Search

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Introduction: Emerging evidence suggests that remnant cholesterol (RC) promotes future atherosclerotic cardiovascular disease (ASCVD) events. Our aim was to estimate the risk associated with RC beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Hypothesis: RC provides incremental prognostic information regarding incident ASCVD, independent of LDL-C and apoB. Methods: We pooled data from 17,532 individuals from Atherosclerosis Risk in Communities study (n=9,748), Multi-Ethnic Study of Atherosclerosis (n=3,049) and Coronary Artery Risk Development in Young Adults (n=4,735), who were ASCVD-free at baseline and had measurements of lipids, apoB and apolipoprotein A1. RC was calculated as non-high-density cholesterol (non-HDL-C) minus LDL-C estimated by the Martin/Hopkins equation. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in discordant/concordant groups of RC and LDL-C across median cutpoints and cutpoints of percentile equivalence to LDL-C targets (70 and 100 mg/dL). Results: Mean age of participants was 52.3±17.9 years, 56.7% women and 34% black. There were 2,143 ASCVD events over median follow-up of 18.7 years. After multivariable adjustment including apoB and HDL-C, logRC was associated with higher ASCVD risk [HR 1.42, 95% CI (1.23-1.63)]. In discordance analyses, the high RC and low LDL-C group (≥/ Conclusion: In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors and LDL-C and apoB levels. RC assessment and management in primary prevention, beyond LDL-C and apoB, is useful and requires further scrutiny.

Introduction: Use of insulin has been associated with worse CV outcomes in patients (pts) with type 2 diabetes T2D. Apabetalone (APB) is a novel selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. In the Phase 3 BETonMACE trial treatment with APB, compared with placebo, resulted in non-significantly fewer major adverse CV events (MACE: CV death, non-fatal MI or stroke) in 2425 pts with T2D and recent acute coronary syndrome (ACS). Objective: In this analysis of BETonMACE we examined the relationship of insulin use to MACE risk and its modification by APB. Methods: Baseline characteristics were compared in insulin-treated (INS) or not insulin-treated (no-INS) pts. The incidence of MACE and treatment hazard ratio (HR) were compared between these two subgroups. Results: 829 (34.2%) pts received insulin at baseline, with or without other diabetes drugs. INS vs no-INS pts were more likely to be female (29 vs 24%), had longer duration of T2D (12.6 vs 6.4 yrs), higher HbA1c (8.4 vs 6.9%) and baseline glucose (156 vs 126 mg/dL), lower use of metformin (73 vs 87%) and sulfonylureas (21 vs 33 %), and higher use of SGLT2 inhibitors (16 vs 6%) and GLP1 receptor agonists (10 vs 2%). MACE in the placebo group was higher in INS than no-INS (17.4% vs 9.7%; HR 1.94; 95% CI 1.39-2.73; p=0.0001). Overall, APB was associated with fewer MACE (HR 0.82, 95% CI 0.65-1.04, p=0.11). The relative reduction in MACE with ABP was similar in INS (HR 0.78, 95% CI. 0.55-1.10, p=0.16) and no-INS (HR 0.87, 95% CI 0.63-1.21, p = 0.42, p interaction =0.64). The absolute reduction in MACE with APB was numerically greater among INS than non-INS (3.69 vs 1.30%). Conclusions: Pts with T2D and recent ACS treated with insulin are at high risk for MACE. High risk of MACE with insulin use is likely through association with other clinical characteristics prognostic for MACE. Insulin treatment may be a marker to identify pts with potential for large absolute reduction in MACE with APB.

Atherosclerosis is a chronic inflammatory disease characterized by lipid-containing inflammatory lesions of large- and medium-sized arteries. It is primarily a disease of the inner layer of the arterial wall, the intima. As the disease advances, the adventitia, however, also participates in the pathogenesis of the atherosclerosis. Herrmann et al1 have proposed that the development of human atherosclerotic lesions can be considered to involve 3 distinct stages. In the first stage, early alterations in cellular function result from the interaction of environmental risk factors and genetic predisposition. The second stage is characterized by the proliferation of adventitial vasa vasorum with subsequent extension of the neovessels into the inner media and eventually into the enlarging plaque. In vulnerable plaques, vessel density increases from 2- to 4-fold in disrupted plaques, compared with several obstructive stable lesions. Chronic lesions can enter the third stage with further neovascularization, especially in the vulnerable shoulder areas of the plaques. At this stage, the intraplaque neovessels may rupture, leading to intraplaque hemorrhage. This may be because of compromised integrity of the microvascular endothelium and plaque weakening secondary to inflammation. The exacerbation of tightly intertwined plaque inflammatory activity and neovascularization results in plaque rupture, leading to arterial thrombosis with ensuing clinical syndromes. Revolution in the field of radiology in the last 3 decades has enabled imaging of inflammation and neovascularization within atherosclerotic tissue. In this article, we review advances in various clinical and preclinical imaging modalities aimed at unraveling the pathobiology of atherosclerosis. The use of ultrasound (US) for molecular imaging of the cardiovascular system is an extension of contrast echocardiographic principles already in clinical use. Nontargeted US contrast agents (UCAs) act purely as intravascular blood tracers behaving as red blood cells within the microcirculation. Targeted UCAs decorated with ligands, by affinity-based interaction, localize to a site where …

