British Heart Foundation Centre for Cardiovascular Science

BACKGROUND: Unlike most noninvasive imaging modalities, coronary computed tomography angiography can characterize subtypes of atherosclerotic plaque. OBJECTIVES: The purpose of this study was to investigate the prognostic implications of adverse coronary plaque characteristics in patients with suspected coronary artery disease. METHODS: In this SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) post hoc analysis, the presence of adverse plaque (positive remodeling or low attenuation plaque), obstructive disease, and coronary artery calcification within 15 coronary segments was assessed on coronary computed tomography angiography of 1,769 patients who were followed-up for 5 years. RESULTS: Among study participants (mean age 58 ± 10 years; 56% male), 608 (34%) patients had 1 or more adverse plaque features. Coronary heart disease death or nonfatal myocardial infarction was 3 times more frequent in patients with adverse plaque (n = 25 of 608 [4.1%] vs. n = 16 of 1,161 [1.4%]; p < 0.001; hazard ratio [HR]: 3.01; 95% confidence interval (CI): 1.61 to 5.63; p = 0.001) and was twice as frequent in those with obstructive disease (n = 22 of 452 [4.9%] vs. n = 16 of 671 [2.4%]; p = 0.024; HR: 1.99; 95% CI: 1.05 to 3.79; p = 0.036). Patients with both obstructive disease and adverse plaque had the highest event rate, with a 10-fold increase in coronary heart disease death or nonfatal myocardial infarction compared with patients with normal coronary arteries (HR: 11.50; 95% CI: 3.39 to 39.04; p < 0.001). However, these associations were not independent of coronary artery calcium score, a surrogate measure of coronary plaque burden. CONCLUSIONS: Adverse coronary plaque characteristics and overall calcified plaque burden confer an increased risk of coronary heart disease death or nonfatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

IMPORTANCE: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated. OBJECTIVE: To investigate whether interstitial lung abnormalities are associated with increased mortality. DESIGN, SETTING, AND POPULATION: Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006). EXPOSURES: Interstitial lung abnormality status as determined by chest CT evaluation. MAIN OUTCOMES AND MEASURES: All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. RESULTS: Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. CONCLUSIONS AND RELEVANCE: In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

UNLABELLED: Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. CONCLUSION: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.

BACKGROUND: Data regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. METHODS: In 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. RESULTS: Among 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. CONCLUSIONS: A risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov numbers, NCT00470587, NCT02355457, NCT01852123, NCT01994577, and NCT03227159; and Australian New Zealand Clinical Trials Registry numbers, ACTRN12611001069943, ACTRN12610000766011, ACTRN12613000745741, and ACTRN12611000206921.).

PURPOSE OF REVIEW: Cost-effective care pathways are integral to delivering sustainable healthcare programmes. Due to the overestimation of coronary artery disease using traditional risk tables, non-invasive testing has been utilised to improve risk stratification and initiate appropriate management to reduce the dependence on invasive investigations. In line with recent technological improvements, cardiac CT is a modality that offers a detailed anatomical assessment of coronary artery disease comparable to invasive coronary angiography. RECENT FINDINGS: The recent publication of the National Institute for Health and Care Excellences (NICE) Clinical Guideline 95 update assesses the performance and cost utility of different non-invasive imaging strategies in patients presenting with suspected anginal chest pain. The low cost and high sensitivity of cardiac CT makes it the non-invasive test of choice in the evaluation of stable angina. This has now been ratified in national guidelines with NICE recommending cardiac CT as the first-line investigation for all patients presenting with chest pain due to suspected coronary artery disease. Additionally, randomised controlled trials have demonstrated that cardiac CT improves diagnostic certainty when incorporated into chest pain pathways. SUMMARY: NICE recommend cardiac CT as the first-line test for the evaluation of stable coronary artery disease in chest pain pathways.

