Phosphatidylthreonine is a procoagulant lipid detected in human blood and elevated in coronary artery disease.

Aminophospholipids (aPL) such as phosphatidylserine are essential for supporting the activity of coagulation factors, circulating platelets, and blood cells. Phosphatidylthreonine (PT) is an aminophospholipid previously reported in eukaryotic parasites and animal cell cultures, but not yet in human tissues. Here, we evaluated whether PT is present in blood cells and characterized its ability to support coagulation. Several PT molecular species were detected in human blood, washed platelets, extracellular vesicles, and isolated leukocytes from healthy volunteers using liquid chromatography-tandem mass spectrometry. The ability of PT to support coagulation was demonstrated in vitro using biochemical and biophysical assays. In liposomes, PT supported prothrombinase activity in the presence and absence of phosphatidylserine. PT nanodiscs strongly bound FVa and lactadherin (nM affinity) but poorly bound prothrombin and FX, suggesting that PT supports prothrombinase through recruitment of FVa. PT liposomes bearing tissue factor poorly generated thrombin in platelet poor plasma, indicating that PT poorly supports extrinsic tenase activity. On platelet activation, PT is externalized and partially metabolized. Last, PT was significantly higher in platelets and extracellular vesicle from patients with coronary artery disease than in healthy controls. In summary, PT is present in human blood, binds FVa and lactadherin, supports coagulation in vitro through FVa binding, and is elevated in atherosclerotic vascular disease. Our studies reveal a new phospholipid subclass, that contributes to the procoagulant membrane, and may support thrombosis in patients at elevated risk.

Aspirin and cancer treatment: systematic reviews and meta-analyses of evidence: for and against.

Aspirin as a possible treatment of cancer has been of increasing interest for over 50 years, but the balance of the risks and benefits remains a point of contention. We summarise the valid published evidence 'for' and 'against' the use of aspirin as a cancer treatment and we present what we believe are relevant ethical implications. Reasons for aspirin include the benefits of aspirin taken by patients with cancer upon relevant biological cancer mechanisms. These explain the observed reductions in metastatic cancer and vascular complications in cancer patients. Meta-analyses of 118 observational studies of mortality in cancer patients give evidence consistent with reductions of about 20% in mortality associated with aspirin use. Reasons against aspirin use include increased risk of a gastrointestinal bleed though there appears to be no valid evidence that aspirin is responsible for fatal gastrointestinal bleeding. Few trials have been reported and there are inconsistencies in the results. In conclusion, given the relative safety and the favourable effects of aspirin, its use in cancer seems justified, and ethical implications of this imply that cancer patients should be informed of the present evidence and encouraged to raise the topic with their healthcare team.

The impact of adopting low-molecular-weight heparin in place of aspirin as routine thromboprophylaxis for patients with hip fracture.

PURPOSE OF THE STUDY: In 2010, the National Institute for Health and Care Excellence (NICE) recommended the use of anticoagulants rather than aspirin as pharmacological thromboprophylaxis after hip fracture. We examine the impact of implementing this change in guidance on the clinical incidence of deep vein thrombosis (DVT). STUDY DESIGN: Demographic, radiographic and clinical data were retrospectively collected for 5039 patients admitted to a single tertiary centre in the UK for hip fracture between 2007 and 2017. We calculated rates of lower-limb DVT and examined the impact of the June 2010 change of departmental policy, from use of aspirin to use of low-molecular-weight heparins (LMWH) in hip fracture patients. RESULTS: Doppler scans were performed in 400 patients in the 180 days after a hip fracture, and identified 40 ipsilateral and 14 contralateral DVTs (p<0.001). The rate of DVT reduced significantly following the 2010 change in departmental policy from aspirin to LMWH in these patients (1.62% vs 0.83%, p<0.05). CONCLUSIONS: The rate of clinical DVT halved following the change from aspirin to LMWH for pharmacological thromboprophylaxis, but the number needed to treat was 127. A figure of <1% for the incidence of clinical DVT in a unit that routinely uses LMWH monotherapy following hip fracture provides a context for discussions of alternative strategies, and for power calculations for future research. These figures are important to policy makers and to researchers as they will inform the design of the comparative studies on thromboprophylaxis agents for which NICE has called.

