Temporal biomarker concentration patterns during the early course of acute coronary syndrome.

OBJECTIVES: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. METHODS: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. RESULTS: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. CONCLUSIONS: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Differences between high-sensitivity cardiac troponin T and I in stable populations: underlying causes and clinical implications.

OBJECTIVES: Measurement of high-sensitivity (hs) cardiac troponin (cTn) T and I is widely studied for cardiac assessment of stable populations. Recent data suggest clinical and prognostic discrepancies between both hs-cTn. We aimed at reviewing published studies with respect to underlying causes and clinical implications. CONTENT: We summarized current evidence on release and clearance mechanisms of cTnT and I, and on preanalytical and assay-related issues potentially portending to differences in measured concentrations. We also performed a systematic review of outcome studies comparing both hs-cTn in the general population, patients with congestive heart failure, stable coronary artery disease and atrial fibrillation. SUMMARY AND OUTLOOK: For the interpretation of concentrations of hs-cTnT, stronger association with renal dysfunction compared to hs-cTnI should be considered. Hs-cTnT also appears to be a stronger indicator of general cardiovascular morbidity and all-cause mortality. Hs-cTnI concentrations tend to be more sensitive to coronary artery disease and ischemic outcomes. These findings apparently reflect variations in the mechanisms of cardiac affections resulting in cTn release. Whether these differences are of clinically relevance remains to be elucidated. However, having the option of choosing between either hs-cTn might represent an option for framing individualized cardiac assessment in the future.

Outcomes in patients with chest pain in emergency departments using high-sensitivity versus conventional troponins.

Objectives. There is a paucity of data regarding the association between the use of high-sensitivity troponin (hs-cTn) compared with conventional troponin (cTn) and outcomes in chest pain patients in emergency departments (EDs). This study examined the impact of hs-cTnT on prognosis in chest pain patients in EDs. Design. In an observational cohort study, we included chest pain patients visiting the EDs of 14 hospitals in Sweden from 2011 to 2016. The study population was retrieved from each hospital, and information on characteristics and outcomes was collected from nationwide registries. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals (HR, 95% CI) for (1) 1-year all-cause mortality, (2) missed acute coronary syndromes (ACSs), (3) use of coronary angiography, and (4) revascularizations within 30 days. Results. We included 170461 patients with chest pain where 62669 patients were tested with cTn while 107792 patients were tested with hs-cTnT. We found 4149 (4.6%) deaths in the cTn group and 6087 (3.7%) deaths in the hs-cTnT group. Patients in the hs-cTnT group had 9% lower mortality (0.91, 0.87-0.94), and were 14% more likely to undergo coronary angiography (1.14, 1.10-1.17), and 12% more likely to be revascularized (1.12, 1.08-1.17) than patients in the cTn group. Conclusions. Patients with chest pain visiting EDs using hs-cTnT had lower mortality and a higher likelihood of undergoing coronary angiographies and revascularizations than those using cTn. There may be a survival benefit of being tested with hs-cTnT compared with cTn in patients seeking medical attention for chest pain.

HEART-score can be simplified without loss of discriminatory power in patients with chest pain - Introducing the HET-score.

BACKGROUND: The History, Electrocardiogram (ECG), Age, Risk factors and Troponin, (HEART) score is useful for early risk stratification in chest pain patients. The aim was to validate previous findings that a simplified score using history, ECG and troponin (HET-score) has similar ability to stratify risk. METHODS: Patients presenting with chest pain with duration of ≥10 min and an onset of last episode ≤12 h but without ST-segment elevation on ECG at 6 emergency departments were eligible for inclusion. The HEART-score and the simplified HET-score were calculated. The endpoint was a composite of myocardial infarction (MI) as index diagnosis, readmission due to new MI or death within 30 days. RESULTS: HEART-score identified 32% as low risk (0-2p), 47% as intermediate risk (3-5p), and 20% as high risk (6-10p) patients. The endpoint occurred in 0.5%, 7.3% and 35.7%, respectively. HET-score identified 39%, 42% and 19% as low- (0p), intermediate- (1-2p) and high-risk (3-6p) patients, with the endpoint occurring in 0.6%, 6.2% and 43.2%, respectively. When all variables included in the HEART-score were included in a multivariable logistic regression analysis, only History (OR, CI [95%]): 2.97(2.16-4.09), ECG (1.61[1.14-2.28]) and troponin level (5.21[3.91-6.95]) were significantly associated with cardiovascular events. When HEART- and HET-score were compared in a ROC-analysis, HET-score had a significantly larger AUC (0.887 vs 0.853, p < 0.001). CONCLUSIONS: Compared with HEART-score, HET-score is simpler and appears to have similar ability to discriminate between chest pain patients with and without cardiovascular event.

