Duration of triple antithrombotic therapy and clinical outcomes after percutaneous coronary intervention in atrial fibrillation.

BACKGROUND: Triple antithrombotic therapy (TAT) with aspirin, a P2Y12 inhibitor, and oral anticoagulation in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) raises concerns about increased bleeding. Regimens incorporating more potent P2Y12 inhibitors over clopidogrel have not been investigated adequately. RESEARCH DESIGN AND METHODS: A retrospective observational study was performed on 387 patients with AF receiving TAT for 1 month (n = 236) or ≤1 week (n = 151) after PCI. Major and clinically relevant non-major bleeding and major adverse cardiac and cerebrovascular events (MACCE) were assessed up to 30 days post-procedure. RESULTS: Bleeding was less frequent with ≤1 week versus 1 month of TAT (3.3 vs 9.3%; p = 0.025) while MACCE were similar (4.6 vs 4.7%; p = 0.998). No differences in bleeding or MACCE were observed between ticagrelor/prasugrel and clopidogrel regimens. For patients receiving ≤1 week of TAT, no excess of MACCE was seen in the subgroup given no further aspirin post-PCI compared with those given aspirin for up to 1 week (3.6 vs 5.2%). CONCLUSIONS: TAT post-PCI for ≤1 week was associated with less bleeding despite greater use of ticagrelor/prasugrel but similar MACCE versus 1-month TAT. These findings support further studies on safety and efficacy of dual therapy with ticagrelor/prasugrel immediately after PCI.

Modelled impact of virtual fractional flow reserve in patients undergoing coronary angiography (VIRTU-4).

BACKGROUND: The practical application of 'virtual' (computed) fractional flow reserve (vFFR) based on invasive coronary angiogram (ICA) images is unknown. The objective of this cohort study was to investigate the potential of vFFR to guide the management of unselected patients undergoing ICA. The hypothesis was that it changes management in >10% of cases. METHODS: vFFR was computed using the Sheffield VIRTUheart system, at five hospitals in the North of England, on 'all-comers' undergoing ICA for non-ST-elevation myocardial infarction acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The cardiologists' management plan (optimal medical therapy, percutaneous coronary intervention (PCI), coronary artery bypass surgery or 'more information required') and confidence level were recorded after ICA, and again after vFFR disclosure. RESULTS: 517 patients were screened; 320 were recruited: 208 with ACS and 112 with CCS. The median vFFR was 0.82 (0.70-0.91). vFFR disclosure did not change the mean number of significantly stenosed vessels per patient (1.16 (±0.96) visually and 1.18 (±0.92) with vFFR (p=0.79)). A change in intended management following vFFR disclosure occurred in 22% of all patients; in the ACS cohort, there was a 62% increase in the number planned for medical management, and in the CCS cohort, there was a 31% increase in the number planned for PCI. In all patients, vFFR disclosure increased physician confidence from 8 of 10 (7.33-9) to 9 of 10 (8-10) (p<0.001). CONCLUSION: The addition of vFFR to ICA changed intended management strategy in 22% of patients, provided a detailed and specific 'all-in-one' anatomical and physiological assessment of coronary artery disease, and was accompanied by augmentation of the operator's confidence in the treatment strategy.

Left ventricular blood flow kinetic energy is associated with the six-minute walk test and left ventricular remodelling post valvular intervention in aortic stenosis.

BACKGROUND: Left ventricular (LV) kinetic energy (KE) assessment by four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) may offer incremental value over routine assessment in aortic stenosis (AS). The main objective of this study is to investigate the LV KE in patients with AS before and after the valve intervention. In addition, this study aimed to investigate if LV KE offers incremental value for its association to the six-minute walk test (6MWT) or LV remodelling post-intervention. METHODS: We recruited 18 patients with severe AS. All patients underwent transthoracic echocardiography for mean pressure gradient (mPG), CMR including 4D flow and 6MWT. Patients were invited for post-valve intervention follow-up CMR at 3 months and twelve patients returned for follow-up CMR. KE assessment of LV blood flow and the components (direct, delayed, retained and residual) were carried out for all cases. LV KE parameters were normalised to LV end-diastolic volume (LVEDV). RESULTS: For LV blood flow KE assessment, the metrics including time delay (TD) for peak E-wave from base to mid-ventricle (14±48 vs. 2.5±9.75 ms, P=0.04), direct (4.91±5.07 vs. 1.86±1.72 µJ, P=0.01) and delayed (2.46±3.13 vs. 1.38±1.15 µJ, P=0.03) components of LV blood flow demonstrated a significant change between pre- and post-valve intervention. Only LV KEiEDV (r=-0.53, P<0.01), diastolic KEiEDV (r=-0.53, P<0.01) and Ewave KEiEDV (r=-0.38, P=0.04) demonstrated association to the 6MWT. However, Pre-operative LV KEiEDV (r=0.67, P=0.02) demonstrated association to LV remodelling post valve intervention. CONCLUSIONS: LV blood flow KE is associated with 6MWT and LV remodelling in patients with AS. LV KE assessment provides incremental value over routine LV function and pressure gradient (PG) assessment in AS.

