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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.

ObjectivesBullying of trainee doctors has been shown to be associated with detrimental outcomes for both doctors and patients. However, there is limited evidence regarding the level of bullying of trainees within medical specialties.MethodsAn annual survey of UK cardiology trainees was conducted through the British Junior Cardiologists’ Association between 2017 and 2020 and asked questions about experiencing and witnessing bullying, and exposure to inappropriate language/behaviour in cardiology departments. Fisher’s exact tests and univariable logistic regression models were used to describe associations between trainee characteristics, and reports of bullying and inappropriate language/behaviour.ResultsOf 1358 trainees, bullying was reported by 152 (11%). Women had 55% higher odds of reporting being bullied (OR: 1.55 95% CI (1.08 to 2.21)). Non-UK medical school graduates were substantially more likely to be bullied (European Economic Area (EEA) OR: 2.22 (1.31 to 3.76), non-EEA/UK OR: 3.16 (2.13 to 4.68)) compared with those graduating from UK-based medical schools. Women were more likely than men to report sexist language (14% vs 4%, pDiscussionBullying and inappropriate language are commonly experienced by cardiology trainees and disproportionately affect women and those who attended non-UK medical schools. Consultants both in cardiology and other specialties are the most commonly reported perpetrators.

Introduction Valve-in-valve transcatheter aortic valve implantation (V-in-V TAVI) has become an increasingly popular alternative to re-do surgery for patients with failing aortic bioprosthetic valves. The Trifecta aortic valve replacement (AVR), designed for supra-annular insertion, consists of a titanium stent with externally mounted leaflets fashioned from bovine pericardium. Several studies have reported premature structural degeneration of the Trifecta valve. There are currently few data regarding the feasibility & efficacy of V-in-V TAVI within Trifecta bioprostheses. Methods This represents a retrospective review of prospectively collected data at our centre for TAVI procedures performed between January 1st 2015 and December 31st 2020 inclusive. In cases of V-in-V TAVI to treat a failing Trifecta valve, we collected demographic, procedural, echocardiographic and short-term follow-up data from electronic records systems for both this NHS Trust and primary care. Results Over a 6-year period, we performed 549 TAVI procedures, of which 51 (9.3%) were V-in-V cases. Of these 51, 15 (29%) were for patients with failing Trifecta valves (9 female, mean age 80.9 ± 5.6yrs;. predominant stenosis in 5 & transvalvular regurgitation in 10). Figures 1 & 2 demonstrate examples of prosthesis stenosis & prosthesis regurgitation treated by V-in-V TAVI. The median time from original AVR to V-in-V TAVI procedure was 59 months (IQR 36.5, range 16–93 months). All procedures were performed via the transfemoral route and 13/15 under conscious sedation. A balloon-expandable TAVI valve was used in 14 patients & a self-expanding valve in 1 patient. Post-procedural echocardiography revealed a mean aortic peak velocity 2.9 ± 0.4m/s & mean aortic gradient 19 ± 5mmHg. Paravalvular aortic regurgitation was absent in 7 cases, trivial in 6 & mild in 2 patients. In-hospital and 30-day mortality were 0%. There were three deaths during follow-up (36, 14 & 3 months post procedure), all of which were non-cardiac in nature. Conclusion V-in-V TAVI is a safe and feasible alternative to re-do surgical AVR for patients with a failing Trifecta aortic bioprosthesis. Unlike other bioprosthetic valves, the Trifecta valve cannot be fractured to enable a larger V-in-V TAVI valve to be implanted. Thus, longer term follow-up of such patients will allow a full understanding of the long-term haemodynamic and clinical outcomes in this patient cohort. Conflict of Interest Nil

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.