Evaluation of quantitative CMR perfusion imaging by comparison with simultaneous 15O-water-PET.

BACKGROUND: We assessed the quantitative accuracy of cardiac perfusion measurements using dynamic contrast-enhanced MRI with simultaneous 15O-water PET as reference with a fully integrated PET-MR scanner. METHODS: 15 patients underwent simultaneous DCE MRI and 15O-water PET scans at rest and adenosine-stress on an integrated PET-MR scanner. Correlation and agreement between MRI- and PET-based global and regional MBF values were assessed using correlation and Bland-Altman analysis. RESULTS: Three subjects were excluded due to technical problems. Global mean (± SD) MBF values at rest and stress were 0.97 ± 0.27 and 3.19 ± 0.70 mL/g/min for MRI and 1.02 ± 0.28 and 3.13 ± 1.16 mL/g/min for PET (P = 0.66 and P = 0.81). The correlations between global and regional MRI- and PET-based MBF values were strong (r = 0.86 and r = 0.75). The biases were negligible for both global and regional MBF comparisons (0.01 and 0.00 mL/min/g for both), but the limits of agreement were wide for both global and regional MBF, with larger variability for high MBF-values. CONCLUSION: The correlation between simultaneous MBF measurements with DCE MRI and 15O-water PET measured in an integrated PET-MRI was strong but the agreement was only moderate indicating that MRI-based quantitative MBF measurements is not ready for clinical introduction.

Prognostic Value of High-Sensitivity Troponin T in Chronic Heart Failure: An Individual Patient Data Meta-Analysis.

BACKGROUND: Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach. METHODS: Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were "troponin" AND "heart failure" OR "cardiac failure" OR "cardiac dysfunction" OR "cardiac insufficiency" OR "left ventricular dysfunction." Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause. RESULTS: Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41-1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33-1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36-1.49), over a median 2.4-year follow-up (all P<0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve-derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction. CONCLUSIONS: In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification.

Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries.

BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD). METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age- and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses. RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-κ-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls. CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts.

A Rule-Out Strategy Based on High-Sensitivity Troponin and HEART Score Reduces Hospital Admissions.

STUDY OBJECTIVE: We evaluate whether a combination of a 1-hour high-sensitivity cardiac troponin algorithm and History, ECG, Age, Risk Factors, and Troponin (HEART) score reduces admission rate (primary outcome) and affects time to discharge, health care-related costs, and 30-day outcome (secondary outcomes) in patients with symptoms suggestive of an acute coronary syndrome. METHODS: This prospective observational multicenter study was conducted before (2013 to 2014) and after (2015 to 2016) implementation of a strategy including level of high-sensitivity cardiac troponin T or I at 0 and 1 hour, combined with the HEART score. Patients with a nonelevated baseline high-sensitivity cardiac troponin level, a 1-hour change in high-sensitivity cardiac troponin T level less than 3 ng/L, or high-sensitivity cardiac troponin I level less than 6 ng/L and a HEART score less than or equal to 3 were considered to be ruled out of having acute coronary syndrome. A logistic regression analysis was performed to adjust for differences in baseline characteristics. RESULTS: A total of 1,233 patients were included at 6 centers. There were no differences in regard to median age (64 versus 63 years) and proportion of men (57% versus 54%) between the periods. After introduction of the new strategy, the admission rate decreased from 59% to 33% (risk ratio 0.55 [95% confidence interval {CI} 0.48 to 0.63]; odds ratio 0.33 [95% CI 0.26 to 0.42]; adjusted odds ratio 0.33 [95% CI 0.25 to 0.42]). The median hospital stay was reduced from 23.2 to 4.7 hours (95% CI of difference -20.4 to -11.4); median health care-related costs, from $1,748 to $1,079 (95% CI of difference -$953 to -$391). The number of clinical events was very low. CONCLUSION: In this before-after study, clinical implementation of a 1-hour high-sensitivity cardiac troponin algorithm combined with the HEART score was associated with a reduction in admission rate and health care burden, with very low rates of adverse clinical events.

Prognosis in relation to high-sensitivity cardiac troponin T levels in patients with myocardial infarction and non-obstructive coronary arteries.

