Till Keller

Diagnostic accuracy of combined cardiac troponin and copeptin assessment for early rule-out of myocardial infarction: : a systematic review and meta-analysis

Aims: This systematic review aimed to investigate the diagnostic accuracy of combined cardiac troponin (cTn) and copeptin assessment in comparison to cTn alone for early rule-out of acute myocardial infarction (AMI). Methods: Primary studies were eligible if they evaluated diagnostic accuracy for cTn with and without copeptin in patients with symptoms suggestive of AMI. AMI was defined according to the universal definition, using detection of cTn as a marker for myocardial necrosis. Eligible studies were identified by searching electronic databases (Medline, EMBASE, Science Citation Index Expanded, CINAHL, Pascal, and Cochrane) from inception to March 2013, reviewing conference proceedings and contacting field experts and the copeptin manufacturer. Results: In 15 studies totalling 8740 patients (prevalence of AMI 16%), adding copeptin improved the sensitivity of cTn assays (from 0.87 to 0.96, p=0.003) at the expense of lower specificity (from 0.84 to 0.56, p<0.001). In 12 studies providing data for 6988 patients without ST-segment elevation, the summary sensitivity and specificity estimates were 0.95 (95% CI 0.89 to 0.98) and 0.57 (95% CI 0.49 to 0.65) for the combined assessment of cTn and copeptin. When a high-sensitivity cTnT assay was used in combination with copeptin, the summary sensitivity and specificity estimates were 0.98 (95% CI 0.96 to 1.00) and 0.50 (95% CI 0.42 to 0.58). Conclusion: Despite substantial between-study heterogeneity, this meta-analysis demonstrates that copeptin significantly improves baseline cTn sensitivity. Management studies are needed to establish the effectiveness and safety of measuring copeptin in combination with high-sensitivity cTnT for early rule-out of AMI without serial testing.

Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation

Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3′ untranslated region (3′ UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx+ regions, which form a long stem–loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3′ UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-γ and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases.

Amyloid-Beta (1-40) and the Risk of Death From Cardiovascular Causes in Patients With Coronary Heart Disease

BACKGROUNDnThe amyloid beta peptide is the major protein constituent of neuritic plaques in Alzheimer disease and appears to play a central role in vascular inflammation pathophysiology.nnnOBJECTIVESnThis study sought to determine the clinical value of amyloid-beta 1-40 (Abeta40) measurement in predicting cardiovascular (CV) mortality in patients with coronary heart disease (CHD) and arterial stiffness progression in young healthy subjects.nnnMETHODSnAbeta40 was retrospectively measured in blood samples collected from 3 independent prospective cohorts and 2 case-control cohorts (total Nxa0= 1,464). Major adverse cardiac events (MACE) were assessed in the 2 prospective cohorts (nxa0= 877) followed for a median of 4.4 years. To look at effects on subclinical disease, arterial stiffness was evaluated at baseline and after 5-year follow-up (nxa0= 107) in young healthy subjects. The primary endpoint was the predictive value of Abeta40 for CV mortality and outcomes in patients with CHD.nnnRESULTSnIn Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, left ventricular ejection fraction, high-sensitivity C-reactive protein, and high-sensitivity troponin T, Abeta40 independently predicted CV death and MACE in patients with CHD (pxa0< 0.05 for all). After multivariate adjustment, Abeta40 levels conferred a substantial enhancement of net reclassification index and integrated discrimination improvement of individuals at risk in the total combined CHD cohort over the best predictive model. Further cohort-based analysis revealed that Abeta40 levels were significantly and independently associated with arterial stiffness progression, incident subclinical atherosclerosis, and incident CHD.nnnCONCLUSIONSnMeasuring blood levels of Abeta40 identified patients at high risk for CV death.

MR-proANP and MR-proADM for risk stratification of patients with acute chest pain

Objective To evaluate mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-atrial natriuretic peptide (MR-proANP) as prognostic biomarkers in a representative ‘real world’ cohort of patients with suspected acute coronary syndrome (ACS). Design Prospective observational multicentre cohort study. Setting Chest pain units of three major hospitals in Germany from 2007 to 2008. Patients Patients presenting with signs and symptoms suggestive of an ACS. Main outcome measures Primary end point was death or non-fatal myocardial infarction (MI), and secondary end point was death, non-fatal MI, stroke, need for coronary revascularisation, and hospital admission for cardiovascular cause or acute heart failure within 6u2005months after enrolment. Results 1386 patients (male/female=920/466) were enrolled. Follow-up information was available for 97.8% of patients (median follow-up time 183u2005days). Forty-three patients reached the primary end point, and 132 the secondary end point. Patients who reached a primary end point had significantly higher MR-proANP (271 vs 101u2005pmol/l, p<0.001) and MR-proADM (0.86 vs 0.59u2005nmol/l, p<0.001) concentrations than those who did not. Cox regression analysis revealed a 2.55-fold risk of death or non fatal MI (95% CI 1.48 to 2.46, p<0.001) for an increment of the log-transformed MR-proANP concentration by 1 SD after adjustment for cardiovascular risk factors, and a 1.91-fold risk (95% CI 1.48 to 2.46, p<0.001) for MR-proADM. Both peptides could result in significant reclassification of patients when added to the Global Registry of Acute Coronary Events risk score, with an overall net reclassification improvement of 41.2% for MR-proADM and 35.7% for MR-proANP. Conclusions MR-proADM and MR-proANP are predictors of future cardiovascular events in patients presenting with acute chest pain and might facilitate the choice of treatment in those patients complementary to established risk scores.