Several stress-associated neuropsychiatric disorders, notably posttraumatic stress disorder and chronic pain and fatigue syndromes, paradoxically exhibit somewhat low plasma levels of the stress hormone cortisol. The effects appear greatest in those initially traumatized in early life, implying a degree of developmental programming, perhaps of both lower cortisol and vulnerability to psychopathology. In these conditions, lowered cortisol is not due to any adrenal or pituitary insufficiency. Instead, two processes appear involved. First, there is increased target cell sensitivity to glucocorticoid action, notably negative feedback upon the hypothalamic-pituitary-adrenal (stress) axis. Altered density of the glucocorticoid receptor is inferred, squaring with much preclinical data showing early life challenges can permanently program glucocorticoid receptors in a tissue-specific manner. These effects involve epigenetic mechanisms. Second, early life trauma/starvation induces long-lasting lowering of glucocorticoid catabolism, specifically by 5α-reductase type 1 (predominantly a liver enzyme) and 11β-hydroxysteroid dehydrogenase type 2 (in kidney), an effect also seen in model systems. These changes reflect a plausible early-life adaptation to increase the persistence of active cortisol in liver (to maximize fuel output) and kidney (to increase salt retention) without elevation of circulating levels, thus avoiding their deleterious effects on brain and muscle. Modestly lowered circulating cortisol and increased vulnerability to stress-associated disorders may be the outcome. This notion implies a vulnerable early-life phenotype may be discernable and indicates potential therapy by modest glucocorticoid replacement. Indeed, early clinical trials with cortisol have shown a modicum of promise.

BACKGROUND: Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both. METHODS: We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270). FINDINGS: Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024). INTERPRETATION: In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen. FUNDING: Chief Scientist Office of the Scottish Government.

BACKGROUND: Coronary artery calcification is pathognomonic of coronary artery disease (CAD). Whether CAD in patients with COPD is linked to lung function, functional capacity and/or clinically relevant outcomes is unknown. The objective was to assess the association between CAD and disease severity, functional capacity and outcomes in patients with COPD. METHODS: Coronary artery calcium score (CACS; Agatston score) was measured using chest CT in patients with COPD, smokers with normal spirometry and non-smokers from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. RESULTS: CACS was measured in 942 subjects: 672 with COPD (mean age±SD, 63±7 years; FEV1 49±16% predicted), 199 smokers with normal spirometry (54±9 years; FEV1 110±12% predicted) and 71 non-smokers (55±9 years; FEV1 114±14% predicted). CACS was higher in patients with COPD than smokers or non-smokers (median (IQR), 128 (492) vs 0 (75) vs 0 (3) Agatston units (AU), p<0.001). In patients with COPD, CACS correlated with age, pack-years, 6 min walking distance, modified Medical Research Council Dyspnoea score and circulating levels of interleukin (IL)-6, IL-8, Clara Cell protein 16, surfactant protein D and peripheral blood neutrophil count, but not with emphysema, exacerbation frequency, % predicted FEV1 or decline in FEV1. CACS was higher in patients with COPD who died than in those who survived until 3-year follow-up (CACS 406 vs 103 AU, p<0.001), and was associated with mortality in a Cox proportional hazards model (p=0.036). CONCLUSIONS: Patients with COPD have more CAD than controls and this is associated with increased dyspnoea, reduced exercise capacity and increased mortality. These data indicate that the presence of CAD in patients with COPD is associated with poor clinical outcomes.