The SARS-CoV2 envelope differs from host cells, exposes procoagulant lipids, and is disrupted in vivo by oral rinses.

The lipid envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an essential component of the virus; however, its molecular composition is undetermined. Addressing this knowledge gap could support the design of antiviral agents as well as further our understanding of viral-host protein interactions, infectivity, pathogenicity, and innate immune system clearance. Lipidomics revealed that the virus envelope comprised mainly phospholipids (PLs), with some cholesterol and sphingolipids, and with cholesterol/phospholipid ratio similar to lysosomes. Unlike cellular membranes, procoagulant amino-PLs were present on the external side of the viral envelope at levels exceeding those on activated platelets. Accordingly, virions directly promoted blood coagulation. To investigate whether these differences could enable selective targeting of the viral envelope in vivo, we tested whether oral rinses containing lipid-disrupting chemicals could reduce infectivity. Products containing PL-disrupting surfactants (such as cetylpyridinium chloride) met European virucidal standards in vitro; however, components that altered the critical micelle concentration reduced efficacy, and products containing essential oils, povidone-iodine, or chlorhexidine were ineffective. This result was recapitulated in vivo, where a 30-s oral rinse with cetylpyridinium chloride mouthwash eliminated live virus in the oral cavity of patients with coronavirus disease 19 for at least 1 h, whereas povidone-iodine and saline mouthwashes were ineffective. We conclude that the SARS-CoV-2 lipid envelope i) is distinct from the host plasma membrane, which may enable design of selective antiviral approaches; ii) contains exposed phosphatidylethanolamine and phosphatidylserine, which may influence thrombosis, pathogenicity, and inflammation; and iii) can be selectively targeted in vivo by specific oral rinses.

Predictors of 30-day and 12-month mortality in left main stem percutaneous coronary intervention 2016-2020: A study from two UK centers.

INTRODUCTION: Left main stem percutaneous coronary intervention (LMS-PCI) is a complex high-risk procedure which can be performed as an alternative to coronary artery bypass graft (CABG) procedure in surgical turn-down patients or where there is equipoise in percutaneous versus surgical strategies. Current guidelines suggest that PCI is an appropriate alternative to CABG in patients with unprotected LMS disease and low SYNTAX score. However, "real world" data on outcomes of LMS-PCI remain limited. This study aims to quantify and determine predictors of mortality following LMS-PCI. METHODS: Using local coronary angioplasty registries from two UK centers, all LMS-PCI cases were identified from 2016 to 2020. Descriptive statistics and multivariate logistic regressions were used to examine the association between baseline and procedural characteristics with 30-day and 12-month mortality. RESULTS: We identified 484 cases of LMS-PCI between 2016 and 2020. There was a year-on-year increase in the number of LMS-PCI, the highest being in 2020. Covariates associated with higher 30-day mortality were age (OR 1.07, 95% CI: 1.02-1.12) and shock preprocedure (OR 23.88, 95% CI: 7.90-72.20). Covariates associated with higher 12-month mortality were age (OR 1.04, 95% CI: 1.01-1.08), acute coronary syndrome (ACS) (OR 2.50, 95% CI: 1.08-5.80), renal disease (OR 5.24, 95% CI: 1.47-18.68), and shock preprocedure (OR 7.93, 95% CI: 3.30-19.05). Overall, 30-day and 12-month mortality in this contemporary data set were 9.5% and 16.7%, respectively, with significantly lower rates in elective cases (p < 0.01). CONCLUSIONS: Older age and cardiogenic shock preprocedure were associated with increased 30-day mortality after LMS-PCI. Twelve-month mortality was associated with older age, ACS presentation, preexisting renal disease, and cardiogenic shock preprocedure.