The new role of diagnostic angiography in coronary physiological assessment.

The role of 'stand-alone' coronary angiography (CAG) in the management of patients with chronic coronary syndromes is the subject of debate, with arguments for its replacement with CT angiography on the one hand and its confinement to the interventional cardiac catheter laboratory on the other. Nevertheless, it remains the standard of care in most centres. Recently, computational methods have been developed in which the laws of fluid dynamics can be applied to angiographic images to yield 'virtual' (computed) measures of blood flow, such as fractional flow reserve. Together with the CAG itself, this technology can provide an 'all-in-one' anatomical and functional investigation, which is particularly useful in the case of borderline lesions. It can add to the diagnostic value of CAG by providing increased precision and reduce the need for further non-invasive and functional tests of ischaemia, at minimal cost. In this paper, we place this technology in context, with emphasis on its potential to become established in the diagnostic workup of patients with suspected coronary artery disease, particularly in the non-interventional setting. We discuss the derivation and reliability of angiographically derived fractional flow reserve (CAG-FFR) as well as its limitations and how CAG-FFR could be integrated within existing national guidance. The assessment of coronary physiology may no longer be the preserve of the interventional cardiologist.

Percutaneous or surgical revascularization for left main stem disease: NOBLE ideas, but do they EXCEL?

Introduction: Although coronary artery bypass grafting (CABG) has traditionally been the standard treatment for significant left main stem (LMS) disease, percutaneous coronary intervention (PCI) using drug-eluting stents (DES) is now considered an acceptable alternative. Areas covered: This article aims to summarise the key findings of the landmark clinical trials on LMS revascularization and the recently published ESC/EACTS guidelines on myocardial revascularization related to LMS disease. Expert opinion: It is unlikely that there will be a further large randomized trial aimed at addressing the issue of the optimum method of revascularization for LMS disease. Both PCI and CABG are reasonable revascularization options for appropriately selected patients with LMS disease. 'Heart Team' approach is vital to guide the management of patients with LMS disease, when there is obvious clinical equipoise and a mandate for complete revascularization. With an aging and increasing co-morbid patient population, clinical equipoise may not always be obvious, making extrapolation of clinical trial results to the 'real world' difficult.

Autoinflammatory constrictive pericarditis and chronic myelomonocytic leukaemia: when one speciality is not enough.

We present a case of constrictive pericarditis with concomitant blood and bone marrow appearances of chronic myelomonocytic leukaemia (CMML). Despite surgical treatment with pericardiectomy, the patient deteriorated into multiorgan failure. Pericardial histology disclosed a typical inflammatory picture with no evidence of monocytic or malignant infiltrate. Following intensive collaboration between cardiologists, haematologists and rheumatologists via daily email exchanges, a diagnosis was reached of autoinflammatory constrictive pericarditis with a non-infiltrative coexisting CMML. The key to achieving a rapid and sustained response was a trial of high-dose steroids followed by intravenous immunoglobulins. This achieved restoration of cardiac function, resolution of symptoms and near normalisation of inflammatory markers. A diagnosis of concurrent CMML was confirmed at 3 months. The patient remains well, taking colchicine and steroids.

Transcatheter versus surgical intervention: lessons from trials of coronary revascularisation.