Background— Baseline C-reactive protein (CRP) levels predict major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina). The association between changes in CRP levels with plaque progression and MACE in the setting of maximally intensive statin therapy is unknown. Methods and Results— The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in the change from baseline of percent atheroma volume on intravascular ultrasound, CRP-modulating effects, or MACE rates, thus allowing for a (prespecified) post hoc analysis to test associations between the changes in CRP levels with coronary disease progression and MACE. Patients with nonincreasing CRP levels (n=621) had higher baseline (2.3 [1.1–4.7] versus 1.1 [0.5–1.8] mg/L; P P P =0.01). Although the (log) change in CRP did not associate with MACE (hazard ratio, 1.18; 95% confidence interval, 0.93–1.50; P =0.17), the (log) on-treatment CRP associated significantly with MACE (hazard ratio, 1.28; 95% confidence interval, 1.04–1.56; P =0.02). On-treatment low-density lipoprotein cholesterol levels did not correlate with MACE (hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P =0.45). Conclusions— Following 24 months of potent statin therapy, on-treatment CRP levels associated with MACE. Inflammation may be an important driver of residual cardiovascular risk in patients with coronary artery disease despite aggressive statin therapy. Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique identifier: NCT000620542.

Background— Previous studies using quantitative coronary angiography have demonstrated that statin therapy slows the progression of coronary stenoses in proportion to average low-density lipoprotein cholesterol levels during therapy. However, no major statin monotherapy study has demonstrated either halted progression or regression of angiographic disease. A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) assessed whether rosuvastatin could regress coronary atherosclerosis by intravascular ultrasound and quantitative coronary angiography. Intravascular ultrasound showed atheroma volume regression in a single coronary artery with Methods and Results— ASTEROID treated 507 coronary disease patients with rosuvastatin 40 mg/d for 24 months. Blinded quantitative coronary angiography analyses of percent diameter stenosis and minimum lumen diameter were performed for up to 10 segments of coronary arteries and major branches with >25% diameter stenosis at baseline. For each patient, the mean of all matched lesions at baseline and study end was calculated. There were 292 patients with 613 matched stenoses. Rosuvastatin reduced low-density lipoprotein cholesterol by 53.3% to 61.1±20.3 mg/dL and increased high-density lipoprotein cholesterol by 13.8% to 48.3±12.4 mg/dL. Mean±SD percent diameter stenosis decreased from 37.3±8.4% (median, 35.7%; range, 26% to 73%) to 36.0±10.1% (median, 34.5%; range, 8% to 74%; P P Conclusions— Rosuvastatin treatment for 24 months to average low-density lipoprotein cholesterol levels well below 70 mg/dL, accompanied by significant increases in high-density lipoprotein cholesterol, produced regression by decreasing percent diameter stenosis and improving minimum lumen diameter as measured by quantitative coronary angiography in coronary disease patients.

Introduction: Infusing high-density lipoprotein (HDL) has been shown to promote plaque regression in patients with acute coronary syndrome (ACS). The factors associated with a greater propensity to regression have not been elucidated. We hypothesized greater plaque regression with HDL infusion would be observed in patients with greater baseline plaque burden. Methods: The CHI-SQUARE study compared the effect of infusing the pre-beta HDL mimetic CER-001 (3 to 12 mg/kg) versus placebo weekly for 5 weeks in patients with a recent ACS on plaque burden using serial intravascular ultrasound. Receiver operating characteristics curve analysis determined that a baseline percent atheroma volume (PAV) ≥30% optimally associated with greater regression. Clinical and imaging characteristics were compared in patients with baseline PAV Results: There were no differences between the groups apart from greater use of statin in patients with baseline PAV ≥30% (100 v. 90%, p=0.01). Patients with a greater baseline PAV were more likely to demonstrate echolucency (20 v. 9%, p=0.02) and ultrasound attenuation (21 v. 7%, p=0.01), consistent with lipidic and inflammatory material. On serial evaluation, PAV decreased with CER-001 infusion in patients with baseline PAV ≥30% by -0.27% (p=0.01 v. baseline), but not in those with baseline PAV Conclusions: Greater plaque regression with CER-001 3 mg/kg was observed in ACS patients with greater atheroma burden and more vulnerable features. The findings identify ACS patients with high-risk plaque features most likely to benefit from HDL mimetic therapy.