The Impact of Intracoronary Imaging on PCI Outcomes in Cases Utilising Rotational Atherectomy: An Analysis of 8,417 Rotational Atherectomy Cases from the British Cardiovascular Intervention Society Database.

Introduction: There is increasing evidence supporting the use of intracoronary imaging to optimize the outcomes of percutaneous coronary intervention (PCI). However, there are no studies examining the impact of imaging on PCI outcomes in cases utilising rotational atherectomy (RA-PCI). Our study examines the determinants and outcomes of using intracoronary imaging in RA-PCI cases including 12-month mortality. Methods: Using the British Cardiac Intervention Society database, data were analysed on all RA-PCI procedures in the UK between 2007 and 2014. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural, and outcome associations with intravascular imaging. Results: Intracoronary imaging was used in 1,279 out of 8,417 RA-PCI cases (15.2%). Baseline covariates associated with significantly more imaging use were number of stents used, smoking history, previous CABG, pressure wire use, proximal LAD disease, laser use, glycoprotein inhibitor use, cutting balloons, number of restenosis attempted, off-site surgery, and unprotected left main stem (uLMS) PCI. Adjusted rates of in-hospital major adverse cardiac/cerebrovascular events (IH-MACCE), its individual components (death, peri-procedural MI, stroke, and major bleed), or 12-month mortality were not significantly altered by the use of imaging in RA-PCI. However, subgroup analysis demonstrated a signal towards reduction in 12-month mortality in uLMS RA-PCI cases utilising intracoronary imaging (OR 0.67, 95% CI 0.44-1.03). Conclusions: Intracoronary imaging use during RA-PCI is associated with higher risk of baseline and procedural characteristics. There were no differences observed in IH-MACCE or 12-month mortality with intracoronary imaging in RA-PCI.

Comparison of an e-learning package with lecture-based teaching in the management of supraventricular tachycardia (SVT): a randomised controlled study.

INTRODUCTION: To compare the impact of an e-learning package with theoretical teaching on the ability of both graduate and undergraduate medical students to learn the management of supraventricular tachycardia. METHODS: We conducted a randomised, controlled, study at two Welsh medical schools. Participants were graduate-entry and undergraduate medical students, who were randomised (in a 1:1 ratio) to either 1 hour of training using an e-learning package or an hour of lecture-based teaching. The outcome was a comparison, within each group and between groups, of median scores achieved in assessments of knowledge through completion of preintervention, immediate post intervention and 2 weeks postintervention questionnaires. RESULTS: Of the 97 participants available for randomisation, 47 underwent teaching using the e-learning package and 50 were taught in the lecture group. Median scores were higher in the e-learning package group than the lecture group, though this difference was not statistically significant (4.00 vs 3.00; p=0.08) immediately after intervention. At 2 weeks post intervention, median scores in the e-learning package group were significantly higher than the median scores in the lecture group (4.00 vs 3.00; p=0.002). This was despite a subanalysis of the results demonstrating that subjects in the lecture group reported having seen more cases compared with those in the e-learning group (32 vs 13; p=0.002). Further, there was a significant fall in score over 2 weeks in the group receiving lecture-based teaching, but no such decrease in those using the e-learning package. CONCLUSION: E-learning seems to be the preferred method of learning and the method that confers longer retention time for both postgraduate and undergraduate medical students.

Endoscopy findings in patients on dual antiplatelet therapy following percutaneous coronary intervention.