In this paper, a cardiac surgeon and an interventional cardiologist draw lessons from the trials of percutaneous coronary intervention/coronary artery bypass graft surgery (PCI/CABG) for the transcatheter aortic valve implantation/surgical aortic valve replacement (TAVI/SAVR) era. Both PCI and CABG are effective treatments, but do the trials ask the right questions? They dwell on the 'either/or' decision for selected patients suitable for both treatments, but provide little guidance for the majority of 'real world' patients with comorbidities precluding CABG, or complex coronary heart disease precluding PCI. The control group must be meaningful and relevant. The pace of technological and therapeutic change causes trials to date rapidly. Procedures often do not reflect everyday practice, such as performing multivessel PCI, copious stenting and full arterial grafting. Composite endpoints such as major adverse cardiovascular and cerebrovascular events (MACCE) provide statistical significance but little insight into patient-orientated needs. There is a variety of temporal, safety, symptomatic and prognostic endpoints, provoking debate over their relative and absolute magnitude and importance; and there are issues of interpretation and inappropriate extrapolation. Trial interpretation, crystallised in the Kaplan-Meier curve, focuses on the relative benefit of one treatment over another, but deserves careful scrutiny. Subgroup analysis tends to exceed its role in dealing with issues such as poor left ventricular function, diabetes, multivessel disease and proximal left anterior descending coronary artery stenosis. Meta-analysis is controversial and guidelines date rapidly, lacking robust evidence in some domains, yet assuming considerable importance. Measures of frailty, physiological measures of blood flow, 'real world' activity levels, and predictions of benefit rarely feature. The multidisciplinary Heart Team meeting, now integral to study design, is challenging to deliver in practice. The PCI/CABG trials, and the issues arising from them, provide salutary lessons in the TAVI/SAVR era.

Study of Two Dose Regimens of Ticagrelor Compared With Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease.

BACKGROUND: Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention for stable coronary artery disease. We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. METHODS: One hundred eighty aspirin-treated stable coronary artery disease patients, who were planned to undergo elective percutaneous coronary intervention in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or 1 of 2 regimens of ticagrelor, either 90 mg (T90) or 60 mg twice daily (T60), both with a 180 mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and postdose at 1 month, by adding adenosine 1 µmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30, and 60 seconds, then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T was measured pre- and 18 to 24 hours postpercutaneous coronary intervention. RESULTS: One hundred seventy-four patients underwent an invasive procedure, of whom 162 received percutaneous coronary intervention (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen postdose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15 seconds, mean±SD: clopidogrel 0.274±0.101 µmol/L; T90 0.278±0.134 µmol/L; T60 0.288±0.149 µmol/L; P=0.37). Similarly, no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P>0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow P2Y12 reaction units, 1 month, mean±SD: predose, T60: 62±47, T90: 40±38, clopidogrel 181±44; postdose, T60: 34±30, T90: 24±21, clopidogrel 159±57; all P<0.0001 for ticagrelor versus clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow P2Y12 reaction units>208, 1 month postdose: 0%, 0%, and 21%, respectively). Median (interquartile range) high-sensitivity troponin T increased 16.9 (6.5-46.9) ng/L for clopidogrel, 22.4 (5.5-53.8) ng/L for T60, and 17.7 (8.1-43.5) ng/L for T90 (P=0.95). There was a trend toward less dyspnea with T60 versus T90 (7.1% versus 19.0%; P=0.09). CONCLUSIONS: Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release after percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02327624.

Pharmacodynamic Effects of a 6-Hour Regimen of Enoxaparin in Patients Undergoing Primary Percutaneous Coronary Intervention (PENNY PCI Study).

