Combining High-Sensitivity Cardiac Troponin I and Cardiac Troponin T in the Early Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Combining 2 signals of cardiomyocyte injury, cardiac troponin I (cTnI) and T (cTnT), might overcome some individual pathophysiological and analytical limitations and thereby increase diagnostic accuracy for acute myocardial infarction with a single blood draw. We aimed to evaluate the diagnostic performance of combinations of high-sensitivity (hs) cTnI and hs-cTnT for the early diagnosis of acute myocardial infarction. METHODS: The diagnostic performance of combining hs-cTnI (Architect, Abbott) and hs-cTnT (Elecsys, Roche) concentrations (sum, product, ratio, and a combination algorithm) obtained at the time of presentation was evaluated in a large multicenter diagnostic study of patients with suspected acute myocardial infarction. The optimal rule-out and rule-in thresholds were externally validated in a second large multicenter diagnostic study. The proportion of patients eligible for early rule-out was compared with the European Society of Cardiology 0/1 and 0/3 hour algorithms. RESULTS: Combining hs-cTnI and hs-cTnT concentrations did not consistently increase overall diagnostic accuracy as compared with the individual isoforms. However, the combination improved the proportion of patients meeting criteria for very early rule-out. With the European Society of Cardiology 2015 guideline recommended algorithms and cut-offs, the proportion meeting rule-out criteria after the baseline blood sampling was limited (6% to 24%) and assay dependent. Application of optimized cut-off values using the sum (9 ng/L) and product (18 ng2/L2) of hs-cTnI and hs-cTnT concentrations led to an increase in the proportion ruled-out after a single blood draw to 34% to 41% in the original (sum: negative predictive value [NPV] 100% [95% confidence interval (CI), 99.5% to 100%]; product: NPV 100% [95% CI, 99.5% to 100%]) and in the validation cohort (sum: NPV 99.6% [95% CI, 99.0-99.9%]; product: NPV 99.4% [95% CI, 98.8-99.8%]). The use of a combination algorithm (hs-cTnI <4 ng/L and hs-cTnT <9 ng/L) showed comparable results for rule-out (40% to 43% ruled out; NPV original cohort 99.9% [95% CI, 99.2-100%]; NPV validation cohort 99.5% [95% CI, 98.9-99.8%]) and rule-in (positive predictive value [PPV] original cohort 74.4% [95% Cl, 69.6-78.8%]; PPV validation cohort 84.0% [95% Cl, 79.7-87.6%]). CONCLUSIONS: New strategies combining hs-cTnI and hs-cTnT concentrations may significantly increase the number of patients eligible for very early and safe rule-out, but do not seem helpful for the rule-in of acute myocardial infarction. CLINICAL TRIAL REGISTRATION: URL (APACE): https://www.clinicaltrial.gov . Unique identifier: NCT00470587. URL (ADAPT): www.anzctr.org.au . Unique identifier: ACTRN12611001069943.

Cardiac Troponin T: Smaller Molecules in Patients with End-Stage Renal Disease than after Onset of Acute Myocardial Infarction.

BACKGROUND: We have found previously that in acute myocardial infarction (AMI), cardiac troponin T (cTnT) is degraded in a time-dependent pattern. We investigated whether cTnT forms differed in patients with chronic cTnT increases, as seen with renal dysfunction, from those in the acute phase of myocardial infarction. METHODS: We separated cTnT forms by gel filtration chromatography (GFC) in end-stage renal disease (ESRD) patients: prehemodialysis (pre-HD) and post-HD (n = 10) and 2 months follow-up (n = 6). Purified (cTnT) standards, quality control materials of the clinical cTnT immunoassay (Roche), and AMI patients' sera also were analyzed. Immunoprecipitation and Western blotting were performed with the original cTnT antibodies from the clinical assay and antibodies against the N- and C-terminal end of cTnT. RESULTS: GFC analysis revealed the retention of purified cTnT at 27.5 mL, identical to that for cTnT in quality controls. For all ESRD patients, one cTnT peak was found at 45 mL, pre- and post-HD, and stable over time. Western blotting illustrated that this peak corresponded to cTnT fragments <18 kDa missing the N- and C-terminal ends. AMI patients' sera revealed cTnT peaks at 27.5 and 45 mL, respectively, corresponding to N-terminal truncated cTnT of 29 kDa and N- and C-terminal truncated fragments of <18 kDa, respectively. CONCLUSIONS: We found that cTnT forms in ESRD patients are small (<18 kDa) and different from forms seen in AMI patients. These insights may prove useful for development of a more specific cTnT immunoassay, especially for the acute and diagnostic phase of myocardial infarction.