PURPOSE OF STUDY: This study examines the associations between dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) and gastrointestinal bleeding (GIB), to explore possible predictors of outcomes. STUDY DESIGN: Retrospective analysis of 3342 patients who underwent PCI between 1 August 2011 and 31 December 2018 in a single centre was carried out. Oesophagogastroduodenoscopies (OGDs) for patients 12 months post-PCI were analysed. RESULTS: Blood loss occurred in 2% of all (3342) patients post-PCI within 12 months. 128 patients (63% male, mean age (SD) of 69.8 (10) years) who had PCI subsequently underwent an OGD within 12 months of the index PCI procedure. GIB occurred within the first 30 days of DAPT in 36% (n=13/36) of cases. There were no thrombotic events associated with cessation of one antiplatelet agent. Increased age, haemoglobin (Hb) ≤109 g/L and Glasgow-Blatchford score ≥8 were associated with increased 12-month mortality. An Hb drop of ≥30 g/L was a sensitive and specific marker for significant pathology and evidence of bleeding on OGD (sensitivity=0.83, specificity=0.81). CONCLUSIONS: GIB bleeding occurred infrequently in the patients post-PCI on DAPT. Risk assessment scores (such as Glasgow-Blatchford and Rockall scores) are useful tools to assess the urgency of OGD and need for endoscopic therapy.

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity.

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE-/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE-/- deletion, and many were absent in Alox-/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

Combined use of rotational and excimer lASER coronary atherectomy (RASER) during complex coronary angioplasty-An analysis of cases (2006-2016) from the British Cardiovascular Intervention Society database.

INTRODUCTION: Combining rotational (RA) and excimer laser coronary atherectomy (ELCA)-RASER atherectomy-is technique utilized in the percutaneous management of calcific coronary disease. The evidence base examining its safety and utility is sparse and limited to small case-series. This study examines the patterns and outcomes of RASER atherectomy use in the largest cohort to date. METHODS: Using the British Cardiac Intervention Society database, data were analyzed on all PCI procedures in the UK between 2006 and 2016. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural, and outcome associations with RASER. RESULTS: We identified 153 (0.02%) RASER atherectomy cases out of 686,358 PCI procedures. Baseline covariates associated with RASER use were age, BMI, diabetes, stable coronary disease, and previous CABG. Procedural co-variates associated with RASER were CTO-PCI, the use of more/longer stents, intravascular imaging, cutting balloons, and microcatheters. Adjusted rates of in-hospital major adverse cardiac/cerebrovascular events (MACCE) were not significantly different with RASER. However, there were higher odds of arterial complications (OR 3.23, 95% CI: 1.58-6.61), slow flow (OR 3.50, 95% CI: 1.29-9.55), and shock induction (OR 9.66, 95% CI: 3.44-27.06). CONCLUSIONS: RASER atherectomy use in complex PCI is associated with higher risk baseline and procedural characteristics. Although increased rates of shock induction, slow flow, and arterial complications were observed, RASER does not increase the likelihood of in-hospital MACCE, major bleeding, or death.

The impact of coronary perforation in percutaneous interventions involving the left main stem coronary artery in the United Kingdom 2007-2014: Insights from the British Cardiovascular Intervention Society database.

BACKGROUND: Percutaneous coronary intervention (PCI) is increasingly utilized for treatment of coronary disease involving the unprotected left main stem (ULMS). However, no studies to date have examined the outcomes of such interventions when complicated by coronary perforation (CP). METHODS: Using the British Cardiovascular Intervention society (BCIS) database, data were analyzed on all ULMS-PCI procedures complicated by CP in England and Wales between 2007 and 2014. Multivariate logistic regressions were used to identify predictors of ULMS CP and to evaluate the association between this complication and outcomes. RESULTS: During 10,373 ULMS-PCI procedures, CP occurred more frequently than in non-ULMS-PCI (0.9 vs. 0.4%, p < .001) with a stable annual incidence. Covariates associated with CP included number of stents used, female gender, use of rotational atherectomy and chronic total occlusion (CTO) intervention. Adjusted odds of adverse outcomes for ULMS-PCI complicated by CP were higher for peri-procedural complications including cardiogenic shock, tamponade, side-branch loss, DC cardioversion, in-hospital major bleeding, transfusion requirement, and peri-procedural myocardial infarction. There were also significantly increased odds for in-hospital major adverse cardiac events (MACCE, OR 8.961, 95% CI [4.902-16.383]) and 30-day mortality (OR 5.301, 95% CI [2.741-10.251]). CONCLUSIONS: CP is an infrequent event during ULMS-PCI and is predicted by female gender, rotational atherectomy, CTO interventions or number of stents used. CP was associated with significantly higher odds of mortality and morbidity, but at rates similar to previously published all-comer PCI complicated by CP.

