Search

Objectives The goal of this study was to assess the predictive power of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mas...

Background Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population. Methods In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m2, 18.5–25.0 kg/m2; 25.0–30.0 kg/m2; 30.0 kg/m2). Primary endpoints included all-cause mortality and HF hospitalization-free survival. Results Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity. Conclusions The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Graphic abstract Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged

Background About 5–10% of all myocardial infarction (MI) patients have non-obstructive coronary arteries (MINOCA). The pathobiology of MINOCA is largely unknown compared to myocardial infarction with obstructive coronaries (MI-CAD). Purpose To investigate whether baseline concentrations and temporal changes of circulating biomarkers may offer insights into the activation of pathophysiological pathways in MINOCA compared to MI-CAD. Methods From the PLATelet inhibition and patient Outcomes (PLATO) trial, we retrospectively identified 114 patients with MINOCA (adjudicated MI, coronary stenoses Results In MINOCA patients, median concentrations decreased during one month from 238 to 9 ng/L for hs-cTnT, from 3.5 to 1.6 mg/L for CRP and from 507 to 228 pmol/L for NT-proBNP (Figure 1 and 2). In MI-CAD patients, median concentrations decreased from 198 to 13 ng/L for hs-cTnT, from 3.2 to 2.3 mg/L for CRP and increased from 372 to 566 pmol/L for NT-proBNP. Compared to MI-CAD, the baseline concentrations were higher in MINOCA for NT-proBNP (p=0.011), but similar for hs-cTnT (p=0.555) and CRP (p=0.834). However, patients with MINOCA had statistically larger reductions of concentrations from baseline to one month for hs-cTnT (p=0.002), CRP (p=0.005) and NT-proBNP (p Conclusions In MINOCA compared to MI-CAD patients, higher concentrations of NT-proBNP and similar concentrations of hs-cTnT and CRP at baseline indicate a higher degree of acute myocardial dysfunction but similar degree of acute myocardial injury and inflammation. Furthermore, concentrations of these biomarkers were lower at one month in MINOCA, suggesting other or less remaining underlying disease processes after MI in MINOCA than MI-CAD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The present study was supported by Swedish Foundation for Strategic Research/Swedish Association of Local Authorities and Regions. The PLATO study and the biomarker analyses were sponsored by AstraZeneca.

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.

Background Cardiac troponin (cTn) elevation is a common finding in acutely admitted patients, even in the absence of acute coronary syndrome. In some of these patients, no etiology of cTn elevation can be identified. The term troponinemia is sometimes used to describe this scenario. Objectives This study aimed to investigate the associations of cTn levels with clinical findings and long-term outcome in acutely admitted patients with suspected acute coronary syndrome who had been discharged without a specified diagnosis. Methods Retrospective registry-based cohort study investigating 48,872 patients (SWEDEHEART [Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies] registry). Patients were stratified into cohorts with cTn levels less than or equal to the assay-specific 99th percentile and separated by assay-specific cTn tertiles in case of higher levels. Results A cTn level >99th percentile was noted in 9,800 (20.1%) patients. The prevalence of cardiovascular risk factors as well as cardiovascular and noncardiovascular comorbidities increased across higher cTn strata. In total, 7,529 (15.4%) patients had a major adverse event (MAE), defined as the composite of all-cause mortality, myocardial infarction, readmission for heart failure, or stroke (median follow-up 4.9 years). MAE risk was associated with higher cTn strata (hazard ratio for highest assay-specific cTn tertile: 2.59; 95% confidence interval: 2.39 to 2.80; hazard ratio in patients without cardiovascular comorbidities, renal dysfunction, left ventricular dysfunction, or significant coronary stenosis: 3.57; 95% confidence interval: 2.30 to 5.54). Conclusions cTn elevation is associated with cardiovascular and noncardiovascular comorbidities and predicts major adverse events in acutely admitted patients, in whom no definite diagnosis could have been established. The term troponinemia is trivializing and should be avoided. Instead, careful work-up is required in these patients.

Background Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is receiving increasing interest as a prognostically adverse entity distinct from myocardial infarction with significant coronary artery disease (MI-CAD). However, data are still limited regarding long-term cardiovascular morbidity and cause-specific mortality in MINOCA. Methods This is a registry-based cohort study using data from patients admitted to Swedish coronary care units. We investigated various nonfatal outcomes (recurrent MI, hospitalization for heart failure or stroke) and fatal outcomes (cardiovascular, respiratory or cancer-related mortality) in 4069 patients without apparent acute cardiovascular disease, used as non-MI controls, 7266 patients with first-time MINOCA and 69 267 patients with first-time MI-CAD. Results Almost all event rates (median follow-up 3.8 years) increased in a stepwise fashion across the three cohorts [rates of major adverse events (MAE; composite of all-cause mortality, recurrent MI, hospitalization for heart failure or stroke): n = 268 (6.6%), n = 1563 (21.5%), n = 17 777 (25.7%), respectively]. Compared to non-MI controls, MINOCA patients had an adjusted hazard ratio (HR) of 2.12 (95% confidence interval 1.84-2.43) regarding MAE. MINOCA patients had a substantial risk of cardiovascular mortality and the highest numerical risks of respiratory and cancer-related mortality. Male sex, previous heart failure and chronic obstructive pulmonary disease had a stronger prognostic impact in MINOCA than in MI-CAD. Female MINOCA patients with atrial fibrillation were at particular risk. Conclusions Patients with first-time MINOCA have a considerable risk of adverse events. This stresses the need for a comprehensive search of the cause of MINOCA, thorough treatment of underlying disease triggers and close follow-up.

