Background High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome. Methods In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6-12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT0185 2123. Findings Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1.10, 95% CI 0.75 to 1.61; p=0.620). Interpretation Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population. Funding The British Heart Foundation. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Aims High-sensitivity cardiac troponin I (cTnI) assays hold promise in detecting the transition from hypertrophy to heart failure in aortic stenosis. We sought to investigate the mechanism for troponin release in patients with aortic stenosis and whether plasma cTnI concentrations are associated with long-term outcome. Methods and results Plasma cTnI concentrations were measured in two patient cohorts using a high-sensitivity assay. First, in the Mechanism Cohort, 122 patients with aortic stenosis (median age 71, 67% male, aortic valve area 1.0 ± 0.4 cm2) underwent cardiovascular magnetic resonance and echocardiography to assess left ventricular (LV) myocardial mass, function, and fibrosis. The indexed LV mass and measures of replacement fibrosis (late gadolinium enhancement) were associated with cTnI concentrations independent of age, sex, coronary artery disease, aortic stenosis severity, and diastolic function. In the separate Outcome Cohort, 131 patients originally recruited into the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact of REgression (SALTIRE) study, had long-term follow-up for the occurrence of aortic valve replacement (AVR) and cardiovascular deaths. Over a median follow-up of 10.6 years (1178 patient-years), 24 patients died from a cardiovascular cause and 60 patients had an AVR. Plasma cTnI concentrations were associated with AVR or cardiovascular death HR 1.77 (95% CI, 1.22 to 2.55) independent of age, sex, systolic ejection fraction, and aortic stenosis severity. Conclusions In patients with aortic stenosis, plasma cTnI concentration is associated with advanced hypertrophy and replacement myocardial fibrosis as well as AVR or cardiovascular death.

To the Editor: Dr Mills and colleagues demonstrated a significant reduction in myocardial infarction (MI) and death in patients with suspected acute coronary syndrome (ACS) through use of a lower-threshold troponin assay. One surprising finding was a modest increase in use of recommended therapies in patients with plasma troponin concentrations of 0.05 to 0.19 ng/mL during the implementation phase, which would be expected to result in reduced events. In fact, revascularization rates were stable despite more than a doubling in coronary angiography. Aspirin, -blocker, and angiotensin-converting enzyme inhibitor use did not differ between the phases. Although more statins were prescribed at discharge in the implementation phase, a similar difference was present on admission, suggesting possible baseline differences between these nonrandomized samples. The most striking difference was in clopidogrel use, 31% in the validation phase vs 61% in the implementation phase. If the outcome difference between the 2 groups was driven by clopidogrel, this would be a substantially greater benefit than demonstrated in prior studies. For example, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial showed a 2.1% absolute risk reduction in death from cardiovascular causes, nonfatal MI, or stroke over 12 months (9.3% in clopidogrel group vs 11.4% in placebo group) for patients with ACS without ST-segment elevation compared with an 18% difference in death or recurrent MI at 12 months (39% in validation cohort vs 21% in implementation cohort) in the report by Mills et al. Determination of the rates of clopidogrel use in patients who did or did not have an event would be interesting. In addition, other than the presence of cardiac risk factors and interventions, little is known about the population. Given the high overall mortality rates and low rates of revascularization despite angiography, many patients may have had noncardiac medical issues, and the results may be due to higher attention to underlying coronary artery disease in a population with comorbid illnesses. This is supported by the low rates of use of recommended therapies. For instance, only 47% of validation phase patients with peak troponin concentrations of 0.05 to 0.19 ng/mL were taking a -blocker at discharge when 69% of these patients carried a diagnosis of ischemic heart disease prior to admission. It would be useful to know the number of patients who underwent stress testing, the percentage diagnosed with ischemic heart disease, other discharge diagnoses, and creatinine levels as alternate explanations for elevated troponin levels. Jeffrey D. Clough, MD, MBA Seth S. Martin, MD Matthew W. Cope, MD

