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Coronary artery disease remains the leading cause of death around the world, even during the COVID-19 pandemic, and it is therefore essential that we continue our quest to improve the prevention, diagnosis, management and outcome of coronary artery disease. Fifty years ago, in 1971, the first CT scan was performed on a machine invented by Sir Godfrey Hounsfield who, even in those early days, realised the potential of CT to assess the heart and coronary arteries.1 Technological advances mean that it is now possible to obtain extensive information on the presence, severity and characteristics of atherosclerotic plaque from coronary CT angiography (CCTA). In addition, it is also possible to use computational modelling to obtain an estimate of fractional flow reserve from static CCTA images (FFRCT). CCTA now plays a central role in the assessment and management of patients with symptoms of suspected coronary artery disease in both national and international guidelines. However, the role of FFRCT in clinical practice is less certain. Norgaard et al 2 present a meta-analysis of the prognostic information provided by FFRCT from a single vendor (HeartFlow) in 5460 patients from 5 observational studies and registries. Coronary artery disease was prevalent in the population, with 72% having at least one stenosis >50% on CCTA and 61% having a positive FFRCT of ≤0.80. Overall event rates were low, with myocardial infarction or all-cause mortality occurring in 0.6% of FFRCT negative patients and 1.4% of FFRCT positive patients. Patients with FFRCT ≤0.80 were threefold more likely to experience myocardial infarction, unplanned coronary revascularisation and major adverse cardiac events, although there was no demonstrable difference in all-cause mortality. In addition, lower FFR …

The Authors’ reply We would like to thank Yalta et al 1 for their interest in our review. We share their enthusiasm for the potential metabolic benefits of sodium-glucose co-transporter 2 (SGLT-2) inhibition. We agree with Yalta et al that in patients with type 2 diabetes or heart failure, there is dysregulated fatty acid oxidation and impaired glucose uptake causing myocardial dysfunction. In this setting of restricted fuel selection and low energetic reserve, ketone bodies are a super-fuel producing Adenosine triphosphate (ATP) more efficiently than free fatty acids or glucose, which usually serve as fuels for …

ObjectivesTo determine the contribution of comorbidities on the reported widespread myocardial abnormalities in patients with recent COVID-19.MethodsIn a prospective two-centre observational study, patients hospitalised with confirmed COVID-19 underwent gadolinium and manganese-enhanced MRI and CT coronary angiography (CTCA). They were compared with healthy and comorbidity-matched volunteers after blinded analysis.ResultsIn 52 patients (median age: 54 (IQR 51–57) years, 39 males) who recovered from COVID-19, one-third (n=15, 29%) were admitted to intensive care and a fifth (n=11, 21%) were ventilated. Twenty-three patients underwent CTCA, with one-third having underlying coronary artery disease (n=8, 35%). Compared with younger healthy volunteers (n=10), patients demonstrated reduced left (ejection fraction (EF): 57.4±11.1 (95% CI 54.0 to 60.1) versus 66.3±5 (95 CI 62.4 to 69.8)%; p=0.02) and right (EF: 51.7±9.1 (95% CI 53.9 to 60.1) vs 60.5±4.9 (95% CI 57.1 to 63.2)%; p≤0.0001) ventricular systolic function with elevated native T1 values (1225±46 (95% CI 1205 to 1240) vs 1197±30 (95% CI 1178 to 1216) ms;p=0.04) and extracellular volume fraction (ECV) (31±4 (95% CI 29.6 to 32.1) vs 24±3 (95% CI 22.4 to 26.4)%; pConclusionsPatients demonstrate right but not left ventricular dysfunction. Previous reports of left ventricular myocardial abnormalities following COVID-19 may reflect pre-existing comorbidities.Trial registration numberNCT04625075.