Delayed onset of action of oral P2Y12 inhibitors in ST-elevation myocardial infarction (STEMI) patients may increase the risk of acute stent thrombosis. Available parenteral anti-thrombotic strategies, to deal with this issue, are limited by added cost and increased risk of bleeding. We investigated the pharmacodynamic effects of a novel regimen of enoxaparin in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Twenty patients were recruited to receive 0.75 mg/kg bolus of enoxaparin (pre-PPCI) followed by infusion of enoxaparin 0.75 mg/kg/6 h. At four time points (pre-anti-coagulation, end of PPCI, 2-3 hours into infusion and at the end of infusion), anti-Xa levels were determined using chromogenic assays, fibrin clots were assessed by turbidimetric analysis and platelet P2Y12 inhibition was determined by VerifyNow P2Y12 assay. Clinical outcomes were determined 14 hours after enoxaparin initiation. Nineteen of 20 patients completed the enoxaparin regimen; one patient, who developed no-reflow phenomenon, was switched to tirofiban after the enoxaparin bolus. All received ticagrelor 180 mg before angiography. Mean (± standard error of the mean) anti-Xa levels were sustained during enoxaparin infusion (1.17 ± 0.06 IU/mL at the end of PPCI and 1.003 ± 0.06 IU/mL at 6 hours), resulting in prolonged fibrin clot lag time and increased lysis potential. Onset of platelet P2Y12 inhibition was delayed in opiate-treated patients. No patients had thrombotic or bleeding complications. In conclusion, enoxaparin 0.75 mg/kg bolus followed by 0.75 mg/kg/6 h provides sustained anti-Xa levels in PPCI patients. This may protect from acute stent thrombosis in opiate-treated PPCI patients who frequently have delayed onset of oral P2Y12 inhibition.

The impact of Objective Mathematical Analysis during Fractional Flow Reserve measurement: results from the OMA-FFR study.

AIMS: Fractional flow reserve (FFR), the reference standard for guiding coronary revascularisation, is most commonly acquired during intravenous adenosine infusion. Results may be sensitive to system- and operator-dependent variability in how pressure data are analysed and interpreted. To quantify FFR objectively, we developed a computational protocol to process the recorded pressure signals in a consistent manner. We studied the impact on lesion (re)classification and compared this with the operator-selected FFR obtained during cardiac catheterisation. METHODS AND RESULTS: The algorithm used a moving average and Fourier transformation to identify the Pd/Pa ratio at its nadir (FFRmin) and during the stable hyperaemic period (FFRstable) in <2 s with 100% repeatability, in 163 coronary stenoses (93 patients). The mean operator-selected FFR (FFRCL) was higher than FFRmin and lower than FFRstable (0.779 vs. 0.762 vs. 0.806, p=<0.01). Compared with FFRmin, FFRstable resulted in 16.5% of all lesions being reclassified, all from significant to non-significant (p<0.01). FFRCL classified lesion significance differently from both FFRstable and FFRmin (11.7% and 6.1% lesions reclassified, respectively, p<0.01). CONCLUSIONS: Subtle differences in how pressure data are analysed and interpreted by the operator during adenosine infusion result in significant differences in the classification of physiological lesion significance. An algorithmic analysis may be helpful in standardising FFR analysis, providing an objective and repeatable result.

Comparison of P2Y12 inhibitors for mortality and stent thrombosis in patients with acute coronary syndromes: Single center study of 10 793 consecutive 'real-world' patients.

Three oral platelet P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are available for reducing the risk of cardiovascular death and stent thrombosis in patients with acute coronary syndromes (ACS). We sought to compare the efficacy of these antiplatelet drugs in contemporary practice. Data were collected for 10 793 consecutive ACS patients undergoing coronary angiography at Sheffield, UK (2009-2015). Since prasugrel use was mostly restricted to the STEMI subgroup, clopidogrel and ticagrelor were compared for all ACS patients, and all three agents were compared in the STEMI subgroup. Differences in outcomes were evaluated at 12 months by KM curves and log-rank test after adjustment for independent risk factors. Of 10 793 patients with ACS (36% STEMI), 43% (4653) received clopidogrel, 11% (1223) prasugrel and 46% (4917) ticagrelor, with aspirin for all. In the overall group, ticagrelor was associated with lower all-cause mortality compared with clopidogrel (adjusted hazard ratio (adjHR) 0.82, 95% confidence intervals (CI) 0.71-0.96, p = 0.01). In the STEMI subgroup, both prasugrel and ticagrelor were associated with a lower mortality compared with clopidogrel (prasugrel vs. clopidogrel: adjHR 0.65, CI 0.48-0.89, p = 0.007; ticagrelor vs. clopidogrel: adjHR 0.70, CI 0.61-0.99, p = 0.05). Of the 7595 patients who underwent PCI, 78 (1.0%) had definite stent thrombosis by 12 months. Patients treated with ticagrelor had a lower incidence of definite stent thrombosis compared with clopidogrel (0.6% vs. 1.1%; adjHR 0.51, CI 0.29-0.89, p = 0.03). In the STEMI subgroup, there was no significant difference between the three groups (ticagrelor 1.0%, clopidogrel = 1.5%, prasugrel = 1.6%; p = 0.29). In conclusion, ticagrelor was superior to clopidogrel for reduction in both mortality and stent thrombosis in unselected invasively managed ACS patients. In STEMI patients, both ticagrelor and prasugrel were associated with lower mortality compared with clopidogrel, but there was no significant difference in the incidence of stent thrombosis.