Background The use of high-sensitivity troponin (hs-cTn) is established in guideline-directed clinical practice to facilitate the diagnosis or exclusion of myocardial infarction (MI). The manufacturer provided 99th percentile for this assay is derived from a small population of relatively healthy individuals but is used as an “upper limit of normal” (ULN) in routine hospital practice. This raises the question: does this ULN actually represent the 99th centile of the distribution of the assay in an all comers hospital population, in most of whom there is no clinical suspicion of an MI? Methods Twenty thousand consecutive patients attending this large University Teaching Trust who had biochemistry tests for any clinical reason, either as in- or outpatient had an hs-cTn assay as part of this study. In those patients in whom hs-cTn was not requested by their supervising clinician, the result of the assay was nested, and never revealed to doctor or patient. Ethical approval for this method required special permission from the national Confidentiality Advisory Group following support from the British Cardiac Patients Association. The Beckman Coulter Access AccuTnI+3 assay was used throughout. These data were combined with the source location for the blood test, as well as the presence of coded co-morbidity since the year 2000. Results There were 18171 patients left once patients discharged with a diagnosis of MI (122) and those suspected of MI (1707) by the clinical team were excluded. There were 4759 inpatients, 9280 outpatients and 4132 patients in the emergency department with 7.3%, 2.0% and 7.4% of these having an hs-cTn level above the manufacturer-provided ULN respectively. Table 1 demonstrates the prevalence of hs-cTn levels above the ULN in hospitalised patients by speciality. In terms of outpatients; cardiothoracic, renal and oncology/haematology patients were the most likely to have an hs-cTn above the ULN with 7.4%, 4.9% and 2.6% respectively above this level. There were 4265 (46%) outpatients in whom there was at least one coded co-morbidity present. These patients were more likely to have an hs-cTn above the ULN than those without a coded co-morbidity (2.8% versus 1.2%, P Conclusion These data suggest that application of a manufacturer-derived 99th centile for hs-cTn assay to a hospital population may be flawed, particularly if any assumption is made that a result above this level may represent acute MI in patients without a classical history. Caution and a good understanding of the assay is imperative for accurate diagnosis and management of hospital patients with an apparently elevated level, but these results also raise interesting questions about what the levels actually indicate in patients in whom the suspicion f acute Mi is low. More data are required. Conflict of Interest Educational support from BAYER

ObjectiveTo 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.DesignProspective, observational cohort study.SettingUniversity Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom, between 29 June 2017 and 24 August 2017.Participants20 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 measuresDistribution of hs-cTnI concentrations of all study participants and specifically the 99th centile.ResultsThe 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.ConclusionsOf 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 registrationClinicaltrials.govNCT03047785.

Purpose of the study Out-of-hospital cardiac arrest (OHCA) has a poor prognosis despite bystander resuscitation and rapid transfer to hospital. Optimal management of patients after arrival to hospital continues to be contentious, especially the timing of emergency coronary angiography±revascularisation. Robust predictors of inhospital outcome would be of clinical value for initial decision-making. Study design A retrospective analysis of consecutive patients who presented to a university hospital following OHCA over a 70-month period (2008–2013). Patients were identified from the emergency department electronic patient registration and coding system. For those patients who underwent emergency percutaneous coronary intervention, details were crosschecked with national databases. Results We identified 350 consecutive patients who were brought to our hospital following OHCA. Return of spontaneous circulation (ROSC) for >20 min was achieved either before arrival or inhospital in 196 individuals. From the 350 subjects, 114 (32.6%) survived to hospital discharge. When sustained ROSC was achieved, either before or inhospital, survival to discharge was 58.2% (114 of 196). Non-shockable rhythm, absence of bystander cardiopulmonary resuscitation, ‘downtime’ >15 min and initial pH ≤7.11 were predictors of inhospital death. 12% patients who underwent angiography in the presence of ST elevation had no acute coronary occlusion. 21% patients with acute coronary occlusion at angiography did not have ST elevation. Conclusions In our cohort of patients with OHCA, those who achieve ROSC had a survival-to-discharge rate of 58.2%. We identified four predictors of inhospital death, which are readily available at the time of patient presentation. Reliance on ST elevation to decide about coronary angiography and revascularisation may be flawed. More data are required.