The Authors’ reply We thank Professor Otto and Dr Bermejo for their interest and astute comments regarding our study.1 The echo frame for determining left ventricular volume at peak aortic velocity is estimated by the measuring the total number of frames from the R wave to the end systole and multiplying this by the fraction of time from the R wave to the peak aortic velocity and from the R wave to the end systole. In the initial report of EF1 in aortic stenosis (AS),2 the intraobserver and interobserver coefficients of variation were 6.7% and 9.8%. We acknowledge that EF1 …

ObjectiveCT quantification of aortic valve calcification (CT-AVC) is useful in the assessment of aortic stenosis severity. Our objective was to assess its ability to track aortic stenosis progression compared with echocardiography.MethodsSubjects were recruited in two cohorts: (1) a reproducibility cohort where patients underwent repeat CT-AVC or echocardiography within 4 weeks and (2) a disease progression cohort where patients underwent annual CT-AVC and/or echocardiography. Cohen’s d-statistic (d) was computed from the ratio of annualised progression and measurement repeatability and used to estimate group sizes required to detect annualised changes in CT-AVC and echocardiography.ResultsA total of 33 (age 71±8) and 81 participants (age 72±8) were recruited to the reproducibility and progression cohorts, respectively. Ten CT scans (16%) were excluded from the progression cohort due to non-diagnostic image quality. Scan-rescan reproducibility was excellent for CT-AVC (limits of agreement −12% to 10 %, intraclass correlation (ICC) 0.99), peak velocity (−7% to +17%; ICC 0.92) mean gradient (−25% to 27%, ICC 0.96) and dimensionless index (−11% to +15%; ICC 0.98). Repeat measurements of aortic valve area (AVA) were less reliable (−44% to +28%, ICC 0.85).CT-AVC progressed by 152 (65–375) AU/year. For echocardiography, the median annual change in peak velocity was 0.1 (0.0–0.3) m/s/year, mean gradient 2 (0–4) mm Hg/year and AVA −0.1 (−0.2–0.0) cm2/year. Cohen’s d-statistic was more than double for CT-AVC (d=3.12) than each echocardiographic measure (peak velocity d=0.71 ; mean gradient d=0.66; AVA d=0.59, dimensionless index d=1.41).ConclusionCT-AVC is reproducible and demonstrates larger increases over time normalised to measurement repeatability compared with echocardiographic measures.

The Authors’ reply: We thank the author for their interest in our report documenting the long-term prognostic importance of convalescent cardiac troponin concentrations.1 First, we agree that when used for risk stratification low cardiac troponin concentrations miss fewer events than applying the sex-specific 99th centile upper reference limit as a single threshold, and indeed we identified the lower troponin threshold of 5 ng/L to be associated with a 5-year negative predictive value for cardiovascular death of 97.1% (95% CI 95.5 to …

Gadolinium-based contrast media are widely used in cardiovascular MRI to identify and to highlight the intravascular and extracellular space. After gadolinium, manganese has the second highest paramagnetic moment and was one of the first MRI contrast agents assessed in humans. Over the last 50 years, manganese-enhanced MRI (MEMRI) has emerged as a complementary approach enabling intracellular myocardial contrast imaging that can identify functional myocardium through its ability to act as a calcium analogue. Early progress was limited by its potential to cause myocardial depression. To overcome this problem, two clinical formulations of manganese were developed using either chelation (manganese dipyridoxyl diphosphate) or coadministration with a calcium compound (EVP1001-1, Eagle Vision Pharmaceuticals). Preclinical studies have demonstrated the efficacy of MEMRI in quantifying myocardial infarction and detecting myocardial viability as well as tracking altered contractility and calcium handling in cardiomyopathy. Recent clinical data suggest that MEMRI has exciting potential in the quantification of myocardial viability in ischaemic cardiomyopathy, the early detection of abnormalities in myocardial calcium handling, and ultimately, in the development of novel therapies for myocardial infarction or heart failure by actively quantifying viable myocardium. The stage is now set for wider clinical translational study of this novel and promising non-invasive imaging modality.