Prospective assessment of a palliative care tool to predict one-year mortality in patients with acute coronary syndrome.

BACKGROUND: Identifying patients with acute coronary syndrome (ACS) who are approaching the end of life and who may not benefit from an aggressive interventional approach is important but clinically challenging. The Gold Standards Framework (GSF) prognostic guide was developed using multidimensional criteria to identify cancer patients who could benefit from end-of-life care. We assessed the utility of the GSF to predict one-year mortality in ACS patients. METHODS: ACS patients admitted between May 2012 and July 2013 at the three participating cardiac centres in Europe were enrolled. Patients were assessed during admission using the GSF, the Global Registry of Acute Coronary Events (GRACE) score, the age, creatinine, ejection fraction (ACEF) score and the New York Percutaneous Coronary Intervention (NY-PCI) risk score. The pre-specified primary outcome was all-cause mortality at one year; secondary outcomes were cardiovascular death, non-cardiovascular mortality, re-hospitalisation for ACS and re-hospitalisation for non-ACS causes. RESULTS: Six hundred and twenty-nine ACS patients were enrolled and one-year follow-up data was available for 626 patients. Fifty-two patients (8.3%) met GSF criteria for end-of-life care. These patients were older, predominantly female, had lower body mass index (BMI), and were less likely to receive angiography (75% vs 95%, p<0.001) and angioplasty (60% vs 77%, p=0.005) compared with patients who did not meet GSF criteria. Patients meeting GSF criteria had higher one-year all-cause mortality (42.3% vs 4.5%, p<0.001), cardiovascular mortality (15.4% vs 2.8%, p<0.001) and non-cardiovascular mortality (26.9% vs 1.7%; p<0.001). Multivariate analysis confirmed that meeting GSF criteria independently predicted all-cause mortality. CONCLUSION: GSF is a multidimensional tool which may be used to identify ACS patients that are at high risk of death and may benefit from end-of-life care.

Optimal medical therapy improves clinical outcomes in patients undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting: insights from the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial at the 5-year follow-up.

BACKGROUND: There is a paucity of data on the use of optimal medical therapy (OMT) in patients with complex coronary artery disease undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting (CABG) and its long-term prognostic significance. METHODS AND RESULTS: The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial is a multicenter, randomized, clinical trial of patients (n=1800) with complex coronary disease randomized to revascularization with percutaneous coronary intervention or CABG. Detailed drug history was collected for all patients at discharge and at the 1-month, 6-month, 1-year, 3-year, and 5-year follow-ups. OMT was defined as the combination of at least 1 antiplatelet drug, statin, ß-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Five-year clinical outcomes were stratified by OMT and non-OMT. OMT was underused in patients treated with coronary revascularization, especially CABG. OMT was an independent predictor of survival. OMT was associated with a significant reduction in mortality (hazard ratio, 0.64; 95% confidence interval, 0.48-0.85; P=0.002) and composite end point of death/myocardial infarction/stroke (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92; P=0.007) at the 5-year follow-up. The treatment effect with OMT (36% relative reduction in mortality over 5 years) was greater than the treatment effect of revascularization strategy (26% relative reduction in mortality with CABG versus percutaneous coronary intervention over 5 years). On stratified analysis, all the components of OMT were important for reducing adverse outcomes regardless of revascularization strategy. CONCLUSIONS: The use of OMT remains low in patients with complex coronary disease requiring coronary intervention with percutaneous coronary intervention and even lower in patients treated with CABG. Lack of OMT is associated with adverse clinical outcomes. Targeted strategies to improve OMT use in postrevascularization patients are warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00114972.

The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study.