Background Biomarkers offer insights into the pathobiology of myocardial infarction (MI). Differences in biomarker concentrations and its prognostic implications in ST-elevation MI (STEMI) and non-STEMI (NSTEMI) are incompletely understood and may offer insights into tailored treatment. Purpose We aimed to characterise differences in activation of pathophysiologic pathways in patients with acute STEMI versus NSTEMI by comparing multiple biomarkers, and investigating their prognostic implications. Methods 538 STEMI and 544 NSTEMI patients were included in our hospitals between 2008–2014. Blood samples were collected shortly after admission and 92 biomarkers were analysed using Proximity Extension Assay and 87 biomarkers using Multiple Reaction Monitoring mass spectrometry. Adjusted Lasso analysis (penalized logistic regression) was used to select biomarkers that discriminated STEMI from NSTEMI patients. For biomarkers that were identified by the Lasso analysis, concentrations (log2-transformed) were then evaluated in adjusted Cox regressions on associations with death or major cardiovascular events (MACE), a composite of death, hospitalization for MI, ischemic stroke or heart failure. Results Eleven biomarkers differed between STEMI and NSTEMI patients (Table) with higher OR (>1.00–1.42) and concentrations in STEMI patients of myoglobin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), serum amyloid A-1 (SAA1) and serum amyloid A-2 (SAA2) protein, ST2 protein, interleukin-6 (IL-6) and chitinase-3-like protein 1 (CHI3L1). NSTEMI patients had lower OR (0.83-0.05) of death or MACE between MI groups. Conclusions In the acute setting, biomarkers indicated greater myocardial dysfunction and inflammation in STEMI patients, whereas NSTEMI patients displayed a heterogeneous and more ambiguous activation of pathophysiologic pathways. These biomarkers were not associated with prognostic differences between STEMI and NSTEMI patients. Therefore, the results do not support treating STEMI and NSTEMI patients differently based on these biomarkers. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish Foundation for Strategic Research. Swedish Association of Local Authorities and Regions. Table 1

Background Sex-differences in the pathobiology of myocardial infarction are well established but incompletely understood. Improved knowledge on this topic may help clinicians to improve management of men and women with myocardial infarction. Methods In this registry-based cohort study (SWEDEHEART), we analyzed 175 circulating biomarkers reflecting various pathobiological axes in 856 men and 243 women admitted to Swedish coronary care units because of myocardial infarction. Two multimarker panels were applied (Proximity Extension Assay [Olink Bioscience], Multiple Reaction Monitoring mass spectrometry). Lasso analysis (penalized logistic regression), multiple testing-corrected Mann-Whitney tests and Cox regressions were used to assess sex-differences in the concentrations of these biomarkers and their implications on all-cause mortality and major adverse events (median follow-up up to 6.6 years). Results Biomarkers provided a very high discrimination between both sexes, when considered simultaneously (c-statistics 0.972). Compared to women, men had higher concentrations of six biomarkers with the most pronounced differences seen for those reflecting atherogenesis, myocardial necrosis and metabolism. Women had higher concentrations of 14 biomarkers with the most pronounced differences seen for those reflecting activation of the renin-angiotensin-aldosterone axis, inflammation and for adipokines. There were no major variations between sexes in the associations of these biomarkers with outcome. Conclusions Severable sex-differences exist in the expression of biomarkers in patients with myocardial infarction. While these differences had no impact on outcome, our data suggest the presence of various sex-related pathways involved in the development of coronary atherosclerosis, the progression to plaque rupture and acute myocardial damage, with a greater heterogeneity in women.

Background: Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms “MI,” “nonobstructive,” “angiography,” and “prognosis” were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran’s Q and I 2 statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI. Results: The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%–4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%–3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%–4.1%] versus 5.6% [95% CI, 4.1%–7.0%]; odds ratio, 0.60 [95% CI, 0.52–0.70], P P =0.09). Conclusions: In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42020145356.

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: β = −0.113; more sensitive cTnT assay: β= −0.186; pooled conventional cTnI assays: β = −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.

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.

Background Natriuretic peptides are established biomarkers of heart failure (HF). The existence of gender-related differences in circulating levels and prognostic value are still controversial. Methods Individual patient data from studies assessing cardiac biomarkers (N-terminal fraction of pro-B-type natriuretic peptide - NT-proBNP - and high-sensitivity troponin T) for risk prediction in stable chronic HF were analysed. Results Women (n=1964, 23%) had higher median [interquartile interval] NT-proBNP concentrations than men (1678 [659–4215] vs. 1294 [522–2973] ng/L, p Over a 2.4-year follow-up (1.6–3.2), 2351 patients (27%) died, and cardiovascular death occurred in 1558/8271 (19%). HF hospitalization was recorded in 2088/7944 (26%) over 2.0 years (1.3–2.6). Women and men had similar areas under the curve for the 3 endpoints, with higher cut-offs among women: all-cause death, 2328 ng/L vs. 1319 ng/L; cardiovascular death, 2328 ng/L vs. 1413 ng/L; HF hospitalization, 1265 ng/L vs. 907 ng/L. In the prognostic model above, the risk of the three endpoints increased by 32%, 35%, and 17%, respectively, per doubling of NT-proBNP in women, and by 41%, 45%, and 30% in men. Conclusions Women with chronic HF display higher NT-proBNP levels than men in the whole population as well as across many patient subgroups. This difference is not entirely explained by heterogeneity in age, BMI, or renal function. NT-proBNP holds independent prognostic significance in both genders, although alternative prognostic cut-offs might be considered for women.

Background The one-hour troponin-algorithm is recommended together with a clinical evaluation for rule-in and rule-out of acute coronary syndrome (ACS) in the emergency department (ED). Since risk factors and many comorbidities are associated with small elevations of high-sensitive cardiac troponin T (hs-cTnT), their additive value for discrimination of ACS have been questioned. However, the importance of the initial troponin level for how risk factors and/or comorbidities associate with early dynamic change in hs-cTnT is poorly studied. Purpose To investigate the association between risk factors and early dynamic change of hs-cTnT among those with an elevated compared to non-elevated initial hs-cTnT. Methods This was a retrospective study among patients admitted to four urban emergency departments (ED) between 2014–2016 with the chief complaint of chest pain and with two clinical routine hs-cTnT measurements at presentation and at >30–104 minutes later. Clinical data from the ED visit were cross-referenced to national registers retrieving information on diagnoses and treatments to identify: cardiovascular disease (CVD, defined as previous myocardial infarction, stroke or peripheral vascular disease), hypertension (HT), hyperlipidemia (HL), diabetes mellitus (DM), chronic kidney disease (CKD), Heart failure (CHF) and atrial fibrillation (AF). The association between risk factors and early dynamic change was studied separately for those with an elevated (>14ng/L, dynamic change set as >20%) and a non-elevated (≤14ng/L, dynamic change set as >2ng/L) initial hs-cTnT. Results 9278 patients were identified. All risk factors and comorbidities were more common among those with an elevated hs-cTnT. Dynamic change was present in 236 (3.4%) of 7024 patients with an initial hs-cTnT ≤14ng/L and 307 (13.6%) of 2254 with an initial hs-cTnT >14ng/L respectively. Among those with non-elevated initial hs-cTnT those with dynamic change were more likely to be older: age >70 (odds ratio (OR); 95% CI: 1.5; 1.1–2.0), have CVD (1.7: 1.2–2.5), HT (1.4; 1.1–1.8), eGFR70 (0.5; 0.4–0.6), CVD (0.5; 0.4–0.7), HT (0.6; 0.46–0.8), eGFR4ng/L (at initial hs-cTnT 50% (initial >14ng/L) were tested but did not affect the overall results. Fig 1. Forest plot dynamic hs-cTnT Conclusions Many risk factors and comorbidities show opposite associations with early dynamic change of hs-cTnT depending on the baseline concentration. The findings stress the importance of initial troponin level when assessing patients with risk factors presenting with ACS symptoms in the ED, however further investigations are needed to establish the definite dependency.

