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 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 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 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 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)