Background: Aortic stenosis is accompanied by progressive left ventricular hypertrophy and fibrosis. We investigated the natural history of these processes in asymptomatic patients and their potential reversal post-aortic valve replacement (AVR). Methods: Asymptomatic and symptomatic patients with aortic stenosis underwent repeat echocardiography and magnetic resonance imaging. Changes in peak aortic-jet velocity, left ventricular mass index, diffuse fibrosis (indexed extracellular volume), and replacement fibrosis (late gadolinium enhancement [LGE]) were quantified. RESULTS: In 61 asymptomatic patients (43% mild, 34% moderate, and 23% severe aortic stenosis), significant increases in peak aortic-jet velocity, left ventricular mass index, indexed extracellular volume, and LGE mass were observed after 2.1±0.7 years, with the most rapid progression observed in patients with most severe stenosis. Patients with baseline midwall LGE (n=16 [26%]; LGE mass, 2.5 g [0.8–4.8 g]) demonstrated particularly rapid increases in scar burden (78% [50%–158%] increase in LGE mass per year). In 38 symptomatic patients (age, 66±8 years; 76% men) who underwent AVR, there was a 19% (11%–25%) reduction in left ventricular mass index ( P &lt;0.0001) and an 11% (4%–16%) reduction in indexed extracellular volume ( P =0.003) 0.9±0.3 years after surgery. By contrast midwall LGE (n=10 [26%]; mass, 3.3 g [2.6–8.0 g]) did not change post-AVR (n=10; 3.5 g [2.1–8.0 g]; P =0.23), with no evidence of regression even out to 2 years. Conclusions: In patients with aortic stenosis, cellular hypertrophy and diffuse fibrosis progress in a rapid and balanced manner but are reversible after AVR. Once established, midwall LGE also accumulates rapidly but is irreversible post valve replacement. Given its adverse long-term prognosis, prompt AVR when midwall LGE is first identified may improve clinical outcomes. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01755936 and NCT01679431.

Incidental coronary and cardiac calcification are frequent findings on non-gated thoracic CT. We recommend that the heart is reviewed on all CT scans where it is visualised. Coronary artery calcification is a marker of coronary artery disease and it is associated with an adverse prognosis on dedicated cardiac imaging and on non-gated thoracic CT performed for non-cardiac indications, both with and without contrast. We recommend that coronary artery calcification is reported on all non-gated thoracic CT using a simple patient-based score (none, mild, moderate, severe). Furthermore, we recommend that reports include recommendations for subsequent management, namely the assessment of modifiable cardiovascular risk factors and, if the patient has chest pain, assessment as per standard guidelines. In most cases, this will not necessitate additional investigations. Incidental aortic valve calcification may also be identified on non-gated thoracic CT and should be reported, along with ancillary findings such as aortic root dilation. Calcification may occur in other parts of the heart including mitral valve/annulus, pericardium and myocardium, but in many cases these are an incidental finding without clinical significance.

The World Health Organization (WHO) estimates that over 800,000 people die by suicide per year, with the majority of these deaths occurring in low and middle income countries (LMIC) (1). During the late 1990s/early 2000s, an estimated 35% of suicides, or 300,000 deaths, were due to intentional pesticide self-poisoning (2). These numbers have since fallen by more than half, as urbanisation in China and pesticide regulation in some Asian countries has reduced the incidence of fatal poisoning (Mew et al, submitted). The WHO now considers pesticide self-poisoning to be one of the three most important means of global suicide (1).

CONTEXT: 5α-Reductase (5αR) types 1 and 2 catalyze the A-ring reduction of steroids, including androgens and glucocorticoids. 5α-R inhibitors lower dihydrotestosterone in benign prostatic hyperplasia; finasteride inhibits 5αR2, and dutasteride inhibits both 5αR2 and 5αR1. In rodents, loss of 5αR1 promotes fatty liver. OBJECTIVE: Our objective was to test the hypothesis that inhibition of 5αR1 causes metabolic dysfunction in humans. DESIGN, SETTING, AND PARTICIPANTS: This double-blind randomized controlled parallel group study at a clinical research facility included 46 men (20-85 years) studied before and after intervention. INTERVENTION: Oral dutasteride (0.5 mg daily; n = 16), finasteride (5 mg daily; n = 16), or control (tamsulosin; 0.4 mg daily; n = 14) was administered for 3 months. MAIN OUTCOME MEASURE: Glucose disposal was measured during a stepwise hyperinsulinemic-euglycemic clamp. Data are mean (SEM). RESULTS: Dutasteride and finasteride had similar effects on steroid profiles, with reduced urinary androgen and glucocorticoid metabolites and reduced circulating DHT but no change in plasma or salivary cortisol. Dutasteride, but not finasteride, reduced stimulation of glucose disposal by high-dose insulin (dutasteride by -5.7 [3.2] μmol/kg fat-free mass/min, versus finasteride +7.2 [3.0], and tamsulosin +7.0 [2.0]). Dutasteride also reduced suppression of nonesterified fatty acids by insulin and increased body fat (by 1.6% [0.6%]). Glucose production and glycerol turnover were unchanged. Consistent with metabolic effects of dutasteride being mediated in peripheral tissues, mRNA for 5αR1 but not 5αR2 was detected in human adipose tissue. CONCLUSION: Dual inhibition of 5αRs, but not inhibition of 5αR2 alone, modulates insulin sensitivity in human peripheral tissues rather than liver. This may have important implications for patients prescribed dutasteride for prostatic disease.