Identification and Characterization of Cardiac Troponin T Fragments in Serum of Patients Suffering from Acute Myocardial Infarction.

BACKGROUND: Cardiac troponin T (cTnT) is the preferred biomarker for the diagnosis of acute myocardial infarction (AMI). It has been suggested that cTnT is present predominantly in fragmented forms in human serum following AMI. In this study, we have used a targeted mass spectrometry assay and epitope mapping using Western blotting to confirm this hypothesis. METHODS: cTnT was captured from the serum of 12 patients diagnosed with AMI using an immunoprecipitation technique employing the M11.7 catcher antibody and fractionated with SDS-PAGE. Coomassie-stained bands of 4 patients at 37, 29, and 16 kDa were excised from the gel, digested with trypsin, and analyzed on a Q Exactive instrument set on targeted Selected Ion Monitoring mode with data-dependent tandem mass spectrometry (MS/MS) for identification. Western blotting employing 3 different antibodies was used for epitope mapping. RESULTS: Ten cTnT peptides of interest were targeted. By using MS/MS, all of these peptides were identified in the 37-kDa, intact, cTnT band. In the 29- and 16-kDa fragment bands, 8 and 4 cTnT-specific peptides were identified, respectively. Some of these peptides were "semitryptic," meaning that their C-termini were not formed by trypsin cleavage. The C-termini of these semitryptic peptides represent the C-terminal end of the cTnT molecules present in these bands. These results were confirmed independently by epitope mapping. CONCLUSIONS: Using LC-MS, we have succeeded in positively identifying the 29- and 16-kDa fragment bands as cTnT-derived products. The amino acid sequences of the 29- and 16-kDa fragments are Ser79-Trp297 and Ser79-Gln199, respectively.

Estimated Glomerular Filtration Rate and Albuminuria Are Associated with Biomarkers of Cardiac Injury in a Population-Based Cohort Study: The Maastricht Study.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased cardiovascular disease mortality risk. It is, however, less clear at what point in the course from normal kidney function to CKD the association with cardiovascular disease appears. Studying the associations of estimated glomerular filtration rate (eGFR) and albuminuria with biomarkers of (subclinical) cardiac injury in a population without substantial CKD may clarify this issue. METHODS: We examined the cross-sectional associations of eGFR and urinary albumin excretion (UAE) with high-sensitivity cardiac troponin (hs-cTn) T, hs-cTnI, and N-terminal probrain natriuretic-peptide (NT-proBNP) in 3103 individuals from a population-based diabetes-enriched cohort study. RESULTS: After adjustment for potential confounders, eGFR and UAE were associated with these biomarkers of cardiac injury, even at levels that do not fulfill the CKD criteria. For example, eGFR 60-<90 mL · min-1 ·(1.73 m2)-1 [vs ≥90 mL · min-1 · (1.73 m2)-1] was associated with a [ratio (95% CI)] 1.21 (1.17-1.26), 1.14 (1.07-1.20), and 1.19 (1.12-1.27) times higher hs-cTnT, hs-cTnI, and NT-proBNP, respectively. The association of eGFR with hs-cTnT was statistically significantly stronger than that with hs-cTnI. In addition, UAE 15-<30 mg/24 h (vs <15 mg/24 h) was associated with a 1.04 (0.98-1.10), 1.08 (1.00-1.18), and 1.07 (0.96-1.18) times higher hs-cTnT, hs-cTnI, and NT-proBNP, respectively. CONCLUSIONS: eGFR and albuminuria were already associated with biomarkers of (subclinical) cardiac injury at levels that do not fulfill the CKD criteria. Although reduced renal elimination may partly underlie the associations of eGFR, these findings support the concept that eGFR and albuminuria are, over their entire range, associated with cardiac injury.