High-sensitivity cardiac troponin assays enable the early risk stratification of patients with suspected acute coronary syndrome to identify those at low risk of myocardial infarction or cardiac death. We evaluated the performance of a novel high-sensitivity cardiac troponin I assay in early rule out pathways.In 1920 patients with suspected acute coronary syndrome, cardiac troponin was measured using the Siemens Atellica high-sensitivity cardiac troponin I assay (99th centile: 34 ng/L women, 53 ng/L men). We evaluated three pathways which use either low risk-stratification thresholds of cardiac troponin (The primary outcome of myocardial infarction or cardiac death at 30 days occurred in 14.4% (277/1920). The High-STEACS pathway ruled out 63% of patients (1218/1920), with five missed events for a negative predictive value (NPV) of 99.5% (95% CI (CI) 99.1% to 99.8%). Similar performance was observed for the ESC 1 hour pathway with an NPV of 99.0% (97.6% to 99.8%). In contrast, the ESC 3 hour pathway ruled out 65% of patients (1248/1920), but missed 25 events for an NPV of 98.0% (97.1% to 98.7%).A novel high-sensitivity cardiac troponin I assay can safely identify patients at low risk of myocardial infarction or cardiac death. Diagnostic pathways that use low cardiac troponin concentrations for risk stratification miss fewer events than those that rely on the 99th centile to rule out myocardial infarction.NCT1852123.

Objective Cardiac myosin-binding protein C (cMyC) is an abundant sarcomeric protein and novel highly specific marker of myocardial injury. Myocyte death characterises the transition from hypertrophy to replacement myocardial fibrosis in advanced aortic stenosis. We hypothesised that serum cMyC concentrations would be associated with cardiac structure and outcomes in patients with aortic stenosis. Methods cMyC was measured in two cohorts in which serum had previously been prospectively collected: a mechanism cohort of patients with aortic stenosis (n=161) and healthy controls (n=46) who underwent cardiac MRI, and an outcome cohort with aortic stenosis (n=104) followed for a median of 11.3 years. Results In the mechanism cohort, cMyC concentration correlated with left ventricular mass (adjusted β=11.0 g/m2 per log unit increase in cMyC, P

Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI can detect tissue-resident macrophage activity and identify cellular inflammation within tissues. We hypothesised that USPIO-enhanced MRI would provide a non-invasive imaging technique that would improve the diagnosis and management of patients with acute myocarditis.Ten volunteers and 14 patients with suspected acute myocarditis underwent T2, T2* and late gadolinium enhancement (LGE) 3T MRI, with further T2* imaging at 24 hours after USPIO (ferumoxytol, 4 mg/kg) infusion, at baseline and 3 months. Myocardial oedema and USPIO enhancement were determined within areas of LGE as well as throughout the myocardium.Myocarditis was confirmed in nine of the 14 suspected cases of myocarditis. There was greater myocardial oedema in regions of LGE in patients with myocarditis when compared with healthy volunteer myocardium (T2 value, 57.1±5.3 vs 46.7±1.6 ms, p0.0001). There was no demonstrable difference in USPIO enhancement between patients and volunteers even within regions displaying LGE (change in R2*, 35.0±15.0 vs 37.2±9.6 sIn patients with acute myocarditis, USPIO-enhanced MRI does not provide additional clinically relevant information to LGE and T2 mapping MRI. This suggests that tissue-resident macrophages do not provide a substantial contribution to the myocardial inflammation in this condition.Clinical trial registration NCT02319278; Results.

OBJECTIVES: Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) often coexist. We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk.METHODS: The SUMMIT (Study to Understand Mortality and MorbidITy) was a multicentre, randomised, double-blind, placebo-controlled, event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD. Here, we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or transient ischaemic attack (TIA)) by Cox regression and by clinician-reported CVD adverse events across the four groups: once-daily inhaled placebo (n=4111), long-acting beta2-agonist (vilanterol (VI) 25 µg; n=4118), corticosteroid (fluticasone furoate (FF) 100 µg; n=4135) and combination therapy (FF/VI; n=4121).RESULTS: Participants were predominantly middle-aged (mean 65 (SD 8) years) men (75%) with overt CVD (66%). The composite CVD endpoint occurred in 688 patients (first event: sudden death (35%), acute coronary syndrome (37%) and stroke or TIA (23%)), and was not reduced in any treatment group versus placebo: VI (HR 0.99, 95% CI 0.80 to 1.22), FF (HR 0.90, 95% CI 0.72 to 1.11) and their combination (HR 0.93, 95% CI 0.75 to 1.14). Outcomes were similar among all subgroups. Adverse events, including palpitations and arrhythmias, did not differ by treatment.CONCLUSIONS: In patients with COPD with moderate airflow limitation and heightened CVD risk, treatment with inhaled VI, FF or their combination has an excellent safety profile and does not impact CVD outcomes.TRIAL REGISTRATION NUMBER: NCT01313676.