Excimer laser coronary atherectomy during complex PCI: An analysis of 1,471 laser cases from the British Cardiovascular Intervention Society database.

INTRODUCTION: Excimer laser coronary atherectomy (ELCA) is a recognized adjunctive therapy utilized in the percutaneous management of complex coronary lesions. Studies examining its safety and utility have been limited by small sample sizes. Our study examines the determinants and outcomes of ELCA. METHODS: Using the British Cardiac Intervention Society database, data were analyzed on all PCI procedures in the UK between 2006-2016. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural and outcome associations with ELCA. RESULTS: We identified 1,471 (0.21%) ELCA cases out of 686,358 PCI procedures. Baseline covariates associated with ELCA use were age, BMI, number of lesions, CTO or restenosis attempted and history of prior MI, CABG or PCI. Procedural co-variates associated with ELCA were the use of glycoprotein inhibitors, intravascular imaging, rotational atherectomy, cutting balloons, microcatheters and intra-aortic balloon pumps. Adjusted rates of in-hospital major adverse cardiac/cerebrovascular events (MACCE) or its individual components (death, peri-procedural MI, stroke and major bleed) were not significantly altered by the use of ELCA. However, there were higher odds of dissection (OR 1.52, 95% CI 1.17-1.98), perforation (OR 2.18, 95% CI 1.44-3.30), slow flow (OR: 1.67, 95% CI 1.18-2.36), reintervention (OR: 2.12, 95% CI 1.14-3.93) and arterial complications (OR: 1.63, 95% CI 1.21-2.21). CONCLUSIONS: ELCA use during complex PCI is associated with higher risk baseline and procedural characteristics. Although increased rates of acute procedural complications were observed, ELCA does not increase likelihood of in-hospital MACCE or its individual components.

Transmembrane adaptor protein WBP1L regulates CXCR4 signalling and murine haematopoiesis.

WW domain binding protein 1-like (WBP1L), also known as outcome predictor of acute leukaemia 1 (OPAL1), is a transmembrane adaptor protein, expression of which correlates with ETV6-RUNX1 (t(12;21)(p13;q22)) translocation and favourable prognosis in childhood leukaemia. It has a broad expression pattern in haematopoietic and in non-haematopoietic cells. However, its physiological function has been unknown. Here, we show that WBP1L negatively regulates signalling through a critical chemokine receptor CXCR4 in multiple leucocyte subsets and cell lines. We also show that WBP1L interacts with NEDD4-family ubiquitin ligases and regulates CXCR4 ubiquitination and expression. Moreover, analysis of Wbp1l-deficient mice revealed alterations in B cell development and enhanced efficiency of bone marrow cell transplantation. Collectively, our data show that WBP1L is a novel regulator of CXCR4 signalling and haematopoiesis.

Securing a cardiology speciality training programme in the UK: how did other people do it?

