Zahi A. Fayad

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

It is essential that the medical profession play a central role in critically evaluating the evidence related to drugs, devices, and procedures for the detection, management, or prevention of disease. Properly applied, rigorous, expert analysis of the available data documenting absolute and relative benefits and risks of these therapies and procedures can improve the effectiveness of care, optimize patient outcomes, and favorably affect the cost of care by focusing resources on the most effective strategies. One important use of such data is the production of clinical practice guidelines that, in turn, can provide a foundation for a variety of other applications, such as performance measures, appropriate use criteria, clinical decision support tools, and quality improvement tools. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of guidelines in the area of cardiovascular disease since 1980. The ACCF/AHA Task Force on Practice Guidelines (Task Force) is charged with developing, updating, and revising practice guidelines for cardiovascular diseases and procedures, and the Task Force directs and oversees this effort. Writing committees are charged with assessing the evidence as an independent group of authors to develop, update, or revise recommendations for clinical practice. Experts in the subject under consideration have been selected from both organizations to examine subject-specific data and write guidelines in partnership with representatives from other medical practitioner and specialty groups. Writing committees are specifically charged to perform a formal literature review; weigh the strength of evidence for or against particular tests, treatments, or procedures; and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that may influence the choice of tests or therapies are considered. When available, information from studies on cost is considered, but data on efficacy and clinical outcomes constitute …

2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults

Alice K. Jacobs, MD, FACC, FAHA, Chair, 2009–2011 Sidney C. Smith, Jr, MD, FACC, FAHA, Immediate Past Chair, 2006–2008 [⁎⁎⁎][1] Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect Nancy Albert, PhD, CCNS, CCRN Christopher E. Buller, MD, FACC[⁎⁎⁎][1] Mark A. Creager, MD, FACC,

Noninvasive In Vivo Human Coronary Artery Lumen and Wall Imaging Using Black-Blood Magnetic Resonance Imaging

BACKGROUND High-resolution MRI has the potential to noninvasively image the human coronary artery wall and define the degree and nature of coronary artery disease. Coronary artery imaging by MR has been limited by artifacts related to blood flow and motion and by low spatial resolution. METHODS AND RESULTS We used a noninvasive black-blood (BB) MRI (BB-MR) method, free of motion and blood-flow artifacts, for high-resolution (down to 0.46 mm in-plane resolution and 3-mm slice thickness) imaging of the coronary artery lumen and wall. In vivo BB-MR of both normal and atherosclerotic human coronary arteries was performed in 13 subjects: 8 normal subjects and 5 patients with coronary artery disease. The average coronary wall thickness for each cross-sectional image was 0.75+/-0.17 mm (range, 0.55 to 1.0 mm) in the normal subjects. MR images of coronary arteries in patients with >/=40% stenosis as assessed by x-ray angiography showed localized wall thickness of 4.38+/-0.71 mm (range, 3.30 to 5.73 mm). The difference in maximum wall thickness between the normal subjects and patients was statistically significant (P<0.0001). CONCLUSIONS In vivo high-spatial-resolution BB-MR provides a unique new method to noninvasively image and assess the morphological features of human coronary arteries. This may allow the identification of atherosclerotic disease before it is symptomatic. Further studies are necessary to identify the different plaque components and to assess lesions in asymptomatic patients and their outcomes.

Lipid Lowering by Simvastatin Induces Regression of Human Atherosclerotic Lesions Two Years’ Follow-Up by High-Resolution Noninvasive Magnetic Resonance Imaging

Background—Statins are widely used to treat hypercholesterolemia and atherosclerotic disease. Noninvasive MRI allows serial monitoring of atherosclerotic plaque size changes. Our aim was to investigate the effects of lipid lowering with simvastatin on atherosclerotic lesions. Methods and Results—A total of 44 aortic and 32 carotid artery plaques were detected in 21 asymptomatic hypercholesterolemic patients at baseline. The effects of statin on these atherosclerotic lesions were evaluated as changes versus baseline in lumen area (LA), vessel wall thickness (VWT), and vessel wall area (VWA) by MRI. Maximal reduction of plasma total and LDL cholesterol by simvastatin (23% and 38% respectively;P <0.01 versus baseline) was achieved after ≈6 weeks of therapy and maintained thereafter throughout the study. Significant (P <0.01) reductions in maximal VWT and VWA at 12 months (10% and 11% for aortic and 8% and 11% for carotid plaques, respectively), without changes in LA, have been reported. Further decreases in VWT and VWA ranging from 12% to 20% were observed at 18 and 24 months. A slight but significant increase (ranging from 4% to 6%) in LA was seen in both carotid and aortic lesions at these later time points. Conclusion—The present study demonstrates that maintained lipid-lowering therapy with simvastatin is associated with significant regression of established atherosclerotic lesions in humans. Our observations indicate that lipid-lowering therapy is associated with sustained vascular remodeling and emphasize the need for longer-term treatment.

