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This review will focus specifically on lipoprotein-associated phospholipase A 2 (Lp-PLA 2) and its inhibitor darapladib. Lp-PLA 2 is bound predominantly to apolipoprotein B (apoB)-containing lipoproteins and highly expressed in the necrotic core of atherosclerotic lesions. It rapidly degrades oxidatively modified phospholipids in modified LDL, for example, leading to formation of proinflammatory and cytotoxic products (i.e., lysophosphatidylcholine and oxidized nonesterified fatty acids). In a study conducted in diabetic and hypercholesterolemic swines, selective Lp-PLA 2 inhibitors (i.e., darapladib) reduced the development of advanced coronary atherosclerosis. Specifically, darapladib treatment considerably decreased the area of plaques and the necrotic cores, and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. In the IBIS 2 study conducted in humans, darapladib significantly halted the increase of the necrotic core volume (-0.5 ± 13.9 mm 3; P = 0.71) that was observed in the cohort receiving placebo (4.5 ± 17.9 mm 3; P = 0.009), resulting in a significant treatment difference of -5.2 mm3 (P = 0.012). In conclusion, despite standard-of-care treatment, patients with coronary artery disease continue to have recurrent cardiovascular events. PLA 2 inhibition may represent a new approach for the treatment of atherosclerosis if the benefit of this intervention is confirmed by the results of ongoing event-driven outcome trials. Copyright

No abstract is provided for this article.

Objectives This study sought to evaluate sex differences in procedural characteristics and clinical outcomes of instantaneous wave-free ratio (iFR)– and fractional flow reserve (FFR)–guided revascularization strategies. Background An iFR-guided strategy has shown a lower revascularization rate than an FFR-guided strategy, without differences in clinical outcomes. Methods This is a post hoc analysis of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate stenosis to guide Revascularization) study, in which 601 women and 1,891 men were randomized to iFR- or FFR-guided strategy. The primary endpoint was 1-year major adverse cardiac events (MACE), a composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization. Results Among the entire population, women had a lower number of functionally significant lesions per patient (0.31 ± 0.51 vs. 0.43 ± 0.59; p < 0.001) and less frequently underwent revascularization than men (42.1% vs. 53.1%; p < 0.001). There was no difference in mean iFR value according to sex (0.91 ± 0.09 vs. 0.91 ± 0.10; p = 0.442). However, the mean FFR value was lower in men than in women (0.83 ± 0.09 vs. 0.85 ± 0.10; p = 0.001). In men, an FFR-guided strategy was associated with a higher rate of revascularization than an iFR-guided strategy (57.1% vs. 49.3%; p = 0.001), but this difference was not observed in women (41.4% vs. 42.6%; p = 0.757). There was no difference in MACE rates between iFR- and FFR-guided strategies in both women (5.4% vs. 5.6%, adjusted hazard ratio: 1.10; 95% confidence interval: 0.50 to 2.43; p = 0.805) and men (6.6% vs. 7.0%, adjusted hazard ratio: 0.98; 95% confidence interval: 0.66 to 1.46; p = 0.919). Conclusions An FFR-guided strategy was associated with a higher rate of revascularization than iFR-guided strategy in men, but not in women. However, iFR- and FFR-guided strategies showed comparable clinical outcomes, regardless of sex. (Functional Lesion Assessment of Intermediate Stenosis to guide Revascularization [DEFINE-FLAIR]; NCT02053038)

The patients treated with EES were older, presented more frequently with acute myocardial infarction, and had more complicated lesions than the other groups. The EES group demonstrated a higher incidence of all-cause mortality than the SES group and a lower incidence of TVR than the BMS group. Multivariate adjustment demonstrated that BMS was associated with higher TVR and MACE risk than EES (adjusted hazard ratio [HR] for TVR: 2.02 [95% confidence interval (CI): 1.11 to 3.67]; adjusted HR for MACE: 2.15 [95% CI: 1.36 to 3.42]); that SES had a clinical outcome similar to that of EES, and that PES had a higher risk of MACE than did EES (adjusted HR: 1.57 [95% CI: 1.02 to 2.44]). Conclusions This study suggests that the use of EES in an unselected population may be as safe as and more effective than BMS, may be as safe and effective as SES, may be as safe as PES, and may be more effective than PES.