Accurate and timely assessment of suspected acute aortic syndrome is crucial in this life-threatening condition. Imaging with CT plays a central role in the diagnosis to allow expedited management. Diagnosis can be made using locally available expertise with optimized scanning parameters, making full use of recent advances in CT technology. Each imaging centre must optimize their protocols to allow accurate diagnosis, to optimize radiation dose and in particular to reduce the risk of false-positive diagnosis that may simulate disease. This document outlines the principles for the acquisition of motion-free imaging of the aorta in this context.

The immune system is alerted to cell death by molecules known as damage-associated molecular patterns (DAMPs). These molecules partly mediate acetaminophen-induced liver injury, an archetypal experimental model of sterile cell death and the commonest cause of acute liver failure in the western world. Cyclophilin A (CypA) is an intracellular protein that is proinflammatory when released by cells. We hypothesized that CypA is released from necrotic liver cells and acts as a DAMP to mediate acetaminophen-induced liver injury. Our data demonstrated that mice lacking CypA (Ppia(-/-)) were resistant to acetaminophen toxicity. Antagonism of the extracellular receptor for CypA (CD147) also reduced acetaminophen-induced liver injury. When injected into a wild-type mouse, necrotic liver from Ppia(-/-) mice induced less of an inflammatory response than did wild-type liver. Conversely, the host inflammatory response was increased when CypA was injected with necrotic liver. Antagonism of CD147 also reduced the inflammatory response to necrotic liver. In humans, urinary CypA concentration was significantly increased in patients with acetaminophen-induced liver injury. In summary, CypA is a DAMP that mediates acetaminophen poisoning. This mechanistic insight presents an opportunity for a new therapeutic approach to a disease that currently has inadequate treatment options.

Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. Here we investigate the ability of the flavones apigenin, luteolin, and wogonin to induce neutrophil apoptosis in vitro and resolve neutrophilic inflammation in vivo. Human neutrophil apoptosis was assessed morphologically and by flow cytometry following incubation with apigenin, luteolin, and wogonin. All three flavones induced time- and concentration-dependent neutrophil apoptosis (apigenin, EC=12.2 μM; luteolin, EC=14.6 μM; and wogonin, EC=28.9 μM). Induction of apoptosis was caspase dependent, as it was blocked by the broad-spectrum caspase inhibitor Q-VD-OPh and was associated with both caspase-3 and caspase-9 activation. Flavone-induced apoptosis was preceded by down-regulation of the prosurvival protein Mcl-1, with proteasomal inhibition preventing flavone-induced Mcl-1 down-regulation and apoptosis. The flavones abrogated the survival effects of mediators that prolong neutrophil life span, including lipoteichoic acid, peptidoglycan, dexamethasone, and granulocyte-macrophage colony stimulating factor, by driving apoptosis. Furthermore, wogonin enhanced resolution of established neutrophilic inflammation in a zebrafish model of sterile tissue injury. Wogonin-induced resolution was dependent on apoptosis in vivo as it was blocked by caspase inhibition. Our data show that the flavones induce neutrophil apoptosis and have potential as neutrophil apoptosis-inducing anti-inflammatory, proresolution agents.

