Jordan Andrews

Near-Infrared Spectroscopy Enhances Intravascular Ultrasound Assessment of Vulnerable Coronary Plaque A Combined Pathological and In Vivo Study

Objectives—Pathological studies demonstrate the dual significance of plaque burden (PB) and lipid composition for mediating coronary plaque vulnerability. We evaluated relationships between intravascular ultrasound (IVUS)–derived PB and arterial remodeling with near-infrared spectroscopy (NIRS)–derived lipid content in ex vivo and in vivo human coronary arteries. Approach and Results—Ex vivo coronary NIRS and IVUS imaging was performed through blood in 116 coronary arteries of 51 autopsied hearts, followed by 2-mm block sectioning (n=2070) and histological grading according to modified American Heart Association criteria. Lesions were defined as the most heavily diseased 2-mm block per imaged artery on IVUS. IVUS-derived PB and NIRS-derived lipid core burden index (LCBI) of each block and lesion were analyzed. Block-level analysis demonstrated significant trends of increasing PB and LCBI across more complex atheroma (Ptrend <0.001 for both LCBI and PB). Lesion-based analyses demonstrated the highest LCBI and remodeling index within coronary fibroatheroma (Ptrend <0.001 and 0.02 versus all plaque groups, respectively). Prediction models demonstrated similar abilities of PB, LCBI, and remodeling index for discriminating fibroatheroma (c indices: 0.675, 0.712, and 0.672, respectively). A combined PB+LCBI analysis significantly improved fibroatheroma detection accuracy (c index 0.77, P=0.028 versus PB; net-reclassification index 43%, P=0.003), whereas further adding remodeling index did not (c index 0.80, P=0.27 versus PB+LCBI). In vivo comparisons of 43 age- and sex-matched patients (to the autopsy cohort) undergoing combined NIRS-IVUS coronary imaging yielded similar associations to those demonstrated ex vivo. Conclusions—Adding NIRS to conventional IVUS-derived PB imaging significantly improves the ability to detect more active, potentially vulnerable coronary atheroma.

Effect of serial infusions of reconstituted high-density lipoprotein (CER-001) on coronary atherosclerosis: Rationale and design of the CARAT study

BACKGROUND High-density lipoprotein (HDL) is believed to have atheroprotective properties, but an effective HDL-based therapy remains elusive. Early studies have suggested that infusion of reconstituted HDL promotes reverse cholesterol transport and vascular reactivity. The CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) is investigating the impact of infusing an engineered pre-beta HDL mimetic containing sphingomyelin (SM) and dipalmitoyl phosphatidlyglycerol (CER-001) on coronary atheroma volume in patients with a recent acute coronary syndrome (ACS). METHODS The CARAT is a phase 2, multicenter trial in which 292 patients with an ACS undergoing intracoronary ultrasonography and showing percent atheroma volume (PAV) greater than 30% are randomly assigned to treatment with ten infusions of CER-001 3 mg/kg or matching placebo, administered at weekly intervals. Intracoronary ultrasonography is repeated at the end of the treatment period. RESULTS The primary endpoint is the nominal change in PAV. Safety and tolerability will also be evaluated. CONCLUSIONS CARAT will establish whether serial 3 mg/kg infusions of an engineered pre-beta HDL mimetic containing SM and dipalmitoyl phosphatidlyglycerol (CER-001) will regress atherosclerotic plaque in patients with a recent ACS.

Confirmation of the Intracoronary Near-Infrared Spectroscopy Threshold of Lipid-Rich Plaques That Underlie ST-Segment–Elevation Myocardial Infarction