Effects of Lipid-Lowering by Simvastatin on Human Atherosclerotic Lesions A Longitudinal Study by High-Resolution, Noninvasive Magnetic Resonance Imaging

Background—This study was designed to investigate the effects of lipid-lowering by simvastatin on human atherosclerotic lesions. Methods and Results—Eighteen asymptomatic hypercholesterolemic patients with documented aortic and/or carotid atherosclerotic plaques were selected for the study. A total of 35 aortic and 25 carotid artery plaques were detected. Serial black-blood MRI of the aorta and carotid artery of the patients was performed at baseline and 6 and 12 months after lipid-lowering therapy with simvastatin. The effects of the treatment on atherosclerotic lesions were measured as changes in lumen area, vessel wall thickness, and vessel wall area, a surrogate of atherosclerotic burden. Simvastatin induced a significant (P <0.01) reduction in total and LDL cholesterol levels at 6 weeks that was maintained thereafter. At 6 months, no changes in lumen area, vessel wall thickness, or vessel wall area were observed. However, at 12 months, significant reductions in vessel wall thickness and vessel wall area, without changes in lumen area, were observed in both aortic and carotid arteries (P <0.001). Conclusions—This in vivo human study demonstrates that effective and maintained lipid-lowering therapy by simvastatin is associated with a significant regression of atherosclerotic lesions. Our observation suggests that statins induce vascular remodeling, as manifested by reduced atherosclerotic burden without changes in the lumen.

Cholesterol Efflux and Atheroprotection Advancing the Concept of Reverse Cholesterol Transport

High-density lipoprotein (HDL) has been proposed to have several antiatherosclerotic properties, including the ability to mediate macrophage cholesterol efflux, antioxidant capacity, antiinflammatory properties, nitric oxide–promoting activity, and ability to transport proteins with their own intrinsic biological activities.1 HDL particles are critical acceptors of cholesterol from lipid-laden macrophages and thereby participate in the maintenance of net cholesterol balance in the arterial wall and in the reduction of proinflammatory responses by arterial cholesterol-loaded macrophages. The pathways that regulate HDL-mediated macrophage cholesterol efflux and disposition of cholesterol involve cell membrane–bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL-mediated cholesterol efflux,2,3 the concentration of the cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse cholesterol transport” (RCT) process; however, macrophage-derived cholesterol represents a minor component of the cholesterol transported by HDL particles.4–7 One important pathway for cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) and cholesterol-deficient and phospholipid-depleted apolipoprotein (apo) A-I complexes (pre-β migrating HDL or very small HDL [HDL-VS]; Figure 2).1,8 Subsequently, the ATP-binding cassette transporter G1 (ABCG1) mediates macrophage cholesterol efflux through interactions (Figure 3) with spherical, cholesterol-containing α-HDL particles (small HDL [HDL-S], medium HDL [HDL-M], large HDL [HDL-L], and very large (HDL-VL).1 In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor that mediates bidirectional lipid transport in the macrophage, which is dependent on the content of cholesterol in lipid-laden macrophages. A more established role for SR-BI in cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this cholesterol …

Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial

BACKGROUND Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. METHODS In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473. FINDINGS 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. INTERPRETATION Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. FUNDING F Hoffmann-La Roche Ltd.