Acute chest pain in the high-sensitivity cardiac troponin era: A changing role for noninvasive imaging?

Management of patients with acute chest pain remains challenging. Cardiac biomarker testing reduces the likelihood of erroneously discharging patients with acute myocardial infarction (AMI). Despite normal contemporary troponins, physicians have still been reluctant to discharge patients without additional testing. Nowadays, the extremely high negative predictive value of current high-sensitivity cardiac troponin (hs-cTn) assays challenges this need. However, the decreased specificity of hs-cTn assays to diagnose AMI poses a new problem as noncoronary diseases (eg, pulmonary embolism, myocarditis, cardiomyopathies, hypertension, renal failure, etc) may also cause elevated hs-cTn levels. Subjecting patients with noncoronary diseases to unnecessary pharmacological therapy or invasive procedures must be prevented. Attempts to improve the positive predictive value to diagnose AMI by defining higher initial cutoff values or dynamic changes over time inherently lower the sensitivity of troponin assays. In this review, we anticipate a potential changing role of noninvasive imaging from ruling out myocardial disease when troponin values are normal toward characterizing myocardial disease when hs-cTn values are (mildly) abnormal.

How Well Do Laboratories Adhere to Recommended Clinical Guidelines for the Management of Myocardial Infarction: The CARdiac MArker Guidelines Uptake in Europe Study (CARMAGUE).

BACKGROUND: We undertook an assessment of current use of evidence-based guidelines for the use of cardiac biomarkers in Europe (EU) and North America (NA). METHODS: In 2013-2014 a web-based questionnaire was distributed via NA and EU biochemical societies. Questions covered cardiac biomarkers measured, analytical methods used, decision thresholds, and use of decision-making protocols. Results were collated using a central database and analyzed using comparative and descriptive nonparametric statistics. RESULTS: In EU, returns were obtained from 442 hospitals, 50% central or university hospitals, and 39% from local hospitals from 35 countries with 395/442 (89%) provided an acute service. In NA there were 91 responses (63.7% central or university hospitals, 19.8% community hospitals) with 76/91 (83.5%) providing an acute service. Cardiac troponin was the preferred cardiac biomarker in 99.5% (EU) and 98.7% (NA), and the first line marker in 97.7% (EU) and 97.4% (NA). There were important differences in the choice of decision limits and their derivations. The origin of the information was also significantly different, with EU vs NA as follows: package insert, 61.9% vs 40%; publications, 17.1% vs 15.0%; local clinical or analytical validation choice, 21.0% vs 45.0%; P = 0.0003. CONCLUSIONS: There are significant differences between EU and NA use of cardiac biomarkers. This probably relates to different availability of assays between EU and NA (such as high-sensitivity troponin assays) and different laboratory practices on assay introduction (greater local evaluation of assay performance occurred in NA).

Diurnal Rhythm of Cardiac Troponin: Consequences for the Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point. The aim of this study was to challenge this diagnostic concept. METHODS: Study 1 examined the presence of a diurnal hs-cTn rhythm by hourly blood sampling, day and night, in 24 individuals without a recent history of AMI. Study 2 assessed morning vs evening diagnostic accuracy of hs-cTnT and hs-cTnI in a prospective multicenter diagnostic study of 2782 unselected patients, presenting to the emergency department with acute chest pain. RESULTS: In study 1, hs-cTnT, but not hs-cTnI, exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime, to peak concentrations in the morning (mean 16.2 ng/L at 8:30 AM and 12.1 ng/L at 7:30 PM). In study 2, the hs-cTnT rhythm was confirmed by higher hs-cTnT concentrations in early-morning presenters compared to evening presenters with an adjudicated diagnosis of noncardiac disease. The diagnostic accuracy [area under the receiver-operation characteristics curve (AUC)] of hs-cTnT at presentation, 1 h, and for the combination of absolute changes with presenting concentration, were very high and comparable among patients presenting early morning as compared to evening (all AUC >0.93). hs-cTnI exhibited no diurnal rhythm with no differences in AUC among early-morning and evening presenters. CONCLUSIONS: Rhythmic diurnal variation of hs-cTnT is a general phenomenon that is not seen with hs-cTnI. While the diurnal hs-cTnT rhythm does not seem to affect the diagnostic accuracy of hs-cTnT for AMI, it should be considered when using hs-cTnT for screening purposes. CLINICAL TRIAL REGISTRATION: 1. Circadian Variation of Cardiac Troponin, NCT02091427, www.clinicaltrials.gov/ct2/show/NCT02091427. 2. Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) Study, NCT00470587, www.clinicaltrials.gov/ct2/show/NCT00470587.