AIMS: Acute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS. METHODS AND RESULTS: A phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31-29.64); placebo group, 43.5 mg day/L (31.15-60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32-0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group [IL-1ra; 3.50 mg/L (2.65-4.62): placebo; 2.21 mg/L (1.67-2.92), P = 0.022]. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group. CONCLUSION: IL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety. CLINICAL TRIAL REGISTRATION EUCTR: 2006-001767-31-GB: www.clinicaltrialsregister.eu/ctr-search/trial/2006-001767-31/GB.

Repeat coronary angiography with previously normal arteries: a futile exercise?

OBJECTIVES: Up to 20% of coronary angiograms reveal normal arteries. How long they stay normal is poorly understood. This study investigated the fate of normal coronary arteries and determined the rate of development of coronary artery disease. METHODS: We interrogated the angiographic archive of the South Yorkshire Cardiothoracic Centre between 2004 and 2013 to identify patients with truly normal coronary arteries who underwent repeat coronary angiography more than 1 year later. Follow up angiograms were scored for the severity and extent of CAD (graded per segment as 0%, 1-50%, >50%). Risk factors for the development of coronary artery disease were documented. Univariate predictors of disease development were identified and entered into a logistic regression model to identify independent predictors. RESULTS: Out of over 25,000 angiographic procedures in the archives we found 6068 patients reported to have normal coronary arteries. Of these, 162 patients had also undergone subsequent repeat coronary angiography. Of these, 97 had truly normal (smooth) coronary arteries at baseline and had undergone repeat angiography >1 year later. At a median 51 months, 87 continued to have normal arteries, and all the remaining 10 had mild disease only (average 37% stenosis in an average 1.2 segments). No patients developed any significant (>50% stenosis) disease. Advanced age, time between angiograms, and smoking status were identified as independent predictors of development of CAD. CONCLUSIONS: Truly normal coronary arteries do not progress to significant disease within a time frame of 4 years. Repeat coronary angiography within that period is probably not indicated.

Hemodynamics and in-stent restenosis: micro-CT images, histology, and computer simulations.

A model that combines the results of in vivo experiment, 3D image data, and computer simulation has been developed. Twelve identical stents were implanted into six healthy pigs and explanted at a range of different post-recovery periods from 6 h to 28 days. The stented vessel segments were embedded in methacrylate resin for the preparation of transverse histological sections and imaged using ultra-high resolution micro-CT. The resulting CT data was used to reconstruct the 3D geometry of the stents and one case was used to inform a 3D computational fluid dynamic model. Derived hemodynamic parameters such as wall shear stress (WSS), axial WSS, and oscillatory shear index were correlated with the distribution of neointimal hyperplasia, assessed from histomorphometric analyses. The direct comparison of hemodynamic parameters and biological response supports the hypothesis that low and oscillatory WSS lead to a greater neointimal response within the stented region. Moreover, the realistic geometry obtained from micro-CT images, characterized by proximal overexpansion and asymmetric deployment of the stent, leads to a markedly non-uniform distribution of WSS values and correlates with asymmetric neo-intimal growth. This correlation cannot be appreciated from studies of idealized geometries.

A novel mouse model of in situ stenting.

AIMS: Animal models of stenting are mostly limited to larger animals or involve substantial abdominal surgery in rodents. We aimed to develop a simple, direct model of murine stenting. METHODS AND RESULTS: We designed a miniature, self-expanding, nitinol wire coil stent that was pre-loaded into a metal stent sheath. This was advanced into the abdominal aorta of the mouse, via femoral access, and the stent deployed. In-stent restenosis was investigated at 1, 3, 7, and 28 days post-stenting. The model was validated by investigation of neointima formation in mice deficient in signalling via the interleukin-1 receptor (IL-1R1), compared with other injury models. Ninety-two per cent of mice undergoing the procedure were successfully stented. All stented vessels were patent. Inflammatory cells were seen in the adventitia and around the stent strut up to 3 days post-stenting. At 3 days, an early neointima was present, building to a mature neointima at 28 days. In mice lacking IL-1R1, the neointima was 64% smaller than that in wild-type controls at the 28-day timepoint, in agreement with other models. CONCLUSION: This is the first description of a successful model of murine in situ stenting, using a stent specifically tailored for use in small thin-walled arteries. The procedure can be undertaken by a single operator without the need for an advanced level of microsurgical skill and is reliable and reproducible. The utility of this model is demonstrated by a reduction in in-stent restenosis in IL-1R1-deficient mice.