High-sensitivity Cardiac Troponin Research Articles

Evidence for stability of cardiac troponin T concentrations measured with a high sensitivity TnT test in serum and lithium heparin plasma after six-year storage at-80 °C and multiple freeze-thaw cycles.

As high-sensitivity cardiac troponin T (hs-cTnT) is making the transition from diagnostic to prognostic use, a long-term stability study of 5th generation hs-cTnT according to EFLM CRESS recommendations was set up for investigation of frozen clinical specimens (two matrices). Study samples collected in serum tubes and lithium heparin tubes with gel from patients admitted for suspected minor myocardial damage were measured directly after completion of the study (0 years), and after 3-year and 6-year storage at-80 °C, and recovery of hs-cTnT concentrations after long-term storage (%hs-cTnT concentration compared to 0-year) was calculated. Hs-cTnT changes were also compared to decisive delta changes, such as the ones proposed in the ESC NSTEMI 0 h/1 h algorithm (<3 or >5 ng/L for ruling out and ruling in suspected NSTEMI patients). Eighty-six patients were included in the study, whereof 28 both lithium heparin plasma and serum samples were collected simultaneously, in others only serum (n=30) or plasma (n=28). Multiple aliquots per patient were made, so that 479 serum and 473 plasma samples were available for analysis. Across the overall hs-cTnT measuring range, median recovery after 6 years was 105.4 % and 106.2 % for serum and plasma, respectively. Based on these decisive delta changes, serum showed consistent results upon long term storage (max 0.8 % of samples above delta threshold of >5 ng/L) as compared to heparin plasma (up to 19.2 % of samples above threshold). Over 6 years of storage at-80 °C, recovery of hs-cTnT in serum and heparin plasma was similar and within common lot-to-lot variation. Yet, when evaluating absolute delta increments around hs-cTnT clinical decision points, long-term stored sera displayed better clinical performance compared to heparin plasma samples.

Effectiveness and Safety of the ESC-TROP (European Society of Cardiology 0h/1h Troponin Rule-Out Protocol) Trial.

European guidelines recommend the use of a 0h/1h hs-cTn (high-sensitivity cardiac troponin) protocol in patients with acute chest pain. We aimed to determine the performance of this protocol in routine care when supplemented with patient history and ECG and a recommendation to refrain from noninvasive testing in low-risk patients. This was a pre- and postimplementation study with concurrent controls. Patients with chest pain were enrolled at 5 Swedish emergency departments (EDs) during a 10-month period in both 2017 and 2018. All hospitals used a 0h/3h hs-cTnT protocol in 2017 and 3 EDs implemented a 0h/1h hs-cTnT protocol during 10 months in 2018. The 2 coprimary outcomes were the incidence of acute myocardial infarction and all-cause death within 30 days and ED length of stay. The study included 26 040 consecutive patients. In the intervention hospitals, 21 (0.40%) of the discharged patients had an acute myocardial infarction/death event during the control period (0h/3h testing) and 22 (0.45%) in the intervention period (0h/1h testing), which met the criteria for noninferiority. There was no significant difference in ED length of stay (ratio 0.99, P=0.48) or ED discharge rate between the periods in the intervention versus the control hospitals. A total of 3142 patients met low-risk 0h/1h hs-cTnT criteria and were discharged, of whom 2 had an acute myocardial infarction/death event. A 0h/1h hs-cTnT protocol incorporating patient history and ECG was as safe as using a 0h/3h protocol but did not reduce ED length of stay or increase the discharge rate. Refraining from noninvasive testing in patients identified as low risk was safe. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03421873.

Cardiac Myosin-binding Protein-C as a Biomarker in the Early Diagnosis of Acute Coronary Syndrome and Differentiation of Its Types

Abstract Background: Coronary heart disease (CHD) is primarily caused by atherosclerotic lesions within the intima of coronary arteries and acute coronary syndrome (ACS) is the main acute clinical manifestation of CHD. The ACS is manifested in one of three subtypes and it is the leading cause of mortality worldwide. The three subtypes of ACS include: acute myocardial infarction (MI) with the electrocardiogram (ECG) presenting ST-segment elevation (STEMI), MI with no ST-segment elevation on ECG (NSTEMI), and the third subtype is unstable angina (UA). The early diagnosis of is important in decreasing morbidity and mortality in ACS patients. Objective: To investigate the role of serum level of cardiac myosin-binding protein-C (cMyC), compared with high-sensitivity cardiac troponin-I (hsCTn-I) in the early diagnosis of ACS and differentiation of its subtypes. Materials and Methods: One hundred and twenty patients (72 males and 48 females), aged ≥30 years selected from those who were admitted to emergency department (ED) of Al-Yarmouk teaching hospital and diagnosed with ACS by cardiologists. The duration between the onset of chest pain and admission to ED should not exceed 3 h in any cohort. Apparenty healthy subjects as controls group for the study were recruited from those who had no current illness, particularly CHD, no other systemic disease and each had a normal ECG. For each study subject, cMybp-C and hsCT-I serum levels on admission were measured using the enzyme-linked immunosorbent assay kits. For each ACS patient, serum level of hsCTn-I level was measured 3 h after admission. Results: The comparison of cMybp-C levels among study groups revealed an overall significant difference and on paired comparison of study groups, the cMybp-C mean level was significantly higher in each ACS subgroup than in controls group (P &lt; 0.001), except in UA subgroup versus controls group. The cMybp-C levels showed a significant positive correlation with hsCT-I levels on admission in STEMI and NSTEMI subgroups but not in UA subgroup. The cMybp-C levels also showed a significant positive correlation with hscT-I levels 3 h after admission in STEMI and NSTEMI subgroups but not in UA subgroup. On receiver operating characteristic curve analysis, the cMybp-C level had a better diagnostic accuracy than hscTn-I on admission in differentiation of patients with “STEMI or NSTEMI” from those with UA or from controls. Conclusion: Serum cMybp-C mean level is significantly higher in ACS patients with STEMI and NSTEMI than in controls and the increase was more significant than hsCTn-I mean level on admission, so it could help the early diagnosis of ACS patients. The serum levels of cMybp-C also had a better diagnostic accuracy than hsCTn-I on admission in differentiation of ACS patients with STEMI or NSTEMI from those with UA or from controls.