Introduction: Total to high-density lipoprotein cholesterol (TC/HDL-C), routinely available from the standard lipid profile, is postulated to characterize atherogenic lipids beyond low density lipoprotein cholesterol (LDL-C) and non-HDL-C Hypothesis: On-treatment TC/HDL-C significantly associates with coronary atheroma progression rates at variable levels of LDL-C, non-HDL-C, apolipoprotein B (apoB), triglycerides (TG), C-reactive protein (CRP), and irrespective of diabetes status, obesity or intensity of statin therapy Methods: We analyzed data from 9 trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography and assessed the effect of on-treatment levels of TC/HDL-C [ Results: Discordance, defined by median cut points, between TC/HDL-C vs. LDL-C, non-HDL-C and apoB was sizeable at 26, 20 and 27%, respectively. Lower (< median) on-treatment TC/HDL-C associated with PAV regression (ΔPAV Conclusion: TC/HDL-C, available at no extra cost, correlates significantly with coronary atheroma progression rates when discordant with other lipid-metabolic parameters and in clinical scenarios such as diabetes, obesity and in patients receiving HIST. Future studies are needed to determine the implications of applying TC/HDL-C for reducing residual risk

There is much current interest in the potential of cholesteryl ester transfer protein (CETP) inhibition as a strategy to reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). There is also great uncertainty. On the one hand, there is a large body of circumstantial evidence suggesting that inhibition of CETP is antiatherogenic and will protect against the development of ASCVD. On the other hand, 2 human clinical outcome trials with CETP inhibitors have failed. However, as outlined below, because of major problems with these 2 human clinical trials, the hypothesis has not been refuted and it remains unknown whether or not CETP inhibition reduces ASCVD risk. This is something we really need to know. The answer will emerge with the results of 2 large ongoing clinical outcome trials designed to test the hypothesis that CETP inhibition reduces ASCVD risk. Response by Hovingh et al on p 432 There is a possibility that the current level of uncertainty about CETP inhibition may impact adversely on the retention of participants in these ongoing clinical trials and thus reduce their power to provide an answer. We believe that everything possible must be done to ensure that the ongoing clinical outcome trials are allowed to proceed to completion with minimal dropout to provide confidence in the result. The purpose of this article is to summarize the large body of evidence showing that CETP inhibition is protective and that continuation of the ongoing trials to completion is essential. To present this evidence, this article addresses a series of fundamental questions. 1. What exactly is the function of CETP? 2. What is the rationale for inhibiting CETP as a strategy to reduce ASCVD risk? 3. What is the relationship between CETP and atherosclerosis in animal studies? 4. What is the relationship between the genetics and activity of CETP and atherosclerosis …

Background— HDLs have antiinflammatory and antioxidant properties in vitro. This study investigates these properties in vivo. Methods and Results— Chow-fed, normocholesterolemic New Zealand White rabbits received a daily infusion of (1) saline, (2) reconstituted HDL (rHDL) containing 25 mg apolipoprotein (apo) A-I and 50 mg of either 1-palmitoyl-2-linoleoyl phosphatidylcholine (PLPC) or 1,2-dipalmitoyl phosphatidylcholine (DPPC), (3) 25 mg lipid-free apoA-I, or (4) 50 mg of either PLPC-small unilamellar vesicles (SUVs) or DPPC-SUVs on each of 3 consecutive days. Nonocclusive carotid periarterial collars were implanted after the second dose of treatment. Forty-eight hours after insertion of the collars, the arteries were removed and analyzed for the presence of reactive oxygen species, the infiltration of neutrophils, and the expression of adhesion proteins and chemokines. Insertion of the periarterial collar induced a 4.1-fold increase in presence of vascular wall reactive oxygen species. This effect was completely abolished in the animals infused with rHDL. The periarterial collar was associated with a dense infiltration of the arterial wall by polymorphonuclear leukocytes. This infiltration was inhibited by 73% to 94% in the animals infused with rHDL, by 75% in the animals infused with lipid-free apoA-I, and by 51% to 65% in animals infused with SUVs. There were no significant differences between the effects of PLPC and DPPC in either the rHDL or SUVs. Endothelial expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 was also increased by the collar insertion and inhibited by rHDL, lipid-free apoA-I, and, to a lesser extent, also by the SUVs. Conclusions— Infusion of rHDL, apoA-I, and phospholipid-SUVs inhibits the early pro-oxidant and proinflammatory changes induced by a periarterial collar in normocholesterolemic rabbits.