BACKGROUND: Atherosclerotic renal artery stenosis is the most common cause of secondary hypertension. Balloon angioplasty with stenting is widely used for the treatment of hypertensive patients with renal artery stenosis but the effectiveness of this procedure in treating hypertension, improving renal function and preventing adverse cardiovascular and renal events remains uncertain. This is an update, to include the results of recent, important large trials, of a review first published in 2003. OBJECTIVES: To compare the effectiveness of balloon angioplasty (with and without stenting) with medical therapy for the treatment of atherosclerotic renal artery stenosis in patients with hypertension. The following outcomes were compared: blood pressure control, renal function, frequency of cardiovascular and renal adverse events, presence or absence of restenosis of the renal artery, side effects of medical therapy, numbers and defined daily doses of antihypertensive drugs. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2014) and CENTRAL (2014, Issue 4). Bibliographies were also reviewed and trial authors were contacted for more information. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing balloon angioplasty with medical therapy in hypertensive patients with haemodynamically significant renal artery stenosis (greater than 50% reduction in luminal diameter) and with a minimum follow-up of six months. DATA COLLECTION AND ANALYSIS: Data were extracted independently on trial design, participants, interventions and outcome measures. A formal meta-analysis was completed to assess the effect on blood pressure, renal function and cardiovascular and renal adverse events. Peto's odds ratios (ORs) and corresponding 95% confidence intervals (CI) for dichotomous outcomes and mean differences (MD) and corresponding 95% CIs for continuous variables were calculated. MAIN RESULTS: Eight RCTs involving 2222 participants with renal artery stenosis were included in the review. The overall quality of evidence included in this review was moderate. Limited pooling of results was possible due to the variable presentation of some of the trial outcomes. Meta-analysis of the four studies reporting change in diastolic blood pressure (BP) found a small improvement in diastolic BP in the angioplasty group (MD -2.00 mmHg; 95% CI -3.72 to -0.27) whilst the meta-analysis of the five studies reporting change in systolic BP did not find any evidence of significant improvement (MD -1.07 mmHg; 95% CI -3.45 to 1.30). There was no significant effect on renal function as measured by serum creatinine (MD -7.99 µmol/L; 95% CI -22.6 to 6.62). Meta-analysis of the three studies that reported the mean number of antihypertensive drugs found a small decrease in antihypertensive drug requirements for the angioplasty group (MD -0.18; 95% CI -0.34 to -0.03). Repeat angiography was only performed on a small number of participants in a single trial and it was therefore not possible to comment on restenosis of the renal artery following balloon angioplasty. Based on the results of the seven studies that reported cardiovascular and renal clinical outcomes there were no differences in cardiovascular (OR 0.91; 95% CI 0.75 to 1.11) or renal adverse events (OR 1.02; 95% CI 0.75 to 1.38) between the angioplasty and medical treatment groups. A small number of procedural complications of balloon angioplasty were reported (haematoma at the site of catheter insertion (6.5%), femoral artery pseudoaneurysm (0.7%), renal artery or kidney perforation or dissection (2.5%) as well as peri-procedural deaths (0.4%)). No side effects of medical therapy were reported. AUTHORS' CONCLUSIONS: The available data are insufficient to conclude that revascularisation in the form of balloon angioplasty, with or without stenting, is superior to medical therapy for the treatment of atherosclerotic renal artery stenosis in patients with hypertension. However, balloon angioplasty results in a small improvement in diastolic blood pressure and a small reduction in antihypertensive drug requirements. Balloon angioplasty appears safe and results in similar numbers of cardiovascular and renal adverse events to medical therapy.