Transcoronary gradients of vascular miRNAs and coronary atherosclerotic plaque characteristics

AIMSnCirculating microRNAs (miRs) may reflect pathophysiologically relevant processes in the atherosclerotically diseased coronary arterial wall. Given the unmet medical need to identify patients with an unstable plaque phenotype, we determined the relation of circulating atherosclerosis-regulatory miRs with plaque phenotypes.nnnMETHODS AND RESULTSnWe assessed coronary atherosclerotic plaque burden and phenotype by optical coherence tomography in 52 patients and measured the levels of circulating miRs across the transcoronary gradient. The overall plaque load was significantly correlated with transcoronary concentration gradients of miR-126-3p (P = 0.04), miR-145-5p (P = 0.01), miR-155-5p (P < 0.01), and miR-29b-3p (P = 0.02), but not with other miRs such as miR-92a-3p. In patients with a high extent of vulnerable plaques as assessed by the presence of thin-cap fibroatheromas (TCFAs), significantly higher transcoronary gradients were observed, particularly for miR-126-3p, miR-126-5p, and miR-145-5p (all P < 0.02). Transcoronary gradients of miR-126-3p (P < 0.01), miR-126-5p (P < 0.01), miR-145-5p (P = 0.01), miR-29b-3p (P = 0.03), and miR-155-5p (P = 0.02) demonstrated a significant discriminatory power to predict the presence of TCFAs (AUC > 0.7 for all). Moreover, aortic and venous coronary sinus levels of miR-29b-3p were inversely correlated with plaque fibrosis, a finding that is consistent with the anti-fibrotic activity of miR-29b-3p.nnnCONCLUSIONnThe overall plaque burden and plaque phenotypes are associated with changes in the kinetics of miR-concentrations across the transcoronary passage. Transcoronary gradients of the anti-atherosclerotic miR-126-3p and miR-145-5p correlated with the extent of TCFAs, suggesting that instable plaques may affect the local uptake or degradation of these miRs.

Immediate Rule-Out of Acute Myocardial Infarction Using Electrocardiogram and Baseline High-Sensitivity Troponin I

AIMSnSerial measurements of high-sensitivity troponin are used to rule out acute myocardial infarction (AMI) with an assay specific cutoff at the 99th percentile. Here, we evaluated the performance of a single admission troponin with a lower cutoff combined with a low risk electrocardiogram (ECG) to rule out AMI.nnnMETHODSnTroponin I measured with a high-sensitivity assay (hs-TnI) was determined at admission in 1040 patients presenting with suspected AMI (BACC study). To rule out AMI we calculated the negative predictive value (NPV) utilizing the optimal hs-TnI cutoff combined with a low risk ECG. The results were validated in 3566 patients with suspected AMI [2-h Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) studies]. Patients were followed for 6 or 12 months.nnnRESULTSn184 of all patients were diagnosed with AMI. An hs-TnI cutoff of 3 ng/L resulted in a NPV of 99.3% (CI 97.3-100.0), ruling out 35% of all non-AMI patients. Adding the information of a low risk ECG resulted in a 100% (CI 97.5-100.0) NPV (28% ruled out). The 2 validation cohorts replicated the high NPV of this approach. The follow-up mortality in the ruled out population was low (0 deaths in BACC and Stenocardia, 1 death in ADAPT).nnnCONCLUSIONSnA single hs-TnI measurement on admission combined with a low risk ECG appears to rule out AMI safely without need for serial troponin testing.nnnTRIAL REGISTRATIONnwww.clinicaltrials.gov (NCT02355457).

Release kinetics of early ischaemic biomarkers in a clinical model of acute myocardial infarction