Backgrounds: Cerebrovascular accidents (CVAs) are a major complication of transcatheter aortic valve implantation (TAVI). Proposed mechanisms include atheroembolization of debris during balloon aortic valvuloplasty, deployment of the device or catheter passage through the aorta. The relationship between aortic atheroma burden and acute CVAs after TAVI has not been established. Methods: Preoperative multislice computed tomographic (MSCT) images in 218 patients treated with TAVI were analyzed. Vessel and lumen areas in each 1-mm cross-sectional image from ascending to abdominal aorta were measured. Total atheroma volume (TAV) was calculated and compared in patients with (n=18) and without (n=200) acute CVAs. Results: Patients with acute CVAs were more likely to have a history of cerebrovascular disease (61 v. 14%, p10.2 cm3 and in the arch >2.8 cm3 as the optimal cutoff for predicting acute CVAs. The incidence of acute CVA was highest (66%) if patients had a history of cerebrovascular disease and TAV in the ascending aorta and arch above these cutoff values (Figure). Conclusions: Patients with acute CVAs after TAVI harbored greater atheroma burden in the ascending aorta and aortic arch. Our finding might underscore preoperative MSCT analysis of aorta atheroma burden to identify high-risk patients for acute CVAs, who may benefit from embolic protection devices during TAVI procedure.

Objectives: The CETP inhibitor evacetrapib (EVA) has been shown to substantially increase HDL-C and apoA-I levels as monotherapy and combined with statins. The effects of EVA on cholesterol efflux capacity and HDL particle distribution have not been described and were evaluated in this study. Methods: Samples from patients (n=398) with elevated LDL-C or low HDL-C enrolled in the multicenter, randomized, double-blind, parallel, placebo-controlled trial (JAMA 2011;306:2099-2109, NCT01105975) were studied. Percent changes from baseline in cholesterol efflux capacity (global, ABCA1- and non-ABCA1-mediated), preβ HDL (measured by immunofixation and 2D-gel), and other HDL subclasses (measured by 2D-gel and NMR) were evaluated after 12 weeks of placebo (PBO), statins alone, EVA alone, and EVA with statins. Results: Results are shown in the table. Statins alone decreased global and ABCA1-mediated cholesterol efflux and preβ-1 HDL (by 2D-gel). EVA alone and combined with statins increased global (28% and 21%, respectively), ABCA1- (17% and 15%, respectively), and non-ABCA1-mediated (35% and 27%, respectively) cholesterol efflux. EVA alone increased preβ-1 as measured by 2D-gel (20%) and immunofixation (32%); EVA combined with statins increased preβ-1 as measured by 2D-gel (27%). While statins alone had no significant effect on large and very large HDL (α-1 and α-2 HDL by 2D-gel, and large HDL by NMR), EVA alone and combined with statins increased these more buoyant HDL particles. Statins alone and EVA alone had no effect on small HDL, whereas EVA combined with statins significantly decreased small HDL particles as measured by NMR. Conclusion: In subjects with elevated LDL-C or low HDL-C, EVA alone and combined with statins increased global, ABCA1- and non-ABCA1-mediated cholesterol efflux. This improved global cholesterol efflux capacity was accompanied by a significant increase in preβ-1 and large and very large HDL particles.

Background— Despite favorable effects on high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, the cholesteryl ester transfer protein inhibitor torcetrapib failed to slow atherosclerosis progression and increased mortality. We investigated the relationship between lipid changes and progression of coronary atherosclerosis. Methods and Results— Intravascular ultrasound was performed at baseline and follow-up in 910 participants randomized to torcetrapib/atorvastatin or atorvastatin monotherapy. The relationship between changes in lipoprotein levels and the primary intravascular ultrasound end point, change in percent atheroma volume, was investigated. Compared with atorvastatin monotherapy, torcetrapib raised HDL-C by 61%, lowered low-density lipoprotein cholesterol by 20%, raised serum sodium (0.44±0.14 mmol/L, P =0.02), and lowered serum potassium (0.11±0.02 mmol/L, P r =−0.17, P P =0.002). Compared with the lowest quartile, torcetrapib-treated patients in the highest quartile of HDL-C change showed the least progression (−0.31±0.27 versus 0.88±0.27%, P =0.001). The highest on-treatment HDL-C quartile showed significant regression of percent atheroma volume (−0.69±0.27%, P =0.01). In multivariable analysis, changes in HDL-C levels independently predicted the effect on atherosclerosis progression ( P =0.001). Conclusions— The majority of torcetrapib-treated patients demonstrated no regression of coronary atherosclerosis. Regression was only observed at the highest HDL-C levels. Torcetrapib raised serum sodium and lowered potassium, consistent with an aldosterone-like effect, which may explain the lack of favorable effects in the full study cohort. Accordingly, other cholesteryl ester transfer protein inhibitors, if they lack this off-target toxicity, may successfully slow atherosclerosis progression.