Despite a large volume of evidence supporting the use of dual antiplatelet therapy in patients with acute coronary syndrome, there remains major uncertainty regarding the optimal duration of therapy. Clinical trials have varied markedly in the duration of therapy, both across and within trials. Recent systematic reviews and meta-analyses suggest that shorter durations of dual antiplatelet therapy are superior because the avoidance of atherothrombotic events is counterbalanced by the greater risks of excess major bleeding with apparent increases in all-cause mortality with longer durations. These findings did not show significant heterogeneity according to whether patients had stable or unstable coronary heart disease. Moreover, the potential hazards and benefits may differ when applied to the general broad population of patients encountered in everyday clinical practice who have markedly higher bleeding and atherothrombotic event rates. Clinicians lack definitive information regarding the duration of therapy in patients with acute coronary syndrome and risk scores do not appear to be sufficiently robust to address these concerns. We believe that there is a pressing need to undertake a broad inclusive safety trial of shorter durations of therapy in real world populations of patients with acute coronary syndrome. The clinical evidence would further inform future research into strategies for personalised medicine.

Non-invasive imaging plays a critical role in the assessment of patients presenting with suspected angina chest pain. However, wide variations in practice across Europe and North America highlight the lack of consensus in selecting the appropriate first-line test for the investigation of coronary artery disease (CAD). CT coronary angiography (CTCA) has a high negative predictive value for excluding the presence of CAD. As such, it serves as a potential ‘gatekeeper’ to downstream testing by reducing the rate of inappropriate invasive coronary angiography. Two recent large multicentre randomised control trials have provided insights into whether CTCA can be incorporated into chest pain care pathways to improve risk stratification of CAD. They demonstrate that using CTCA enhances diagnostic certainty and improves the targeting of appropriate invasive investigations and therapeutic interventions. Importantly, reductions in cardiac death and non-fatal myocardial infarction appear to be attained through the more appropriate use of preventative therapy and coronary revascularisation when guided by CTCA. With this increasing portfolio of evidence, CTCA should be considered the non-invasive investigation of choice in the evaluation of patients with suspected angina pectoris due to coronary heart disease. Clinical trial number NCT01149590, post-results.

Aortic stenosis is the major cause of valve disease in the Western world and a growing healthcare burden. We lack medication capable of slowing disease progression and so rely on aortic valve replacement in patients with severe disease and symptoms. Predicting when this will occur is challenging with the literature suggesting on average slow progression with wide individual variation (rate of change in the mean gradient of ∼3±3 mm Hg/year). Annual or biannual clinical review is therefore required in all patients with serial echocardiography performed in order to track progressive valve narrowing.1 This incurs significant costs and a method capable of predicting the future natural history of aortic stenosis and the likely timing of valve surgery could help streamline patient care. It is on this background that Nguyen et al 2 investigated whether an association exists between baseline aortic stenosis severity and the rate of disease progression. In 149 patients with largely mild and moderate disease, the average rate of haemodynamic progression after a mean follow-up of 2.9±1.0 years was again +3±3 mm Hg/year (mean gradient). As anticipated the fastest rates of progression were observed in those patients with the most advanced aortic stenosis …

Many patients self-present or are referred by primary care to the emergency department with chest pain because of the potential that they may be suffering an acute myocardial infarction, one of the most common causes of death worldwide.1 Owing to diagnostic uncertainty, the majority of these patients are admitted, and, in some centres, chest pain is responsible for up to 40% of all unplanned hospital admissions.2 The majority of these admissions are unnecessary and place additional burden on healthcare systems that are already struggling to cope with increasing emergency care attendances. Approaches to improve the accurate identification of patients with myocardial infarction would therefore be welcome and a potential major benefit. Cardiac troponins are regulatory muscle proteins that are released into the circulation after acute myocardial injury. Assays that quantify cardiac isoforms of troponin have greater specificity and sensitivity for the diagnosis of myocardial infarction than traditional cardiac enzymes.3 ,4 Recent advances have led to greatly improved assay sensitivity, permitting quantification of extremely low serum concentrations of troponin with excellent precision. High-sensitivity cardiac troponin assays have limits of detection 10–100-fold lower than contemporary assays and are able to detect troponin in the circulation of the majority of healthy persons.4 These assays have the potential to transform how we assess patients with chest pain in the emergency room. Myocardial infarction is defined as a rise and/or fall in cardiac troponin with at least one value above the 99th centile upper reference limit in the context …

