Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial.

BACKGROUND: CSL112 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 RESULTS: Patients 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 (T(max)≈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). CONCLUSIONS: CSL112 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 REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

Homozygous factor V Leiden mutation in type IV Ehlers-Danlos patient.

Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders caused by collagen synthesis defects. Several hemostatic abnormalities have been described in EDS patients that increase the bleeding tendencies of these patients. This case report illustrates a patient with an unusual presentation of a patient with type IV EDS, platelet δ-storage pool disease and factor V Leiden mutation. Young woman having previous bilateral deep vein thrombosis and pulmonary emboli coexisting with ruptured splenic aneurysm and multiple other aneurysms now presented with myocardial infarction. Presence of factor V Leiden mutation raises the possibility that the infarct was due to acute coronary thrombosis, although coronary artery aneurysm and dissection with myocardial infarction is known to occur in vascular type EDS. This is the first report in the medical literature of factor V Leiden mutation in an EDS patient which made the management of our patient challenging with propensity to both bleeding and clotting.

Reproducibility of IVUS border detection for carotid atherosclerotic plaque assessment.

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 (κ(quadratic)=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.

Vascular endoluminal delivery of mesenchymal stem cells using acoustic radiation force.

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 balloon-injured 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.

TUNEL assay for identifying ablated myocardium.

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.