We thank Dr Kaneda and Drs Sutton, Blumenthal, and Kapur for their interest and commentaries on our analysis.1 In response to Dr Kaneda’s request for sensitivity analyses, we applied the same conservative assumptions employed in the intravascular ultrasound (IVUS) analysis2 to all noncompleters and to those with ischemic events and found that statistically significant regression occurred in both percentage diameter stenosis (%DS) and minimum lumen diameter. With regard to the assessment of disease progression, as in previous quantitative coronary angiography (QCA) studies that we referenced,3 the prespecified outcome variable was the change in baseline stenoses >25%. This is very reasonable because some studies have shown that only progression of stenoses present at baseline was predictive of coronary events.4 In A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden (ASTEROID), 379 of the 507 randomized patients (75%) had both a baseline and a follow-up QCA study. Sixteen of these patients (4.2%) developed a new lesion of >25% stenosis that represented an increase of at least 20% from baseline. Of those 379 patients, the 292 (77%) with baseline …

Racial and ethnic subgroups are frequently under-represented in clinical trials of statin therapy. Apolipoprotein (Apo) B provides a measure of atherogenic particles in blood, a predictor for coronary heart disease (CHD) events. Reducing LDL-C to current goals may still leave an excess of atherogenic lipoproteins. A study of predominantly Caucasian high-risk patients suggested that statin therapy may alter the relationship between Apo B and commonly measured lipoproteins. Therapeutic responses in non-Caucasians have not been well studied. This study sought to examine the effect of racial and ethnic backgrounds on these relationships. A pooled analysis of data obtained in the rosuvastatin clinical development program was used to identify 12,269 high CHD risk patients of varying race/ethnic descent (Caucasian, African, Asian, and Hispanic Latino). The relationships between Apo B and both LDL-C and non-HDL-C were compared at baseline and after therapy with rosuvastatin, atorvastatin, or simvastatin. At baseline, an Apo B of 90 mg/dL corresponded to an LDL-C of 114.4 mg/dL for blacks and ~109 mg/dL for Asians and Hispanics (Table ). On statin therapy, to reach an Apo B of 90 mg/dL, blacks required an LDL-C of 87.2 mg/dL, while Hispanics required an LDL-C of 78.3 mg/dL. The baseline non-HDL-C that corresponded to an Apo B of 90 mg/dL was highest for Caucasians and lowest for Asians, with almost no differences observed among the ethnic groups on statin therapy. To achieve the Apo B target of 90 mg/dL, statin therapy required 20 –30 mg/dL lower targets for both LDL-C and non-HDL-C. The strong correlation between Apo B and non-HDL-C on statin therapy (R 2 =0.88 to 0.92) suggests that non-HDL-C may be a useful surrogate for Apo B in all high-risk patients. For all race/ethnic groups, in order to achieve an Apo B target of 90 mg/dL with statin therapy, LDL-C and non-HDL-C targets need to be closer to those currently recommended for very high CHD risk.

Reducing LDL-C to current goals may still leave an excess of atherogenic lipoproteins as reflected in apolipoprotein (Apo) B levels. Apo B provides a measure of atherogenic particles in blood, a predictor of CHD events. Patients with diabetes mellitus (DM) are at increased CHD risk and warrant intensive therapy. Recent joint ADA and ACCF guidelines recommend reducing Apo B to ). Achieving Apo B of 90 mg/dL or 80 mg/dL required much more aggressive LDL-C and non-HDL-C goals on statin therapy. Of note, this effect and resultant targets were very similar in DM and non-DM. Achieving with statin therapy Apo B of 90 mg/dL in high-risk patients requires LDL-C target of ~80 mg/dL and non-HDL-C target of ~108 mg/dL. The on-therapy LDL-C target (2 =0.77– 0.81) and very well with non-HDL-C (R 2 =0.88 – 0.90). Non-HDL-C may be a useful surrogate for direct Apo B measurement. High-risk DM and non-DM patients require lower LDL-C and non-HDL-C targets during statin therapy in order to reduce Apo B to the recommended level.

