Bivalirudin versus heparin in primary PCI: clinical outcomes and cost analysis.

Background: The evidence for benefits of bivalirudin over heparin has recently been challenged. We aimed to analyse the safety and cost-effectiveness following reintroduction of heparin instead of bivalirudin as the standard anticoagulation for primary percutaneous coronary intervention (PPCI) in a high-volume centre. Methods and results: This analysis was an open-label, prospective registry including all patients admitted to our centre for PPCI from April 2014 to April 2016. Heparin was reintroduced as standard anticoagulant in April 2015. During the 2 years, 1291 patients underwent a PPCI, 662 in the Bivalirudin protocol period (Cohort B) and 629 in the Heparin protocol period (Cohort H). Baseline and procedural characteristics were not significantly different, except for a higher use of thromboaspiration and femoral access in the earlier Cohort B. Glycoprotein 2b3a (Gp2b3a) antagonists were used in 24% of the patients in Cohort B versus 28% in Cohort H (P<0.01). We did not observe any differences in death at 180 days (11.03% in Cohort B vs 11.29% in Cohort H)(HR 95% CI 0.98 (0.72 to 1.33), P=0.88). The incidence of any bleeding complications at 30 days did not differ between the two periods (21.9% vs 21.9%, P=0.99). The cost related to the anticoagulants amounted to £246 236 in Cohort B versus £4483 in Cohort H (£324 406 vs £102 347 when adding Gp2b3a antagonists). Conclusion: We did not find clinically relevant changes in patient outcomes, including bleeding complications with reintroduction of heparin in our PPCI protocol. However, the use of heparin was associated with a major reduction in treatment costs

Impact of proctoring on success rates for percutaneous revascularisation of coronary chronic total occlusions.

OBJECTIVE: To assess the impact of proctoring for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in six UK centres. METHODS: We retrospectively analysed 587 CTO procedures from six UK centres and compared success rates of operators who had received proctorship with success rates of the same operators before proctorship (pre-proctored) and operators in the same institutions who had not been proctored (non-proctored). There were 232 patients in the pre-proctored/non-proctored group and 355 patients in the post-proctored group. Complexity was assessed by calculating the Japanese CTO (JCTO) score for each case. RESULTS: CTO PCI success was greater in the post-proctored compared with the pre-proctored/non-proctored group (77.5% vs 62.1%, p<0.0001). In more complex cases where JCTO≥2, the difference in success was greater (70.7% vs 49.5%, p=0.0003). After proctoring, there was an increase in CTO PCI activity in centres from 2.5% to 3.5%, p<0.0001 (as a proportion of total PCI), and the proportion of very difficult cases with JCTO score ≥3 increased from 15.3% (35/229) to 29.7% (105/354), p<0.0001. CONCLUSIONS: Proctoring resulted in an increase in procedural success for CTO PCI, an increase in complex CTO PCI and an increase in total CTO PCI activity. Proctoring may be a valuable way to improve access to CTO PCI and the likelihood of procedural success

Safety and efficacy of the hybrid approach in coronary chronic total occlusion percutaneous coronary intervention: The Hybrid Video Registry

Objectives The aim of the Hybrid Video Registry (HVR) is to assess the acute safety and efficacy of the Hybrid Approach in comparison to other contemporary methods of CTO‐PCI. Background: Recently, multiple techniques in Percutaneous Coronary Intervention (PCI) for coronary Chronic Total Occlusions (CTO) have been synthesized into a method referred to as the “Hybrid Approach”. Methods About 194 video‐taped timed live cases from CTO‐PCI training workshops were analyzed by independent data abstractors and compared to three contemporary CTO‐PCI registries stratified by case complexity based on the J‐CTO score. Results Overall procedural success was 95% of all cases attempted with an excellent safety profile. In the most complex lesion subset, which made up 45% of all HVR cases, success was 92.8%, which was significantly higher than either the Royal Bromptom (78.9%), or Japanese‐CTO (73.3%) registries, P = 0.04 Hybrid vs. Royal Brompton, P = 0.006 Hybrid vs. Japanese‐CTO). The Hybrid Approach was also associated with shorter procedure times and lower contrast utilization. Conclusions In a real world angiographic registry of complex CTOs, the Hybrid Approach to CTO‐PCI is safe, and may be superior to other contemporary approaches to CTO intervention with respect to procedural success and efficiency among a diverse group of operators and lesion complexity

Functional compensation of glutathione S-transferase M1 (GSTM1) null by another GST superfamily member,GSTM2