Objective: To define the 99th percentile of high sensitivity cardiac troponin I (hs-cTnI) concentration for a hospital population. Design: Prospective study of 20,000 consecutive patients undergoing blood sampling for any reason at a large teaching hospital. Setting: University Hospital Southampton NHS Trust (UHS). Participants: 20,000 consecutive individuals, inpatient or outpatient, undergoing blood tests at UHS for any clinical reason. Hs-cTnI concentrations (Beckman Coulter Access AccuTnI 3 assay) were nested for analysis in all cases except those in whom the supervising physician had requested hs-cTnI for clinical reasons. Main outcome measures: Distribution of hs-cTnI concentrations of all study patients. Results: The 99th percentile of hs-cTnI for the whole population (n=20,000) was 296 ng/L, compared to a manufacturer quoted 99th percentile of 40 ng/L (currently used clinically as the "upper limit of normal", ULN). In 1 in 20 (5.4%, n=1080) of the total population hs-cTnI concentrations were above 40 ng/L. After exclusion of individuals diagnosed with an acute myocardial infarction (AMI) (n=122), or those in whom troponin was requested (n=1707), the 99th percentile of the remainder (n=18,171) was 189 ng/L. The 99th percentile for inpatients (n=4759) and outpatients (n=9280) was 563 ng/L and 65 ng/L, respectively. Patients from the emergency department (n=3706) had a 99th percentile of 215 ng/L, with 6.1% (n=491) above the quoted ULN. 39% (n=48) of all individuals from the critical care units (n=123) and 15.7% (n=87) of all medical inpatients had a hs-cTnI concentration above the quoted ULN. Conclusions: In 20,000 consecutive patients undergoing a blood test for any reason at this hospital 1 in 20 have a hs-cTnI above the manufacturer quoted ULN. These data highlight the need for clinical staff to interpret hs-cTnI concentrations carefully, particularly when applying the manufacturer's ULN to diagnose AMI. The use of hs-cTn to diagnose AMI in any patient without a typical history may be flawed. Funding Statement: Unrestricted Research Grant – Beckman Coulter Declaration of Interests: M. Mariathas – none declared, R. Allan – none declared, B. Olechowski – none declared, S. Ramamoorthy – none declared, M. Azor – none declared, Z. Nicholas – none declared, A. Calver – none declared, S. Corbett – none declared, M. Mahmoudi – none declared, J. Rawlins – none declared, I. Simpson – none declared, J. Wilkinson – none declared, C. Kwok- none declared, M. Mamas- none declared, P. Cook – none declared, N. Curzen – unrestricted research grants from: Boston Scientific; Haemonetics; Heartflow; Beckmann Coulter. Speaker fees/consultancy from: Haemonetics, Abbot Vascular; Heartflow; Boston Scientific. Travel sponsorship – Biosensors, Abbot, Lilly/D-S; St Jude Medical, Medtronic. Ethics Approval Statement: This research project was undertaken according to the principles of Good Clinical Practice and the Declaration of Helsinki. The study was approved by the local ethical committee who then referred it to the Health Research Authority (HRA) UK for further approval (Rec reference: 17/SC/0042, IRAS project ID: 215262). The method did not require knowledge or consent from patients.

We describe the case of a 45-year-old woman presenting with troponin positive cardiac-sounding chest pain. An initial emergency angiogram demonstrated two vessel coronary disease, including a distal right coronary artery occlusion. No percutaneous coronary intervention was performed and the patient was treated medically. At re-presentation with further pain a few days later, coronary angiography demonstrated no significant coronary lesions. After consideration of other multisystem symptoms and raised eosinophil count, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) presenting with coronary arteritis. This case should remind physicians to be vigilant and to consider non-atherosclerotic causes of acute coronary syndrome presentation, which should not always result in a stent.

Background— The use of coronary angiography (CA) for diagnosis and management of chest pain (CP) has several flaws. The assessment of coronary artery disease using fractional flow reserve (FFR) is a well-validated technique for describing lesion-level ischemia and improves clinical outcome in the context of percutaneous coronary intervention. The impact of routine FFR at the time of diagnostic CA on patient management has not been determined. Methods and Results— Two hundred patients with stable CP underwent CA for clinical indications. The supervising cardiologist (S.C.) made a management plan based on CA (optimal medical therapy alone, percutaneous coronary intervention, coronary artery bypass grafting, or more information required) and also recorded which stenoses were significant. An interventional cardiologist then measured FFR in all patent coronary arteries of stentable diameter (≥2.25 mm). S.C. was then asked to make a second management plan when FFR results were disclosed. Overall, after disclosure of FFR data, management plan based on CA alone was changed in 26% of patients, and the number and localization of functional stenoses changed in 32%. Specifically, of 72 cases in which optimal medical therapy was recommended after CA, 9 (13%) were actually referred for revascularization with FFR data. By contrast, of 89 cases in whom management plan was optimal medical therapy based on FFR, revascularization would have been recommended in 25 (28%) based on CA. Conclusions— Routine measurement of FFR at CA has important influence both on which coronary arteries have significant stenoses and on patient management. These findings could have important implications for clinical practice. Clinical Trial Registration— URL: http://www.clinicaltrial.gov . Unique identifier: NCT01070771.