Heart failure in nursing home residents; a cross-sectional study to determine the prevalence and clinical characteristics.

BACKGROUND: Heart failure (HF) is expected to be highly prevalent in nursing home residents, but precise figures are scarce. The aim of this study was to determine the prevalence of HF in nursing home residents and to get insight in the clinical characteristics of residents with HF. METHODS: The study followed a multi-centre cross-sectional design. Nursing home residents (n = 501) in the southern part of the Netherlands aged over 65 years and receiving long-term somatic or psychogeriatric care were included in the study. The diagnosis of HF and related characteristics were based on data collected from actual clinical examinations (including history, physical examination, ECG, cardiac markers and echocardiography), patient records and questionnaires. A panel of two cardiologists and a geriatrician ultimately judged the data to diagnose HF. RESULTS: The overall prevalence of HF in nursing home residents was 33 %, of which 52 % had HF with preserved ejection fraction. The symptoms dyspnoea and oedema and a cardiac history were more common in residents with HF. Diabetes mellitus, chronic obstructive pulmonary disease (COPD) were also more prevalent in those with HF. Residents with HF had a higher score on the Mini Mental State Examination. 54 % of those with HF where not known before, and in 31 % with a history of HF, this diagnosis was not confirmed by the expert panel. CONCLUSION: This study shows that HF is highly prevalent in nursing home residents with many unknown or falsely diagnosed with HF. Equal number of HF patients had reduced and preserved left-ventricular ejection fraction. TRIAL REGISTRATION: The Netherlands National Trial Register NTR2663 (27-12-2010).

Risk stratification with the use of serial N-terminal pro-B-type natriuretic peptide measurements during admission and early after discharge in heart failure patients: post hoc analysis of the PRIMA study.

OBJECTIVE: The aim of this work was to assess the prognostic value of absolute N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration in combination with changes during admission because of acute heart failure (AHF) and early after hospital discharge. BACKGROUND: In AHF, readmission and mortality rates are high. Identifying those at highest risk for events early after hospital discharge might help to select patients in need of intensive outpatient monitoring. METHODS AND RESULTS: We evaluated the prognostic value of NT-proBNP concentration on admission, at discharge, 1 month after hospital discharge and change over time in 309 patients included in the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. Primary outcome measures were mortality and the combined end point of heart failure (HF) readmission or mortality. In a multivariate Cox regression analysis, change in NT-proBNP concentration during admission, change from discharge to 1 month after discharge, and the absolute NT-proBNP concentration at 1 month after discharge were of independent prognostic value for both end points (hazard ratios for HF readmission or mortality: 1.71, 95% confidence interval [CI] 1.13-2.60, Wald 6.4 [P = .011] versus 2.71, 95% CI 1.76-4.17, Wald 20.5 [P < .001] versus 1.81, 95% CI 1.13-2.89, Wald 6.1 [P = .014], respectively. CONCLUSIONS: Knowledge of change in NT-proBNP concentration during admission because of AHF in combination with change early after discharge and the absolute NT-proBNP concentration at 1 month after discharge allows accurate risk stratification.

Cardiac troponin in ischemic cardiomyocytes: intracellular decrease before onset of cell death.