The gene for glutathione-S-transferase (GST) M1 (GSTM1), a member of the GST-superfamily, is widely studied in cancer risk with regard to the homozygous deletion of the gene (GSTM1 null), leading to a lack of corresponding enzymatic activity. Many of these studies have reported inconsistent findings regarding its association with cancer risk. Therefore, we employed in silico, in vitro, and in vivo approaches to investigate whether the absence of a functional GSTM1 enzyme in a null variant can be compensated for by other family members. Through the in silico approach, we identified maximum structural homology between GSTM1 and GSTM2. Total plasma GST enzymatic activity was similar in recruited individuals, irrespective of their GSTM1 genotype (positive/null). Furthermore, expression profiling using real-time PCR, western blotting, and GSTM2 overexpression following transient knockdown of GSTM1 in HeLa cells confirmed that the absence of GSTM1 activity can be compensated for by the overexpression of GSTM

Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in <i>C. elegans</i>

Parkinson's disease (PD), the second most prevalent neurodegenerative disease after Alzheimer's disease, is linked to the gradual loss of dopaminergic neurons in the substantia nigra. Disease loci causing hereditary forms of PD are known, but most cases are attributable to a combination of genetic and environmental risk factors. Increased incidence of PD is associated with rural living and pesticide exposure, and dopaminergic neurodegeneration can be triggered by neurotoxins such as 6-hydroxydopamine (6-OHDA). In C. elegans, this drug is taken up by the presynaptic dopamine reuptake transporter (DAT-1) and causes selective death of the eight dopaminergic neurons of the adult hermaphrodite. Using a forward genetic approach to find genes that protect against 6-OHDA-mediated neurodegeneration, we identified tsp-17, which encodes a member of the tetraspanin family of membrane proteins. We show that TSP-17 is expressed in dopaminergic neurons and provide genetic, pharmacological and biochemical evidence that it inhibits DAT-1, thus leading to increased 6-OHDA uptake in tsp-17 loss-of-function mutants. TSP-17 also protects against toxicity conferred by excessive intracellular dopamine. We provide genetic and biochemical evidence that TSP-17 acts partly via the DOP-2 dopamine receptor to negatively regulate DAT-1. tsp-17 mutants also have subtle behavioral phenotypes, some of which are conferred by aberrant dopamine signaling. Incubating mutant worms in liquid medium leads to swimming-induced paralysis. In the L1 larval stage, this phenotype is linked to lethality and cannot be rescued by a dop-3 null mutant. In contrast, mild paralysis occurring in the L4 larval stage is suppressed by dop-3, suggesting defects in dopaminergic signaling. In summary, we show that TSP-17 protects against neurodegeneration and has a role in modulating behaviors linked to dopamine signaling

Intravascular lithotripsy for treatment of calcific coronary lesions in ST elevation myocardial infarction.

AIMS: To describe the utility and safety of intravascular lithotripsy (IVL) in the setting of primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: We performed a retrospective analysis, across six UK sites of all patients in whom IVL was used for coronary calcium modification of the culprit lesion during primary PCI for STEMI. The 72 patients were included. IVL was used in de-novo culprit lesions in 57 (79%) of cases and culprit in-stent restenoses in 11 (15%) of cases. In four cases (6%) it was used in a newly deployed stent when this was under-expanded due to inadequate calcium modification. Of the 30 cases in which intracoronary imaging was available for stent analysis, the average stent expansion was 104%. Intra-procedural stent thrombosis occurred in one case (1%), and no-reflow in three cases (4%). The 30 day MACE rates were 18%. CONCLUSION: IVL appears to be feasible and safe for use in the treatment of calcific coronary artery disease in the setting of STEMI

Volume Regulated Anion Channel Currents of Rat Hippocampal Neurons and Their Contribution to Oxygen-and-Glucose Deprivation Induced Neuronal Death

Volume-regulated anion channels (VRAC) are widely expressed chloride channels that are critical for the cell volume regulation. In the mammalian central nervous system, the physiological expression of neuronal VRAC and its role in cerebral ischemia are issues largely unknown. We show that hypoosmotic medium induce an outwardly rectifying chloride conductance in CA1 pyramidal neurons in rat hippocampal slices. The induced chloride conductance was sensitive to some of the VRAC inhibitors, namely, IAA-94 (300 µM) and NPPB (100 µM), but not to tamoxifen (10 µM). Using oxygen-and-glucose deprivation (OGD) to simulate ischemic conditions in slices, VRAC activation appeared after OGD induced anoxic depolarization (AD) that showed a progressive increase in current amplitude over the period of post-OGD reperfusion. The OGD induced VRAC currents were significantly inhibited by inhibitors for glutamate AMPA (30 µM NBQX) and NMDA (40 µM AP-5) receptors in the OGD solution, supporting the view that induction of AD requires an excessive Na+-loading via these receptors that in turn to activate neuronal VRAC. In the presence of NPPB and DCPIB in the post-OGD reperfusion solution, the OGD induced CA1 pyramidal neuron death, as measured by TO-PRO-3-I staining, was significantly reduced, although DCPIB did not appear to be an effective neuronal VRAC blocker. Altogether, we show that rat hippocampal pyramidal neurons express functional VRAC, and ischemic conditions can initial neuronal VRAC activation that may contribute to ischemic neuronal damage