Background: In a recent individual patient data meta-analysis, high-sensitivity troponin T (hs-TnT) emerged as robust predictor of prognosis in stable chronic heart failure (HF). In the same population, we compared the relative predictive performances of hs-TnT, N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), hs-C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) for prognosis. Methods and results: 9289 patients (66 +/- 12 years, 77% men, 85% LVEF = 90: hs-TnT 13 ng/L and NT-proBNP 825 ng/L; eGFR < 30: hs-TnT 40 ng/L and NT-proBNP 4608 ng/L). Patient categorization according to these cut-offs effectively stratified patient prognosis across all eGFR classes. Conclusions: hs-TnT conveys independent prognostic information from NT-proBNP, while hs-CRP does not. Concomitant assessment of eGFR may further refine risk stratification. Patient classification according to hs-TnT and NT-proBNP cut-offs specific for the eGFR classes holds prognostic significance. (C) 2018 Elsevier B.V. All rights reserved.

Aims Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2)). Methods In an individual patient dataset, BMI was calculated as weight (kg)/height (m) 2 , and PBF through the Jackson–Pollock and Gallagher equations. Results Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5–2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4–33.0%) with the Jackson–Pollock equation, and 28.0% (23.8–33.5%) with the Gallagher equation, with an extremely strong correlation ( r = 0.996, p 2, third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome. Conclusion In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients.

We aimed to evaluate the diagnostic sensitivity for myocardial infarction (MI) when using an undetectable level of high-sensitivity cardiac troponin T (hs-cTnT 5 ng/L) at presentation combined with a non-ischemic electrocardiogram (ECG), to rule out MI in a non-ST-segment elevation MI (NSTEMI) cohort presenting ≤2 h from symptom onset. We also aimed to compare baseline characteristics and 30-day outcome in NSTEMI patients presenting with and without hs-cTnT 5 ng/L.All patients admitted to five centers in Sweden 2011-2015, after the introduction of hs-cTnT, who presented ≤2 h from symptom onset and received a final diagnosis of NSTEMI, were identified through the SWEDEHEART registry. These data and data of hs-cTnT levels were verified in the hospitals' medical records. The registry provided baseline and outcome data.Twenty-four (2.6%) of 911 NSTEMI patients presented with hs-cTnT 5 ng/L. In patients presenting1-≤2 h from symptom onset the sensitivity for MI when combining hs-cTnT and ECG was 99.4% (95% CI 98.4%-99.8%). In patients presenting ≤1 h, and in patients aged ≤65 years without prior MI, the sensitivity was insufficient. NSTEMI patients presenting with hs-cTnT 5 ng/L were younger and had less often a prior MI. A total of 62.5 vs. 63.5% of the NSTEMI patients presenting with and without hs-cTnT 5 ng/L underwent revascularization within 30 days and 4.5 and 3.2% died respectively.Hs-cTnT 5 ng/L at presentation combined with a non-ischemic ECG may be used to rule out MI in patients presenting as early as1 h from symptom onset with a sufficient sensitivity.

Cardiac troponin (cTn) levels are commonly used as a clue whether or not to initiate beneficial treatments in patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS). The current view is that patients with cTn elevation should undergo invasive assessment aiming at coronary

Background: Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCAs) is an increasingly recognized entity. No previous study has evaluated predictors for new major adverse cardiacvascular events (MACEs) and death in patients with MINOCA. Methods: We conducted an observational study of MINOCA patients recorded between July 2003 and June 2013 and followed until December 2013 for outcome events. Out of 199,163 MI admissions, 9092 consecutive unique patients with MINOCA were identified. The mean age was 65.5 years and 62% were women. MACE was defined as all-cause mortality, rehospitalization for acute MI, ischemic stroke and heart failure. Hazard ratio and 95% confidence interval (HR; 95% CI) was calculated using Cox-regression. Results: A total of 2147 patients (24%) experienced a new MACE and 1254 patients (14%) died during the mean follow-up of 4.5 years. Independent predictors for MACE after adjustment, were older age (1.05; 1.04–1.06), diabetes (1.44; 1.21–1.70), hypertension (1.25; 1.09–1.43), current smoking (1.38; 1.15–1.66), previous myocardial infarction (1.38; 1.04–2.82), previous stroke (1.69; 1.35–2.11), peripheral vascular disease (1.55; 1.97–2.23), chronic obstructive pulmonary disease (1.63; 1.32–2.00), reduced left ventricular ejection fraction (2.00; 1.54–2.60), lower level of total cholesterol (0.88; 0.83–0.94) and higher level of creatinine (1.01; 1.00–1.03). Independent predictors for all cause death were age, current smoking, diabetes, cancer, chronic obstructive pulmonary disease, previous stroke, reduced left ventricular fraction, lower level of total cholesterol and higher levels of creatinine and CRP. Conclusions: The clinical factors predicting new MACE and death of MINOCA patients seem to be strikingly similar to factors previously shown to predict new cardiovascular events in patients with MI and obstructive coronary artery disease.

Background It remains unknown how the introduction of high-sensitivity cardiac troponin T (hs-cTnT) has affected the incidence, prognosis, and use of coronary angiographies and revascularizations in patients with myocardial infarction (MI). Objectives The aim of this study was to investigate how the incidence of MI and prognosis after a first MI was affected by the introduction of hs-cTnT. Methods In a cohort study, the authors included all patients with a first MI from the Swedish National Patient Registry from 2009 to 2013. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for risk of all-cause mortality, reinfarction, coronary angiographies, and revascularizations in patients with MI diagnosed using hs-cTnT compared with those diagnosed using conventional troponins (cTn). Results During the study period, 47,133 MIs were diagnosed using cTn and 40,746 using hs-cTnT. The rate of MI increased by 5% (95% CI: 0% to 10%) after the introduction of hs-cTnT. During 3.9 ± 2.8 years of follow-up, there were 33,492 deaths, with no difference in the risk of all-cause mortality (adjusted HR: 1.00; 95% CI: 0.97 to 1.02). There were, in total, 15,766 reinfarctions during 3.1 ± 2.3 years of follow-up, with the risk of reinfarction reduced by 11% in patients diagnosed using hs-cTnT (adjusted HR: 0.89; 95% CI: 0.86 to 0.91). The use of coronary angiographies (adjusted HR: 1.16; 95% CI: 1.14 to 1.18) and revascularizations (adjusted HR: 1.13; 95% CI: 1.11 to 1.15) increased in the hs-cTnT group. Conclusions In a nationwide cohort study including 87,879 patients with a first MI, the introduction of hs-cTnT was associated with an increased incidence of MI, although with no impact on survival. We also found a reduced risk of reinfarction alongside increased use of coronary angiographies and revascularizations.