We wished to determine the effect of an acute coronary syndrome (ACS) on putative endothelial progenitor cell (EPC) populations, and define their relationship to coronary artery disease (CAD) severity and clinical outcome, in order to clarify their clinical relevance.A prospective cohort study conducted in a tertiary referral cardiac centre.Two-hundred-and-one patients undergoing coronary angiography for suspected angina or ACS.Putative EPC populations were determined by flow cytometry. CAD was quantified using the Gensini scoring system. Survival free from revascularisation, recurrent myocardial infarction and death were determined at 3 years.Circulating CD34(+)VEGFR-2(+) and CD34(+)VEGFR-2(+)CD133(+) cells were rare (0.007% of mononuclear cells), were not increased in patients with ACS, and were unrelated CAD severity or clinical outcome (p0.1 for all). By contrast, CD34(+)CD45(-) cells were increased in patients with CAD compared with those with normal coronary arteries (p=0.008) and correlated with atheroma burden (r=0.44, p0.001). Increased concentrations of circulating CD34(+)CD45(-) cells were associated with a shorter cumulative event-free survival (p0.02). Proangiogenic monocytes (CD14(+)VEGFR-2(+)Tie-2(+)) and endothelial cell-colony forming units were increased in patients with ACS (p0.01 for both), however, concentrations reflected myocardial necrosis, and did not predict the extent of CAD or clinical outcome.Traditional EPC populations, CD34(+)VEGFR-2(+) and CD34(+)VEGFR-2(+)CD133(+) are not related to the extent of CAD or clinical outcome. However, CD34(+)CD45(-) cells are increased in patients with CAD and predict future cardiovascular events. It is likely that CD34(+)CD45(-) concentrations reflect the extent of vascular injury and atheroma burden.

The assessment of coronary artery disease has advanced beyond the mere quantification of luminal stenosis to include mult-modality imaging that is capable of assessing the extent and functional significance of a stenosis and the possible vulnerability of a lesion. CT coronary angiography is now an established technique for the investigation of coronary artery disease, and the potential for CT myocardial perfusion imaging is being established. However, the optimal methods for CT myocardial perfusion image acquisition, image analysis and quantification have yet to be defined. CT coronary angiography with modern imaging techniques has a sensitivity approaching 100%.1 However, the specificity of this technique is reduced by its propensity to overestimate heavily calcified stenosis.2 For such patients, additional imaging procedures may be required to assess adequately the significance of their coronary artery disease. In addition, it has been established that the selection of patients for coronary revascularisation is best performed by identifying inducible myocardial ischaemia.3 It would therefore be a major advance if CT myocardial perfusion imaging could be performed in patients with coronary artery disease of uncertain severity and as a means of planning coronary revascularisation, especially as an optional follow-on procedure to CT coronary angiography. Previous research studies have compared CT myocardial perfusion imaging with other functional imaging techniques such as MRI, radionucleotide perfusion imaging and fractional flow reserve measurements made during invasive coronary angiography, and have identified sensitivities of 83–91% and specificities of 72–98%.4 At present, beam hardening, motion and reconstruction artifacts are important limitations for CT myocardial perfusion imaging. Nevertheless, CT myocardial perfusion imaging is additive to CT coronary angiography5 and useful in the assessment of patients with coronary artery stents.6 However, the primary method used in …