Objective To determine the release kinetics of different biomarkers with potential as novel early ischaemic biomarkers in patients with acute coronary syndrome (ACS); it is difficult to establish the detailed release kinetics in patients with acute myocardial infarction (AMI). Methods We analysed the release kinetics of soluble fms-like tyrosine kinase (sFlt-1), ischaemia modified albumin (IMA), and heart-type fatty acid binding protein (hFABP) in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n=21) undergoing TASH were included. Blood samples were collected before TASH and 15, 30, 45, 60, 75, 90, and 105u2005min and 2, 4, 8, and 24u2005h after TASH. sFlt-1 and hFABP were quantified in serum, and IMA was quantified in plasma using immunoassays. Results sFLT-1 and hFABP increased significantly 15u2005min after induction of AMI vs baseline as follows: sFlt-1, 3657.5u2005ng/L (IQR 2302.3–4475.0) vs 76.0u2005ng/L (IQR 71.2–88.8) (p<0.001); hFABP, 9.0u2005ng/mL (IQR 7.0–15.4) vs 4.6u2005ng/mL (IQR 3.4–7.1) (p<0.001). sFlt-1 demonstrated a continuous decrease after the 15th min. hFABP showed a continuous increase until the 8th hour with a decline afterwards. The IMA concentrations increased significantly 30u2005min after induction of AMI vs baseline, with values of 26.0u2005U/mL (IQR 21.8–38.6) vs 15.6u2005U/mL (IQR 10.1–24.7) (p=0.02), and then decreased after 75u2005min. Conclusions sFlt-1 and hFABP increased very early after induction of myocardial ischaemia, showing different release kinetics. The additional information provided by these findings is helpful for developing their potential combined use with cardiac troponins in patients with suspected AMI.

Local expression of myocardial galectin-3 does not correlate with its serum levels in patients undergoing heart transplantation

BACKGROUNDnGalectins are a family of soluble lectins expressed in a variety of tissues, which play many important regulatory roles in inflammation, immunity, and cancer. The up-regulation of galectin-3 in hypertrophied hearts and the development of fibrosis have been shown in experimental studies. Increased galectin-3 levels are associated with poor long-term survival in end-stage heart failure (HF). We examined the relationship between plasma galectin-3 levels and the myocardial tissue expression of galectin-3 in patients with end-stage HF.nnnMATERIAL AND METHODSnExpression of galectin-3 was assessed by real-time PCR and immunohistochemistry in left ventricle and atrial myocardium of patients (n=12) with end-stage HF undergoing heart transplantation. All patients gave informed consent. Serum expression of galectin-3 was assessed by ELISA in serum from 20 patients with end-stage HF and in 20 healthy volunteers who served as controls.nnnRESULTSnExpression of galectin-3 was similar in the myocardium of patients in comparison to the control group, independently of the anatomical area (HF vs. healthy ventricle: 1.73E-02 vs. 1.50 E-02; HF vs. healthy atrium: 1.32E-02 vs. 1.16E-02). However, serum expression of galectin-3 was significantly higher in the end-stage HF patients compared to the healthy controls (13.02±10.6 vs. 3.7±1.3 ng/ml; p<0.05).nnnCONCLUSIONSnPlasma galectin-3 levels correlate with the ejection fraction and are elevated in patients with HF. However, the myocardial expression of galectin-3 does not correlate with the ventricular ejection fraction. Our data support the use of galectin-3 as a marker of heart insufficiency.

Identification of acute myocardial infarction in patients with atrial fibrillation and chest pain with a contemporary sensitive troponin I assay

BackgroundThe introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.MethodsContemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.ResultsIn the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.ConclusionsTroponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.

Transcoronary Concentration Gradient of microRNA-133a and Outcome in Patients With Coronary Artery Disease

Circulating levels of microRNA (miR)-133a are increased in patients with coronary atherosclerotic disease (CAD). Whether the cardiac release of this miR provides any prognostic information in patients with CAD is currently unknown. We aimed to investigate if changes in concentration of miR-133a trough the coronary circulation may be associated with patients cardiovascular outcome. We enrolled 111 patients (82 with stable CAD and 29 with acute coronary syndromes [ACS]) who underwent coronary angiography. Circulating levels of miR-133a were measured across the transcoronary circulation. Major adverse cardiac events (MACE: death, nonfatal myocardial infarction, and need for revascularization) were recorded through a median follow-up of 32xa0months. An increased transcoronary concentration gradient of miR133a showed a significant association with overall rate of MACE at follow-up in patients with both stable CAD and ACS (pxa0= 0.011 and pxa0= 0.002, respectively). At the single end point-analysis, increased transcoronary concentration gradients of miR133a were significantly associated with increased rate of death in patients with ACS (pxa0=xa00.017) and with increased incidence of new revascularization because of in-stent restenosis in patients with stable CAD (pxa0= 0.026). Kaplan-Meier curves showed a significantly worse event-free survival in patients with greater transcoronary gradients of miR133a (pxa0= 0.026 in stable CAD group and pxa0= 0.007 for ACS group). Nevertheless, these findings lost their significance after adjustment for common cardiovascular risk factor and high-sensitivity troponin-T. In conclusions, the release of miR133a, as measured by its transcoronary concentration gradient, is associated with a higher incidence of MACE in patients with CAD, but it does not add significant prognostic information compared with traditional prognostic biomarkers, therefore limiting its potential usefulness in the clinical practice. Nevertheless, the differential modulation of miR-133a release in the coronary circulation may reflect pathophysiological mechanism involved in CAD progression and complications and suggest a novel potential role for this miR in the development of in-stent restenosis.