Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

Diagnostic accuracy and discrimination of ischemia by fractional flow reserve CT using a clinical use rule: results from the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography study.

BACKGROUND: Fractional flow reserve (FFR) is the gold standard for determining lesion-specific ischemia. Computed FFRCT derived from coronary CT angiography (coronary CTA) correlates well with invasive FFR and accurately differentiates between ischemia-producing and nonischemic lesions. The diagnostic performance of FFRCT when applied in a clinically relevant way to all vessels ≥ 2 mm in diameter stratified by sex and age has not been previously examined. METHODS: Two hundred fifty-two patients and 407 vessels underwent coronary CTA, FFRCT, invasive coronary angiography, and invasive FFR. FFRCT and FFR ≤ 0.80 were considered ischemic, whereas CT stenosis ≥ 50% was considered obstructive. The diagnostic performance of FFRCT was assessed following a prespecified clinical use rule which included all vessels ≥ 2 mm in diameter, not just those assessed by invasive FFR measurements. Stenoses <30% were assigned an FFR of 0.90, and stenoses >90% were assigned an FFR of 0.50. Diagnostic performance of FFRCT was stratified by vessel diameter, sex, and age. RESULTS: By FFR, ischemia was identified in 129 of 252 patients (51%) and in 151 of 407 vessels (31%). Mean age (± standard deviation) was 62.9 ± 9 years, and women were older (65.5 vs 61.9 years; P = .003). Per-patient diagnostic accuracy (83% vs 72%; P < .005) and specificity (54% vs 82%, P < .001) improved significantly after application of the clinical use tool. These were significantly improved over standard coronary CTA values before application of the clinical use rule. Discriminatory power of FFRCT also increased compared with baseline (area under the receiver operating characteristics curve [AUC]: 0.93 vs 0.81, P < .001). Diagnostic performance improved in both sexes with no significant differences between the sexes (AUC: 0.93 vs 0.90, P = .43). There were no differences in the discrimination of FFRCT after application of the clinical use rule when stratified by age ≥ 65 or <65 years (AUC: 0.95 vs 0.90, P = .10). CONCLUSIONS: The diagnostic accuracy and discriminatory power of FFRCT improve significantly after the application of a clinical use rule which includes all clinically relevant vessels >2 mm in diameter. FFRCT has similar diagnostic accuracy and discriminatory power for ischemia detection in men and women irrespective of age using a cut point of 65 years.

Lung ultrasound in heart failure: Lessons from re-analysis of Lung Ultrasound 2011 database.

Introduction: In the setting of patients presenting with shortness of breath to an Emergency Department a simple lung ultrasound protocol aimed at detecting pulmonary oedema has been shown to have diagnostic accuracy of 85%. This article reviews data from the original study, in an attempt to determine whether adjusting the protocol and/or interpretive criteria would improve results. Method: A large lung ultrasound project provided the dataset. Inter-rater and intertest discrepancies were reviewed. Then original stored images and comments were retrospectively analysed using alternate interpretive criteria. Specific variations included changing the number of B-lines required to define 'wet lung' and assessing other pleural line abnormalities. Where they had been acquired cardiac loops were reviewed in addition to the lung images. Results: The 204 original studies available were reviewed. Some disagreement could be attributed to inexperience and unclear definitions. Adjusting the number of B-lines did not improve diagnostic accuracy. All positive scans, with numerous B-lines were reviewed using more advanced diagnostic criteria (pleural line abnormalities) and the number of false positives was decreased. In cases where cardiac views were available, their inclusion was beneficial. Conclusion: A simple lung ultrasound protocol to assess for 'wet lung' in patients presenting to Emergency Departments provides diagnostic accuracy of around 85% in the hands of relative novices. More advanced interpretation of the same_ultrasound images, and the addition of cardiac views, is likely to further improve diagnostic accuracy.

Optimising pharmacotherapy for secondary prevention of non-invasively managed acute coronary syndrome.