Apelin, the endogenous ligand for the G-protein-coupled APJ receptor, is emerging as a key hormone in cardiovascular homoeostasis. It is expressed in a diverse range of tissues with particular preponderance for the cardiovascular system, being found in both the heart and vasculature. Apelin is the most potent in vitro inotrope yet identified and causes endothelium- and nitric oxide-dependent vasodilatation. It also appears to have a role in lipid and glucose metabolism as well as fluid homoeostasis. One of the key emerging features of the apelin--APJ system is its interaction with the renin-angiotensin system with the respective receptors sharing marked sequence homology, forming heterodimers, and mediating opposing physiological actions. To date, both preclinical and limited clinical studies suggest that the apelin--APJ system may have an important role in the pathogenesis of heart failure. Although the apelin--APJ system is downregulated, the inotropic actions of apelin persist and are enhanced in failing hearts without inducing ventricular hypertrophy. In combination with its interaction with the renin-angiotensin system, APJ agonism may provide a new therapeutic target in the treatment of acute and chronic heart failure. In this review, we highlight key aspects of the apelin--APJ system in health and disease, and consider its translational and therapeutic potential. The diverse actions of the apelin--APJ system have implications for understanding the pathophysiology of, and development of treatments for, several major cardiovascular diseases.

The need to improve the translation of basic and fundamental research findings into routine clinical practice was one of the main observations of the ‘Review of UK Health Research Funding’ by Sir David Cooksey.1 This has been reinforced by the National Health Service review2 from Professor the Lord Darzi, who highlighted that research is an under-recognised force for health-service and system reform. Indeed, encouraging innovation improves quality of healthcare, and continuous enquiry brings continuous improvement. These sentiments are not unique to the United Kingdom and have been promoted by governments and healthcare providers across the world. Moreover, research translation is of major interest to a pharmaceutical industry that has been faced with an unprecedented number of potential therapeutic targets that need to be developed in a strategic, effective and timely manner. Better target validation and proof-of-concept studies coupled with earlier attrition of ineffective compounds or misleading therapeutic paradigms will facilitate more focused and successful development of the next generation of therapeutic agents. Thus, there is a major drive to translate and realise the scientific, societal and economic benefits of clinical research findings by academia, governments and healthcare industries. What is translational research? This term continues to be used and interpreted in a range of ways; usually reflecting the viewpoint of each observer. This mirrors the continuum of the process from discovery of a basic scientific phenomenon all the way through to the widespread use of a healthcare innovation (figure 1). However, the Cooksey report described two areas of translational medicine research that were seen as blocks to the rapid and effective delivery of healthcare innovation: ( a ) the translation of scientific findings into the clinic and ( b ) the …

Objective: To determine whether exposure to secondhand smoke is associated with early prognosis following acute coronary syndrome. Design, setting and participants: We interviewed consecutive patients admitted to nine Scottish hospitals over 23 months. Information was obtained, via questionnaire, on age, sex, smoking status, postcode of residence and admission serum cotinine concentration was measured. Follow-up data were obtained from routine hospital admission and death databases. Results: Of the 5815 participants, 1261 were never-smokers. Within 30 days, 50 (4%) had died and 35 (3%) had a non-fatal myocardial infarction. All-cause deaths increased from 10 (2.1%) in those with cotinine ⩽0.1 ng/ml to 22 (7.5%) in those with cotinine >0.9 ng/ml (χ 2 test for trend p 0.9 ng/ml: adjusted OR 4.80, 95% CI 1.95 to 11.83, p = 0.003). The same dose response was observed for cardiovascular deaths and death or myocardial infarction. Conclusions: Secondhand smoke exposure is associated with worse early prognosis following acute coronary syndrome. Non-smokers need to be protected from the harmful effects of secondhand smoke.