An 80-year-old man developed severe haemodynamic instability during a transapical aortic valve implantation. He was not suitable for a conventional surgical approach due to comorbidities and patent aortocoronary bypass grafts also limited further stabilizing actions. As a bail-out procedure, we demonstrate the feasibility of transapical arterial cannulation by crossing a newly implanted TAVI valve in order to establish an emergency bypass circuit

Summary Background Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, mostly clopidogrel, is the default therapy in both acute coronary syndrome (ACS) and after intracoronary stents. It is well established that responses to antiplatelet therapy (APT), particularly clopidogrel, are subject to considerable interindividual variability. Objectives We investigated whether responses to APT in individuals vary significantly over time. Methods Simultaneous assay with VerifyNow™ and short thrombelastography (s-TEG) was performed before and at four time points over 6 months after hospital discharge in 40 patients receiving DAPT. Serum thromboxane B2 levels were also measured. Results While aspirin response units (ARU) by VerifyNow™ and serum thromboxane B2 levels remained stable over time, arachidonic acid (AA)–mediated platelet aggregation with s-TEG (i.e. area under the curve at 15 min in AA channel, AUC15AA) increased at 1 week compared with predischarge (P

Abstract Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.

Background Trans-catheter aortic valve implantation (TAVI) is an effective treatment for high risk patients with severe aortic stenosis. As with all prosthetic valves, it is important to document accurate post-procedural gradients for future comparison. This study aimed to determine whether there was a difference between gradients measured immediately post-procedure by trans-oesophageal echocardiography (TOE) compared with the pre-discharge trans-thoracic echocardiogram (TTE). We also compared pre-TAVI gradients obtained by TTE vs. TOE. Methods We used local and national databases to gather demographics on TAVI patients from our centre and to identify peak and mean aortic gradients measured by TTE and TOE prior to TAVI and also immediately following TAVI deployment (TOE) and prior to discharge (TTE). Data were compared using the paired t-test. Results We identified 106 TAVI patients with complete echocardiographic data-sets. The mean age was 81+/-8 yrs and 62(54%) were male. All patients received an Edwards Sapien valve. Pre-TAVI, there were no significant differences between TOE and TTE for both peak (72.2+/-24.8 mmHg vs 71.9+/- 24.0 mmHg, p = 0.83) and mean (41.4+/-15.0 mmHg vs 42.4+/-14.9 mmHg,p = 0.22) gradients. However, following TAVI, the peak trans-valvular gradients by TOE vs. TTE were 12+/-6 mmHg vs 22+/-9 mmHg (p Conclusions Although TTE and TOE perform similarly prior to TAVI, the immediate post-procedural assessment of trans-aortic gradients by TOE leads to significant under-estimation compared to TTE. Intra-procedural TOE should not be used to define baseline peak and mean aortic gradients after TAVI.

Objective Previous studies have demonstrated significant heterogeneity in responses to antiplatelet therapy (APT), and high residual platelet reactivity is associated with the risk of ischaemic events, including stent thrombosis (ST). The prevalence of APT hyporesponsiveness in a ‘real world’ registry of ST patients and the feasibility of personalising APT are reported. Patients and setting 39 consecutive patients admitted to a single regional cardiothoracic centre with definite ST were prospectively evaluated. Interventions Response to aspirin and clopidogrel was measured following discharge using short thrombelastography (TEG), a rapid, well validated near patient platelet function test. Treatment modification in hyporesponders comprised an increase in aspirin dose and/or changing clopidogrel to prasugrel or ticagrelor. Short TEG was repeated following treatment modification to ensure an adequate response had been achieved. Results 12 (31%) patients had an adequate response to both aspirin and clopidogrel, 16 (41%) were hyporesponsive to clopidogrel alone, one (3%) was hyporesponsive to aspirin alone and 10 (26%) were hyporesponsive to both aspirin and clopidogrel. Following treatment modification, an adequate response to aspirin and P2Y12 agent was achieved in 10 (91%) and 22 (85%) patients, respectively. None has presented with a further ST episode. Conclusions There is a high prevalence of hyporesponsiveness to APT in patients with ST. Improved APT efficacy can be achieved by tailored therapy. Short TEG is a plausible platelet function test that can be used to deliver point of care personalised APT.

