BackgroundCSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.Methods and ResultsPatients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug–related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (Tmax≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001).ConclusionsCSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation.Clinical Trial RegistrationURL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

Restoration of functional endothelium is a requirement for preventing late stent thrombosis. We propose a novel method for targeted delivery of stem cells to a site of arterial injury using ultrasound-generated acoustic radiation force. Mesenchymal stem cells (MSCs) were surface-coated electrostatically with cationic gas-filled lipid microbubbles (mb-MSC). mb-MSC was characterized microscopically and by flow cytometry. The effect of ultrasound (5 MHz) on directing mb-MSC movement toward the vessel wall under physiologic flow conditions was tested in vitro in a vessel phantom. In vivo testing of acoustic radiation force-mediated delivery of mb-MSCs to ballooninjured aorta was performed in rabbits using intravascular ultrasound (1.7 MHz) during intra-aortic infusion of mb-MSCs. Application of ultrasound led to marginalization and adhesion of mb-MSCs to the vessel phantom wall, whereas no effect was observed on mb-MSCs in the absence of ultrasound. The effect was maximal when there were 7 -1 microbubbles/cell (n = 6). In rabbits (n = 6), adherent MSCs were observed in the ultrasound-treated aortic segment 20 min after the injection (334 -137 MSCs/cm 2 ), whereas minimal adhesion was observed in control segments not exposed to ultrasound (2 -1 MSCs/cm 2 , p < 0.05). At 24 h after mb-MSC injection and ultrasound treatment, the engrafted MSCs persisted and spread out on the luminal surface of the artery. The data demonstrate proof of principle that acoustic radiation force can target delivery of therapeutic cells to a specific endovascular treatment site. This approach may be used for endoluminal cellular paving and could provide a powerful tool for cell-based re-endothelialization of injured arterial segments.

Plaque composition is a potentially important diagnostic feature for carotid artery stenting (CAS). The purpose of this investigation is to evaluate the reproducibility of manual border correction in intravascular ultrasound with virtual histology (VH IVUS) images. Three images each were obtained from 51 CAS datasets on which automatic border detection was corrected manually by two trained observers. Plaque was classified using the definitions from the CAPITAL (Carotid Artery Plaque Virtual Histology Evaluation) study, listed in order from least to most pathological: no plaque, pathological intimal thickening, fibroatheroma, fibrocalcific, calcified fibroatheroma, thin-cap fibroatheroma, and calcified thin-cap fibroatheroma. Inter-observer variability was quantified using both weighted and unweighted Kappa statistics. Bland-Altman analysis was used to compare the cross-sectional areas of the vessel and lumen. Agreement using necrotic core percentage as the criterion was evaluated using the unweighted Kappa statistic. Agreement between classifications of plaque type was evaluated using the weighted Kappa statistic. There was substantial agreement between the observers based on necrotic core percentage (κ = 0.63), while the agreement was moderate (κquadratic = 0.60) based on plaque classification. Due to the time-consuming nature of manual border detection, an improved automatic border detection algorithm is necessary for using VH IVUS as a diagnostic tool for assessing the suitability of patients with carotid artery occlusive disease for CAS.

The terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay identifies apoptosis and is used in transplant pathology to detect cardiac allograft rejection. We illustrate the use of TUNEL in identifying segments of ablated ventricular myocardium, and discuss its advantages over conventional histopathological stains. The TUNEL assay can be useful to investigators of catheter ablation therapy.

A 65-year-old man with a permanent pacemaker placed for atrioventricular block presented to the emergency department with 4 days of fever, gastrointestinal complaints, and back pain. On presentation, he was febrile, tachycardic, and hypotensive, with a significant leukocytosis. Urine and blood cultures grew methicillin-sensitive staphylococcus aureus in 6/6 bottles. The patient was initiated on appropriate antibiotic coverage, including nafcillin, resulting in sterilization of blood cultures. Transesophageal echocardiography revealed a vegetation on the pacing wire, likely involving the tricuspid valve, necessitating removal of the pacing lead (online-only Data Supplement Movies I and II). Four weeks into his antibiotic course, continued fevers along with a new holosystolic murmur at the apex of his heart prompted repeat echocardiography, which revealed a persistent mobile echodensity on the tricuspid valve and a new mobile echodensity on the mitral valve, as well, associated with severe mitral regurgitation (online-only Data Supplement Movie III). The patient was considered for valve replacement surgery, and preoperative coronary angiography was performed. Figure 1A shows multiple mycotic aneurysms (arrows) in coronary vessels that were not present 4 months earlier ( Figure 1B). Based on the involvement of multiple epicardial vessels, and in light of the patient's clinical status (which included difficult-to-control gastrointestinal bleeding and renal insufficiency), a decision was made to treat the patient conservatively with antibiotics. The patient defervesced, remained hemodynamically stable, and finished a 12-week course of nafcillin.Despite aggressive medical management of his valvular disease, he presented to the clinic 6 months later with shortness of breath, cyanosis, ascites, and lower-extremity edema. Repeat transesophageal echocardiography revealed severe mitral regurgitation (online-only Data Supplement Movie IV) and moderate tricuspid regurgitation. He was admitted for medical optimization of his congestive heart failure before cardiac surgery. Regadenoson positron emission tomography myocardial perfusion imaging revealed a large area of ischemia in the left anterior descending and circumflex artery distributions (Figure 2). Repeat cardiac catheterization revealed enlargement and septation of the aneurysms (Figure 3). He underwent mitral valve repair with chordoplasty to A1 and A2 and coronary artery bypass grafting with left internal mammary artery to the left anterior descending artery, saphenous vein graft to the obtuse marginal artery, and saphenous vein graft to the posterior descending artery and left posterior left ventricular branch. His postoperative course was uncomplicated, his breathing improved, and repeat transthoracic echocardiography showed only mild mitral regurgitation (online-only Data Supplement