Xue-Qiao Zhao

Intracoronary Thrombus and Platelet Glycoprotein IIb/IIIa Receptor Blockade With Tirofiban in Unstable Angina or Non–Q-Wave Myocardial Infarction Angiographic Results From the PRISM-PLUS Trial (Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms)

BACKGROUNDnThe present study describes the effects of tirofiban, a nonpeptide platelet glycoprotein (GP) IIb/IIIa receptor blocker, on the characteristics of culprit lesions in patients with unstable angina (UA) or non-Q-wave myocardial infarction (NQWMI).nnnMETHODS AND RESULTSnOf 1915 patients enrolled in PRISM-PLUS, 1491 had a readable film obtained a median of 65 hours after randomization. A core laboratory examined the culprit lesions for intracoronary thrombus burden (primary end point) and for TIMI flow grade distribution and severity of the obstruction and of underlying coronary artery disease (secondary end points). The combination of tirofiban plus heparin compared with heparin alone significantly reduced the intracoronary thrombus burden of the culprit lesions (OR=0.77, P=0.022), improved the perfusion grade (OR=0.65, P=0.002), and decreased the severity of the obstruction (P=0.037), but it did not influence the severity of the underlying plaque. Persistence of a thrombus in 45% of patients was associated with a 2.4-fold increase in the odds of death at 30 days (P=0.005) and a 2-fold increase in the odds of myocardial infarction (P=0.002).nnnCONCLUSIONSnThe addition of tirofiban to heparin reduced the thrombus burden of the culprit lesion and improved distal perfusion in patients with UA or NQWMI, which supports the clinical benefit observed with the combination treatment.

Relationship of Lipoproteins to Cardiovascular Events in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) Trial

OBJECTIVESnThis study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial.nnnBACKGROUNDnDuring a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)-lowering therapy did not reduce CV events compared with LDL-C-lowering therapy alone.nnnMETHODSnSubjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (≤ 150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization.nnnRESULTSnCV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (≥ 198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (hazard ratio: 0.74, p = 0.073). In-trial LDL-C levels, non-HDL-C levels, and the total cholesterol/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group.nnnCONCLUSIONSnBaseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289).

Original ResearchMR Imaging of Carotid Plaque Composition During Lipid-Lowering Therapy: A Prospective Assessment of Effect and Time Course

OBJECTIVESnThe purpose of this study was to test the lipid depletion hypothesis and to establish the time course of change in carotid plaque morphology and composition during lipid therapy using high-resolution magnetic resonance imaging (MRI).nnnBACKGROUNDnLipid therapy is thought to improve plaque stability and reduce cardiovascular events by targeting the plaque rupture risk features such as large lipid core, thin fibrous cap, and high level of inflammatory infiltrates. However, the plaque stabilizing process during lipid therapy has not been clearly demonstrated in humans and in vivo.nnnMETHODSnSubjects with coronary or carotid artery disease, apolipoprotein B ≥120 mg/dl, and lipid treatment history <1 year, were randomly assigned to atorvastatin monotherapy or to atorvastatin-based combination therapies with appropriate placebos for 3 years. All subjects underwent high-resolution, multicontrast bilateral carotid MRI scans at baseline and annually for 3 years. All images were analyzed for quantification of wall area and plaque composition blinded to therapy, laboratory results, and clinical course.nnnRESULTSnAfter 3 years of lipid therapy, the 33 subjects with measurable lipid-rich necrotic core (LRNC) at baseline had a significant reduction in plaque lipid content: LRNC volume decreased from 60.4 ± 59.5 mm(3) to 37.4 ± 69.5 mm(3) (p < 0.001) and %LRNC (LRNC area/wall area in the lipid-rich regions) from 14.2 ± 7.0% to 7.4 ± 8.2% (p < 0.001). The time course showed that %LRNC decreased by 3.2 (p < 0.001) in the first year, by 3.0 (p = 0.005) in the second year, and by 0.91 (p = 0.2) in the third year. Changes in LRNC volume followed the same pattern. Percent wall volume (100 × wall/outer wall, a ratio of volumes) in the lipid-rich regions significantly decreased from 52.3 ± 8.5% to 48.6 ± 9.7% (p = 0.002). Slices containing LRNC had significantly more percent wall volume reduction than those without (-4.7% vs. -1.4%, p = 0.02).nnnCONCLUSIONSnIntensive lipid therapy significantly depletes carotid plaque lipid. Statistically significant plaque lipid depletion is observed after 1 year of treatment and continues in the second year, and precedes plaque regression. (Using Magnetic Resonance Imaging to Evaluate Carotid Artery Plaque Composition in People Receiving Cholesterol-Lowering Medications [The CPC Study]; NCT00715273).