BACKGROUND: Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) is a recently recognized condition where biomarkers and prognosis are less well studied than in MI with obstructive coronary artery disease (MI-CAD). We therefore aimed to investigate the one-year prognostic value of high-sensitivity cardiac troponin T (hs-cTnT) levels in MINOCA in comparison to MI-CAD. METHODS: In this registry-based cohort study, we used data from patients with a discharge diagnosis of MI, admitted between 2009 and 2013 to Swedish hospitals using the hs-cTnT assay. Only patients without previously known coronary artery disease were considered. Patients with and without coronary stenosis >50% were regarded to have MI-CAD and MINOCA, respectively. Assessed outcomes included all-cause mortality, cardiovascular (CV) mortality and major CV events (MACE), defined as the composite of CV death or admissions for non-fatal MI, heart failure (HF) or ischemic stroke. RESULTS: The study cohort consisted of 1639 MINOCA and 17,304 MI-CAD patients. In adjusted analyses, hs-cTnT (ln) in MINOCA patients predicted all-cause mortality (HR 1.32 [95% CI 1.11-1.56]), CV mortality (HR 2.11 [95% CI 1.51-2.96]) and MACE (HR 1.44 [95% CI 1.20-1.72]). Hs-cTnT (ln) also predicted readmissions for HF (HR 1.51 [95% CI 1.51-2.96]) but not non-fatal MI or stroke. Interaction analyses suggested that hs-cTnT (ln) was at least as prognostic in patients with MINOCA compared to MI-CAD. CONCLUSIONS: Hs-cTnT levels in MINOCA patients are strong and independent predictors of adverse outcome. Consideration of hs-cTnT levels is important for risk assessment of MINOCA patients.

High-Sensitivity Cardiac Troponin-Based Strategies for the Assessment of Chest Pain Patients-A Review of Validation and Clinical Implementation Studies.

BACKGROUND: The introduction of high-sensitivity cardiac troponin (hs-cTn) assays has improved the early assessment of chest pain patients. A number of hs-cTn-based algorithms and accelerated diagnostic protocols (ADPs) have been developed and tested subsequently. In this review, we summarize the data on the performance and clinical utility of these strategies. CONTENT: We reviewed studies investigating the diagnostic and prognostic performance of hs-cTn algorithms [level of detection (LoD) strategy, 0/1-h, 0/2-h, and 0/3-h algorithms) and of hs-cTn-based ADPs, together with the implications of these strategies when implemented as clinical routine. The LoD strategy, when combined with a nonischemic electrocardiogram, is best suited for safe rule-out of myocardial infarction and the identification of patients eligible for early discharge from the emergency department. The 0/1-h algorithms appear to identify most patients as being eligible for rule-out. The hs-cTn-based ADPs mainly focus on prognostic assessment, which is in contrast with the hs-cTn algorithms. They identify smaller proportions of rule-out patients, but there is increasing evidence from prospective studies on their successful clinical implementation. Such information is currently lacking for hs-cTn algorithms. CONCLUSIONS: There is a trade-off between safety and efficacy for different hs-cTn-based strategies. This trade-off should be considered for the intended strategy, along with its user-friendliness and evidence from clinical implementation studies. However, several gaps in knowledge remain. At present, we suggest the use of an ADP in conjunction with serial hs-cTn results to optimize the early assessment of chest pain patients.

Sex-Specific Versus Overall Clinical Decision Limits for Cardiac Troponin I and T for the Diagnosis of Acute Myocardial Infarction: A Systematic Review.

BACKGROUND: The overall clinical decision limits of high-sensitivity cardiac troponin I (hs-cTnI; 26 ng/L) and T (hs-cTnT; 14 ng/L) may contribute to underdiagnosis of acute myocardial infarction in women. We performed a systematic review to investigate sex-specific and overall 99th percentiles of hs-cTnI and hs-cTnT derived from healthy reference populations. CONTENT: We searched in PubMed and EMBASE for original studies, and by screening reference lists. Reference populations designed to establish 99th percentiles of hs-cTnI (Abbott) and/or hs-cTnT (Roche), published between January 2009 and October 2017, were included. Sex-specific and overall 99th percentile values of hs-cTnI and hs-cTnT were compared with overall clinical decision ranges (hs-cTnI, 23-30 ng/L; hs-cTnT, 13-25 ng/L). Twenty-eight studies were included in the systematic review. Of 16 hs-cTnI and 18 hs-cTnT studies, 14 (87.5%) and 11 (61.1%) studies reported lower female-specific hs-cTn cutoffs than overall clinical decision ranges, respectively. Conversely, male-specific thresholds of both hs-cTnI and hs-cTnT were in line with currently used overall thresholds, particularly hs-cTnT (90% concordance). The variation of estimated overall 99th percentiles was much higher for hs-cTnI than hs-cTnT (29.4% vs 80.0% of hs-cTnI and hs-cTnT studies reported values within the current overall clinical decision range, respectively). SUMMARY: Our data show substantially lower female-specific upper reference limits of hs-cTnI and hs-cTnT than overall clinical decision limits of 26 ng/L and 14 ng/L, respectively. The statistical approach strongly affects the hs-cTnI threshold. Downward adjustment of hs-cTn thresholds in women may be warranted to reduce underdiagnosis of acute myocardial infarction in women.

Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis.

Background: High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI). Purpose: To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain. Data Sources: EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016). Study Selection: Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization. Data Extraction: Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies. Data Synthesis: Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died. Limitation: Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies. Conclusion: A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome. Primary Funding Source: Emergency Care Foundation.

Application of Cardiac Troponin in Cardiovascular Diseases Other Than Acute Coronary Syndrome.

BACKGROUND: Increased cardiac troponin concentrations in acute coronary syndrome (ACS) identify patients with ongoing cardiomyocyte necrosis who are at increased risk. However, with the use of more precise assays, cardiac troponin increases are commonly noted in other cardiovascular conditions as well. This has generated interest in the use of cardiac troponin for prognostic assessment and clinical management of these patients. In this review, we have summarized the data from studies investigating the implications of cardiac troponin concentrations in various acute and chronic conditions beyond ACS, i.e., heart failure, myocarditis, Takotsubo cardiomyopathy, aortic dissection, supraventricular arrhythmias, valve disease, pulmonary arterial hypertension, stroke, and in the perioperative setting. CONTENT: Cardiac troponin concentrations are often detectable and frankly increased in non-ACS conditions, in particular when measured with high-sensitivity (hs) assays. With the exception of myocarditis and Takotsubo cardiomyopathy, cardiac troponin concentrations carry strong prognostic information, mainly with respect to mortality, or incipient and/or worsening heart failure. Studies investigating the prognostic benefit associated with cardiac troponin-guided treatments however, are almost lacking and the potential role of cardiac troponin in the management of non-ACS conditions is not defined. SUMMARY: Increased cardiac troponin indicates increased risk for adverse outcome in patients with various cardiovascular conditions beyond ACS. Routine measurement of cardiac troponin concentrations can however, not be generally recommended unless there is a suspicion of ACS. Nonetheless, any finding of an increased cardiac troponin concentration in a patient without ACS should at least prompt the search for possible underlying conditions and these should be managed meticulously according to current guidelines to improve outcome.

Impact of Sex on Cardiac Troponin Concentrations-A Critical Appraisal.

BACKGROUND: The use of sex-specific cutoffs for cardiac troponin (cTn) is currently debated. Although endorsed by scientific working groups, concerns have been raised that sex-specific cutoffs may have only a small clinical effect at the cost of increased complexity in decision-making. METHODS: We reviewed studies investigating the interrelations between high-sensitivity (hs) cTn results and sex, diagnoses, and outcome. Investigated populations included community-dwelling subjects and patients with stable angina, congestive heart failure, or acute chest pain including those with acute coronary syndromes. RESULTS: Men usually have higher hs-cTn concentrations compared with women, regardless of the assessed population or the applied assay. The distribution and prognostic implications of hs-cTn concentrations indicate that women have a broader cardiovascular risk panorama compared with men, particularly at lower hs-cTn concentrations. At higher concentrations, particularly above the 99th percentile, this variation is often attenuated. Sex-specific hs-cTn 99th percentiles have so far shown clinical net benefit in only 1 study assessing patients with chest pain. However, several methodological aspects need to be considered when interpreting study results, e.g., issues related to the determination of the 99th percentiles, the selection bias, and the lack of prospective and sufficiently powered analyses. CONCLUSIONS: Available studies do not show a consistent clinical superiority of sex-specific hs-cTn 99th percentiles. This may reflect methodological aspects. However, from a pathobiological perspective, the use of sex-specific hs-cTn 99th percentiles makes sense for the ruling in of myocardial infarction. We propose a new approach to hs-cTn 99th cutoffs taking into account the analytical properties of the used assays.

Cardiac Troponins and Their Prognostic Importance in Patients with Suspected Acute Coronary Syndrome and Renal Dysfunction.

