Distinct effects of AMPAR subunit depletion on spatial memory.

Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3ΔFb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3-/- mice showed premature mortality. Gria1/3ΔFb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3ΔFb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1-/- and Gria3-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.

Association between troponin level and medium-term mortality in 20 000 hospital patients.

INTRODUCTION: Cardiac troponin (cTn) concentrations above the manufacturer recommended upper limit of normal (ULN) are frequently seen in hospital patients without a clinical presentation consistent with type 1 myocardial infarction, and the significance of this is uncertain. The aim of this study was to assess the relationship between medium-term mortality and cTn concentration in a large consecutive hospital population, regardless of whether there was a clinical indication for performing the test. METHOD: This prospective observational study included 20 000 consecutive in-hospital and outpatient patients who had a blood test for any reason at a large teaching hospital, and in whom a hs-cTnI assay was measured, regardless of the original clinical indication. Mortality was obtained via NHS Digital. RESULTS: A total of 20 000 patients were included in the analysis and 18 282 of these (91.4%) did not have a clinical indication for cardiac troponin I (cTnI) testing. Overall, 2825 (14.1%) patients died at a median of 809 days. The mortality was significantly higher if the cTnI concentration was above the ULN (45.3% vs 12.3% p<0.001 log rank). Multivariable Cox analysis demonstrated that the log10 cTnI concentration was independently associated with mortality (HR 1.76 (95% CI 1.65 to 1.88)). Landmark analysis, excluding deaths within 30 days, showed the relationship between cTnI concentration and mortality persisted. CONCLUSION: In a large, unselected hospital population, in 91.4% of whom there was no clinical indication for testing, cTnI concentration was independently associated with medium-term cardiovascular and non-cardiovascular mortality in the statistical model tested.

TAVI Between a Rock and a Hard Place in a Transplanted Heart.

We describe a 61-year-old male patient at our institution who was being reviewed by the heart team for consideration of transcatheter aortic valve intervention. Gated cardiac computed tomography revealed extensive eccentric calcification of the left ventricular outflow tract (LVOT) extending into the mitral valve leaflet and a large aortic annulus (33 mm; mean annular diameter/area, 854 mmsup2;). This is larger than all recommended manufacturer annular size limits, although observational data support the use of both Edwards Sapien 3 and Medtronic Evolut R in such annuli.

Relation of High-Sensitivity Troponin to 1 Year Mortality in 20,000 Consecutive Hospital Patients Undergoing a Blood Test for Any Reason.

This was an observational study of the 1-year outcomes of the 20,000 patients included in the original CHARIOT study. The aim of the study was to assess the association between high sensitivity troponin I (hs-cTnI) concentration and 1 year mortality in this cohort. The original CHARIOT study included a consecutive cohort of in- and out-patients undergoing blood tests for any reason. Hs-cTnI concentrations were measured regardless of whether the clinician requested them. These results were nested and not revealed to the team unless requested for clinical reasons. One year mortality data was obtained from NHS Digital as originally planned. Overall, 1782 (8.9%) patients had died at 1 year. Multivariable Cox regression analysis showed that a hs-cTnI concentration above the upper limit of normal was independently associated with the hazard of mortality (HR 2.23; 95% confidence intervals 1.97 to 2.52). Furthermore, the log (10) hs-cTnI concentration was independently associated with the hazard of 1 year mortality (HR 1.77; 95% confidence intervals 1.64 to 1.91). In conclusion, in a large, unselected hospital population of both in- and out-patients, in 18,282 (91.4%) of whom there was no clinical indication for testing, hs-cTnI concentration was associated with 1 year mortality.

'Valve for Life': tackling the deficit in transcatheter treatment of heart valve disease in the UK.

Transcatheter aortic valve implantation (TAVI) is a proven treatment for life-threatening aortic valve disease, predominantly severe aortic stenosis. However, even among developed nations, access to TAVI is not uniform. The Valve for Life initiative was launched by the European Association of Percutaneous Cardiovascular Interventions in 2015 with the objective of improving access to transcatheter valve interventions across Europe. The UK has been identified as a country with low penetration of these procedures and has been selected as the fourth nation to be included in the initiative. Specifically, the number of TAVI procedures carried out in the UK is significantly lower than almost all other European nations. Furthermore, there is substantial geographical inequity in access to TAVI within the UK. As a consequence of this underprovision, waiting times for TAVI are long, and mortality among those waiting intervention is significant. This article reviews these issues, reports new data on access to TAVI in the UK and presents the proposals of the UK Valve for Life team to address the current problems in association with the British Cardiovascular Intervention Society.

Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.

The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2aN615S), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca2+ signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.

Frequency and impact of incidental findings on computed tomography during work-up for transcatheter aortic valve implantation: single centre experience and review of the literature.

OBJECTIVE: To assess the frequency and impact of incidental findings (IF) on CT during work-up for transcatheter aortic valve intervention (TAVI). METHODS: A consecutive cohort of patients referred for consideration of TAVI who underwent a CT scan between 2009 and 2018 were studied retrospectively. CT reports were reviewed for the presence of IFs and categorised based upon their clinical significance: (a) insignificant-findings that did not require specific treatment or follow-up; (b) intermediate-findings that did not impact on the decision-making process but required follow-up; (c) significant-findings that either required urgent investigation or meant that TAVI was clinically inappropriate. RESULTS: A total of 652 patients were included, whose median age was 82 years. One or more insignificant IF was found in 95.6% of patients. Intermediate IFs were documented in 5.4%. 91 (14%) patients had at least one significant IF. These included possible malignancy in 67 (74%). The ultimate decision to offer aortic valve intervention was only changed by the presence of an IF in 3.5% of cases. CONCLUSION: Clinically significant IFs are detected in more than 1 in 10 of patients undergoing CT as part of a TAVI work-up, although just over half of these patients still receive aortic valve intervention. ADVANCES IN KNOWLEDGE: This study is the largest UK cohort, which, when combined with a review of existing literature, provides a clear picture of the frequency and clinical impact of IFs found at CT for TAVI assessment.

True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study.

OBJECTIVE: To determine the distribution, and specifically the true 99th centile, of high sensitivity cardiac troponin I (hs-cTnI) for a whole hospital population by applying the hs-cTnI assay currently used routinely at a large teaching hospital. DESIGN: Prospective, observational cohort study. SETTING: University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom, between 29 June 2017 and 24 August 2017. PARTICIPANTS: 20 000 consecutive inpatients and outpatients undergoing blood tests for any clinical reason. Hs-cTnI concentrations were measured in all study participants and nested for analysis except when the supervising doctor had requested hs-cTnI for clinical reasons. MAIN OUTCOME MEASURES: Distribution of hs-cTnI concentrations of all study participants and specifically the 99th centile. RESULTS: The 99th centile of hs-cTnI for the whole population was 296 ng/L compared with the manufacturer's quoted level of 40 ng/L (currently used clinically as the upper limit of normal; ULN). Hs-cTnI concentrations were greater than 40 ng/L in one in 20 (5.4%, n=1080) of the total population. After excluding participants diagnosed as having acute myocardial infarction (n=122) and those in whom hs-cTnI was requested for clinical reasons (n=1707), the 99th centile was 189 ng/L for the remainder (n=18 171). The 99th centile was 563 ng/L for inpatients (n=4759) and 65 ng/L for outpatients (n=9280). Patients from the emergency department (n=3706) had a 99th centile of 215 ng/L, with 6.07% (n=225) greater than the recommended ULN. 39.02% (n=48) of all patients from the critical care units (n=123) and 14.16% (n=67) of all medical inpatients had an hs-cTnI concentration greater than the recommended ULN. CONCLUSIONS: Of 20 000 consecutive patients undergoing a blood test for any clinical reason at our hospital, one in 20 had an hs-cTnI greater than the recommended ULN. These data highlight the need for clinical staff to interpret hs-cTnI concentrations carefully, particularly when applying the recommended ULN to diagnose acute myocardial infarction, in order to avoid misdiagnosis in the absence of an appropriate clinical presentation. TRIAL REGISTRATION: Clinicaltrials.gov NCT03047785.

Transcatheter aortic valve implantation: where are we now?

Transcatheter aortic valve implantation (TAVI) was first used in clinical practice in 2002. Since 2002, there has been a rapid increase in TAVI activity in patients with symptomatic severe aortic stenosis. This has been supported by systematic randomized data comparing TAVI against the gold standard treatment for the last 50 years' surgical aortic valve replacement. TAVI is now currently a recommended therapeutic intervention in the treatment of severe aortic stenosis patients who are deemed either high risk or inoperable. The indications for TAVI continue to expand. Within this review we will focus on the current guidelines for TAVI, the evidence for it, the complications of TAVI, postprocedure care, the technology available to clinicians now and finally the future perspectives for TAVI.

Jamaica's Critically Endangered Butterfly: A Review of the Biology and Conservation Status of the Homerus Swallowtail (Papilio (Pterourus) homerus Fabricius).