We appreciate the input on our paper [(1)][1] from Dr. Miles, who addresses an important issue with respect to any retrospective registry-based study. The International Classification of Diseases-10th revision codes provided in the SWEDEHEART (Swedish Web-system for Enhancement and Development of

The importance of sex on cardiac troponin levels is increasingly recognized. We investigated whether the entities associated with troponin leakage and the prognostic consequences thereof would differ between elderly men and women from the community.Cardiac troponin I (cTnI) levels were measured using a high-sensitivity assay (Abbott Laboratories) in 70-year old men (n = 502) and women (n = 502) from the PIVUS study. All study participants were followed up for 10 years regarding all-cause mortality and incident cardiovascular (CV) disease.Median cTnI levels were 4.1 and 3.0 ng/L in men and women, respectively (p0.001). By multiple linear regression, the relative contribution of lower left-ventricular ejection fraction and ischemic ECG changes to cTnI levels was greater in men compared to women. For other clinical and echocardiographic variables, similar associations were found. cTnI independently predicted all-cause mortality in men (n = 93 [18.5%]; hazard ratio [HR] 1.38 [1.12-1.70]) and women (n = 62 [12.4%]; HR 1.59 [1.11-2.28]) but not incident CV disease in subjects being CV healthy at baseline (n = 163/857). The interaction terms of sex on the associations of cTnI with both outcomes were non-significant. Sex-specific cut-offs did not improve prognostication. Variations in the pattern of entities associated with cTnI leakage had no impact on event rates.We found some differences in the entities associated with higher cTnI levels in elderly community-dwelling men and women. However, this did not translate into differences in the associations of cTnI with adverse outcome.

Background Cardiac troponin is the preferred biomarker for diagnosing myocardial infarction (MI). Objectives The aim of this study was to examine the implications of introducing high-sensitivity cardiac troponin T (hs-cTnT) into clinical practice and to define at what hs-cTnT level risk starts to increase. Methods We analyzed data from 48,594 patients admitted because of symptoms suggesting an acute coronary syndrome and who were entered into a large national registry. Patients were divided into Group 1, those with hs-cTnT Results There were 5,790 (11.9%), 6,491 (13.4%), 10,476 (21.6%), and 25,837 (53.2%) patients in Groups 1, 2, 3, and 4, respectively. In Groups 1 to 4, the proportions with MI were 2.2%, 2.6%, 18.2%, and 81.2%. There was a stepwise increase in the proportion of patients with significant coronary stenoses, left ventricular systolic dysfunction, and death during follow-up. When dividing patients into 20 groups according to hs-cTnT level, the adjusted mortality started to increase at an hs-cTnT level of 14 ng/l. Conclusions Introducing hs-cTnT into clinical practice has led to the recognition of a large proportion of patients with minor cardiac troponin increases (14 to 49 ng/l), the majority of whom do not have MI. Although a heterogeneous group, these patients remain at high risk, and the adjusted mortality rate started to increase at the level of the 99th percentile in healthy controls.

Background Cardiac troponin (cTn) levels reflect infarct size and depressed left ventricular ejection fraction (LVEF) in patients with non–ST elevation acute coronary syndrome (NSTE-ACS). However, there is very limited information on whether cTn measured with a high-sensitivity (hs) assay would provide incremental prognostic information to the LVEF in NSTE-ACS patients. Methods This was a registry-based study (SWEDEHEART registry) investigating 20,652 NSTE-ACS patients with available information on hs-cTnT (highest level recorded during the hospitalization) and the LVEF estimated using echocardiography. All patients had been followed for 1 year. Results Hs-cTnT levels independently predicted major cardiovascular events (MACE) in cohorts with normal, slightly depressed, moderately depressed, and severely depressed LVEF. The adjusted hazard ratios in these cohorts were 1.18 (95% CI 1.13-1.23), 1.12 (95% CI 1.06-1.18), 1.12 (95% CI 1.06-1.19), and 1.21 (95% CI 1.13-1.30), respectively. Hs-cTnT levels were particularly predictive for cardiovascular mortality and readmission for heart failure. Excluding patients with previous cardiac disease did not affect the overall interrelations of hs-cTnT and LVEF with MACE. Conclusions Hs-cTnT levels provide incremental prognostic value independent of the LVEF in patients with NSTE-ACS. Hs-cTnT is particularly predictive for MACE in patients with severely depressed LVEF but also in those with a normal LVEF. Accordingly, a normal LVEF should not be used as an argument not to target patients to thorough workup.

Background Measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) might be useful for monitoring of cardiovascular disease in the elderly. However, it is not clear whether changes in these biomarkers are associated with changes in the cardiovascular risk profile and if this pattern could be modified by changes in lifestyle habits or medications. Methods We measured levels of NT-proBNP and cTnI in community-dwelling subjects (PIVUS study) upon visits scheduled at age 70 ( n =1007), 75 ( n =825) and 80 ( n =602). The associations of these biomarkers with repeated measurements of clinical variables (risk factors, lifestyle habits, echocardiographic data and medications) were investigated using sex-adjusted linear mixed random effect models. Results NT-proBNP and cTnI were positively associated with increasing age. NT-proBNP, but not cTnI, was affected by changes of renal function and the degree of obesity. NT-proBNP was more closely related than cTnI to changes in echocardiographic estimates of cardiac geometry and function. Biomarker levels and/or their changes were inversely associated with a physically more active lifestyle (both NT-proBNP and cTnI) and statin treatment at age 70 (only cTnI). Changes in smoking status or antihypertensive treatment had no effect on biomarker levels. Conclusions Changes in NT-proBNP and cTnI levels are associated with different patterns of cardiovascular disease burden when using a longitudinal approach. However, levels of both biomarkers and their changes also reflect changes in the cardiovascular risk profile that might be modifiable. This is an important aspect for the use of any cardiovascular biomarker in an elderly population.

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 (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 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.

