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MicroRNAs (miRNAs) play important roles in the pathogenesis of cardiovascular diseases. Circulating miRNAs were recently identified as biomarkers for various physiological and pathological conditions. In this study, we aimed to identify the circulating miRNA fingerprint of vulnerable coronary artery disease (CAD) and explore its potential as a novel biomarker for this disease. The Taqman low-density miRNA array and coexpression network analyses were used to identify distinct miRNA expression profiles in the plasma of patients with typical unstable angina (UA) and angiographically documented CAD (UA group, n = 13) compared to individuals with non-cardiac chest pain (control group, n = 13). Significantly elevated expression levels of miR-106b/25 cluster, miR-17/92a cluster, miR-21/590-5p family, miR-126*, and miR-451 were observed in UA patients compared to controls. These findings were validated by real-time PCR in another 45 UA patients, 31 stable angina patients, and 37 controls. In addition, miR-106b, miR-25, miR-92a, miR-21, miR-590-5p, miR-126* and miR-451 were upregulated in microparticles (MPs) isolated from the plasma of UA patients (n = 5) compared to controls (n = 5). Using flow cytometry and immunolabeling, we further found that Annexin V(+) MPs were increased in the plasma samples of UA patients compared to controls, and the majority of the increased MPs in plasma were shown to be Annexin V(+) CD31(+) MPs. The findings suggest that Annexin V(+) CD31(+) MPs may contribute to the elevated expression of the selected miRNAs in the circulation of patients with vulnerable CAD. The circulating miRNA signature, consisting of the miR-106b/25 cluster, miR-17/92a cluster, miR-21/590-5p family, miR-126* and miR-451, may be used as a novel biomarker for vulnerable CAD. Chinese Clinical Trial Register, ChiCTR-OCH-12002349.

Hyperglycaemia could substantially increase the risk of ischaemic heart disease in patients with type 2 diabetes. We investigated whether intensive lowering of glucose concentrations affects risk. We assessed 10 251 adults aged 40–79 years with established type 2 diabetes, mean glycated haemoglobin A1c (HbA1c) concentration of 67 mmol/mol (8·3%), and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy (target HbA1c less than 42 or 53–63 mmol/mol [less than 6·0% or 7·0–7·9%], respectively). We assessed fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina, and new angina during active treatment (mean 3·7 years) plus a further mean 1·2 years. This trial is registered with ClinicalTrials.gov, number NCT00000620. Myocardial infarction was less frequent in the intensive than in the standard therapy group during active treatment (hazard ratio [HR] 0·80, 95% CI 0·67–0·96; p=0·015) and overall (0·84, 0·72–0·97; p=0·02). Findings were similar for combined myocardial infarction, coronary revascularisation, and unstable angina (active treatment HR 0·89, 95% CI 0·79–0·99, overall 0·87 0·79–0·96) and for coronary revascularisation alone (0·84, 0·75–0·94) and unstable angina alone (0·81, 0·67–0·97) during full follow-up. With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant. Raised glucose concentration is a modifiable risk factor for ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors. National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Eye Intitute, and Centers for Disease Control and Prevention.

At least 30% of patients with non–ST-elevation acute coronary syndrome present without evidence of myonecrosis using current generation troponin assays. A new generation of research assays for troponin that offer a >10-fold increase in analytical sensitivity has emerged. To perform a pilot study to evaluate the clinical sensitivity of a new ultra-sensitive nanoparticle assay for cardiac troponin I (nano-cTnI), we identified 50 patients with unstable angina (serial negative cTnI) and 50 patients with non–ST-elevation myocardial infarction with an initially negative current generation cTnI result. We measured cTnI using an assay (Nanosphere, Northbrook, IL) that can detect pg/mL concentrations of cTnI (detection-limit 0.0002 μg/L). Measured at 0, 2, and 8 hours with the nano-cTnI assay 44%, 62%, and 82% of patients with unstable angina defined by the current-generation assay had an elevated nano-cTnI result (≥0.003 μg/L, 99th percentile decision-limit, coefficient of variation <10%). In patients with definite myocardial injury (current-generation cTnI ≥0.1 μg/L) but an initially negative cTnI, 72% and 98% had a nano-cTnI ≥0.003 μg/L at 0 and 2 hours. No patient had a positive current-generation cTnI without an elevated nano-cTnI level. In this pilot study using a nanoparticle assay for cTnI, myocardial injury was detectable in a substantial proportion of patients presently classified as having unstable angina, suggesting that ischemia with rest pain without injury is rare. The emergence of a new generation of troponin assays has the potential to lead to new clinical applications based on enhanced analytical performance at very low concentrations of troponin.