AIM: Cardiac troponin I (cTnI) and T (cTnT) are the most important biomarkers in the diagnosis of acute myocardial infarction (AMI). Nevertheless, they can be elevated in the absence of AMI. It is unclear if such elevations represent irreversible cardiomyocyte-damage or leakage from viable cardiomyocytes. Our objective is to evaluate whether cTn is released from viable cardiomyocytes in response to ischemia and to identify differences in the release of cTn and its molecular forms. METHODS AND RESULTS: HL-1 cardiomyocytes (mouse) were subjected to ischemia (modeled by anoxia with glucose deprivation). The total contents and molecular forms of cTn were determined in culture media and cell lysates. Cell viability was assessed from the release of lactate dehydrogenase (LDH). Before the release of LDH, the intracellular cTn content in ischemic cells decreased significantly compared to control (52% for cTnI; 23% for cTnT) and was not matched by a cTn increase in the medium. cTnI decreased more rapidly than cTnT, resulting in an intracellular cTnT/cTnI ratio of 25.5 after 24 h of ischemia. Western blots revealed changes in the relative amounts of fragmented cTnI and cTnT in ischemic cells. CONCLUSIONS: HL-1 cardiomyocytes subjected to simulated ischemia released cTnI and cTnT only in combination with the release of LDH. We find no evidence of cTn release from viable cardiomyocytes, but did observe a significant decrease in cTn content, before the onset of cell death. Intracellular decrease of cTn in viable cardiomyocytes can have important consequences for the interpretation of cTn values in clinical practice.

Posttranslational modifications of cardiac troponin T: an overview.

Cardiac troponin (cTn) is an important sarcomeric protein complex situated on the thin filament and is involved in the regulation of cardiac muscle contraction. This regulation is primarily controlled by Ca(2+) binding to troponin C and in addition fine-tuned by the posttranslational modification of cTnI and cTnT. The vast majority of cTnT modifications involve the phosphorylation by protein kinase C (PKC) or other kinases and the N-terminal cleavage by caspase and calpain. In vitro studies employing reconstituted detergent-skinned fiber bundles and cell culture generally show a detrimental effect of cTnT phosphorylation on muscle contraction, which is backed by some in vivo studies finding increased cTnT phosphorylation in heart failure, but contradicted by others. In addition, N-terminal cleavage of cTnT is thought to be another factor influencing cardiac contraction. Time-dependent degradation of cTnT has been observed in human serum upon myocardial infarction. These molecular changes might influence the immunoreactivity of cTnT in the clinical immunoassay and have consequences for the clinical interpretations of these measurements. No consensus has yet been reached on the occurrence and extent of these observations and their underlying processes are subject of intense scientific debate. This review will focus on discussing these modifications, their implications on physiology and disease and summarizes the complex interplays of different enzymes on the molecular forms of cTnT and their associated effects.

The role of cardiovascular magnetic resonance imaging and computed tomography angiography in suspected non-ST-elevation myocardial infarction patients: design and rationale of the CARdiovascular Magnetic rEsoNance imaging and computed Tomography Angiography (CARMENTA) trial.

BACKGROUND: Although high-sensitivity cardiac troponin (hs-cTn) substantially improves the early detection of myocardial injury, it lacks specificity for acute myocardial infarction (MI). In suspected non-ST-elevation MI, invasive coronary angiography (ICA) remains necessary to distinguish between acute MI and noncoronary myocardial disease (eg, myocarditis), unnecessarily subjecting the latter to ICA and associated complications. This trial investigates whether implementing cardiovascular magnetic resonance (CMR) or computed tomography angiography (CTA) early in the diagnostic process may help to differentiate between coronary and noncoronary myocardial disease, thereby preventing unnecessary ICA. STUDY DESIGN: In this prospective, single-center, randomized controlled clinical trial, 321 consecutive patients with acute chest pain, elevated hs-cTnT, and nondiagnostic electrocardiogram are randomized to 1 of 3 strategies: (1) CMR, or (2) CTA early in the diagnostic process, or (3) routine clinical management. In the 2 investigational arms of the study, results of CMR or CTA will guide further clinical management. It is expected that noncoronary myocardial disease is detected more frequently after early noninvasive imaging as compared with routine clinical management, and unnecessary ICA will be prevented. The primary end point is the total number of patients undergoing ICA during initial admission. Secondary end points are 30-day and 1-year clinical outcome (major adverse cardiac events and major procedure-related complications), time to final diagnosis, quality of life, and cost-effectiveness. CONCLUSION: The CARMENTA trial investigates whether implementing CTA or CMR early in the diagnostic process in suspected non-ST-elevation MI based on elevated hs-cTnT can prevent unnecessary ICA as compared with routine clinical management, with no detrimental effect on clinical outcome.