About half of all patients who experience an acute coronary syndrome (ACS) in Australia have their conditions managed non-invasively - that is, they do not undergo coronary angiography and revascularisation in hospital. ACS patients whose conditions are managed non-invasively may not receive the same level of evidence-based care as those who receive coronary revascularisation. This article reviews the optimal pharmacological management of ACS managed non-invasively. There is strong evidence to support the prescription of dual antiplatelet therapy (DAPT; aspirin with a P2Y12 inhibitor). DAPT should continue for 12 months after an ACS, then aspirin should be continued indefinitely. Anticoagulation with warfarin or a novel oral anticoagulant may be needed if atrial fibrillation occurs; the combination with DAPT increases the risk of bleeding. Unless contraindicated, high-intensity statin therapy should be prescribed for all post-ACS patients irrespective of their cholesterol level. Non-statin lipid therapy has not been shown to improve outcomes. Use of ß-adrenergic blockers is recommended in most guidelines, but the clinical trials to support this recommendation were performed more than 30 years ago, and routine long-term use may not be relevant to modern treatment, except when there is cardiac failure or left ventricular dysfunction. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are also widely recommended, but the evidence for benefit is stronger when there is left ventricular dysfunction. Calcium-channel blockers, nitrates, antiarrhythmic drugs, digoxin and diuretics do not improve outcomes in post-ACS patients.

Reduced iodine load with CT coronary angiography using dual-energy imaging: a prospective randomized trial compared with standard coronary CT angiography.

BACKGROUND: There is concern regarding the administration of iodinated contrast to patients with impaired renal function because of the increased risk of contrast-induced nephropathy. OBJECTIVE: Evaluate image quality and feasibility of a protocol with a reduced volume of iodinated contrast and utilization of dual-energy coronary CT angiography (DECT) vs a standard iodinated contrast volume coronary CT angiography protocol (SCCTA). METHODS: A total of 102 consecutive patients were randomized to SCCTA (n = 53) or DECT with rapid kVp switching (n = 49). Eighty milliliters and 35 mL of iodinated contrast were administered in the SCCTA and DECT cohorts, respectively. Two readers measured signal and noise in the coronary arteries; signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. A 5-point signal/noise Likert scale was used to evaluate image quality; scores of <3 were nondiagnostic. Agreement was assessed through kappa analyses. RESULTS: Demographics and radiation dose were not significantly different; there was no difference in CNR between both cohorts (P = .95). A significant difference in SNR between the groups (P = .02) lost significance (P = .13) when adjusted for body mass index. The median Likert score was inferior for DECT for reader 1 (3.6 ± 0.6 vs 4.3 ± 0.6; P < .001) but not reader 2 (4.1 ± 0.6 vs 4.3 ± 0.5; P = .06). Agreement in diagnostic interpretability in the DECT and SCCTA groups was 91% (95% confidence interval, 86%-100%) and 96% (95% confidence interval, 90%-100%), respectively. CONCLUSION: DECT resulted in inferior image quality scores but demonstrated comparable SNR, CNR, and rate of diagnostic interpretability without a radiation dose penalty while allowing for >50% reduction in contrast volume compared with SCCTA.

Diagnostic accuracy of basic lung ultrasound in breathless patients over 60 years of age; stressing the protocol.

Introduction: Emergency department differentiation of pulmonary oedema from chronic obstructive airways disease causing acute breathlessness is inaccurate 25% of the time despite clinical acumen, clinician-reported chest x-ray and ECG. This research investigates whether a basic lung ultrasound protocol (LUS) could improve identification of pulmonary oedema in breathless elderly patients. Method: Researchers prospectively sampled patients over 60 years, describing any breathlessness on presentation to a suburban emergency department. LUS studies were acquired by experienced or novice sonologists, interpreted by a blinded reviewer and compared with cardiologist chart audit for diagnosis at admission (gold standard). The admitting doctor's diagnosis, blinded to LUS, was compared with the chart audit result. Results: 204 LUS were collected, 145 by experienced sonologist and 59 by inexperienced. Diagnostic accuracy compared to cardiologist audit was 86.2% (95% CI 80.9 to 90.3), significantly higher than 70.2%, diagnostic accuracy for admission diagnosis, difference in proportion of 16% (95%CI 7.7 to 24.4%). Conclusion: A simple lung scanning protocol can help exclude pulmonary oedema in any breathless elderly patient.

Comparison of a basic lung scanning protocol against formally reported chest x-ray in the diagnosis of pulmonary oedema.