The Homerus swallowtail, Papilio (Pterourus) homerus Fabricius, is listed as an endangered species and is endemic to the Caribbean island of Jamaica. The largest butterfly in the Western Hemisphere, P. homerus once inhabited seven of Jamaica's 14 parishes and consisted of at least three populations; however, now only two stronghold populations remain, a western population in the rugged Cockpit Country and an eastern population in the Blue and John Crow Mountains. Despite numerous studies of its life history, much about the population biology, including estimates of total numbers of individuals in each population, remains unknown. In addition, a breeding program is needed to establish an experimental population, which could be used to augment wild populations and ensure the continued survival of the species. Here, we present a review of the biology of P. homerus and recommendations for a conservation plan.

Variation in emergency percutaneous coronary intervention in ventilated patients in the UK: Insights from a national database.

AIMS: Pre-procedural ventilation is a marker of high risk in PCI patients. Causes include out-of-hospital cardiac arrest (OHCA) and cardiogenic shock. OHCA occurs in approximately 60,000 patients in the UK per annum. No consensus exists regarding the need/timing of coronary angiography ± revascularization without ST elevation. The aim was to describe the national variation in the rate of emergency PCI in ventilated patients. METHODS AND RESULTS: Using the UK national database for PCI in 2013, we identified all procedures performed as 'emergency' or 'salvage' for whom ventilation had been initiated before the PCI. Of the 92,589 patients who underwent PCI, 1342 (5.5%) fulfilled those criteria. There was wide variation in practice. There was no demonstrable relationship between the number of emergency PCI patients with pre-procedure ventilation per annum and (i) total number of PPCIs in a unit (r=-0.186), and (ii) availability of 24h PCI, (iii) on-site surgical cover. CONCLUSION: We demonstrated a wide variation in practice across the UK in rates of pre-procedural ventilation in emergency PCI. The majority of individuals will have suffered an OHCA. In the absence of a plausible explanation for this discrepant practice, it is possible that (a) some patients presenting with OHCA that may benefit from revascularization are being denied treatment and (b) procedures may be being undertaken that are futile. Further prospective data are needed to aid in production of guidelines aiming at standardized care in OHCA.

Coronary Intervention with the Excimer Laser: Review of the Technology and Outcome Data.

Excimer laser coronary atherectomy (ELCA) is a long-established adjunctive therapy that can be applied during percutaneous coronary intervention (PCI). Technical aspects have evolved and there is an established safety and efficacy record across a number of clinical indications in contemporary interventional practice where complex lesions are routinely encountered. The role of ELCA during PCI for thrombus, non-crossable or non-expandable lesions, chronic occlusions and stent under-expansion are discussed in this review. The key advantage of ELCA over alternative atherectomy interventions is delivery on a standard 0.014-inch guidewire. Additionally, the technique can be mastered by any operator after a short period of training. The major limitation is presence of heavy calcification although when rotational atherectomy (RA) is required but cannot be applied due to inability to deliver the dedicated RotaWireTM (Boston Scientific), ELCA can create an upstream channel to permit RotaWire passage and complete the case with RA - the RASER technique.

AXXESS™ Stent: Delivery Indications and Outcomes.

The successful treatment of coronary bifurcation lesions remains one of the challenges of interventional cardiology. The current consensus of the European Bifurcation Club based on published data advocates a provisional strategy, treating the main vessel (MV) with a single stent covering the side branch (SB), with bailout SB stenting as required. The success of this approach may be limited by failure to attain SB access after MV stenting but is preferred in most situations over routine SB plus MV stent techniques, which are associated with a significant increase in the rate of major adverse cardiac events. The AXXESS self-expanding biolimus-eluting stent has been developed as a solution to these challenges within the coronary circulation and maintains provisional MV stent approach but with added assurance of maintained SB access. It has a unique conical structure that is positioned spanning the carina, with scaffold extending into the carina of both the MV and SB. The purpose of this article is to describe the indication, implantation technique and outcome data supporting the use of the AXXESS stent in the treatment of coronary bifurcation lesions.

Optical coherence tomography following percutaneous coronary intervention with Excimer laser coronary atherectomy.

The indications for Excimer laser coronary atherectomy (ELCA) have been refined in modern interventional practice. With the expanding role for optical coherence tomography (OCT) providing high-resolution intra-coronary imaging, this article examines the appearance of the coronary lumen after ELCA. Each indication for ELCA is discussed and illustrated with a clinical case, followed by detailed analysis of the OCT imaging pre and post ELCA. The aim of the article is to provide information to interventional cardiologists to facilitate decision making during PCI, when ELCA has been used as part of the interventional strategy.