The primary goal of a randomized clinical trial is to make comparisons among two or more treatments. For example, in a two-arm trial with continuous response, the focus may be on the difference in treatment means; with more than two treatments, the comparison may be based on pairwise differences. With binary outcomes, pairwise odds ratios or log odds ratios may be used. In general, comparisons may be based on meaningful parameters in a relevant statistical model. Standard analyses for estimation and testing in this context typically are based on the data collected on response and treatment assignment only. In many trials, auxiliary baseline covariate information may also be available, and it is of interest to exploit these data to improve the efficiency of inferences. Taking a semiparametric theory perspective, we propose a broadly applicable approach to adjustment for auxiliary covariates to achieve more efficient estimators and tests for treatment parameters in the analysis of randomized clinical trials. Simulations and applications demonstrate the performance of the methods.

The ICTUS trial was a study that compared an early invasive with a selective invasive treatment strategy in patients with non-ST-elevation acute coronary syndrome (nSTE-ACS). The study reported no difference between the strategies for frequency of death, myocardial infarction, or rehospitalisation after 1 year. We did a follow-up study to assess the effects of these treatment strategies after 4 years. 1200 patients with nSTE-ACS and an elevated cardiac troponin were enrolled from 42 hospitals in the Netherlands. Patients were randomly assigned either to an early invasive strategy, including early routine catheterisation and revascularisation where appropriate, or to a more selective invasive strategy, where catheterisation was done if the patient had refractory angina or recurrent ischaemia. The main endpoints for the current follow-up study were death, recurrent myocardial infarction, or rehospitalisation for anginal symptoms within 3 years after randomisation, and cardiovascular mortality and all-cause mortality within 4 years. Analysis was by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN82153174. The in-hospital revascularisation rate was 76% in the early invasive group and 40% in the selective invasive group. After 3 years, the cumulative rate for the combined endpoint was 30·0% in the early invasive group compared with 26·0% in the selective invasive group (hazard ratio 1·21; 95% CI 0·97–1·50; p=0·09). Myocardial infarction was more frequent in the early invasive strategy group (106 [18·3%] vs 69 [12·3%]; HR 1·61; 1·19–2·18; p=0·002). Rates of death or spontaneous myocardial infarction were not different (76 [14·3%] patients in the early invasive and 63 [11·2%] patients in the selective invasive strategy [HR 1·19; 0·86–1·67; p=0·30]). No difference in all-cause mortality (7·9%vs 7·7%; p=0·62) or cardiovascular mortality (4·5%vs 5·0%; p=0·97) was seen within 4 years. Long-term follow-up of the ICTUS trial suggests that an early invasive strategy might not be better than a more selective invasive strategy in patients with nSTE-ACS and an elevated cardiac troponin, and implementation of either strategy might be acceptable in these patients.

In patients with chest pain at rest but no ST-segment elevation on the electrocardiogram, the diagnoses of unstable angina and non–Q-wave myocardial infarction are usually considered together because they cannot be distinguished clinically or angiographically. 1 – 4 The discrimination between these conditions is usually made by testing for elevated levels of a serum cardiac marker that indicates myocardial necrosis when non–Q-wave myocardial infarction is present. 5 The extent of myocardial necrosis is an important determinant of the risk of death. 6 , 7 It is therefore desirable to identify a serum marker whose release bears a close relation to the degree of myocardial damage. . . .

Although statistical evidence is clear regarding the dangerousness of unstable angina (UA), a form of coronary heart disease (CHD) characterised by high mortality and morbidity globally, it is important to recognise that diagnostic precision for the condition is unfavourable. In the present research, to gain insight into candidate biomarkers, the author draws on 1H NMR-based serum metabolic profiling to analyze the unstable angina pectoris (UAP) metabolic signatures; this constitutes an effective way to produce medical diagnosis. 101 unstable angina pectoris patients and 132 healthy controls were enrolled and 22 serum samples from each group were analyzed. Effective separation was noted regarding the UAP and control groups, and, for the former group considered in relation to their counterpart, the serum concentrations of Lac, m-I, lipid, VLDL, 3-HB, and LDL were higher whereas the concentrations of Thr, Cr, Cho, PC/GPC, Glu, Gln, Lys, HDL, Ile, Leu, and Val were lower. The conclusion drawn in view of the results is that the plasma metabolomics examined by 1H NMR displayed promise for biomarker identification for UA. In addition to this, the analysis illuminated the metabolic processes of UA.