Time-dependent degradation pattern of cardiac troponin T following myocardial infarction.

BACKGROUND: Cardiac troponin T (cTnT) is widely used for the diagnosis of acute myocardial infarction (AMI). However, it is still unclear whether degraded cTnT forms circulate in the patient's blood. We therefore aimed to elucidate which cTnT forms are detected by the clinical assay. METHODS: Separation of cTnT forms by gel filtration chromatography (GFC) was performed in sera from 13 AMI patients to examine cTnT degradation. The GFC eluates were subjected to Western blot analysis with the original antibodies from the Roche immunoassay used to mimic the clinical cTnT assay. To investigate the degradation pattern with time, standardized serum samples of 18 AMI patients collected 0-72 h after admission were analyzed by Western blot analysis. RESULTS: GFC analysis of AMI patients' sera revealed 2 cTnT peaks with retention volumes of 5 and 21 mL. Western blot analysis identified these peaks as cTnT fragments of 29 and 14-18 kDa, respectively. Furthermore, the performance of direct Western blots on standardized serum samples demonstrated a time-dependent degradation pattern of cTnT, with fragments ranging between 14 and 40 kDa. Intact cTnT (40 kDa) was present in only 3 patients within the first 8 h after hospital admission. CONCLUSIONS: These results demonstrate that the Roche cTnT immunoassay detects intact as well as degraded cTnT forms in AMI patients' sera during the period of diagnostic testing. Moreover, following AMI, cTnT is degraded in a time-dependent pattern.

Do laboratories follow heart failure recommendations and guidelines and did we improve? The CARdiac MArker Guideline Uptake in Europe (CARMAGUE).

BACKGROUND: Natriuretic peptides (NP) are well-established markers of heart failure (HF). During the past 5 years, analytical and clinical recommendations for measurement of these biomarkers have been published in guidelines. The aim of this follow-up survey was to investigate how well these guidelines for measurement of NP have been implemented in laboratory practice in Europe. METHODS: Member societies of the European Federation of Clinical Chemistry and Laboratory Medicine were invited in 2009 to participate in a web-based audit questionnaire. The questionnaire requested information on type of tests performed, decision limits for HF, turn-around time and frequency of testing. RESULTS: There was a moderate increase (12%) of laboratories measuring NP compared to the initial survey in 2006. The most frequently used HF decision limits for B-type NP (BNP) and N-terminal BNP (NT-proBNP) were, respectively, 100 ng/L and 125 ng/L, derived from the package inserts in 55%. Fifty laboratories used a second decision limit. Age or gender dependent decision limits were applied in 10% (8.5% in 2006). The vast majority of laboratories (80%) did not have any criteria regarding frequency of testing, compared to 33% in 2006. CONCLUSIONS: The implementation of NP measurement for HF management was a slow process between 2006 and 2009 at a time when guidelines had just been established. The decision limits were derived from package insert information and literature. There was great uncertainty concerning frequency of testing which may reflect the debate about the biological variability which was not published for most of the assays in 2009.

Troponin T measurements by high-sensitivity vs conventional assays for risk stratification in acute dyspnea.