Objective—In a previous exploratory analysis, intracoronary near-infrared spectroscopy (NIRS) found the majority of culprit lesions in ST-segment–elevation myocardial infarction (STEMI) to contain a maximum lipid core burden index in 4 mm (maxLCBI4mm) of >400. This initial study was limited by a small sample size, enrollment at a single center, and post hoc selection of the maxLCBI4mm ≥400 threshold. This study was designed a priori to substantiate the ability of NIRS to discriminate STEMI culprit from nonculprit segments and to confirm the performance of the maxLCBI4mm ≥400 threshold. Approach and Results—At 2 centers in the United States and Sweden, 75 STEMI patients underwent intracoronary NIRS imaging after establishing thrombolysis in myocardial infarction 3 flow, but before stenting. Blinded core laboratory analysis defined the culprit segment as the 10-mm segment distal to the proximal angiographic culprit margin. The remaining vessel was divided into contiguous 10-mm nonculprit segments. The maxLCBI4mm of culprit segments (median [interquartile range]: 543 [273–756]) was 4.4-fold greater than nonculprit segments (median [interquartile range]: 123 [0–307]; P<0.001). Receiver-operating characteristic analysis demonstrated that maxLCBI4mm differentiated culprit from nonculprit segments with high accuracy (c-statistic=0.83; P<0.001). A threshold maxLCBI4mm ≥400 identified STEMI culprit segments with a sensitivity of 64% and specificity of 85%. Conclusions—This study substantiates the ability of NIRS to accurately differentiate STEMI culprit from nonculprit segments and confirms that a threshold maxLCBI4mm ≥400 is detected by NIRS in the majority of STEMI culprits.

Near-Infrared Spectroscopy Enhances Intravascular Ultrasound Assessment of Vulnerable Coronary Plaque

Objectives—Pathological studies demonstrate the dual significance of plaque burden (PB) and lipid composition for mediating coronary plaque vulnerability. We evaluated relationships between intravascular ultrasound (IVUS)–derived PB and arterial remodeling with near-infrared spectroscopy (NIRS)–derived lipid content in ex vivo and in vivo human coronary arteries. Approach and Results—Ex vivo coronary NIRS and IVUS imaging was performed through blood in 116 coronary arteries of 51 autopsied hearts, followed by 2-mm block sectioning (n=2070) and histological grading according to modified American Heart Association criteria. Lesions were defined as the most heavily diseased 2-mm block per imaged artery on IVUS. IVUS-derived PB and NIRS-derived lipid core burden index (LCBI) of each block and lesion were analyzed. Block-level analysis demonstrated significant trends of increasing PB and LCBI across more complex atheroma (Ptrend <0.001 for both LCBI and PB). Lesion-based analyses demonstrated the highest LCBI and remodeling index within coronary fibroatheroma (Ptrend <0.001 and 0.02 versus all plaque groups, respectively). Prediction models demonstrated similar abilities of PB, LCBI, and remodeling index for discriminating fibroatheroma (c indices: 0.675, 0.712, and 0.672, respectively). A combined PB+LCBI analysis significantly improved fibroatheroma detection accuracy (c index 0.77, P=0.028 versus PB; net-reclassification index 43%, P=0.003), whereas further adding remodeling index did not (c index 0.80, P=0.27 versus PB+LCBI). In vivo comparisons of 43 age- and sex-matched patients (to the autopsy cohort) undergoing combined NIRS-IVUS coronary imaging yielded similar associations to those demonstrated ex vivo. Conclusions—Adding NIRS to conventional IVUS-derived PB imaging significantly improves the ability to detect more active, potentially vulnerable coronary atheroma.

Exploring the natural history of atherosclerosis with intravascular ultrasound.

Intravascular ultrasound has emerged as the preferred imaging modality for the characterization of atherosclerotic plaque within the coronary arteries. Ultrasonic imaging reveals the presence of more extensive atheroma than suggested by conventional angiography in patients with coronary artery disease. The ability to precisely quantify atheroma volume in an arterial segment at different time points provides the unique opportunity to investigate the factors that influence the natural history of atheroma progression. Accordingly, serial intravascular ultrasound has been incorporated into a number of clinical trials that have evaluated the impact of medical therapies that modify established risk factors and novel pathological targets. This article will review the increasing role of imaging modalities in the assessment of atherosclerosis and factors that influence its natural history.

Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden

BACKGROUND CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. METHODS CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. RESULTS A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (-0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (-0.96%±0.34% vs. -0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97). CONCLUSIONS Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy.

Coronary Endothelium-Dependent Vasoreactivity and Atheroma Volume in Subjects With Stable, Minimal Angiographic Disease Versus Non-ST-Segment-Elevation Myocardial Infarction An Intravascular Ultrasound Study