OBJECTIVES: To assess the prognostic implications of standardized reporting systems for coronary computed tomography angiography (CCTA) and coronary artery calcium scores (CACS) in patients with stable chest pain. BACKGROUND: The Coronary Artery Disease Reporting And Data System (CAD-RADS) and Coronary Artery Calcium - Data and Reporting System (CAC-DRS) aim to improve communication of CACS and CCTA results, but its influence on prognostication is unknown. METHODS: Images from 1769 patients who underwent CCTA as part of the Scottish Computed Tomography of the HEART (SCOT-HEART) multi-center randomized controlled trial were assessed. CACS were classified as CAC-DRS 0 to 3 based on Agatston scores. CCTA were classified as CAD-RADS 0 to 5 based on the most clinically relevant finding per patient. The primary outcome was the five-year events of fatal and non-fatal myocardial infarction. RESULTS: Patients had a mean age of 58 ± 10 years and 56% were male. CAC-DRS 0, 1, 2 and 3 occurred in 642 (36%), 510 (29%), 239 (14%) and 379 (21%) patients respectively. CAD-RADS 0, 1, 2, 3, 4A, 4B and 5 occurred in 622 (35%), 327 (18%), 211 (12%), 165 (9%), 221 (12%), 42 (2%) and 181 (10%) patients respectively. Patients classified as CAC-DRS 3 were at an increased risk of fatal or non-fatal myocardial infarction compared to CAC-DRS 0 patients (hazard ratio (HR) 9.41; 95% confidence interval (CI) 3.24, 27.31; p < 0.001). Patients with higher CAD-RADS categories were at an increased risk of fatal or non-fatal myocardial infarction, with patients classified as CAD-RADS 4B at the highest risk compared to CAD-RADS 0 patients (HR 19.14; 95% CI 4.28, 85.53; p < 0.001). CONCLUSION: Patients with higher CAC-DRS and CAD-RADS scores were at increased risk of subsequent fatal and non-fatal myocardial infarction. This confirms that the classification provides additional prognostic discrimination for future coronary heart disease events.