BACKGROUND: Application to cardiology specialty training is competitive with uncertainty among candidates as to what the secret recipe for a successful appointment is. We aimed to investigate objective variables, which were demonstrated by successful appointees to cardiology training schemes in the UK. METHODS: Data from successful cardiology applicants for the years 2014 to 2016 were obtained from the Joint Royal Colleges of Physicians Training Board under the Freedom of Information Act. These data included basic demographics as well as objective scores awarded for selection categories such as qualifications, academic, teaching and other achievements. RESULTS: There were a total of 976 applicants during the study period, of whom 423 were successfully appointed, generating a competition ratio of 2.3 applicants for each position. There was an increasing proportion of successful female applicants (22% in 2014, 28% in 2015 and 32% in 2016). Median scores for postgraduate exams (14/14), presentations (6/6) and quality improvement (10/10) scores corresponded to maximum possible scores, whereas median scores for additional undergraduate and postgraduate degrees were 0. Median scores for prizes, publications and teaching experience were 6/10, 4/8 and 9/10, respectively. CONCLUSION: The secret to a successful cardiology training appointment is associated with completion of all postgraduate clinical exams, completion and presentation of quality improvement projects, national presentations and substantial teaching achievements. At least half of the successful candidates had no additional undergraduate or postgraduate degrees but had evidence of some prizes and publications. The ratio of successful female candidates is rising, but remains less than males in cardiology training.

Acute coronary syndrome on Friday the 13th: a case for re-organising services?

BACKGROUND: Friday the 13th is described as an "unlucky" day that brings misfortune. There are few studies on the question, and none on its effect in cardiovascular patients. The recently misreported "weekend effect" has led to changes in the junior doctor contract in England, providing greater staffing levels on weekends. Should we make similar provisions for Friday the 13th? METHODS: A retrospective analysis of a large database for patients admitted to hospitals in South Wales with an acute coronary syndrome (ACS) during 1999-2014. Mortality rates for 217 admission day number/name combinations and for Friday the 13th were compared in a Cox proportional hazards regression model. RESULTS: 56 062 ACS patients were identified. There were no significant differences in 13-year mortality between most admission dates (211 of 216) and Friday the 13th. However, a statistically significant reduction in mortality was identified for five dates: Thursday the 15th (HR, 0.77; 95% CI, 0.59-0.999), Wednesday the 18th (HR, 0.76; 95% CI, 0.58-0.99), Monday the 28th (HR, 0.76; 95% CI, 0.57-0.99), Monday the 30th (HR, 0.75; 95% CI, 0.57-0.99) and Tuesday the 31st (HR, 0.71; 95% CI, 0.51-0.99). CONCLUSION: On most days, there was no difference in the 13-year mortality rate for patients admitted with their first ACS from that for "unlucky" Friday the 13th. However, patients admitted on five day/number combinations were 20-30% more likely to survive at 13 years. These findings could be explained by subgroup analysis inflation of the type I error, although supernatural causes merit further investigation. Our findings should be taken into account in future junior doctor contract negotiations, and may provide a case for reduced staffing levels on these lucky days.

Stent failure: the diagnosis and management of intracoronary stent restenosis.

INTRODUCTION: Despite advances in stent technology for percutaneous coronary intervention (PCI) in the treatment of coronary disease, these procedures can be complicated by stent failure manifested as intracoronary stent restenosis (ISR). Even with advances in stent technology and medical therapy, this complication is reported to affect around 10% of all percutaneous coronary intervention (PCI) procedures. Depending on stent type (drug-eluting versus bare metal), ISR has subtle differences in mechanism and timing and offers different challenges in diagnosing etiology and subsequent treatment options. AREAS COVERED: This review will be visiting the definition, pathophysiology, and risk factors of ISR. EXPERT OPINION: The evidence behind management options has been illustrated with the aid of real life clinical cases and summarized in a proposed management algorithm.

Predictors of 1- and 12-month mortality in bifurcation coronary intervention: a contemporary perspective.

Aim: Bifurcation-PCI is performed frequently, although without extensive evidence to back up a definitive solution for its complexity. We set out to identify factors associated with 1- and 12-month mortality after bifurcation-PCI between 2017 and 2021 in our tertiary center in Wales, UK. Results: Of 732 bifurcation PCI cases (mean age 69; 25% female), 67% were in ACS, 42% were left main PCI and 25.3% involved two-stent strategy. 30-day and 12-month mortality were 1.9 and 8.2%, respectively. Age, diabetes, smoking and renal failure are associated with mortality after bifurcation-PCI, while the choice between provisional and 2-stent strategies did not impact mortality/TLR. Conclusion: Awareness of 'real-world' outcomes of bifurcation-PCI should be used for appropriate patient selection, technique planning and procedural consent.