Atherosclerosis Inflammation Imaging with 18F-FDG PET: Carotid, Iliac, and Femoral Uptake Reproducibility, Quantification Methods, and Recommendations

Atherosclerosis imaging with 18F-FDG PET is useful for tracking inflammation within plaque and monitoring the response to drug therapy. Short-term reproducibility of this technique in peripheral artery disease has not been assessed, and the optimal method of 18F-FDG quantification is still debated. We imaged 20 patients with vascular disease using 18F-FDG PET twice, 14 d apart, and used these data to assess reproducibility measures and compare 2 methods of 18F-FDG uptake measurement. We also reviewed the literature on quantification methods to determine the optimal measures of arterial 18F-FDG uptake for future studies. Methods: Twenty patients with vascular disease underwent PET/CT of the iliac, femoral, and carotid arteries 90 min after 18F-FDG administration. In 19 patients, repeat testing was performed at 2 wk. Coregistration and attenuation correction were performed with CT. Vessel 18F-FDG uptake was measured as both the mean and maximum blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). We assessed interscan, interobserver, and intraobserver agreement. Results: Nineteen patients completed both imaging sessions. The carotid and peripheral arteries all have excellent short-term reproducibility of the 18F-FDG signal, with intraclass correlation coefficients all greater than 0.8 for all measures of reproducibility. Both mean and maximum TBR measurements for quantifying 18F-FDG uptake are equally reproducible. 18F-FDG uptake was significantly higher in the carotid arteries than in both iliac and femoral vessels (P < 0.001 for both). Conclusion: We found that both mean and maximum TBR in the carotid, iliac, and femoral arteries were highly reproducible. We suggest the mean TBR be used for tracking systemic arterial therapies, whereas the maximum TBR is optimal for detecting and monitoring local, plaque-based therapy.

Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI.

We investigated the ability of targeted immunomicelles to detect and assess macrophages in atherosclerotic plaque using MRI in vivo. There is a large clinical need for a noninvasive tool to assess atherosclerosis from a molecular and cellular standpoint. Macrophages play a central role in atherosclerosis and are associated with plaques vulnerable to rupture. Therefore, macrophage scavenger receptor (MSR) was chosen as a target for molecular MRI. MSR-targeted immunomicelles, micelles, and gadolinium–diethyltriaminepentaacetic acid (DTPA) were tested in ApoE−/− and WT mice by using in vivo MRI. Confocal laser-scanning microscopy colocalization, macrophage immunostaining and MRI correlation, competitive inhibition, and various other analyses were performed. In vivo MRI revealed that at 24 h postinjection, immunomicelles provided a 79% increase in signal intensity of atherosclerotic aortas in ApoE−/− mice compared with only 34% using untargeted micelles and no enhancement using gadolinium–DTPA. Confocal laser-scanning microscopy revealed colocalization between fluorescent immunomicelles and macrophages in plaques. There was a strong correlation between macrophage content in atherosclerotic plaques and the matched in vivo MRI results as measured by the percent normalized enhancement ratio. Monoclonal antibodies to MSR were able to significantly hinder immunomicelles from providing contrast enhancement of atherosclerotic vessels in vivo. Immunomicelles provided excellent validated in vivo enhancement of atherosclerotic plaques. The enhancement seen is related to the macrophage content of the atherosclerotic vessel areas imaged. Immunomicelles may aid in the detection of high macrophage content associated with plaques vulnerable to rupture.

In Vivo Magnetic Resonance Evaluation of Atherosclerotic Plaques in the Human Thoracic Aorta A Comparison With Transesophageal Echocardiography

BACKGROUND The structure and composition of aortic atherosclerotic plaques are associated with the risk of future cardiovascular events. Magnetic resonance (MR) imaging may allow accurate visualization and characterization of aortic plaques. METHODS AND RESULTS We developed a noninvasive MR method, free of motion and blood flow artifacts, for submillimeter imaging of the thoracic aortic wall. MR imaging was performed on a clinical MR system in 10 patients with aortic plaques identified by transesophageal echocardiography (TEE). Plaque composition, extent, and size were assessed from T1-, proton density-, and T2- weighted images. Comparison of 25 matched MR and TEE cross-sectional aortic plaque images showed a strong correlation for plaque composition (chi(2) = 43.5, P<0.0001; 80% overall agreement; n = 25) and mean maximum plaque thickness (r = 0.88, n = 25; 4.56+/-0.21 mm by MR and 4.62+/-0.31 mm by TEE). Overall aortic plaque extent as assessed by TEE and MR was also statistically significant (chi(2) = 61.77, P<0.0001; 80% overall agreement; n = 30 regions). CONCLUSIONS This study demonstrates that noninvasive MR evaluation of the aorta compares well with TEE imaging for the assessment of atherosclerotic plaque thickness, extent, and composition. This MR method may prove useful for the in vivo study of aortic atherosclerosis.