Antioxidant Vitamins and Lipid Therapy: End of a Long Romance?

During the past decade, the perception flourished that lipid and antioxidant therapy were 2 independent avenues for cardiovascular protection. However, studies have shown that commonly used antioxidant vitamin regimens do not prevent cardiovascular events. We found that the addition of antioxidant vitamins to simvastatin-niacin therapy substantially blunts the expected rise in the protective high density lipoprotein (HDL)2 cholesterol and lipoprotein(A-I) subfractions of HDL, with apparent adverse effects on the progression of coronary artery disease. To better understand this effect, 12 apolipoproteins, receptors, or enzymes that contribute to reverse cholesterol transport have been examined in terms of their relationship to HDL2 and lipoprotein(A-I) levels and the potential for antioxidant modulation of their gene expression. Three plausible candidate mechanisms are identified: (1) antioxidant stimulation of cholesteryl ester transfer protein expression/activity, (2) antioxidant suppression of macrophage ATP binding cassette transmembrane transporter A1 expression, and/or (3) antioxidant suppression of hepatic or intestinal apolipoprotein A-I synthesis or increase in apolipoprotein A-I catabolism. In summary, antioxidant vitamins E and C and beta-carotene, alone or in combination, do not protect against cardiovascular disease. Their use for this purpose may create a diversion away from proven therapies. Because these vitamins blunt the protective HDL2 cholesterol response to HDL cholesterol-targeted therapy, they are potentially harmful in this setting. We conclude that they should rarely, if ever, be recommended for cardiovascular protection.

Types of Change in Coronary Stenosis Severity and Their Relative Importance in Overall Progression and Regression of Coronary Disease

Angiographic clinical trials of the progression and regression of obstructive coronary disease have expressed their results in terms of the average change in a large group of atherosclerotic lesions within a smaller group of patients randomized to a particular treatment. In most cases, the changes are first expressed as an average over all lesions per patient which is then averaged over all patients in each group. Since individual lesions have a variety of different characteristics in the baseline angiogram, the above averaging process tends to obscure insight into (1) the relative probability of progression and regression among lesions with different baseline characteristics, (2) the relative frequency of these high and low probability lesions in the general lesion population, and (3) the impact of therapy on progression and regression in lesions of defined baseline subtype. The Familial Atherosclerosis Treatment Study (FATS)’ examined the effect of two intensive lipid-altering strategies, as compared to a modest conventional approach, on measured disease progression in 120 patients who completed the protocol, including randomization to therapy, a baseline angiogram, and a follow-up angiogram at 2.5 years. The primary end point was change in percent stenosis averaged among the worst lesions found in each of nine proximal coronary segments in each patient. In many cases, the “worst” segmental disease was mild, or even absent. Proximal disease, per patient, averaged 35% diameter stenosis (%S) at baseline. It increased (net progression) by 2.10 %S among the conventionally treated patients and improved (net regression) by -0.75 and -0.85 in each of the two intensively treated groups.’ We have examined the contribution to this averaged net

Humans With Atherosclerosis Have Impaired ABCA1 Cholesterol Efflux and Enhanced High-Density Lipoprotein Oxidation by MyeloperoxidaseNovelty and Significance