Purpose of Review Cardiac troponin (cTn) plays an essential role for assessment of outcome in acute coronary syndrome (ACS). However, the prognostic value of cTn is not absolute. In this mini-review, we summarize the evidence on the utility of established biomarkers of left-ventricular dysfunction, hemodynamic stress, inflammation, and renal dysfunction for risk prediction beyond cTn in ACS. Recent Findings Only few biomarkers consistently demonstrate additive prognostic value to cTn levels. The B-type natriuretic peptides (NPs) and growth-differentiation factor-15 (GDF-15) are most promising in this regard. However, there are uncertainties regarding the role of these biomarkers for guidance of treatment decisions, and their prognostic increment to cTn levels measured with high-sensitivity assays is largely unknown. Summary The NPs and GDF-15 provide the strongest prognostic increment to cTn levels in ACS. However, the role of these biomarkers for clinical decision-making in contemporary settings has still to be defined.

Background: The aim of this study was to examine the value of predischarge exercise electrocardiogram (ECG) testing of chest pain patients in whom acute myocardial infarction (MI) had been ruled out by means of high-sensitivity troponins, ECG and history. Methods: All patients hospitalised for chest pain who underwent exercise ECG testing before discharge from the Department of Cardiology, Södersjukhuset, Stockholm, Sweden from January 2011 to June 2012 were included. Endpoints were death, MI and post-discharge revascularisation within 90 and 365 days, respectively. The background one-year risk of death and MI for a corresponding age, gender and calendar time-matched Swedish population was also examined. Results: A total of 951 patients were included. In 585 patients (61.5%) the exercise ECG test was negative, in 94 (9.9%) positive and in 272 (28.6%) inconclusive. There were no significant differences regarding death or MI between patients with a positive or a negative test, neither at 90 ( n=1 (1.1%) vs. n=1 (0.2%)) nor at 365 days ( n=2 (2.1%) vs. n=4 (0.7%)) of follow-up. In total there were nine (0.9%) deaths and 10 (1.1%) MIs within 365 days. The one-year rates of death (1.3%) and MI (0.5%) in a matched Swedish population were comparable. Conclusions: Predischarge exercise ECG testing after rule out of MI did not predict subsequent death or MI in a population of patients hospitalised for chest pain. Furthermore, the risks of death and MI in this population were comparable to a matched Swedish population. These findings suggest that patients could be discharged without this test.

BackgroundMany acute cardiovascular events such as myocardial infarction (MI) follow circadian rhythms. Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a newly noticed entity with limited data on onset pattern and its impact on prognosis.Material and methodsIn this observational study of Swedish MINOCA patients registered in the SWEDEHEART registry between 2003-2013 and followed until December 2013 we identified 9,092 unique patients with MINOCA out of 199,163 MI admissions in total. Incidence rate ratios (IRR) were calculated for whole hours, parts of the day, weekdays, months, seasons and major holidays.ResultsThe mean age was 65.5 years, 62.0% were women and 16.6% presented with STEMI. The risk for MINOCA proved to be most common in the morning (IRR = 1.70, 95% CI [1.63-1.84]) with a peak at 08.00 AM (IRR = 2.25, 95% CI [1.96-2.59]) and on Mondays (IRR = 1.28, 95% CI [1.18-1.38]). No altered risk was detected during the different seasons, the Christmas and New Year holidays or the Swedish Midsummer festivities. There was no association between time of onset of MINOCA and short- or long-term prognosis.ConclusionThe onset of MINOCA shows a circadian and circaseptan variation with increased risk at early mornings and Mondays, similar to previous studies on all MI, suggesting stress related triggering. However, during holidays were traditional MI increase, we did not see any increase for MINOCA. No association was detected between time of onset and prognosis, indicating that the underlying pathological mechanisms of MINOCA and the quality of care are similar at different times of onset but triggering mechanism may be more active early mornings and Mondays.

BACKGROUND A rise or fall of cardiac troponin is a prerequisite for the diagnosis of acute myocardial infarction. Defining significant changes requires knowledge of both biological and analytical variation. The short-term biological variation of cardiac troponin in healthy individuals is 3%–48%. However, healthy individuals may not be representative for patients in whom cardiac troponin measurement is often of clinical importance. Therefore, we studied the individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease. METHODS Twenty-four patients scheduled for elective coronary angiography were included. Blood samples were drawn once at enrollment and serially at six 4-h intervals on the day before coronary angiography. Cardiac troponin was measured with hs-cTn assays from Abbott Laboratories (premarket cTnI assay) and Roche Diagnostics (Elecsys® cTnT assay with two different lots). RESULTS The short-term individual variation in cardiac troponin I (cTnI) was 14%, the reference change value (RCV) 49%, and RCV-log-normal (rise/fall) 54%/−35%. The corresponding values for cTnT were 7%, 23%, and 26%/−21%. The long-term variation for cTnI was 24%, RCV 69%, and RCV-log-normal (rise/fall) 97%/−49%. The corresponding values for cTnT were 11%, 32%, and 37%/−27%. CONCLUSIONS The short-term individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease is similar to the biological variation previously demonstrated in healthy individuals. Our results suggest that a change in cardiac troponin concentrations of >50% can be used in attempting to diagnose acute myocardial injury. To detect significant long-term changes in cardiac troponin concentrations, larger changes will be required.

The levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) are closely related to cardiac abnormalities and adverse outcomes in the general population. However, little is known about the course of NT-proBNP levels over time, the underlying conditions, and the prognostic effect of changes. To investigate these issues, we measured the NT-proBNP levels (Elecsys 2010, Roche Diagnostics) in community-dwellers participating in the Prospective Investigation of the Vasculature in Uppsala Seniors study at 70 (n = 1,005) and 75 (n = 817) years of age. The total follow-up was 8.0 years. In subjects with available results from both examinations, the median NT-proBNP levels increased from 106 pg/ml (25th to 75th percentile 62 to 174) to 125 pg/ml (25th to 75th percentile 73-234; p0.001). The change in NT-proBNP levels was positively and independently related to male gender, baseline information on ischemic electrocardiographic changes, renal dysfunction, impaired left ventricular ejection fraction, and intercurrent cardiovascular events (e.g., myocardial infarction, stroke, or coronary revascularization). The change in NT-proBNP levels independently predicted mortality after the measurements at 75 years of age (all-cause mortality, adjusted hazard ratio 2.4, 95% confidence interval 1.6 to 3.6; cardiovascular mortality, adjusted hazard ratio 2.3, 95% confidence interval 1.2 to 4.5). Compared to those without significant NT-proBNP changes (n = 606), subjects with increasing levels (n = 162) had markedly increased all-cause mortality (adjusted hazard ratio 4.3, 95% confidence interval 2.1 to 8.8). No subject with decreasing NT-proBNP levels (n = 49) died. In conclusion, repeat measurements of NT-proBNP might add useful information to the routine clinical assessment in subjects aged ≥ 70 years, because changes in their levels were associated with cardiovascular risk indicators and strongly predictive of mortality.