BACKGROUND: Cardiac troponin T measured by a high-sensitivity assay (hs-cTnT) recently proved to be of prognostic value in several populations. The hs-cTnT assay may also improve risk stratification in acute dyspnea. METHODS: We prospectively studied the prognostic value of hs-cTnT in 678 consecutive patients presenting to the emergency department with acute dyspnea. On the basis of conventional cardiac troponin T assay (cTnT) and hs-cTnT assay measurements, patients were divided into 3 categories: (1) neither assay increased (cTnT<0.03 µg/L, hs-cTnT<0.016 µg/L), (2) only hs-cTnT increased≥0.016 µg/L (cTnT<0.03 µg/L), and (3) both assays increased (cTnT≥0.03 µg/L, hs-cTnT≥0.016 µg/L). Moreover, the prognostic value of hs-cTnT was investigated if cTnT was not detectable (<0.01). RESULTS: One hundred seventy-two patients were in the lowest, 282 patients in the middle, and 223 patients in the highest troponin category. Patients in the second and third categories had significantly higher mortality compared to those in the first category (90-day mortality rate 2%, 10%, and 26% in groups 1, 2, and 3, respectively, P<0.001; 1-year mortality rate 9%, 21%, and 39%, P<0.001). Importantly, in patients with undetectable cTnT (n=347, 51%), increased hs-cTnT indicated worse outcome [90-day mortality, odds ratio 4.26 (95% CI 1.19-15.21); 1-year mortality, hazard ratio 2.27 (1.19-4.36), P=0.013], whereas N-terminal pro-brain-type natriuretic peptide (NT-proBNP) was not predictive of short-term outcome. CONCLUSIONS: hs-cTnT is associated with mortality in patients presenting with acute dyspnea. hs-cTnT concentrations provide additional prognostic information to cTnT and NT-proBNP testing in patients with cTnT concentrations below the detection limit. In particular, the hs-cTnT cutoff of 0.016 µg/L enables identification of low-risk patients.

Circulating biomarkers and abdominal aortic aneurysm size.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a degenerative disease of the abdominal aorta leading to progressive dilatation, intra-luminal thrombus (ILT) formation, and rupture. Understanding the natural history of AAA is essential, because different processes and, therefore, different biomarkers, could be involved at each stage of disease progression. The purpose of the present study was to investigate the relationship between systemic expression of biomarkers of inflammation and extracellular matrix remodeling and aneurysm size in AAA patients. METHODS AND RESULTS: All consecutive patients admitted to the (out-) patient clinic of the surgical department of two large community centers were prospectively included. Patients were divided into three groups based on their aneurysm diameter: small (30-44 mm; n = 59), medium-sized (45-54 mm; n = 64) or large (≥ 55 mm; n = 95) AAA. Linear regression modeling showed that age and serum hsCRP concentration were positively associated, whereas serum HDL and IgG concentrations were negatively associated with aneurysm size. This regression model was corrected for possible bias due to statin use and center of inclusion; and also indicated that in general men have larger aneurysms compared with women. CONCLUSIONS: Different aneurysm sizes showed different expression pattern of HDL, IgG, and hsCRP. These biomarkers may be useful in predicting AAA progression.

A comprehensive review of upper reference limits reported for (high-)sensitivity cardiac troponin assays: the challenges that lie ahead.

Cardiac troponins (cTn) are the preferred markers for the diagnosis of acute myocardial infarction (AMI). The guidelines recommend the use of the 99th percentile upper reference concentration of a healthy population as the diagnostic cut-off for AMI. However, a broad range of upper reference limits is still employed, complicating the diagnosis of AMI. This overview is meant to assist laboratory specialists to define an appropriate cut-off value for the diagnosis of AMI. Therefore, we provide an overview of the analytical performance and upper reference limits of seven (high-)sensitivity cTn assays: Roche high-sensitivity cTnT and ADVIA Centaur, Stratus CS, Dimension Vista, Vitros ECi, Access and Architect cTnI assays. It is shown that none of the reference populations completely met the guidelines, including those in package inserts. Forty percent of the studies collected less than the advised minimum of 300 subjects. Many studies (50%) did not report their inclusion criteria, while lower 99th percentile limits were observed when more stringent selection criteria were applied. Higher troponin cut-offs were found in men and elderly subjects, suggesting sex- and age-specific cut-offs would be considered. Therefore, there is still need for a large, rigorously screened reference population to more accurately establish cTn upper reference limits.

The prevalence and management of heart failure in Dutch nursing homes; design of a multi-centre cross-sectional study.