Temporal Trends in In-Hospital Outcomes Following Unprotected Left-Main Percutaneous Coronary Intervention: An Analysis of 14 522 Cases From British Cardiovascular Intervention Society Database 2009 to 2017.

BACKGROUND: Percutaneous coronary intervention (PCI) is increasingly used as a treatment option for unprotected left main stem artery (unprotected left main stem percutaneous intervention) disease. However, whether patient outcomes have improved over time is uncertain. METHODS: Using the United Kingdom national PCI database, we studied all patients undergoing unprotected left main stem percutaneous intervention between 2009 and 2017. We excluded patients who presented with ST-segment-elevation, cardiogenic shock, and with an emergency indication for PCI. RESULTS: Between 2009 and 2017, in the study-indicated population, 14 522 unprotected left main stem percutaneous intervention procedures were performed. Significant temporal changes in baseline demographics were observed with increasing patient age and comorbid burden. Procedural complexity increased over time, with the number of vessels treated, bifurcation PCI, number of stents used, and use of intravascular imaging and rotational atherectomy increased significantly through the study period. After adjustment for baseline differences, there were significant temporal reductions in the occurrence of peri-procedural myocardial infarction (P<0.001 for trend), in-hospital major adverse cardiac or cerebrovascular events (P<0.001 for trend), and acute procedural complications (P<0.001 for trend). In multivariable analysis examining the associates of in-hospital major adverse cardiac or cerebrovascular events, while age per year (odds ratio, 1.02 [95% CIs, 1.01-1.03]), female sex (odds ratio, 1.47 [1.19-1.82]), 3 or more stents (odds ratio, 1.67 [05% [1.02-2.67]), and patient comorbidity were associated with higher rates of in-hospital major adverse cardiac or cerebrovascular events, by contrast use of intravascular imaging (odds ratio, 0.56 [0.45-0.70]), and year of PCI (odds ratio, 0.63 [0.46-0.87]) were associated with lower rates of in-hospital major adverse cardiac or cerebrovascular events. CONCLUSIONS: Despite trends for increased patient and procedural complexity, in-hospital patient outcomes have improved after unprotected left main stem percutaneous intervention over time.

A novel thromboxane A2 receptor D304N variant that abrogates ligand binding in a patient with a bleeding diathesis.

We investigated the cause of mild mucocutaneous bleeding in a 14-year-old male patient (P1). Platelet aggregation and ATP secretion induced by arachidonic acid and the thromboxane A(2) receptor (TxA(2)R) agonist U46619 were reduced in P1 compared with controls, whereas the responses to other platelet agonists were retained. P1 was heterozygous for a transversion within the TBXA2R gene predictive of a D304N substitution in the TxA(2)R. In Chinese hamster ovary-K1 cells expressing the variant D304N TxA(2)R, U46619 did not increase cytosolic free Ca(2+) concentration, indicating loss of receptor function. The TxA(2)R antagonist [(3)H]-SQ29548 showed an approximate 50% decrease in binding to platelets from P1 but absent binding to Chinese hamster ovary-K1 cells expressing variant D304N TxA(2)R. This is the second naturally occurring TxA(2)R variant to be associated with platelet dysfunction and the first in which loss of receptor function is associated with reduced ligand binding. D304 lies within a conserved NPXXY motif in transmembrane domain 7 of the TxA(2)R that is a key structural element in family A G protein-coupled receptors. Our demonstration that the D304N substitution causes clinically significant platelet dysfunction by reducing ligand binding establishes the importance of the NPXXY motif for TxA(2)R function in vivo.