Background: Both unrecognized myocardial infarction (UMI) and elevated levels of biomarkers are common in patients with stable coronary artery disease (CAD). The objective of this study was to determine the association between levels of cardiac biomarkers, UMI and extent of CAD in patients with stable CAD. Methods: A total of 235 patients (median age: 65 years; 34% women) with stable CAD without previously known myocardial infarction were examined with late gadolinium enhancement cardiovascular magnetic resonance imaging and coronary angiography. Blood samples were drawn at enrolment and high sensitivity cardiac troponin I (cTnI), NT-proBNP and Galectin-3 were analyzed. Results: UMI was detected in 58 patients (25%). The median levels of cTnI, NT-proBNP and Galectin-3 were significantly higher in patients with UMI compared to those without, (p < 0.001, p = 0.006 and p = 0.033, respectively). After adjustment for cardiovascular risk factors, left ventricular ejection fraction and renal function, cTnI remained independently associated with the presence of UMI (p = 0.031) and the extent of CAD (p = 0.047). Neither NT-proBNP, nor Galectin-3, was independently associated with UMI or extent of CAD. Conclusions: The independent association between levels of cTnI and UMI indicates a common pathophysiological pathway for the cTnI elevation and development of UMI. Clinical Trial Registration: ClinicalTrials.gov (NCT01257282).

Biomarkers may be of value to identify individuals at risk of developing atrial fibrillation (AF). Using a multimarker approach, this study investigated if the biomarkers; NT-proBNP, high-sensitivity cardiac troponin (hs-cTn), growth differentiation factor-15 (GDF-15), cystatin C and high-sensitivity C-reactive protein (CRP) are independent predictors for incident AF.Blood samples were collected from 883 individuals in the Uppsala Longitudinal Study of Adult Men (ULSAM) and 978 individuals in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Participants were followed for 10-13years with n=113 incident AF cases in ULSAM and n=148 in PIVUS. The associations between biomarkers and incident AF were analysed in Cox proportional hazards regression models.The hazard ratio (HR) for incident AF was significant for all five biomarkers in unadjusted analyses in both cohorts. Only NT-proBNP remained significant when adjusting for cardiovascular risk factors and the other biomarkers (HR (1SD) 2.05 (1.62-2.59) (ULSAM) and 1.56 (1.30-1.86) (PIVUS), both p0.001). The C-index improved from 0.64 to 0.69 in ULSAM and from 0.62 to 0.68 in PIVUS, by adding NT-proBNP to cardiovascular risk factors (both p0.001). The C-index of the CHARGE-AF risk score increased from 0.62 to 0.68 (ULSAM) and 0.60 to 0.66 (PIVUS) by addition of NT-proBNP (p0.001).Using a multimarker approach NT-proBNP was the strongest predictor of incident AF in two cohorts, and improved risk prediction when added to traditional risk factors. NT-proBNP significantly improved the predictive ability of the novel CHARGE-AF risk score, although the predictive value remained modest.

Objective Cardiac troponin levels differ between the sexes, with higher values commonly seen in men. The use of sex-specific troponin thresholds is, thus, subject of an ongoing debate. We assessed whether sex-specific cardiac troponin T (cTnT) 99 th percentiles would improve risk prediction in patients admitted to Swedish coronary care units due to suspected acute coronary syndrome. Methods In this retrospective register-based study (48,250 patients), we investigated the prediction of all-cause mortality and the composite of cardiovascular death or nonfatal myocardial infarction within 1 year using the single 99 th cTnT percentile (>14 ng/L) or sex-specific cTnT 99 th percentiles (>16/9 ng/L). Results A total of 1078 men (3.0%) with cTnT 15-16 ng/L and 1854 women (8.4%) with cTnT 10-14 ng/L would have been reclassified regarding their cTnT status by the means of sex-specific 99 th percentiles. The prevalence of cardiovascular risk factors and crude event rates increased across higher cTnT strata in both men and women. Multivariable-adjusted Cox models, however, did not demonstrate better risk prediction by sex-specific 99 th percentiles. Assessing cTnT as a continuous variable demonstrated an increase in multivariable-adjusted risk starting at levels around 10-12 ng/L in both men and women. Conclusions We found no evidence supporting the use of sex-specific cTnT 99 th percentiles in men and women admitted because of suspected acute coronary syndrome. This likely depends on sex-specific differences in disease mechanisms associated with small cTnT elevations. From a pragmatic perspective, a single cTnT cutoff slightly below 14 ng/L seems to be preferable as a threshold for medical decision-making.

Background Clinically unrecognized myocardial infarctions (UMI) are not uncommon and may be associated with adverse outcome. The aims of this study were to determine the prognostic implication of UMI in patients with stable suspected coronary artery disease (CAD) and to investigate the associations of UMI with the presence of CAD. Methods and Findings In total 235 patients late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging and coronary angiography were performed. For each patient with UMI, the stenosis grade of the coronary branch supplying the infarcted area was determined. UMIs were present in 25% of the patients and 67% of the UMIs were located in an area supplied by a coronary artery with a stenosis grade >= 70%. In an age-and gender-adjusted model, UMI independently predicted the primary endpoint (composite of death, myocardial infarction, resuscitated cardiac arrest, hospitalization for unstable angina pectoris or heart failure within 2 years of follow-up) with an odds ratio of 2.9; 95% confidence interval 1.1-7.9. However, this association was abrogated after adjustment for age and presence of significant coronary disease. There was no difference in the primary endpoint rates between UMI patients with or without a significant stenosis in the corresponding coronary artery. Conclusions The presence of UMI was associated with a threefold increased risk of adverse events during follow up. However, the difference was no longer statistically significant after adjustments for age and severity of CAD. Thus, the results do not support that patients with suspicion of CAD should be routinely investigated by LGE-CMR for UMI. However, coronary angiography should be considered in patients with UMI detected by LGE-CMR. Författare 3-8 delar på tredje författarskapet.