Endothelial progenitor cells (EPCs) are circulating mononuclear cells with the capacity to mature into endothelial cells and contribute to vascular repair. We assessed the effect of local vascular injury during percutaneous coronary intervention (PCI) on circulating EPCs in patients with coronary artery disease.Prospective case-control study in a university teaching hospital.54 patients undergoing elective coronary angiography.EPCs were quantified by flow cytometry (CD34(+)KDR(+) phenotype) complemented by real-time polymerase chain reaction (PCR), and the colony forming unit (CFU-EC) functional assay, before and during the first 24 hours after diagnostic angiography (n = 27) or PCI (n = 27).Coronary intervention, but not diagnostic angiography, resulted in an increase in blood neutrophil count (p0.001) and C-reactive protein concentrations (p = 0.001) in the absence of significant myocardial necrosis. Twenty-four hours after PCI, CFU-ECs increased threefold (median [IQR], 4.4 [1.3-13.8] vs 16.0 [2.1-35.0], p = 0.01), although circulating CD34(+)KDR(+) cells (0.019% (SEM 0.004%) vs 0.016% (0.003%) of leucocytes, p = 0.62) and leucocyte CD34 mRNA (relative quantity 2.3 (0.5) vs 2.1 (0.4), p = 0.21) did not. There was no correlation between CFU-ECs and CD34(+)KDR(+) cells.Local vascular injury following PCI results in a systemic inflammatory response and increases functional CFU-ECs. This increase was not associated with an early mobilisation of CD34(+)KDR(+) cells, suggesting these cells are not the primary source of EPCs involved in the immediate response to vascular injury.

Patients with diabetes mellitus have an increased risk of developing atherosclerosis and its sequelae. Atherosclerosis is an inflammatory disease involving multiple interactions between platelets, leucocytes and endothelial cells.1 Clopidogrel, a specific antagonist of the ADP P2Y12 receptor, inhibits both platelet activation and aggregation induced by ADP.2 Although clopidogrel has well-documented antithrombotic actions, its potential anti-inflammatory effects have been little investigated. We examined whether specific platelet inhibition with clopidogrel would reduce systemic inflammatory markers and specifically platelet, monocyte and endothelial activation in patients with type 2 diabetes mellitus. We enrolled 20 patients with type 2 diabetes mellitus without clinical evidence of cardiovascular disease, malignancy, chronic inflammatory disorders, intercurrent illness, renal or hepatic insufficiency or contraindications to clopidogrel who had not taken antiplatelet agents within the preceding two weeks. Ethical approval was obtained from the local ethics committee and all participants provided written informed consent. They were treated with clopidogrel 75 mg daily for 28 days. Fasting peripheral venous blood samples were obtained at baseline and at 28 days. Plasma concentrations of soluble CD40 ligand (sCD40L) (Bender MedSystems) and sE-selectin (R&D Systems) were determined by enzyme-linked immunosorbent assays. Plasma concentrations of the chemokine regulated on activation normal T cell expressed presumed secreted (RANTES, CCL5) were assessed with the human chemokine flow cytometric bead array (BD Biosciences). To evaluate …

Objectives: To determine the in vitro effects of unfractionated heparin, fractionated heparin and direct thrombin inhibition on platelet–monocyte aggregation, and to establish the in vivo effects of unfractionated heparin and direct thrombin inhibition on platelet–monocyte aggregates in patients scheduled for percutaneous coronary intervention (PCI).Design: Platelet–monocyte aggregates were assessed in whole blood from 18 healthy volunteers after the addition of unfractionated heparin (1 U/ml), enoxaparin (0.8 U/ml) or lepirudin (5.6 µg/ml), and in 28 patients scheduled for elective PCI before and after administration of 100 U/kg of unfractionated heparin or 0.75 mg/kg bivalirudin. The influence of P-selectin-mediated platelet–monocyte aggregation was assessed with specific blocking antibodies.Results: Addition of unfractionated heparin in vitro was associated with a higher level of platelet–monocyte aggregates than in controls (20.1 (1.9)% v 16.2 (1.6)%, respectively, p < 0.001). However, platelet–monocyte aggregation was not affected by enoxaparin or lepirudin (16.9 (2.0)% and 17.0 (2.2)%, respectively, NS). Intravenous unfractionated heparin in vivo also resulted in an increase in platelet–monocyte aggregates (absolute Δ 7.1 (2.7)%, p < 0.01), whereas intravenous bivalirudin had no effect (absolute Δ −1.5 (2.4)%, NS). The addition of P-selectin blockade abolished any increase in platelet–monocyte aggregates associated with heparin.Conclusions: In vitro and in vivo unfractionated heparin is associated with increased platelet–monocyte aggregation through a P-selectin-dependent mechanism. These findings provide a potential explanation for the superior cardiovascular outcomes associated with fractionated heparins and direct thrombin inhibitors.