BACKGROUND: Heart failure is likely to be particularly prevalent in the nursing home population, but reliable data about the prevalence of heart failure in nursing homes are lacking. Therefore the aims of this study are to investigate (a) the prevalence and management of heart failure in nursing home residents and (b) the relation between heart failure and care dependency as well as heart failure and quality of life in nursing home residents. METHODS/DESIGN: Nursing home residents in the southern part of the Netherlands, aged over 65 years and receiving long-term somatic or psychogeriatric care will be included in the study. A panel of two cardiologists and a geriatrician will diagnose heart failure based on data collected from actual clinical examinations (including history, physical examination, ECG, cardiac markers and echocardiography), patient records and questionnaires. Care dependency will be measured using the Care Dependency Scale. To measure the quality of life of the participating residents, the Qualidem will be used for psychogeriatric residents and the SF-12 and VAS for somatic residents. CONCLUSION: The study will provide an insight into the actual prevalence and management of heart failure in nursing home residents as well as their quality of life and care dependency. TRIAL REGISTRATION: Dutch trial register NTR2663.

The extent of coronary atherosclerosis is associated with increasing circulating levels of high sensitive cardiac troponin T.

OBJECTIVE: This study explored the relationship between coronary atherosclerotic plaque burden and quantifiable circulating levels of troponin measured with a recently introduced high sensitive cardiac troponin T (hs-cTnT) assay. METHODS AND RESULTS: Cardiac patients suspected of having coronary artery disease (CAD) but without acute coronary syndrome were studied. Cardiac troponin T levels were assessed using the fifth-generation hs-cTnT assay. All patients (n=615) underwent cardiac computed tomographic angiography (CCTA). On the basis of CCTA, patients were classified as having no CAD or mild (<50% lesion), moderate (50% to 70% lesion), severe (>70% lesion), or multivessel CAD (multiple >70% lesions). As a comparison, high-sensitivity C-reactive protein levels were measured. Progressively increasing hs-cTnT levels were found in patients with mild (median, 4.5 ng/L), moderate (median, 5.5 ng/L), severe (median, 5.7 ng/L), and multivessel (median, 8.6 ng/L) CAD compared with patients without CAD (median, 3.7 ng/L) (all P<0.01). For high-sensitivity C-reactive protein and N-terminal pro-B-type natriuretic peptide, no such relationship was observed. In patients without CAD, 11% showed hs-cTnT levels in the highest quartile, compared with 62% in the multivessel disease group (P<0.05). Multivariance analysis identified hs-cTnT as an independent risk factor for the presence of CAD. CONCLUSIONS: In patients without acute coronary syndrome, even mild CAD is associated with quantifiable circulating levels of hs-cTnT.

Inflammation, overhydration and cardiac biomarkers in haemodialysis patients: a longitudinal study.

BACKGROUND: Inflammation, overhydration and elevated cardiac biomarkers are related to outcome in haemodialysis (HD) patients. Here, we explored the relationship between the body composition (BC), inflammation and cardiac biomarker concentrations in HD patients longitudinally. METHODS: A total of 44 HD patients were followed for 6 months. BC was assessed by multifrequency bioimpedance (BIA). Serum concentrations of cardiac troponin T (cTnT), high-sensitive C-reactive protein (hsCRP), brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) were assessed at 2 monthly intervals. The longitudinal data analysis was conducted with a marginal model. RESULTS: During the follow-up, the parameters describing the BC were highly predictive of both BNP and NT-proBNP and independent of gender, time, hsCRP and cTnT concentrations. The intracellular water (ICW)/body weight (BW) ratio (reflecting malnutrition) exerted a negative effect, whereas the extracellular water (ECW)/BW ratio (reflecting overhydration) had a positive effect on BNP and NT-proBNP concentrations. HsCRP and cTnT concentrations were significantly associated with each other. Furthermore, NT-proBNP concentrations were predictive of cTnT and hsCRP concentrations. CONCLUSIONS: In the present study, we find a significant relation between BIA-derived BC parameters and natriuretic peptide concentrations. This relationship was independent of the cardiac history of the patient and suggests that the natriuretic peptide levels are to some degree modifiable by changing a patient's fluid distribution. Moreover, cTnT, BNP, NT-proBNP and hsCRP were significantly related, showing a complex relation between overhydration, malnutrition, inflammation and cardiac biomarkers in dialysis patients.