–189: LDLlowering drug
optional)

CHD Risk Equivalents
• Other clinical forms of atherosclerotic
disease (peripheral arterial disease,
abdominal aortic aneurysm, and
symptomatic carotid artery disease)
• Diabetes
• Multiple risk factors that confer a 10year risk for CHD >20%


LDL Cholesterol Goal and Cutpoints for
Therapeutic Lifestyle Changes (TLC) and Drug
Therapy in Patients with CHD and CHD
Risk Equivalents (10-Year Risk >20%)

LDL Goal

<100 mg/dL

LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes (TLC)

LDL Level at Which to
Consider Drug Therapy

100 mg/dL

130 mg/dL
(100–129 mg/dL:
drug optional)

LDL-Lowering Therapy in Patients With
CHD and CHD Risk Equivalents
Baseline LDL Cholesterol: 130 mg/dL
• Intensive lifestyle therapies
• Maximal control of other risk factors
• Consider starting LDL-lowering drugs
simultaneously with lifestyle therapies


LDL-Lowering Therapy in Patients With
CHD and CHD Risk Equivalents
Baseline (or On-Treatment) LDL-C: 100–129 mg/dL
• LDL-lowering therapy
– Initiate or intensify lifestyle therapies
– Initiate or intensify LDL-lowering drugs

• Treatment of metabolic syndrome
– Emphasize weight reduction and physical activity

• Drug therapy for other lipid risk factors
– For high triglycerides/low HDL cholesterol
– Fibrates or nicotinic acid


Implications for Cardiovascular Risk
Stratification and Treatment: NCEP III
• Should we add to this high-risk group
requiring more intensive LDL-C initiation

levels and goals, the following?
– Persons with significant carotid disease (e.g., at
or above 5th quintile of combined IMT)
– Persons with “significant” coronary calcium
(e.g., those above 75th %tile seen to be at 4-6fold or greater risk of events)
– Persons with significant LV mass or LVH


Implications on Cardiovascular Risk
Stratification and Treatment: JNC-VI
• JNC-VI currently recommends initiating drug treatment
without delay for hypertension in persons with known
CVD or diabetes at 130/85 mmHg or higher, and in
those with at least 1 risk factor when BP is at 140/90
mmHg or higher.
• Should the presence of significant carotid disease, CT
coronary calcium, or other evidence warrant treatment
at the more aggressive, lower cut-point?


Conclusions
• Mounting data show surrogate measures of atherosclerosis predict
CHD risk and are sensitive to monitoring effects of therapeutic
interventions.
• Noninvasive methods to measure subclinical atherosclerosis and
its progression provide an opportunity to enhance primary
prevention efforts
• Noninvasive identification of the vulnerable plaque (e.g., using
MRI) may help identify those at highest risk.
• Patient compliance to risk-reduction may be enhanced by

knowledge of disease (e.g., CAC)


Conclusions (cont.)

• Identification of those with the greatest amount of subclinical
atherosclerosis may provide a better rationale for aggressive
treatment (lipids, HTN) of those with borderline levels,
allowing us to better target limited resources.
• Surrogate measures of atherosclerosis can also allow:
– 1) testing of epidemiologic hypotheses related to CHD
– 2) designing clinical trials testing efficacy of therapies
– 3) monitoring preventive therapies to reduce risk of clinical
events