1. Nitric oxide (NO) is a potent endogenous vasodilator and plays a role in the control of resting vascular tone. Patients with cirrhosis have a hyperdynamic circulation with reduced blood pressure and decreased peripheral resistance, and it is possible that increased production of NO due to induction of NO synthase may be involved in maintaining this vasodilatation. We have examined this possibility by studying the effects of local infusions of NG-monomethyl-l-arginine (an inhibitor of NO synthase) in the forearm arteriolar bed and the superficial dorsal hand veins of patients with alcoholic cirrhosis. 2. Drugs were either infused locally into the brachial artery and forearm blood flow was measured by venous occlusion plethysmography, or into a vein on the back of the hand and vein diameter was measured using a linear displacement technique. 3. Basal forearm blood flow was increased and vascular resistance was decreased in the patients with alcoholic cirrhosis compared with healthy control subjects. Noradrenaline and NG-monomethyl-l-arginine caused dose-dependent falls in forearm blood flow in both healthy control subjects and patients with cirrhosis. There was no significant difference in the responses to either noradrenaline or NG-monomethyl-l-arginine between the two groups. 4. In the superficial hand veins there was no change in vein size in response to NG-monomethyl-l-arginine infused alone, and venoconstriction to local infusion of noradrenaline was unaffected by co-infusion with NG-monomethyl-l-arginine. 5. Our results confirm that patients with alcoholic cirrhosis are vasodilated compared with healthy control subjects. Our findings show that basal NO-mediated vasodilatation occurs in the forearm arterial bed, but not the superficial hand veins, of these patients. However, since the response to local NO synthesis inhibition was similiar in the two groups, increased production of NO due to induction of NO synthase is unlikely to account fully for the vasodilatation seen in patients with mild to moderate alcoholic cirrhosis.

Background The optimal duration of clopidogrel treatment, particularly following drug-eluting stent (DES) implantation, remains contentious. Previous studies have observed a clustering of adverse events following clopidogrel cessation 1 year after DES, the aetiology of which is poorly understood. Objective To investigate, in the prospective CESSATION study, the effect of clopidogrel withdrawal at 1 year after DES implantation on (i) arachidonic acid (AA)- and adenosine diphosphate (ADP)-induced platelet aggregation, and (ii) biomarkers of vascular inflammation, including soluble CD40 ligand (sCD40L), high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6). Methods and results The prospective CESSATION study was undertaken in 33 patients receiving aspirin and due to discontinue clopidogrel 1 year after DES. Platetet reactivity was measured using short thromboelastography, and compliance with aspirin determined from serum thromboxane B 2 (TXB 2 ) levels. Venesection was performed at 4 weeks and 24 h before, and at 24 h, 48 h, 1, 2 and 4 weeks after, clopidogrel cessation. Following clopidogrel withdrawal, there was (i) a predictable increase in ADP-induced platelet aggregation (ii) an unexpected significant increase in AA-induced platelet aggregation (iii) a decline in IL-6 and hsCRP at 1 week and 4 weeks respectively; and (iv) a non-significant increase in sCD40L at 4 weeks TXB 2 levels were consistently suppressed, indicating complete inhibition of cyclo-oxygenase-1 by aspirin. Conclusion An aspirin-independent, time-dependent increase in AA-induced platelet activation following clopidogrel withdrawal in patients with a DES has been described. New insights into a potential mechanism for the observed clustering of adverse events that occur early after clopidogrel cessation have been provided. These findings raise the question as to whether AA-induced clotting is an appropriate test of aspirin sensitivity.

Patients with insulin-dependent diabetes mellitus have an increased mortality and morbidity due to vascular complications. Nitric oxide from the vascular endothelium contributes to the control of normal vascular tone, and endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disease. In this study we have examined basal and stimulated nitric oxide-mediated vasodilatation in insulin-dependent diabetics and age- and sex-matched healthy controls. Drugs were infused locally into the brachial artery and forearm blood flow measured using venous occlusion plethysmography. Noradrenaline and NG-monomethyl-L-arginine produced similar reductions in resting forearm blood flow in healthy controls. However, in the diabetics, NG-monomethyl-L-arginine was significantly less effective than noradrenaline. Comparing between groups, the response to NG-monomethyl-L-arginine was also significantly less in the diabetics compared with the healthy controls. The response to sodium nitroprusside was significantly less in the diabetics compared with the healthy controls, whereas the responses to both acetylcholine and verapamil were the same in the two groups. The results provide evidence for an abnormality of basal nitric oxide-mediated dilatation in the forearm arterial bed of patients with insulin-dependent diabetes mellitus, and suggest that the vascular smooth muscle is less sensitive to nitric oxide.