Introduction: Eosinophilic esophagitis is a chronic disease of the esophagus predominantly triggered by food antigens but diagnostic tests to identify food triggers in individual patients do not yet exist. Recent studies have shown that immunoglobulin G4 (IgG4) co-localizes with food proteins in the esophageal tissue of eosinophilic esophagitis (EoE) patients. Knowing that cow’s milk is the main food trigger of EoE, we hypothesized that co-localization with IgG4 is associated with EoE disease activity. Methods: We performed a case control study nested within the prospective University of Virginia (UVA) EoE Cohort. Fifteen patients were selected from the UVA EoE Cohort (10 EoE patients and 5 controls). Esophageal biopsies were obtained at the time of each endoscopy. We examined paired samples from individuals with a) active EoE and remission on swallowed steroids, b) active EoE and remission on diet elimination, c) non-EoE controls (n=5 in each group). Immunofluorescence was performed using primary antibodies directed against IgG4 and milk proteins (Bos d 4,5,8). Images were captured using a Leica confocal microscope. Co-localization was determined using Pearson’s Correlation Coefficient on Imaris imaging software. Between-group comparisons were made using Mann-Whitney U test on GraphPad Prism software. Results: Immunofluorescence staining was performed on 75 esophageal biopsies (15 patients, ages 19-41 yo, 53% male). There was significantly more IgG4-milk protein co-localization in patients with active EoE compared to remission samples in the same patients (p=0.02, p=0.002, and p=0.002 for Bos d 4, 5, and 8, respectively). There was no significant difference in co-localization between remission samples and controls (p=0.57, p=0.21, p=0.74 for Bos d 4, 5, and 8, respectively). Median co-localization levels in active EoE patients were also significantly higher than non-EoE controls. Notably, all five patients in remission on swallowed steroids still demonstrated co-localization but at a lesser intensity compared to active samples and was not statistically significant (p=0.07). (Figure) Conclusion: Our findings demonstrate that IgG4 co-localization with milk proteins is associated with disease activity in EoE. Whether these deposits contribute to the underlying inflammation of EoE, and whether IgG4 co-localization could be used to identify specific food triggers in EoE patients remains unknown and warrants further study.Figure 1.: Esophageal biopsies with immunofluorescence staining for IgG4 (green), Bos d 5 (red), and nuclei (blue). (A) Active EoE and co-localization of IgG4 and Bos d 5 (yellow). (B) Paired remission sample (swallowed steroids) from patient in fig. 1A. (C) Control patient consuming dairy.

Background:SYNTAX score II (SSII) provides individualized estimates of 4-year mortality after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in order to facilitate decision-making between these revascularization methods. The purpose of the present study was to assess SSII in a real-world multicenter registry with distinct regional and epidemiological characteristics.Methods and Results:Long-term mortality was analyzed in 3,896 patients undergoing PCI (n=2,190) or CABG (n=1,796) from the Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG registry cohort-2. SSII discriminated well in both CABG and PCI patient groups (concordance index [c-index], 0.70; 95% CI: 0.68–0.72; and 0.75, 95% CI: 0.72–0.78) surpassing anatomical SYNTAX score (SS; c-index, 0.50; 95% CI: 0.47–0.53; and 0.59, 95% CI: 0.57–0.61). SSII had the best discriminative ability to separate low-, medium- and high-risk tertiles, and calibration plots showed good predictive performance for CABG and PCI groups. Use of anatomical SS as a reference improved the overall reclassification provided by SSII, with a net reclassification index of 0.5 (P<0.01).Conclusions:SSII has robust prognostic accuracy, both in CABG and in PCI patient groups and, compared with the anatomical SS alone, was more accurate in stratifying patients for late mortality in a real-world complex coronary artery disease Eastern population. (Circ J 2014; 78: 1942–1949)

No abstract is provided for this article.