Summary Aims The increasing importance of cardiac disease has generated an interest in improved screening strategies regarding preclinical cardiac abnormalities and employing measurement of circulating biomarkers. This review focuses on the utility of the B-type natriuretic peptides (NP) and the cardiac troponins (cTns) for this purpose. Results Both the NPs and the cTns are closely related to cardiac structural and functional abnormalities that may progress to symptomatic heart disease, e.g., left ventricular (LV) hypertrophy, LV systolic and diastolic dysfunction. Both biomarkers provide incremental information to each other. However, biomarker results may be confounded by several non-cardiac conditions, and decision thresholds and recommendations on further clinical work-up are as yet not specified. Furthermore, cost issues will probably preclude widespread biomarker screening in general populations. Conclusions Measurement of the NPs or cTns is an attractive option for screening for cardiac abnormalities. This may be particularly effective in patients at higher risk for developing overt heart disease. Nevertheless, appropriate diagnostic and therapeutic responses to biomarker results need to be defined before routine screening can be recommended in the community setting.

Background High-sensitive (hs) cardiac troponin assays are clinically useful in various cardiac conditions. We aimed to extend current evidence by assessing the relations of hs-cardiac troponin T (hs-cTnT) and I (hs-cTnI) to invasive hemodynamic data and outcome in stable patients with left-ventricular (LV) dysfunction or precapillary pulmonary hypertension (PAH). Methods Hs-cTnT (Roche Diagnostics) and hs-cTnI (Beckman-Coulter) were measured in 103 stable patients with LV-dysfunction and 56 patients with precapillary PAH referred for right-heart catheterization. Results Up to 47.6% of patients with LV-dysfunction, and up to 37.5% of patients with precapillary PAH had hs-troponin levels above the respective 99th percentiles. In patients with LV-dysfunction, both hs-troponins exhibited significant associations to hemodynamics, NT-proBNP and mortality (hs-cTnT: age/sex-adjusted HR 2.0 [95% CI 1.3–3.1]; hs-cTnI: age/sex-adjusted HR 1.9 [1.2–2.8]). Both hs-troponins demonstrated weaker associations to hemodynamics in patients with precapillary PAH but correlated significantly to NT-proBNP. Mortality was only predicted by hs-cTnI (age/sex-adjusted HR 3.0 [1.5–6.1]). Conclusions Hs-troponins are related to indices of impaired myocardial performance in patients with LV-dysfunction and precapillary PAH. Both hs-troponins were also predictive for mortality in patients with LV-dysfunction. In precapillary PAH, only hs-cTnI was independently prognostic which might depend on the superior analytical performance of this assay.

Patients with unrecognized myocardial infarction (UMI) scars detected by delayed-enhanced magnetic resonance imaging (DE-MRI) have a decreased left ventricular ejection fraction and an increased left ventricular mass. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of heart failure, and troponin I (TnI) is a marker of myocardial injury. The primary aim of this study was to investigate whether NT-proBNP plasma levels (in addition to ejection fraction) differed in patients with UMI scars compared with normal participants. The second aim was to compare whether the TnI levels differed in those two groups.Data from the Prospective Investigation of Vasculature in Uppsala Seniors study were used. The participants who had undergone cardiac MRI were included in this study (n=248). Patients were divided into three groups depending on the existence of a myocardial infarction (MI) scar in DE-MRI and their earlier history of MI. In all the patients, a peripheral blood sample was collected and the plasma levels of NT-proBNP and TnI were determined.Patients with UMI had higher plasma levels of NT-proBNP (median 140.2 ng/l; 25th-75th percentiles: 79-225.5) than no-MI participants (median 94.9 ng/l; 25th-75th percentiles: 59.2-144.2; P=0.01) and lower levels than patients with recognized MI (median 310.4 ng/l; 25th-75th percentiles: 122.6-446.5; P=0.02). Plasma TnI values did not differ among the three groups.Patients with UMI scars detected by DE-MRI have increased plasma levels of NT-proBNP that is known to correlate with an increased risk of future cardiovascular adverse events.

Background The Universal Definition of Myocardial Infarction incorporates elevated cardiac troponin levels (> 99th percentile) together with a significant rise/fall of troponins as biochemical criterion. We sought to evaluate the clinical implications of the relative change of cardiac troponin I (cTnI) levels with respect to the Universal Definition in patients with acute chest pain. Methods cTnI (Stratus CS) was measured serially in 454 patients within 24 h from admission. Acute myocardial infarction (AMI) was defined using the criteria adapted to the ESC/ACC consensus document, or corresponding to the Universal Definition together with prespecified cTnI changes of ≥ 20%, ≥ 50% and ≥ 100%. Follow-up was completed after 5.8 years. Results A peak cTnI level above the 99th percentile together with a cTnI change of ≥ 20% was found in 160 patients of whom 25 did not have AMI according to the ESC/ACC criteria. These 160 patients had a significantly raised mortality (HR 2.5 [95% CI 1.7–3.8]). Higher cTnI deltas were not associated with higher mortalities but identified smaller patient cohorts at risk. Conclusions The Universal Definition of AMI together with a ≥ 20% cTnI change appears to improve the discrimination of acute from chronic causes of cTnI release, and allows a reliable identification of patients at risk.

Background Approximately 5% to 10% of all patients with myocardial infarction have nonobstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking. Methods In this analysis from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry, we investigated 5830 patients with myocardial infarction with nonobstructive coronary arteries (group 1) and 54,637 patients with myocardial infarction with significant coronary artery disease (≥50% stenosis; group 2). Multivariable- and propensity score–adjusted statistics were used to assess the reduction in the 1-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6 to 10 weeks after the hospitalization and achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, nonsmoking, and participation in exercise training). Results Patients in group 1 were less often followed up compared with patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6- to 10-week follow-up was associated with a 3% to 20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24%-32% risk reduction) and, to a smaller extent, by participation in exercise training (10%-23% risk reduction). Conclusions Selected secondary preventive measures are associated with prognostic benefit in patients with myocardial infarction with nonobstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses.

Background ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in heart failure and ST-segment elevation myocardial infarction, but its prognostic value in non-ST-elevation acute coronary syndrome (NSTE-ACS) has not been established. Methods We measured ST2 at randomization and after 24, 48, and 72 hours in 403 NSTE-ACS patients from the GUSTO IV study, and studied its kinetics and its associations to clinical baseline factors and 1-year mortality. Results Median ST2 levels decreased from 28.4 U/mL at randomization to 21.8 U/mL at 72 hours (P < .001). Peak levels were noted 6 to 17 hours after symptom onset. Randomization ST2 levels were independently associated to N-terminal pro-B-type natriuretic peptide but otherwise exhibited only weak relations to cardiovascular risk factors and comorbidities, and biomarkers of myocardial necrosis or inflammation. ST2 was related to 1-year mortality independently of clinical risk indicators (odds ratio 2.3 [95% CI 1.1-4.6], P = .03) but lost its predictive value after additional adjustment for prognostic biomarkers, in particular N-terminal pro-B-type natriuretic peptide. Conclusions ST2 levels are elevated early in NSTE-ACS and predict 1-year mortality. Our data indicate that ST2 represents an interesting novel pathophysiologic pathway in the setting of ischemia-related myocardial dysfunction. However, future prospective evaluations in larger populations are needed before the clinical utility of ST2 can be determined. (Am Heart J 2010; 159: 788-94.)