Rationale: The efflux capacity of high-density lipoprotein (HDL) with cultured macrophages associates strongly and negatively with coronary artery disease status, indicating that impaired sterol efflux capacity might be a marker—and perhaps mediator—of atherosclerotic burden. However, the mechanisms that contribute to impaired sterol efflux capacity remain poorly understood. Objective: Our aim was to determine the relationship between myeloperoxidase-mediated oxidative damage to apolipoprotein A-I, the major HDL protein, and the ability of HDL to remove cellular cholesterol by the ATP-binding cassette transporter A1 (ABCA1) pathway. Methods and Results: We quantified both site-specific oxidation of apolipoprotein A-I and HDL’s ABCA1 cholesterol efflux capacity in control subjects and subjects with stable coronary artery disease or acute coronary syndrome. Subjects with coronary artery disease and acute coronary syndrome had higher levels of chlorinated tyrosine 192 and oxidized methionine 148 compared with control subjects. In contrast, plasma levels of myeloperoxidase did not differ between the groups. HDL from the subjects with coronary artery disease and acute coronary syndrome was less able to accept cholesterol from cells expressing ABCA1 compared with HDL from control subjects. Levels of chlorinated tyrosine and oxidized methionine associated inversely with ABCA1 efflux capacity and positively with atherosclerotic disease status. These differences remained significant after adjusting for HDL-cholesterol levels. Conclusions: Our observations indicate that myeloperoxidase may contribute to the generation of dysfunctional HDL with impaired ABCA1 efflux capacity in humans with atherosclerosis. Quantification of chlorotyrosine and oxidized methionine in circulating HDL might be useful indicators of the risk of cardiovascular disease that are independent of HDL-cholesterol.

MR carotid plaque imaging and contrast-enhanced MR angiography identifies lesions associated with recent ipsilateral thromboembolic symptoms: an in vivo study at 3T.

BACKGROUND AND PURPOSE: Recent research has suggested the importance of plaque composition to identify patients at risk for stroke. This study aims to identify specific plaque features on 3T carotid MR imaging and CE-MRA associated with recent carotid thromboembolic symptoms in patients with mild/moderate versus severe stenosis. MATERIALS AND METHODS: Ninety-seven consecutive patients (symptomatic, 13; asymptomatic, 84) with 50%–99% stenosis by sonography or CT angiography underwent carotid plaque imaging combined with MRA at 3T. The symptomatic carotid artery or the most stenotic asymptomatic carotid artery was chosen as the index vessel to be analyzed. Plaque features were compared by symptomatic status in patients with mild/moderate (30%–70%) versus severe (70%–99%) stenosis on MRA. RESULTS: Ninety (92.8%) patients had sufficient image quality for interpretation. In 50 patients with mild/moderate stenosis, there were significant associations between the presence of the following plaque characteristics and symptoms: thin/ruptured fibrous cap (100% versus 36%, P = .006) and lipid-rich necrotic core (100% versus 39%, P = .022), with marginal association with hemorrhage (86% versus 33%, P = .055). In 40 patients with severe stenosis, only the angiographic presence of ulceration (86% versus 36%, P = .039) was associated with symptoms. CONCLUSIONS: Several plaque components identified on 3T MR imaging are correlated with recent ipsilateral carotid thromboembolic symptoms. These preliminary results also suggest that associations between plaque characteristics and symptom history may vary by degree of stenosis. If confirmed in larger studies, carotid MR imaging may distinguish stable from unstable lesions, particularly in individuals with mild/moderate stenosis in whom the role of surgical intervention is currently unclear.