Introduction: Brief lung scan protocols have been recommended as a useful adjunct to identify pulmonary oedema in the breathless elderly patient. Some papers quote diagnostic accuracies above that of chest x-ray. Method: We recruited a prospective convenience sample of patients over sixty years of age reporting any breathlessness on presentation to the emergency department. Those who received both bedside lung scan and chest x-ray later had their case notes audited by an expert cardiologist for the cause of their breathlessness at presentation. Admission diagnosis was also extracted. Results: 204 comparative data sets were collected. Compared with cardiologist chart review, delayed expert radiology report had a diagnostic accuracy of 92.2% (95%CI 87.6 to 95.1). Bedside interpretation of lung scan protocol had a diagnostic accuracy of 85.3% (95%CI 79.8 to 89.5). The difference of 6.9% between the two accuracy measures was significant (95%CI 0.69 to 13.1). Admission diagnosis accuracy, which encompasses inexpert x-ray interpretation was 70.2%(95%CI 62.9 to 76.6), significantly less than either lung scan or expert chest x-ray report. Conclusion: For identifying heart failure in breathless patients, urgent chest x-ray with delayed formal report has not been shown to be redundant. Basic lung scan protocols should not yet replace chest x-ray, but may be more reliable in the interim than inexpert clinician interpretation of chest x-rays.

T cells signaled by NF-kappa B- dendritic cells are sensitized not anergic to subsequent activation.

Paradoxically, while peripheral self-tolerance exists for constitutively presented somatic self Ag, self-peptide recognized in the context of MHC class II has been shown to sensitize T cells for subsequent activation. We have shown that MHC class II(+)CD86(+)CD40(-) DC, which can be generated from bone marrow in the presence of an NF-kappa B inhibitor, and which constitutively populate peripheral tissues and lymphoid organs in naive animals, can induce Ag-specific tolerance. In this study, we show that CD40(-) human monocyte-derived dendritic cells (DC), generated in the presence of an NF-kappa B inhibitor, signal phosphorylation of TCR zeta, but little proliferation or IFN-gamma in vitro. Proliferation is arrested in the G(1)/G(0) phase of the cell cycle. Surprisingly, responding T cells are neither anergic nor regulatory, but are sensitized for subsequent IFN-gamma production. The data indicate that signaling through NF-kappa B determines the capacity of DC to stimulate T cell proliferation. Functionally, NF-kappa B(-)CD40(-)class II(+) DC may either tolerize or sensitize T cells. Thus, while CD40(-) DC appear to "prime" or prepare T cells, the data imply that signals derived from other cells drive the generation either of Ag-specific regulatory or effector cells in vivo.

Induction of immune tolerance by dendritic cells: implications for preventative and therapeutic immunotherapy of autoimmune disease.

Dendritic cells (DC) have a key role in controlling the immune response, by determining the outcome of antigen presentation to T cells. Through costimulatory molecules and other factors, DC are involved in the maintenance of peripheral tolerance through modulation of the immune response. This modulation occurs both constitutively, and in inflammation, in order to prevent autoimmunity and to control established immune responses. Dendritic cell control of immune responses may be mediated through cytokine or cell-contact dependent mechanisms. The molecular and cellular basis of these controls is being understood at an increasingly more complex level. This understanding is reaching a level at which DC-based therapies for the induction of immune regulation in autoimmunity can be tested in vivo. This review outlines the current state of knowledge of DC in immune tolerance, and proposes how DC might control both T cell responses, and themselves, to prevent autoimmunity and maintain peripheral tolerance.

Nuclear RelB+ cells are found in normal lymphoid organs and in peripheral tissue in the context of inflammation, but not under normal resting conditions.

Differentiated dendritic cells (DC) have been identified by the presence of nuclear RelB (nRelB) and HLA-DR, and the absence of CD20 or high levels of CD68, in lymph nodes and active rheumatoid arthritis synovial tissue. The current studies aimed to identify conditions in which nRelB is expressed in human tissues, by single and double immunohistochemistry of formalin-fixed peripheral and lymphoid tissue. Normal peripheral tissue did not contain nRelB+ cells. nRelB+ DC were located only in T- or B-cell areas of lymphoid tissue associated with normal organs or peripheral tissues, including tonsil, colon, spleen and thymus, or in association with T cells in inflamed peripheral tissue. Inflamed sites included skin delayed-type hypersensitivity reaction, and a wide range of tissues affected by autoimmune disease. Nuclear RelB+-HLA-DR- follicular DC were located in B-cell follicles in lymphoid organs and in lymphoid-like follicles of some tissues affected by autoimmune disease. Lymphoid tissue T-cell areas also contained nRelB(-)-HLA-DR+ cells,some of which expressed CD123 and/or CD68. Nuclear RelB+ cells are found in normal lymphoid organs and in peripheral tissue in the context of inflammation, but not under normal resting conditions.