We thank Drs Stuehlinger, Metzler, and Cooke for their interest and comments on our study. We agree that the mechanism(s) promoting increased systemic levels of asymmetric dimethylarginine (ADMA) in the setting of acute myocardial infarction complicated by cardiogenic shock may be multifactorial and remains to be fully elucidated. We agree that ADMA may be elevated as a consequence of myocardial ischemia or reperfusion and that ADMA may play a role in the pathogenesis of …

Background— It is unclear whether abnormalities of arginine and nitric oxide metabolism are related to hemodynamic dysfunction and mortality in patients with cardiogenic shock (CS) after acute myocardial infarction. Methods and Results— Plasma metabolites reflecting arginine bioavailability, nitric oxide metabolism, and protein oxidation were analyzed by mass spectrometry in patients with CS (n=79) and age- and gender-matched patients with coronary artery disease and normal left ventricular function (n=79). CS patients had higher levels of asymmetric dimethylarginine (ADMA; P P P =0.0003), nitrotyrosine ( P P P P =0.03), and ratio of arginine to ornithine plus citrulline) ( P =0.0003). CS patients with elevated ADMA levels were 3.5-fold (95% confidence interval, 1.4 to 11.3; P =0.02) more likely to die in 30 days than patients with low ADMA levels. ADMA remained the only independent predictor of mortality on multiple logistic regression analysis. In patients with normal renal function, symmetric dimethylarginine levels inversely correlated with mean arterial pressure and systemic vascular resistance, whereas levels of ADMA correlated with pulmonary capillary wedge pressure and both systolic and diastolic pulmonary artery pressures. Despite dramatic elevations, levels of protein oxidation products did not predict hemodynamic dysfunction or mortality in CS patients. Conclusions— CS is characterized by an arginine-deficient and highly specific pro-oxidant state, with elevated levels of methylated arginine derivatives, including endogenous nitric oxide synthase inhibitors. Levels of methylated arginine derivatives strongly correlate with hemodynamic dysfunction. Among all clinical and laboratory parameters monitored, ADMA levels were the strongest independent predictor of 30-day mortality.

Background: While the importance of coronary artery disease in females has become increasingly recognized, little is known regarding the impact of gender with regard to changes in arterial wall dimensions with progression and regression of atherosclerosis. This study investigated the remodeling response of the artery wall accompanying changes in atheroma burden in response to use of medical therapies, stratified according to gender. Methods: 1533 patients (27.5% female) underwent serial intravascular ultrasound evaluation of a single coronary artery in the context of clinical trials that assess the impact of medical therapies on plaque progression. The relationship between gender and remodeling of the arterial wall at baseline and its serial change in association with plaque progression and regression were studied. Results: Females were older (59 v 57 years, p2 , p3 , p=0.09) and larger lumen (143.7 v 137.7 mm 3 , p=0.01) volumes. The remodeling index at the most diseased site did not differ between genders (0.95 v 0.95, p=0.95). No differences were observed between genders with regard to changes in EEM (−5.6 v −6.2 mm 3 , p=0.29) and lumen (−4.9 v −4.5 mm 3 , p=0.82) volumes and remodeling index (−0.02 v −0.03, p=0.43) in response to use of medical therapies. Similarly, there were no differences between genders with regard to the percentage of patients undergoing expansion (34.7 v 35.5%, p=0.86) or contraction (20.4 v 21.8%, p=0.69) of lumen volume in association with regression of atherosclerotic plaque. Conclusion: A similar pattern of remodeling of the arterial wall was observed between genders in association with serial changes in atheroscle-rotic plaque. This further highlights our understanding of the pathological interactions between atherosclerosis and the arterial wall in females.

Background: Administration of the CETP inhibitor torcetrapib does not slow the rate of progression of coronary atherosclerosis. The reason for the lack of therapeutic efficacy remains unknown. This analysis investigated the relationship between changes in HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) and atheroma volume in patients treated with torcetrapib. Methods: 910 patients with angiographic coronary artery disease underwent IVUS imaging within a single coronary artery before and during 24 months of treatment with torcetrapib (n = 464) or placebo (n = 446) on a background of atorvastatin therapy. The relationship between changes in levels of HDL-C and LDL-C and both percent atheroma volume (PAV) and total atheroma volume (TAV) was evaluated in patients treated with torcetrapib. Results: Administration of torcetrapib raised HDL-C by 61% and lowered LDL-C by 20% when compared to atorvastatin alone. An inverse relationship was observed between changes in HDL-C and both PAV (r = −0.17, p < 0.001) and TAV (r = −0.17, p < 0.001). Patients with the highest level of HDL-C (> 87 mg/dL) had the lowest rate of progression of PAV (−0.7 v +0.7%, p = 0.0003) and TAV (−9.2 v −4.6 mm 3 , p = 0.09). The greatest elevation in level of HDL-C (> 80%) was associated with the lowest progression of PAV (−0.3 v +0.9%, p = 0.002) and TAV (−12.6 v −3.4 mm 3 , p = 0.0006). Patients undergoing regression (any reduction in PAV) had greater absolute levels (73 v 66 mg/dL, p = 0.02) and changes (59.5 v 48.3%, p = 0.02) of HDL-C. No difference in the impact of torcetrapib on changes in PAV (+0.3 v +0.1%, p = 0.34) and TAV (−9.1 v −9.3 mm 3 , p = 0.95) was observed in patients with baseline levels below or above 40 mg/dL. No relationship was observed between changes in LDL-C and either PAV (r = 0.06, p = 0.20) or TAV (r = 0.07, p = 0.12) in torcetrapib treated patients. On multivariate analysis, changes in levels of HDL-C independently predicted the impact of torcetrapib on progression of PAV (p = 0.007) and TAV (p = 0.004). Conclusion: Increasing levels of HDL-C from torcetrapib treatment were associated with a beneficial impact of torcetrapib on plaque progression. This is consistent with the generation of functional HDL particles and suggests other effects to be responsible for the lack of benefit of torcetrapib.