Periprocedural myocardial injury is a prognostically important complication of percutaneous coronary intervention (PCI). However, it still remains unclear whether and how intensive atorvastatin therapy attenuates the unfavorable inflammatory responses of monocytes associated with PCI. The aim of the study was to investigate the impact of intensive atorvastatin therapy on inflammatory responses of monocytes in Chinese patients with unstable angina who received PCI in order to explore the potential anti-inflammatory mechanism. Ninety-six patients with unstable angina were randomly assigned to atorvastatin 80 mg (intensive) or atorvastatin 20 mg (conventional) treatment at a 1:1 ratio. Creatine kinase MB (CK-MB), cTnI, hs-CRP, and IL-6 were assessed, and circulating CD14 + monocytes were simultaneously obtained using CD14 MicroBeads 2 h before and 24 h after PCI. Plasma levels of CK-MB, cTnI, hs-CRP, and IL-6 were higher in the conventional dose group versus those in the intensive dose group following PCI. Furthermore, intensive atorvastatin treatment markedly reduced the expressions and responses of Toll-like receptor 2 (TLR2), TLR4, and CCR2 of CD14 + monocytes versus the conventional dose group and significantly increased the activated peroxisome-proliferator-activated receptor (PPAR) γ in the CD14 + monocytes post-PCI. Notably, the changes in responses of TLR2, TLR4, and CCR2 of CD14 + monocytes between the two groups were all reversed by PPARγ antagonist and augmented by PPARγ agonist. In conclusion, a single high (80 mg) loading dose of atorvastatin reduced the inflammatory response in Chinese patients with unstable angina following PCI. The anti-inflammatory role of intensive atorvastatin was possibly due to attenuation of inflammatory response in monocytes via PPARγ activation.

The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed that pravastatin therapy over 6 years reduced mortality and cardiovascular events in patients with previous acute coronary syndromes and average cholesterol concentrations. We assessed the longer-term effects of initial treatment with pravastatin on further cardiovascular events and mortality over a total follow-up period of 8 years. In the main trial, 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol concentration of 4·0–7·0 mmol/L were randomly assigned pravastatin 40 mg daily or placebo and followed up for 6 years. Subsequently, all patients were offered open-label pravastatin for 2 more years. Major cardiovascular events and adverse events were compared according to initial treatment assignment. 7680 (97% of those still alive) had 2 years of extended follow-up. 3766 (86%) of those assigned placebo and 3914 (88%) assigned pravastatin agreed to take open-label pravastatin. During this period, patients originally assigned pravastatin had almost identical cholesterol concentrations to those assigned placebo, but a lower risk of death from all causes (219 [5·6%] vs 255 [6·8%], p=0·029), coronary heart disease (CHD) death (108 [2·8%] vs 137 [3·6%], p=0·026), and CHD death or non-fatal myocardial infarction (176 [4·5%] vs 196 [5·2%], p=0·08). Over the total 8-year period, all-cause mortality was 888 (19·7%) in the group originally assigned placebo and 717 (15·9%) in the group originally assigned pravastatin, CHD mortality was 510 (11·3%) versus 395 (8·8%), myocardial infarction was 570 (12·7%) versus 435 (9·6%; each p<0·0001), and stroke was 272 (6·0%) versus 224 (5·0%; p=0·015). Stronger evidence of separate treatment benefits than in the main trial was seen in important prespecified subgroups (women, patients aged ≥70 years, and those with total cholesterol <5·5 mmol/L). Pravastatin had no significant adverse effects. The evidence of sustained treatment benefits and safety of long-term pravastatin treatment reinforces the importance of long-term cholesterol-lowering treatment for almost all patients with previous CHD events.

Clopidogrel-naive patients subjected to coronary angiography may be candidates for percutaneous coronary intervention (PCI). Clopidogrel loading with 600 mg at least 2 hours before the procedure is advised for such patients. However, there is no direct evidence that delaying PCI for 2 hours after clopidogrel loading is superior to ad hoc PCI. After coronary angiography, clopidogrel-naive patients (N = 199) with stable or unstable angina, candidates for PCI, were loaded with 900 mg of clopidogrel and then randomized to ad hoc PCI (ad hoc group, n = 103) or delayed PCI 2 hours after loading (delayed group, n = 96). Combined primary end point was death/periprocedural myocardial infarction (MI)/stroke/reintervention within 30 days post-PCI. Secondary end points were periprocedural MI; periprocedural creatine kinase-MB elevation >3 × upper limit of normal; any periprocedural increase of creatine kinase-MB, troponin-I, or myoglobin above upper limit of normal; Thrombolysis in Myocardial Infarction flow <3 after PCI; thrombocytopenia with platelet count of <70,000/mL; major bleeding defined according to the Thrombolysis in Myocardial Infarction criteria; and elevation of high-sensitivity C-reactive protein and soluble P selectin. Primary end point occurred in 12.6% ad hoc group versus 15.6% delayed group patients ( P = .34). High-sensitivity C-reactive protein increased in both groups post-PCI (analysis of variance P < .0001) without difference between groups ( P = .5). Major bleeding occurred in 2.9% ad hoc group versus 3.1% delayed group patients ( P = .9). No significant difference was observed in any other secondary end point. In clopidogrel-naive patients, a strategy of delaying PCI for 2 hours after high-dose clopidogrel loading does not seem to confer any benefit compared to ad hoc PCI.