The publication of the NICE Guideline on Identification and Management of Familial Hypercholesterolaemia (FH) in 2008, served as a catalyst for the Scottish Lipid Forum to implement a system of genetic and cascade screening for familial heterozygous hypercholesterolaemia (FH) in Scotland. We describe the first ninety mutation positive families identified in one Health Board area where the prevalence is estimated at 1000 cases. There are two designated Lipid Clinics and also a two further clinics that deal with Lipid problems. These two designated Lipid clinics amalgamated their databases in 2010 and the mutations of these first ninety families identified as genetically positive for familial hypercholesterolaemia are described. The positive pickup rate from all samples sent was 34% similar to other studies. When there was a possible family connection between two probands only one was included. Unclassified variants were also included. Sixty-five families were identified at one centre and twenty-five at the other. The male:female ratio of probands was not significantly different. There were no reports of the PCSK9 (Arg374Tyr) mutation, ten unclassified variants were found and seven Apo B 3500 (c.1058G>A; p.Arg3527Gln) mutations. LDLR MPLA showed evidence of four duplications of exons 11–12, three deletions of exon 1, a single deletion involving 2–6, a single deletion involving exons 3–6 and also a single deletion of exons 11–12.LDL sequencing yielded seven c.660delC; p.Asp221Trhfx44 mutations, five c.1444G>A; p.Asp482Asn, five c.682G>T; p.Glu228X, four c.2054C>T; p.Pro685Leu, three c.933delA; p.Glu312SerfsX58, and two c.313+1G>A mutations with a further 37 different point mutations being identified. Of particular note is that commercially available kits would only have picked up 34% (FH20) or 57% (FH48) of these mutations.

UNLABELLEDThe Model for End-Stage Liver Disease (MELD) or similar scoring system is proposed in the UK for prioritization for liver transplantation. We evaluated the reproducibility of creatinine measurements and therefore MELD scores in four liver transplant units in the UK.METHODSAll transplant units were invited to participate; four agreed to do so, contributing 36 patients awaiting liver transplantation. Blood was collected from these 36 and divided into aliquots then sent to the four participating centres. Every centre measured creatinine and bilirubin for every patient. The results were analysed for the degree of agreement between centres for creatinine and MELD scores using the Bland-Altman method and Wilcoxon rank test.RESULTSThe mean creatinine value varied from 101 mumol/l in centre C to 110 micromol/l for the same sample in centre A, with significant differences between the four centres (P < 0.05, Wilcoxon signed-rank test). The MELD scores were significantly different between centre C and all other centres (P < 0.05).CONCLUSIONThis study demonstrates lack of agreement in measurement of serum creatinine and MELD scoring between four UK transplant centres. A difference in two MELD points can have a significant impact on patient outcome, and these factors will have to be addressed if a UK-wide transplant list is to be initiated.

Background Accurate risk stratification soon after admission for patients with acute coronary syndromes (ACS) is vital in guiding management. Clinical risk scores and B-type natriuretic peptide (BNP) can predict mortality and re-infarction in ACS, but it is unknown whether BNP provides prognostic information over and above that of the clinical risk scores. Methods 142 unselected patients with ACS were prospectively studied. BNP was measured and patients were stratified according to BNP and Global Registry of Acute Coronary Events (GRACE) score. In-hospital and 30-day events were characterised. Results 20.4% of ACS subjects had ST-elevation myocardial infarction (MI), 14.1%, non-ST elevation MI and 65.5% unstable angina. Elevated BNP predicted inhospital and 30-day heart failure (p<0.01), and the risk of in-hospital recurrent ACS (p<0.05). Increasing GRACE score predicted in-hospital recurrent ACS (p<0.05), heart failure (p<0.001), arrhythmias (p<0.05) and angioplasty (p<0.05). GRACE score also predicted 30-day heart failure (p<0.05). In contrast, the predictive accuracy of troponin elevation was less robust. Conclusion BNP and the GRACE score predict complementary outcomes from ACS, but both predicted heart failure. BNP is a powerful indicator of heart failure in patients with ACS and provides prognostic information above and beyond conventional biomarkers and risk scores.