Objectives. This study sought to prospectively evaluate the performance of a laser guide wire in crossing chronic total coronary occlusions in patients with a failed previous mechanical guide wire attempt. Background. Despite continued refinement of mechanical hardware available for coronary angioplasty, restoration and maintenance of blood flow through a chronically occluded coronary artery remains a true challenge. Methods. Fifty patients with a chronic total coronary occlusion and a previous failed attempt at recanalization using mechanical guide wires were included. A mechanical attempt to cross the occlusion was repeated. In case of failure, an additional attempt was made with the laser guide wire. Results. The median age of occlusion was 22 weeks (range 5 to 200), and the occlusion length was 23 ± 11 mm (mean ± SD). A repeat mechanical attempt was successful in six cases (12%). Dissection occurred in five other cases, and device crossover was not attempted. Thus, in 39 patients an attempt was made with the laser guide wire, with successful recanalization in 23 (59%). Thereby the overall success rate increased from 12% to 58% (29 of 50 patients). The amount of contrast medium used was 515 ± 154 ml, fluoroscopy time was 99 ± 43 min, and total procedure time was 2 h 48 min (±55 min). Procedural success was achieved in 26 cases and clinical success (procedural success without in hospital events) in 24. In-hospital events were two non–Q wave myocardial infarctions related to subacute reocclusion. In one patient, a balloon dilation after laser guide wire perforation resulted in tamponade requiring pericardiocentesis. After a successful procedure, the angina class decreased from 2.9 ± 0.2 to 1.4 ± 0.7 at 3 months of clinical follow-up. Six-month angiographic follow-up was completed in all 24 eligible patients and showed vessel patency in 20 (80%). Conclusions. The use of the laser guide wire for recanalization of chronic total coronary occlusions refractory to treatment with mechanical guide wires is feasible and relatively safe and was successful in 59% of cases. This device must thus be considered a valuable addition to the interventional armamentarium and accordingly will be evaluated in a randomized clinical trial.

The basic defect in cystic fibrosis centres on abnormal ion transport in affected tissues such as the respiratory tract. Heart-lung transplantation provides a limited supply of native lower airways from these patients. The feasibility of in vitro studies of bioelectric properties and ion fluxes in lower airways, obtained at heart-lung transplantation from patients with cystic fibrosis, has been assessed. Comparison was made with airways from patients without cystic fibrosis.Tissue segments were mounted in Ussing chambers under open circuit conditions. The basal potential difference in tissues from nine patients with cystic fibrosis was -3.6 mV (SE 0.3 mV), not different from tissues from 12 patients without cystic fibrosis of -3.6 mV (0.5 mV). Amiloride (10 microM) caused a significantly greater fall in potential difference in bronchi from patients with cystic fibrosis (83.5% (SE 2.9%)) than in those from controls (55.1% (7.1%)). Isoprenaline (100 microM) produced no significant change in bioelectric properties in non-cystic fibrosis tissues, but induced a 26.2% (6.3%) increase in potential difference in cystic fibrosis airways. The latter response was reduced by amiloride pretreatment. Mucosal chloride substituted Krebs-Henseleit solution caused no change in bioelectric properties in cystic fibrosis airways. Sodium substituted Krebs solution produced a substantial fall in potential difference similar in magnitude to that seen after amiloride. Isotropic flux measurements showed no significant differences between non-cystic fibrosis and cystic fibrosis airways. No net movement of Na+ or Cl- was detected under open circuit conditions in either group.Cystic fibrosis bronchi obtained at heart-lung transplantation provide a viable source of tissue for in vitro studies of bioelectric properties. The increased response to amiloride characteristic of the upper airways in cystic fibrosis is retained in these tissues, as is the reduced chloride conductance. Although no differences in isotopic fluxes were seen between non-cystic fibrosis and cystic fibrosis tissues, heavily infected airways from patients with cystic fibrosis may not be suitable for ion flux measurements.