A 52-year-old female was admitted to the hospital with a 1-month history of increasing breathlessness, exertional chest tightness, palpitation, and lethargy. Echocardiography revealed a secundum atrial septal defect. Cardiac catheterization confirmed the diagnosis, and the coronary angiogram revealed a critical 90% stenosis in the midright coronary artery (RCA). Under general anaesthesia, two 15-mm intracoronary stents were placed in the RCA with an excellent angiographic result. The atrial septal defect was then closed percutaneously using the Angel-Wings atrial septal defect occluder device. Perioperative transesophageal echocardiography confirmed satisfactory positioning of the Angel Wings device and color flow mapping showed no residual shunt across the atrial septum. The patient was discharged home the following day. Percutaneous closure of atrial septal defects offers the chance to replace an open heart surgical procedure with a minimally invasive treatment that allows discharge from the hospital on the day after the closure. To date, adult patients who have concomitant coronary artery disease and an atrial septal defect have undergone surgery even if their coronary lesion was amenable to percutaneous treatment with angioplasty. We describe a patient in whom stenting of the RCA and percutaneous closure of an atrial septal defect were performed concomitantly. (J Interven Cardiol 2000;13:35–38)

Stenting of a coronary artery narrowing across a bifurcation with a side branch artery may result in a significant angiographic stenosis (nipping) of the side branch. If this causes symptoms of chest pain or ischaemic ECG changes at the time of the procedure, additional angioplasty (with or without stent insertion) through the stent struts is usually undertaken to improve blood flow into the side branch, but this increases subsequent risks of restenosis and stent thrombosis in the main vessel. In the absence of symptoms or ECG abnormalities, the functional significance of side branch nipping is uncertain and opinion on whether to treat a nipped side branch remains divided.1–4 The coronary pressure-derived fractional flow reserve (FFR) is a lesion-specific means of determining the functional significance of coronary artery narrowings, but its value in assessing side branch nipping is not known. This pilot study aimed to assess the correlation between the FFR across nipped side branch arteries that have been crossed by main vessel stents, with the degree of angiographic narrowing at the side branch ostium. The potential role of the coronary pressure wire in guiding treatment of the nipped side branch is considered. This study was registered with Southampton University NHS Trust R&D Department and approved by the local ethics committee. All patients gave written informed consent. All patients were scheduled for elective percutaneous intervention (PCI) for symptoms of chronic stable …

A 46-year-old woman was admitted to our hospital with acute shortness of breath and pre-syncope. She had known massive uterine fibroids with a history of menorrhagia and dysmenorrhoea, and had been awaiting total abdominal hysterectomy and bilateral salpingo-oophorectomy. She had no past or family history of venous thromboembolism (VTE). She was an ex-smoker with a 16-pack/year smoking history. On examination, she looked unwell, was sweaty and clammy, but apyrexial. Her heart rate was 130 per minute and her blood pressure was 140/95 mmHg. She was tachypnoeic with a respiratory rate of 28 breaths per minute; however, her chest was clear. Abdominal examination revealed an enormous uterus, equivalent to the size of a 30-week pregnancy. There was no clinical evidence of deep vein thrombosis (DVT). She was hypoxic: oxygen saturation on air was 88%; arterial blood gas measurement on 100% oxygen—pH 7.4, PO2 29.0mmHg, PCO2 3.5mmHg, bicarbonate 18.5mmol/L, base excess of 7.5 mol/L. Her full blood count revealed a microcytic anaemia with a mean cellular volume of 67.9 fl (normal: 81–99 fl) and haemoglobin of 9.4 g/dL (normal: 12.0–15.0 g/L). Her D-dimer was significantly elevated at 1.7 Ag/mL (normal