Analysis of cerebrospinal fluid (CSF) has an important role to play in the diagnosis of subarachnoid hemorrhage (SAH) (1). Computed tomography, the first line of investigation for suspected SAH, shows a decrease in diagnostic accuracy as the time interval between the suspected hemorrhage and the time of investigation increases. A computed tomography scan would be positive in 98% of patients presenting within 12 h after an event, but positivity decreases to ∼50% in patients presenting after 1 week, 30% after 2 weeks, and 0% after 3 weeks (2). An increase in bilirubin in the CSF is the key finding supporting the occurrence of SAH (3). Guidelines for the analysis of CSF for bilirubin in suspected SAH have recently been published in the United Kingdom (3). The presence of bilirubin is assessed by calculating the net bilirubin absorbance (NBA) according to Chalmers’ modification (4) to the original method of Chalmers and Kiley (5). A single NBA cut point of 0.007 absorbance units (AU) is recommended in the decision tree for interpretation and reporting of results (3). The interpretative comment “No evidence to support SAH” is advised if the NBA value is ≤0.007 AU and no oxyhemoglobin is detected. In contrast, if the corrected NBA is >0.007 AU and no oxyhemoglobin is detected, the interpretative comment “Consistent with SAH” is recommended (3). Laboratories and clinicians need to define and be aware of the quality of the tests they provide when these tests are the basis for clinical decisions. To the best of our knowledge, the analytical imprecision profile for NBA has not been published to date. Our laboratory has performed 92 analyses of CSF for suspected SAH in the last year. Of …

Abstract Background Hypercholesterolaemia is a recognized risk factor for the development of arteriosclerosis. There is compelling evidence to support the use of lipid-lowering strategies in all hypercholesterolaemic patients with arteriosclerotic disease. In peripheral arterial disease (PAD), national guidelines recommend treatment if total cholesterol exceeds 5·0 mmol l−1. The prevalence of hypercholesterolaemia in patients with PAD was determined and the adequacy of lipid management before vascular referral was examined. Methods This was a prospective study of 233 consecutive patients admitted electively to this vascular surgery unit between December 1997 and December 1998. Some 68 patients were admitted with carotid disease, 81 with an aneurysm and 84 with intermittent claudication. A fasting venous blood sample was obtained from each patient. Results There were 175 men and 58 women, of median age 67 (range 37–85) and 68 (range 47–85) years respectively. Only 35 patients (15 per cent) were previously known to be hypercholesterolaemic; all but one were receiving treatment (one dietary, 33 statin). Of the remaining 198 patients, 124 (63 per cent) had a serum cholesterol level above 5·0 mmol l−1. A further 17 patients (9 per cent) had total cholesterol/high-density lipoprotein: cholesterol ratio greater than 5·0; these patients may also benefit from lipid-lowering therapy. In total, 141 (80 per cent) of 176 hypercholesterolaemic patients were undiagnosed at the time of hospital admission. Conclusion Hypercholesterolaemia is an important and correctable risk factor found in the majority of patients with PAD, but despite national guidelines and clear evidence from randomized controlled trials it is simply not being diagnosed in primary care. All elective patients with PAD should be screened for hypercholesterolaemia during their admission.