BACKGROUND: Cardiac troponin (cTn) is important for risk assessment in patients with suspected acute coronary syndrome (ACS). cTn concentrations may, however, be affected by renal dysfunction, and the clinical importance of this interrelation is not well established. We investigated the association between cTnT and cTnI (measured with conventional assays and a more sensitive assay) with the estimated glomerular filtration rate (eGFR) and also assessed the ability of cTn to predict the 1-year all-cause mortality. METHODS: This retrospective registry-based study used data from 309454 admissions to Swedish coronary care units. cTn associations with eGFR and mortality were assessed using different regression models and by calculating multivariable-adjusted c-statistics. RESULTS: cTnT concentrations exhibited stronger associations with eGFR than cTnI concentrations (conventional cTnT assay: ß = -0.113; more sensitive cTnT assay: ß= -0.186; pooled conventional cTnI assays: ß = -0.098). Overall, cTnT provided greater prognostic accuracy than cTnI. This was most evident in non-ACS patients with normal or mildly reduced eGFR when using the more sensitive assay. Despite higher mortality rates, no consistent increases in the c-statistics of cTn were seen with severely reduced eGFR irrespective of the presence of ACS or non-ACS. CONCLUSIONS: cTnT concentrations exhibited stronger associations with reduced eGFR than cTnI concentrations in patients admitted because of suspected ACS. cTnT, particularly when measured using the more sensitive assay, also tended to be a stronger prognosticator. However, the relative significance of the obtained results must be considered in the context of the severity of renal dysfunction and whether ACS is present.

Consequences of implementing a cardiac troponin assay with improved sensitivity at Swedish coronary care units: an analysis from the SWEDEHEART registry.

AIMS: Cardiac troponin (cTn) assays with improved sensitivity are increasingly utilized for the assessment of patients admitted because of suspected acute coronary syndrome (ACS). However, data on the clinical consequences of the implementation of such assays are limited. METHODS AND RESULTS: In a retrospective register-based study (37 710 coronary care unit admissions; SWEDEHEART registry), we compared the case mix, the use of diagnostic procedures, treatments, and 1-year all-cause mortality 1 year before the implementation of a cTn assay with improved sensitivity (study period 1) and 1 year thereafter (study period 2). During study period 2, more at-risk patients were admitted and more patients had cTn levels above the myocardial infarction cut-off (ACS patients +13.1%; non-ACS patients +160.1%). cTn levels above this cut-off exhibited stronger associations with mortality risk in study period 2 (adjusted HR 4.45 [95% confidence interval, CI, 3.36-5.89]) compared with period 1 (adjusted HR 2.43 [95% CI 2.11-2.80]), similar as for the cTn ratio relative to the respective 99th percentile. While there was no multivariable-adjusted increase in the use of diagnostic procedures, significant trends towards more differentiated treatment depending on the cause of cTn elevation, i.e. ACS or non-ACS, were noted. CONCLUSIONS: The implementation of a cTn assay with improved sensitivity was associated with an increase in the number of patients who due to their cTn-status were identified as suitable for beneficial therapies. There was no inappropriate increase in hospital resource utilization. As such, cTn assays with improved sensitivity provide an opportunity to improve the clinical management of patients with suspected ACS.

Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community.

BACKGROUND: There is increasing interest in measurements of cardiovascular (CV) biomarker concentrations for risk prediction in the general population. We investigated the prognostic utility of a panel of novel CV biomarkers including biomarker changes over time. METHODS: We measured concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional proadrenomedullin, high-sensitivity cardiac troponin I, growth-differentiation factor-15 (GDF-15), soluble ST2 (sST2), and galectin-3 at baseline and 5 years later in 1016 elderly individuals participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Assessed outcomes included all-cause mortality and fatal and nonfatal CV events (in participants without CV disease at baseline) during 10 years of follow-up. RESULTS: GDF-15 exhibited the strongest association with all-cause mortality (n = 158) with a hazard ratio (HR) per 1-SD increase in standardized ln GDF-15 of 1.68 (95% CI, 1.44-1.96). NT-proBNP was the only biomarker to predict CV events (n = 163; HR 1.54 [95% CI, 1.30-1.84]). GDF-15 and NT-proBNP also improved metrics of discrimination and reclassification of the respective outcomes. Changes in GDF-15 concentrations between 70 and 75 years predicted all-cause mortality whereas changes in NT-proBNP predicted both outcomes. The other biomarkers and their temporal changes provided only moderate prognostic value apart from sST2 which had a neutral relationship with adverse events. CONCLUSIONS: Evaluation of temporal changes in GDF-15 and NT-proBNP concentrations improves risk prediction in an elderly population. These findings are of considerable interest given the emphasis on biomarkers as tools to identify and monitor at-risk individuals with preclinical and potentially modifiable stages of CV disease.