Background: Atherogenic dyslipidemia (AD) is characterized by the combination of elevated serum triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and small-dense low-density lipoprotein cholesterol (LDL-C) and has emerged as a powerful risk factor of coronary disease. The effect of AD on the progression of plaque burden remains incompletely defined. This analysis aimed to determine the impact of AD on measures of atherosclerotic progression in patients receiving intensive lipid lowering therapy. Methods: 910 patients with angiographic coronary artery disease treated with atorvastatin to a goal LDL-C of 100 ± 15mg/dl received torcetrapib or placebo. Atheroma burden was determined by intravascular ultrasound performed at baseline and following 24 months of treatment. Baseline and changes in atheroma burden were investigated in patients stratified according to the presence or absence of an AD phenotype (HDL-C < 45 mg/dL for men and < 50mg/dL for women, triglycerides 150 – 600mg/dL and LDL-C < 160mg/dL) Results: 20.4% of patients met the criteria for AD. Patients with AD were younger (55.5 v 58 years, p=0.003), had higher body mass index (30.9 v 29.3 kg/m2, p5%, 12.9% v 24.2%, p=0.001) and more likely to undergo substantial progression (increase in PAV >5%, 34.9% v 23.2%, p=0.001) No differences were observed between treatment groups with regard to changes in PAV (0.59 v 0.99%, p=0.727) or TAV (−5.7 v −3.8 mm3, p=0.461) in patients with AD. On multivariate analysis, the presence of atherogenic dyslipidemia was an independent predictor of increase in PAV (p=0.004) and TAV (p=0.045). Conclusions: Despite aggressive lipid lowering therapy, AD is an independent predictor of accelerated progression of atherosclerosis. With a rise in the prevalence of obesity and its metabolic complications there is an increasing need to intensively modify factors that place these patients at high risk.

Background : The development of cardiac allograft vasculopathy (CAV) portends an adverse clinical outcome in heart transplant recipients. Previous studies of clinical predictors of CAV have investigated small cohorts and have not evaluated the volumetric extent of disease. This study determined predictors of progression of the volumetric severity of vasculopathy in a large cohort of heart transplant recipients. Methods : Serial intravascular ultrasound examinations were performed in 119 heart transplant recipients at 1 month and 1 year following transplantation. Clinical predictors of serial changes in atheroma volume were determined. In particular, the impact of donor and recipient age stratified according to the median was investigated. Results : Patients ( donor age 33.3 ± 14.2 years, recipient age 54.5 ± 12.6 years, 71.9 % male) demonstrated an increase in atheroma volume (64.2 ± 41.7 mm 3 at 1 month vs. 78.1 ± 53.4 mm 3 at 1 year, p < 0.001) and a decrease in lumen volume (334.2 ± 197.3 mm 3 at 1 month vs. 321.6 ± 187.8 mm 3 at 1 year, p = 0.001). Greater increases in atheroma volume were observed in the setting of older donor age (r = 0.24, p = 0.008), older recipient age (r = 0.23, p = 0.01) and recipients not treated with an angiotensin-converting enzyme (ACE) inhibitor (without ACE inhibitor, 21.1 ± 33.3 mm 3 vs. with ACE inhibitor, 9.1 ± 27.6 mm 3 , p = 0.03). In multivariate analysis, donor age ( p = 0.01) and the lack of treatment with an ACE inhibitor ( p = 0.02) remained independent predictors of increases in atheroma volume. Increased disease progression with age was attenuated with the use of ACE inhibitors (table ). Conclusion : Donor age and ACE inhibitor treatment are major determinants of CAV progression. This analysis suggests that treatment with ACE inhibitors would attenuate age-related progression of CAV. Large randomized clinical trials are warranted to ascertain such a beneficial effect.