Paracetamol (acetaminophen) overdose is a common medical emergency. The decision to treat with acetylcysteine is predominately based on the dose of drug ingested and a timed blood paracetamol concentration. These risk markers are used because most patients present to hospital soon after overdose, before hepatotoxicity can be excluded using current biomarkers such as serum alanine aminotransaminase activity (ALT). To improve patient stratification, sensitive liver-specific and mechanism-based biomarkers are in development 1-3. In a recent study we demonstrated that the liver-enriched microRNA, miR-122, and the necrosis marker proteins high-mobility group box 1 (HMGB1) and keratin-18 (K18) identified hepatotoxicity on hospital admission with areas under their respective receiver operator curves >90% and negative predictive values >95% 1. Here we present a case that demonstrates their potential utility. A 25-year-old man attended the Royal Infirmary of Edinburgh 4.5 h after a single Co-codamol overdose (60–70 tablets, total 30–35 g paracetamol/480–560 mg codeine). Blood was drawn 4.5 h after overdose and the paracetamol concentration was 107 mg l−1 (Table 1). The patient was deemed at low risk of hepatotoxicity applying the criteria that were standard UK practice at that time 4 and, therefore, the paracetamol concentration was interpreted using the ‘200-line’ on the UK paracetamol treatment nomogram (line starting at 200 mg l−1 at 4 h post-ingestion). According to the UK guidance used at the time of presentation, acetylcysteine treatment was not indicated and the patient was discharged after psychiatric review. The patient returned to hospital 43 h after overdose because he had been vomiting and felt lethargic. Repeat blood tests (43 h post-overdose) demonstrated hepatotoxicity with coagulopathy (Table 1). The patient was immediately treated with intravenous acetylcysteine and recovered fully. ALT (U l−1) (ULN 50) miR-122 (let-7d normalized) (ULN 5.2) HMGB1 (ng ml−1) (ULN 0.9) Necrosis K18 (U l−1) (ULN 480) Retrospectively, biomarkers were measured (by a researcher blind to the patient's data) in the patient's first presentation sample (taken 4.5 h after overdose) and hepatotoxicity was unambiguously reported (Table 1). MiR-122 is a liver-enriched microRNA that is released into the circulation following paracetamol-induced hepatotoxicity. Both rodent and human studies demonstrate it is elevated early, when ALT is still normal 1, 3, 5. At 4.5 h after overdose in this patient, miR-122 was elevated 50-fold above the upper limit of normal (ULN). HMGB1 and K18 are proteins released by necrotic cells that are elevated in the circulation of rodents and humans with paracetamol toxicity 2, 6. In this patient they both reported toxicity on first hospital presentation (approximately 8-fold above ULN). At the time of first presentation to hospital, the UK guidelines were correctly applied and the patient was not treated. This misclassification may reflect the patient having increased susceptibility to hepatotoxicity, the time of overdose being earlier than reported, drug absorption being delayed by codeine or a second overdose after first discharge from hospital. However, had the new biomarkers been available toxicity would have been identified at first presentation. Since this case, the UK guidelines have changed and a single ‘100-line’ (line starting at 100 mg l−1 at 4 h post-ingestion) is used for treatment decisions in all patients, meaning this case would now be correctly classified as needing treatment. However, this lowering of the treatment threshold is likely to result in increased hospital bed occupancy and overall financial cost, for only marginal benefits 7. Adoption of these biomarkers into clinical practice could target treatment to patients at elevated risk of hepatotoxicity. In North America, Australia and New Zealand, where a ‘150-line’ is used (line starting at 150 mg l−1 at 4 h post-ingestion), this patient would still not be treated. This case report demonstrates the potential of new blood biomarkers for hospital front door stratification. This may improve patient identification for trials of new management pathways, facilitate earlier, safe, patient discharge and/or identify the rare patient with hepatotoxicity missed by current biomarkers. All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

5α-Reduced glucocorticoids (GCs) are formed when one of the two isozymes of 5α-reductase reduces the Δ(4-5) double bond in the A-ring of GCs. These steroids are largely viewed inert, despite the acceptance that other 5α-dihydro steroids, e.g. 5α-dihydrotestosterone, retain or have increased activity at their cognate receptors. However, recent findings suggest that 5α-reduced metabolites of corticosterone have dissociated actions on GC receptors (GRs) in vivo and in vitro and are thus potential candidates for safer anti-inflammatory steroids. 5α-Dihydro- and 5α-tetrahydro-corticosterone can bind with GRs, but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However, a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the GR and recently the abilities of 5α-reduced GCs to suppress inflammation have been demonstrated in vitro and in vivo. Thus, the balance of parent GC and its 5α-reduced metabolite may critically affect the profile of GR signalling. 5α-Reduction of GCs is up-regulated in liver in metabolic disease and may represent a pathway that protects from both GC-induced fuel dyshomeostasis and concomitant inflammatory insult. Therefore, 5α-reduced steroids provide hope for drug development, but may also act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5α-reductase inhibitors, drugs that are commonly administered long term for the treatment of benign prostatic hyperplasia.

OBJECTIVE: 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. DESIGN AND SETTING: A prospective cohort study conducted in a tertiary referral cardiac centre. PATIENTS: Two-hundred-and-one patients undergoing coronary angiography for suspected angina or ACS. MAIN OUTCOME MEASURES: 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. RESULTS: 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 (p>0.1 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, p<0.001). Increased concentrations of circulating CD34(+)CD45(-) cells were associated with a shorter cumulative event-free survival (p<0.02). Proangiogenic monocytes (CD14(+)VEGFR-2(+)Tie-2(+)) and endothelial cell-colony forming units were increased in patients with ACS (p<0.01 for both), however, concentrations reflected myocardial necrosis, and did not predict the extent of CAD or clinical outcome. CONCLUSIONS: 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.