Objectives—To assess procedural outcome, complications, and clinical follow up in 218 patients who underwent treatment with 297 Multi-link (Guidant) stents implanted without the use of intravascular ultrasound (IVUS) or quantitative coronary angiography (QCA), and using aspirin alone as antiplatelet therapy. Methods—The case records and angiograms were reviewed and the patients were contacted by telephone to determine their symptoms and any adverse events at follow up. Data were analysed using Fisher's exact test. Results—Of the 218 patients included in the study, 45 had multivessel intracoronary intervention, and 55 had unstable angina. The mean (SD) length of hospital stay following the procedure was 2.0 (2.1) days. There were two early deaths at less than 30 days, and two deaths during follow up at more than 100 days. Ten patients suffered complications during the first 30 days: four had subacute stent thrombosis, of whom two died and two were treated successfully with coronary artery bypass grafting; five had a non-Q wave myocardial infarction; and one had a femoral false aneurysm. Patient outcome was analysed according to stent diameter (3.0 mm or less, or 3.5 mm or more) and by angina status (stable or unstable). In patients in whom at least one stent was 3.0 mm diameter, four of 86 patients suffered acute stent occlusion, whereas in the 132 patients in whom all stents were at least 3.5 mm diameter there were no cases of stent occlusion (p = 0.02). In the unstable angina group two of 55 patients suffered acute stent occlusion compared to two of 163 patients in the stable angina group (NS). In patients with unstable angina and at least one stent of 3.0 mm diameter, the acute occlusion rate was 7.1% (two of 28 patients). Three of the four patients with stent occlusion had undergone complex procedures. Twenty eight patients were restudied for recurrent symptoms during the follow up period. Of these, eight patients had restenosis within their stent. In seven of these patients the stent size was 3.0 mm diameter, and in the remaining patient the stent size was 4.0 mm diameter. Three of the 28 patients restudied had developed new disease remote from the stented site, and 17 had patent stents and no significant other coronary lesion. Conclusions—This study suggests that coronary intervention using the Multi-link stent is safe and effective using aspirin alone, without IVUS or QCA, when stent diameter is greater than 3.0 mm. All cases of stent occlusion in this series occurred in patients in whom at least one stent was 3.0 mm diameter, with stent occlusion being higher in patients with unstable angina compared to those with stable angina. Additional antiplatelet therapy may be beneficial in those patients in whom Multi-link stent diameter is less than 3.5 mm, particularly in those with unstable angina, but is not necessary for patients receiving Multi-link stents of 3.5 mm diameter or greater. Keywords: intracoronary Multi-link stents; aspirin; stent occlusion

1. The vascular and hormonal effects of l- and d-arginine were compared in healthy subjects and in patients with insulin-dependent diabetes mellitus or untreated essential hypertension. 2. Infusion of l- or d-arginine (40 μmol/l) in the forearm vascular bed, sufficient to increase the local concentration approximately 20-fold, had no effect on blood flow or the vasodilator response to acetylcholine (30 and 100 nmol/min) in patients with insulin-dependent diabetes (n = 7) or essential hypertension (n = 7), or in age- and sex-matched control subjects (n = 7 in both groups). 3. Systemic infusion of 10 g of l-arginine (n = 5) or d-arginine (n = 3) increased plasma concentration of arginine approximately 20-fold without altering supine or erect haemodynamics. Increases in plasma insulin, prolactin and glucagon were seen with both enantiomers. The stereopurity of arginine was confirmed in a cell-culture assay system. 4. We conclude that, in healthy subjects and patients with essential hypertension or insulin-dependent diabetes, synthesis of nitric oxide within the vasculature is not limited by substrate availability. At high concentrations of arginine, non-stereospecific effects, including alterations in hormone concentration, occur. It remains to be determined whether these non-stereospecific hormonal changes might contribute to certain haemodynamic effects of arginine.

Introduction A clustering of adverse events, in particular stent thrombosis (ST) has been observed following clopidogrel cessation 1-year after drug-eluting stenting (DES), the aetiology of which is poorly understood. We investigated the effect of withdrawing clopidogrel in DES patients using a simple, rapid, reproducible near-patient platelet function test known as short Thrombelastography (s-TEG) that has been developed and validated by this group. Methods 33 patients on aspirin and due to stop clopidogrel at 1 year following DES were investigated. Venesection was performed at (i) 4 weeks and 24 h pre clopidogrel cessation (ii) 24 h, 48 h, 1, 2 and 4 weeks post clopidogrel cessation. At all time-points, platelet reactivity was determined using s-TEG and thromboxane (TX) B2, IL-6, CD40 ligand and high sensitivity CRP were measured. Results Clopidogrel cessation produced (i) a predictable increase in ADP-induced platelet aggregation, and (ii) an unexpected and significant rise in AA-induced platelet aggregation. TXB2 was consistently suppressed confirming inhibition of COX by aspirin. Conclusion We have described for the first time an aspirin-independent increase in AA-induced clotting following clopidogrel withdrawal in DES patients. As well as potentially helping to explain the observed clustering of ST events early after clopidogrel withdrawal, these findings raise the question as to whether AA-induced clotting is an appropriate test of aspirin sensitivity. Our results also confirm s-TEG as a plausible candidate for near-patient platelet function testing in this field.