Geometric and Compositional Appearance of Atheroma in an Angiographically Normal Carotid Artery in Patients with Atherosclerosis

BACKGROUND AND PURPOSE: Arterial remodeling may enable atherosclerotic disease without luminal stenosis. We sought to assess the prevalence and characteristics of atherosclerosis in angiographically normal carotid arteries. MATERIALS AND METHODS: Forty-six arteries with 0% stenosis by MRA were evaluated with multicontrast carotid MR imaging at 3T. For each artery, the percentage wall volume (wall volume/[lumen volume + wall volume] × 100%) and the presence versus absence of an LRNC, calcification, IPH, and fibrous cap rupture were recorded. In addition, the relative size of each plaque component (eg, percentage LRNC = LRNC volume/wall volume × 100%), when present, was calculated. RESULTS: The mean of percentage wall volume in arteries with 0% stenosis was 43.0 ± 6.9% with a range from 31.6% to 60.1%. An LRNC was present in 67.4% (31/46) of arteries, calcification was present in 65.2% (30/46), IPH was present in 8.7% (4/46), and fibrous cap rupture was present in 4.3% (2/46). In arteries with an LRNC (n = 31), the average percentage LRNC volume was 8.8 ± 7.3% with a range from 1.0% to 31.5%. For calcification (n = 30), the mean percentage calcification volume was 3.8 ± 4.2% with a range of 0.1%–17.4%. The mean percentage IPH volume (n = 4) was 2.7 ± 1.7% with a range of 0.5%–4.1%. CONCLUSIONS: These findings indicate that stenosis by MRA may underestimate the presence of carotid atherosclerosis, and they demonstrate the need for improved methods for accurately identifying carotid atherosclerotic plaque severity.

A Noninvasive Imaging Approach to Assess Plaque Severity: The Carotid Atherosclerosis Score

BACKGROUND AND PURPOSE: The presence of IPH and/or FCR in the carotid atherosclerotic plaque indicates a high-risk lesion. The aim of this multicenter cross-sectional study was to establish the characteristics of lesions that may precede IPH and/or FCR. We further sought to construct a CAS that stratifies carotid disease severity. MATERIALS AND METHODS: Three hundred forty-four individuals from 4 imaging centers with 16%–99% carotid stenosis by duplex sonography underwent carotid MR imaging. In approximately 60% of the study sample (training group), multivariate analysis was used to determine factors associated with IPH and FCR. Statistically significant parameters identified during multivariate analysis were used to construct CAS. CAS was then applied to the remaining arteries (40%, test group), and the accuracy of classification for determining the presence versus absence of IPH or, separately, FCR was determined by ROC analysis and calculation of the AUC. RESULTS: The maximum proportion of the arterial wall occupied by the LRNC was the strongest predictor of IPH (P < .001) and FCR (P < .001) during multivariate analysis of the training group. The subsequently derived CAS applied to the test group was an accurate classifier of IPH (AUC = 0.91) and FCR (AUC = 0.93). Compared with MRA stenosis, CAS was a stronger classifier of both IPH and FCR. CONCLUSIONS: LRNC quantification may be an effective complementary strategy to stenosis for classifying carotid atherosclerotic disease severity. CAS forms the foundation for a simple imaging-based risk-stratification system in the carotid artery to classify severity of atherosclerotic disease.

Importance of endothelial function in mediating the benefits of lipid-lowering therapy

Trials of lipid lowering by various methods have clearly demonstrated the benefits, clinically and angiographically. Evidence of slowed arterial disease progression and even regression has been convincing but modest, at best. For example, among those treated intensively in the Familial Atherosclerosis Treatment Study (FATS), the mean improvement in proximal stenosis severity was <1% per patient, and only 12% of all lesions showed convincing regression. Despite these modest arterial benefits, the associated reductions in major cardiovascular events have been surprisingly great (24-35% in 3 recent large trials and > or =50% in angiographic trials using combination therapies). The process of plaque disruption helps explain this discrepancy. Disruption can be predicted by a large accumulation of core lipid in the plaque and a high density of lipid-laden macrophages in its thinned fibrous cap. Lesions with these characteristics comprise only 10-20% of the overall lesion population but account for 60-90% of the acute clinical events. Lipid-lowering therapy has beneficial effects on these high-risk features of plaque morphology. The composite of data presented here supports the hypothesis that lipid-lowering therapy selectively depletes lipids from this relatively small but dangerous subgroup of fatty lesions, effectively stabilizing them.