Background— Epicardial plaque burden and endothelial function are recognized predictors of coronary events. We aimed to investigate mechanistic relationships between atheroma volume and endothelial function in patients with non–ST-segment–elevation myocardial infarction (NSTEMI) using intravascular ultrasound. Methods and Results— In coronary vessels of patients with near-normal or minimal angiographic disease (n=23) and NSTEMI (n=24), intravascular ultrasound-derived measures (percent atheroma volume), arterial remodeling index, and segmental lumen volumes were performed in contiguous 5-mm epicardial segments. Repeat intravascular ultrasound imaging was performed after consecutive 5-minute intracoronary infusions (vehicle solution, 0.30 &mgr;g/min and 0.60 &mgr;g/min intracoronary salbutamol) to measure changes in segmental lumen volume (endothelium-dependent function). Male sex, diabetes mellitus, smoking, higher triglycerides, and lower high-density lipoprotein cholesterol were more prevalent in the NSTEMI group. Patients with NSTEMI demonstrated greater segmental percent atheroma volume (40.4±12 versus 27.5±14%, P<0.001), remodeling index (1.2 [1.0–1.5] versus 1.0 [0.9–1.0], P<0.001), and displayed less endothelium-dependent vasomotion (% change segmental lumen volume: 2.1±0.89 versus 5.1±0.89%, P=0.02) compared to patients with minimal angiographic disease. No significant difference in endothelial function between both groups was observed when controlling for plaque burden. Multivariate analysis for change in segmental lumen volume identified percent atheroma volume (&bgr;=−0.18, P=0.0004), high-sensitivity C-reactive protein >2 mg/L (&bgr;=−3.1, P=0.03), diabetes mellitus (&bgr;=−6.9, P<0.0001), low-density lipoprotein cholesterol levels (&bgr;=−0.04, P=0.01), and smoking (&bgr;=–3.2, P=0.01) as independent associates. Conclusions— Although coronary endothelial vasoreactivity is blunted in the setting of NSTEMI, this is a reflection of the greater volume of atherosclerosis and cardiovascular risk factors. Thus, the relationship between coronary endothelium-dependent vasomotor reactivity and atheroma volume remains constant irrespective of the nature of the clinical presentation.

Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial: A Randomized Clinical Trial

Importance CER-001 is a negatively charged, engineered pre-&bgr; high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography. Objective To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. Design, Setting, and Participants A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016. Interventions Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins. Main Outcomes and Measures The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P = .15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P = .66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P = .005 compared with baseline), but not with CER-001 (−0.09%; P = .67 compared with baseline; between group differences, 0.32%; P = .15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P = .49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. Conclusions and Relevance Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden. Trial Registration ClinicalTrials.gov Identifier: NCT2484378

Therapeutic modulation of the natural history of coronary atherosclerosis: lessons learned from serial imaging studies.

Despite advances in risk prediction, preventive and therapeutic strategies, atherosclerotic cardiovascular disease remains a major public health challenge worldwide, carrying considerable morbidity, mortality and health economic burden. There continues to be a need to better understand the natural history of this disease to guide the development of more effective treatment, integral to which is the rapidly evolving field of coronary artery imaging. Various imaging modalities have been refined to enable detailed visualization of the pathological substrate of atherosclerosis, providing accurate and reproducible measures of coronary plaque burden and composition, including the presence of high-risk characteristics. The serial application of such techniques, including coronary computed tomography angiography (CTA), intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have uncovered important insights into the progression of coronary plaque over time in patients with stable and unstable coronary artery disease (CAD), and its responsiveness to therapeutic interventions. Here we review the use of different imaging modalities for the surveillance of coronary atherosclerosis and the lessons they have provided about the modulation of CAD by both traditional and experimental therapies.

Lipid Lowering Therapy to Modify Plaque Microstructures: Insights from Optical Coherence Tomography Imaging

Due to the pandemics of obesity and diabetes mellitus, especially in the Western countries, atherosclerotic cardiovascular disease (ASCVD) has become a major health burden and is expected to increase in the future. Modifying lipid targets, especially low-density lipoprotein cholesterol (LDL-C) level, has become the first-line therapy for primary and secondary prevention of ASCVD. Intravascular imaging modalities have contributed to elucidating clinical efficacy of lipid lowering therapy on atherosclerotic plaques. Optical coherence tomography (OCT) is a high-resolution imaging tool enables visualization of plaque microstructures associated with its instability. This modality has demonstrated favorable changes in plaque microstructures under lowering LDL-C level. In addition, clinical studies using OCT have suggested potential association of other lipid targets, including triglyceride and high-density lipoprotein cholesterol with plaque microstructures. Given continuing cardiovascular risks despite statin therapy, OCT will be an important imaging modality to evaluate novel therapeutic approaches that potentially modulates plaque instability.