Case presentation: A 38-year-old man underwent angiography 2 weeks after a non–ST-segment myocardial infarction. He was overweight and prehypertensive, with a blood pressure of 134/86 mm Hg. His biochemical parameters included low-density lipoprotein cholesterol (LDL-C) 127 mg/dL, high-density lipoprotein cholesterol (HDL-C) 38 mg/dL, and C-reactive protein (CRP) 3.2 mg/L. Angiography revealed mild disease throughout the coronary arteries and a hazy appearance that involved the proximal left anterior descending coronary artery. Intravascular ultrasound (IVUS) imaging revealed diffuse and extensive atherosclerosis with evidence of plaque rupture at multiple sites (Figure 1). In the presence of no significant luminal stenoses, the patient was treated medically with aspirin and low-dose statin therapy. Figure 1. Illustrative example of coronary angiography of the left anterior descending artery that appears to be free of irregularities, apart from a hazy appearance in the proximal segment. A representative cross-sectional tomographic image obtained by IVUS examination (top right) within the proximal segment (white arrow on angiogram) revealed substantial atheroma within the arterial wall. The bottom right segment illustrates a tomographic image of atheroma containing significant ulceration (5 o’clock) at the site of the gold arrow on the angiogram. The application of IVUS in this case highlights a number of important points with regard to the natural history of atherosclerosis and its modification by use of established medical therapies. The ability to image the entire arterial wall represents a significant advantage over coronary angiography. In the presence of minimal luminal stenoses, IVUS imaging in patients with coronary symptoms typically reveals extensive and diffuse atherosclerosis.1 Application of serial IVUS imaging in prospective clinical trials has enabled a greater understanding of the impact of antiatherosclerotic interventions on patients with established coronary artery disease (CAD). Ultrasonic coronary imaging has revealed essential details about the natural history of atherosclerosis. Atheroma formation begins at a …

Background— Coronary plaque progression and instability are associated with expansive remodeling of the arterial wall. However, the remodeling response during plaque-stabilizing therapy and its relationship to markers of lipid metabolism and inflammation are incompletely understood. Methods and Results— Serial intravascular ultrasound (IVUS) data from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial were obtained during 18 months of intensive versus moderate lipid-lowering therapy. In a subgroup of 210 patients, focal coronary lesions with mild luminal narrowing were identified. Lumen area, external elastic membrane (EEM) area, and plaque area were determined at the lesion and proximal reference sites at baseline and during follow-up. The remodeling ratio (RR) was calculated by dividing the lesion EEM area by the reference EEM area. The relationship between the change in remodeling, change in plaque area, lipid profile, and inflammatory markers was examined. At the lesion site, a progression in plaque area (8.9±25.7%) and a decrease in the RR (−3.0±11.2%) occurred during follow-up. In multivariable analyses, the percentage change in plaque area ( P P P =0.027), and hypertension at baseline ( P =0.014) showed a significant, direct relation with the RR at follow-up. Lesion location in the right coronary artery ( P =0.006), percentage change in triglyceride levels ( P =0.049), and age ( P =0.037) demonstrated a significant, inverse relation with the RR at follow-up. Changes in LDL cholesterol, HDL cholesterol, and treatment group demonstrated no significant associations. Conclusions— Constrictive remodeling of the arterial wall was observed during plaque-stabilizing therapy with statin medications and appears related to their antiinflammatory effects.

Over the course of the past century, increasing evidence has accumulated to implicate a central role for atherogenic lipoproteins in the pathogenesis of atherosclerotic cardiovascular disease. This is supported by the importance of cholesterol measurement for risk prediction and the use of lipid-modifying therapies in primary and secondary prevention. Recent reports have suggested that particle-based measurements of atherogenic lipoproteins may provide additional information in risk stratification.1 In particular, persistently elevated measures of low-density lipoprotein (LDL) particles in patients whose LDL cholesterol appears optimally controlled may identify individuals more likely to benefit from more intensive lipid lowering. Article see p 1189 In parallel, there has been considerable interest in the potential protective properties of high-density lipoproteins (HDL) for the development of new risk-prediction markers and cardiovascular therapeutics. This is based on observations from large population cohorts of an inverse relationship between HDL cholesterol (HDL-C) levels and prospective risk of cardiovascular events2 and of favorable effects with HDL-targeted interventions in animal models of atherosclerosis.3 Although HDL-C is used in traditional risk stratification, and raising HDL-C levels may contribute to the clinical …