Background There is an expectation that with the adoption of more sensitive cardiac troponin (cTn) assays, unstable angina would become a rarity. However, recent data from the SWEDEHEART registry demonstrated that 15% of patients admitted with non-ST-elevation acute coronary syndrome still were regarded as having unstable angina. We aimed to further investigate the clinical characteristics and outcome of these patients. Methods This was a retrospective, registry-based analysis (SWEDEHEART) including 3204 unstable patients, 18,194 non-ST-elevation myocardial infarction (NSTEMI) patients, and 977 controls without acute cardiovascular disease. All patients had available data on peak cTnT levels (more sensitive assay) and 1-year outcome. Results The annual proportions of patients with unstable angina (2009-2013) among those with non-ST-elevation acute coronary syndrome ranged from 9.4% to 15.3%. Only 1239 unstable angina patients (39.7%) had a peak cTnT level ≤14 ng/L. Patients with unstable angina tended to be younger than those with NSTEMI but had higher prevalence of most cardiovascular risk factors and more advanced coronary artery disease. Compared with controls, the adjusted hazard ratios (95% confidence interval) regarding major cardiovascular events were 2.97 (1.30-6.78) and 5.44 (2.54-11.65) in unstable angina patients with peak cTnT ≤14 ng/L and >14 ng/L, respectively. Conclusion The diagnosis of unstable angina is still commonly used, even in the era of more sensitive cTn assays. Minor cTnT elevation is common, which makes unstable angina difficult to distinguish from NSTEMI. Patients with unstable angina have a nonneglectable cardiovascular risk. We suggest that the clinical management of patients presenting with unstable symptoms should depend on their estimated cardiovascular risk rather than on strictly applied diagnostic criteria.

ObjectivesThe aim of this study was to assess risk prediction by different biomarkers in patients with an ongoing non–ST-segment elevation acute coronary syndrome (NSTE-ACS) and after clinical stabilization.BackgroundDifferent biomarkers reflect different aspects of the pathobiology in NSTE-ACS. However, there is little information regarding their relative prognostic value during the time course of disease.MethodsThe N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), cardiac troponin I (cTnI), and the estimated glomerular filtration rate (eGFR) were measured at randomization and after 6 weeks and 6 months in 877 NSTE-ACS patients included in the FRISC (FRagmin and fast revascularization during InStability in Coronary artery disease) II trial. The biomarkers' prognostic value during 5-year follow-up was evaluated by Cox regression models, calculation of the c-statistics, and estimation of the net reclassification improvement (NRI).ResultsAmong the biomarkers measured at randomization, NT-proBNP was the strongest predictor for mortality (adjusted hazard ratio [HR]: 1.7; 95% confidence interval [CI]: 1.3 to 2.1; p < 0.001). Even during follow-up, NT-proBNP demonstrated the strongest association to the composite end point of death/myocardial infarction (adjusted HR at 6 weeks: 1.5; 95% CI: 1.3 to 1.7; p < 0.001; adjusted HR at 6 months: 1.4; 95% CI: 1.2 to 1.7; p = 0.001). Even CRP was independently predictive at 6 months for the composite end point (adjusted HR: 1.3; 95% CI: 1.1 to 1.5; p = 0.003). Only 6-week results of NT-proBNP provided significant incremental prognostic value to established risk indicators regarding the composite end point (c-statistics 0.69 [p = 0.03]; NRI 0.11 [p = 0.03]).ConclusionsThe NT-proBNP is an independent risk predictor in patients with ongoing NSTE-ACS and after clinical stabilization. The CRP exhibits increasing predictive value at later measurements. However, only NT-proBNP provided incremental prognostic value and might therefore be considered as a complement for early follow-up controls after NSTE-ACS.

The Universal Definition of Myocardial Infarction (acute myocardial infarction [AMI]) requires detection of increasing or decreasing cardiac biomarkers (preferably cardiac troponin) with ≥1 value >99 th percentile, together with either clinical symptoms, new ischemic electrocardiographic changes, or typical imaging findings indicative of myocardial necrosis as diagnostic criteria for AMI. However, a small cardiac troponin elevation together with ST-T segment abnormalities may also occur in clinically stable populations. Accordingly, 0.6% of elderly subjects from a community sample (PIVUS Study) and 6.7% of patients stabilized after an acute coronary syndrome (FRISC II Study) would have been labeled AMI following the Universal Definition of AMI when diagnostic classification had been based on a single cardiac troponin I result. In conclusion, our results emphasized the importance of a significant change in cardiac troponin to avoid misdiagnosis of AMI.

Recently, a high prevalence of small persistent cardiac troponin I (cTnI) elevations has been reported in patients who had been stabilized after a recent episode of acute coronary syndrome (ACS). We now have studied the associations of persistently elevated cTnI levels to cardiac performance, inflammation, coagulation, coronary status, and treatment strategy in these patients.Cardiac troponin I was determined at 6 weeks, 3 months, and 6 months after randomization in 898 stabilized ACS patients from the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC) II trial and using the high-sensitive Access AccuTnI assay (Beckman Coulter, Fullerton, CA). All patients were followed up for at least 5 years. Persistent cTnI elevation0.01 microg/L at the 3 measurement instances was detected in 233 patients (26%). N-terminal pro-brain natriuretic peptide (NT-proBNP) at 6 months (OR 2.5, 95% CI 2.0-3.1), male sex (OR 2.2, 95% CI 1.4-3.7), and randomization to an early invasive strategy (OR 1.8, 95% CI 1.2-2.7) independently predicted persistently elevated cTnI levels. Persistently cTnI-positive patients in the invasive cohort had significantly lower NT-proBNP levels compared to noninvasively treated patients, indicating that the mechanisms causing cTnI elevation in this group may be prognostically less harmful. No independent associations were found for markers of inflammation or coagulation.Persistent cTnI elevation occurs frequently late after an ACS. The NT-proBNP level at 6 months was the strongest predictor for elevated cTnI levels that thus appear to be predominantly related to impaired left ventricular function.