1. Using venous occlusion plethysmography, we have investigated the forearm blood flow response in healthy subjects to the acute plasma volume expansion caused by a rapid intravenous infusion of saline. The contribution made to this response by nitric oxide has been investigated using local intra-arterial infusions of the nitric oxide synthase inhibitor NG-monomethyl-l-arginine. 2. The infusion of 1000 ml of saline over 25 min caused plasma volume to increase by about 7%, and resulted in a rise in forearm blood flow, with no change in arterial blood pressure. The onset of the blood flow response occurred within 10 min and blood flow remained elevated above baseline 20 mm after the end of the saline infusion. 3. Local intra-arterial infusion of NG-monomethyl-l-arginine alone caused a reduction in forearm blood flow which was maximal at the end of the infusion and gradually recovered to baseline levels over 40 min. 4. When local intra-arterial infusion of NG-monomethyl-l-arginine was followed by plasma volume expansion, the calculated effect of NG-monomethyl-l-arginine was such as to abolish the vasodilator response to saline. 5. The effect of local intra-arterial infusion of NG-monomethyl-l-arginine on forearm blood flow was greater when the drug was given after volume expansion had occurred, than when it was given before the administration of saline. However, in control experiments the vasoconstrictor response to noradrenaline was also enhanced after the administration of the volume load in comparison with the response to noradrenaline given alone. 6. These results are consistent with the possibility that increased local synthesis of nitric oxide contributes to the vasodilator response to volume expansion.

There is indirect evidence that the nitric oxide system may be impaired in hypertensive patients. The objective of this study was to examine basal nitric oxide-mediated dilation in hypertensive patients.The forearm blood flow (FBF) response to noradrenaline and NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide synthesis, was compared in seven untreated hypertensive patients and 17 normotensive controls.Drugs were infused locally into the brachial artery and FBF measured using venous occlusion plethysmography.In normotensives noradrenaline (60, 120 and 240 pmol/min) and L-NMMA (1,2 and 4 mumol/min) produced similar reductions in resting FBF. In the hypertensives L-NMMA was significantly less effective than noradrenaline, such that the threshold dose for L-NMMA vasoconstriction was increased and the overall response to L-NMMA reduced. Furthermore, when noradrenaline was used as an internal control there was a significant negative relationship between the response to L-NMMA and blood pressure. When the responses to L-NMMA and noradrenaline were compared between groups, the response to L-NMMA was significantly less in hypertensives compared with normotensives, whereas there was no statistical difference in the response to noradrenaline between the two groups.The results suggest an abnormality of basal nitric oxide-mediated dilation in the forearm arteriolar bed of patients with untreated essential hypertension.

PURPOSE To review recent research into the function of endothelial cells in relation to diabetes and hypertension, and the implications for cardiovascular control. ENDOTHELIAL FUNCTIONS Endothelial cells extract and inactive circulating hormones, convert inactive precursors into vasoactive products, and synthesize and secrete vasodilator and vasoconstrictor mediators, which also modify platelet function and cell growth. DIABETES Abnormalities in endothelial cell morphology and function are recognized features of diabetes. Diminished endothelium-dependent relaxation and enhanced endothelium-dependent contraction have been described. HYPERTENSION Similar defects in endothelial cell function have been demonstrated in animal and human hypertension. These might lead to increased vascular tone, vasospasm, platelet activation and atheroma. THERAPY Certain drugs modify or mimic endothelium-derived mediators. Endothelial dysfunction may contribute to cardiovascular pathology, but the precise clinical and therapeutic significance of modifying endothelial function remains to be determined.

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.

Nitric oxide (NO) is a widespread biological mediator with myriad functions. We have demonstrated that methylated arginines capable of inhibiting NO synthesis circulate in the plasma of healthy volunteers and are excreted unchanged in the urine. Up to 10 mg of asymmetric dimethylarginine is excreted in the urine every day, and this compound inhibits NO synthesis in vitro and in vivo, in animals and in humans. This finding raises the possibility that these compounds may act as endogenous regulators of the L-arginine:NO pathway in health and disease.