Familial hypercholesterolaemia (FH) is an inherited autosomal codominant disorder caused by many different mutations in the low-density lipoprotein receptor (LDLR) gene. The one described most frequently in patients with FH from England, arises from a G-->A transition at the first nucleotide of codon 80, resulting in the substitution of lysine for glutamic acid at residue 80 of the mature protein, FH E80K. We describe a simple method to detect this mutation in genomic DNA using the polymerase chain reaction (PCR). A 69 base pair (bp) fragment of exon 3 of the LDLR gene is amplified using a mutagenic upstream PCR primer. This substitutes a T for an A residue in the amplified product, 2 bp upstream from the mutant site, generating a restriction site for the endonuclease Taq I, in normal, but not in mutant DNA. Following digestion of amplified DNA with Taq I, normal but not mutant DNA is cut into two fragments of 29 and 40 bp, which are readily identified by polyacrylamide gel electrophoresis. Using this method, 410 patients with clinically diagnosed FH, attending lipid clinics in Edinburgh (72), Newport (158), Walsall (30) and Southampton (150), were screened for the mutation. Five individuals tested positive as heterozygotes, one from Edinburgh, three from Newport and one from Southampton. This finding was confirmed by DNA sequence analysis. We conclude that FH due to this mutation occurs in individuals throughout Great Britain and that it can be detected accurately using this simple technique. DNA from these and other individuals previously identified to be heterozygous for FH E80K, was then studied using PCR of highly informative microsatellite markers flanking the LDLR gene. Sixteen of 17 apparently unrelated individuals heterozygous for FH E80K also were heterozygous for an identical size (239 nucleotide) allele, of polymorphic microsatellite D19S394, located approximately 250 kb away from the LDLR gene. This supports the hypothesis that FH E80K in these 16 individuals arose from a single ancestor less than 1000 years ago.

Familial ligand-defective apolipoprotein (apo) B-100 (FDB) is an autosomal codominant disorder which may give rise to hypercholesterolaemia. It is caused by the substitution of glutamine for arginine at codon 3500 of the apo B gene (apo B R3500Q), resulting in decreased binding of low density lipoprotien (LDL) to the LDL receptor. In order to search for other mutations in this region of the apo B gene, we have screened genomic DNA, obtained from 412 hypercholesterolaemic individuals, using heteroduplex analysis. Additional heteroduplex bands were observed following analysis of DNA from 11 individuals, nine of whom were heterozygous for apo B R3500Q: The two remaining individuals, both of Celtic origin, were shown by DNA sequencing to be heterozygous for a C --> T transition, at nucleotide 10 800 of the apo B gene, resulting in the substitution of cysteine for arginine at codon 3531 (ape B R3531C). Both had a strong family history of atherosclerosis and family studies revealed a further four individuals heterozygous for the mutation, three of whom were hypercholesterolaemic. Individuals heterozygous for apo B R3531C and R3500Q had mean +/- S.E.M. cholesterol concentrations of 7.82 +/- 0.68 and 8.53 +/- 0.31 mmol/l, respectively. These values were significantly higher than the value of 5.51 +/- 0.23 mmol/l observed in their unaffected relatives. These findings suggest that apo B R3531C is both less common in the UK and gives rise to a less severe form of hypercholesterolaemia than the classical 3500 mutation. In one of the families, the R3531C mutation occurred on a haplotype, compatible with that previously assigned to the mutation in a North American family also of Celtic origin. This is consistent with the mutation having been inherited from a common distant ancestor in individuals of Celtic origin. (C) 1997 Elsevier Science Ireland Ltd.

Familial defective apolipoprotein (apo) B-100 (FDB) is an autosomal codominant disorder, which may be associated with hypercholesterolaemia. The defect is caused by the substitution of glutamine for arginine at amino acid residue 3500 of apo B-100. A total of 357 hypercholesterolaemic patients, 48 with a clinical diagnosis of familial hypercholesterolaemia attending lipid clinics in Scotland and Wales, were screened for the presence of FDB. Seven unrelated individuals, five of whom had a family history of coronary heart disease, and a further 11 first-degree relatives, were shown to be heterozygous for the mutation. Pedigree analysis demonstrated the mutation to be present on a single haplotype, suggesting that in Britain it is inherited from a common ancestor. Treatment of 11 heterozygous individuals with lipid-lowering medication showed falls in total and low density lipoprotein cholesterol ranging from 11·6 to 38·8% and 5·3 to 49·5%, respectively. In view of the condition's association with coronary heart disease and hypercholesterolaemia, it may be worthwhile identifying carriers attending lipid clinics, so that affected siblings can be offered cholesterol-lowering treatment where necessary.