High-sensitive cardiac troponin T in patients with idiopathic inflammatory myopathies

Abstract Introduction Patients with idiopathic inflammatory myopathies (IIM) may have positive blood tests of cardiac troponin in absence of clinically detected cardiac disease. This situation is more common using high-sensitive cardiac troponin T (hs-cTnT) but there is limited information of the expected results according to type of IIM and prognostic value of this test in this group of patients. Methods Prospective study with 32 healthy controls and 61 patients with IIM without known cardiac condition. These patients with IIM were followed for 25 months. High-sensitive cardiac troponin T (Roche Elecsys hs-cTnT) was measured at baseline in both groups and a value of 14 pg/ml was the percentile 99th and considered the upper limit of normality (ULN). Results The median value of hs-cTnT was higher in patients with myopathies [12.0 (5.0; 35.0) vs. 5.0 (4.0; 6.2) P&amp;lt; 0.001] and the frequency of abnormal values were also more common in patients with IIM compared to controls (45.9% vs 6.2%, p&amp;lt;0.001). The frequency varied according to the type of myositis: Inclusion Body Myosytis (75%), Polymyositis (66.7%) , Dermatomyositis (42.1%) and Antisynthetase syndrome (38.5%). In terms of magnitude, 57% had mild elevations (1 to 3 x ULN) while 11% had levels 3 to 5 times ULN and 32% had troponin values &amp;gt; 5x ULN (Figure 1). Among patients with IIM, elevated levels of hs-cTnT were not associated with left ventricle global longitudinal strain &amp;lt; 18% or lower ejection fraction and was not associated with cardiovascular events during 25 months of follow-up (Figure 2). Conclusion Abnormal values of high-sensitive cardiac troponin T are common in patients with idiopathic inflammatory myopathies including levels similar to myocardial infaction. This elevation was not associated with echocardiographic abnormalities or cardiovascular events in patients with IIM.Figure 1Figure 2

Comparison of multiple high sensitivity cardiac troponin assays for early low risk rule out of myocardial infarction: SCORECARD

Abstract Background/Introduction The use of a single low high-sensitivity cardiac troponin measurement to rule out myocardial infarction (MI) at presentation is advocated by international guidelines. Studies have not systematically compared high-sensitivity cardiac troponin (hs-cTn) I and T assays to determine which values should be used to rule out MI in patients with suspected acute coronary syndrome. Methods In a pooled analysis from three prospective observational cohort studies the lowest cTn concentration was determined that gave a negative predictive value (NPV) of ≥99.5% for MI or death at 30 days on presentation to the emergency department. EDTA or lithium heparin plasma or serum samples collected at presentation were measured using five hs-cTnI assays (Abbott ARCHITECT i2000, Beckman Coulter Access 2, Siemens Atellica IM, Ortho-Clinical Diagnostics VITROS 5600, LSI Medience PATHFAST) and one hs-cTnT assay (Roche Cobas e411). The diagnostic outcome of MI or death at 30 days was adjudicated according to the Fourth Universal Definition of MI. Optimal thresholds were determined to identify the highest proportion of patients that could be considered for discharge for a NPV of ≥99.5% for each assay. Results Among 941 patients, MI or death at 30 days occurred in 113 (12%). Optimized thresholds varied between assays ranging from &amp;lt;2 to &amp;lt;7 ng/L (Table) that identified between 22% and 60% of patients as low risk (0-1%) for MI or death at 30 days. Conclusions Our data identify differences in the effectiveness of thresholds between hs-cTnI and hs-cTnT assays for the same safety performance to rule out MI on presentation using a single measurement. In some cases, these thresholds differ from those used in clinical practice. Due to lack of assay standardization, optimal decision thresholds should be defined and validated for each high sensitivity cTn assay.

Associations of Cardiac myosin binding protein C to Troponin I in patients with chronic heart failure during exercise. A substudy of the SMARTEX-HF trial

Abstract Aim Cardiac myosin binding protein C (cMyC) has shown promise being more sensitive than cardiac troponins, rising faster after myocardial infarction[i]. Its association to hs-cTnI in heart failure patients during physical activity is not known. The aim of this study was to assess the association between a novel biomarker: cMyC and the clinically used high sensitivity cardiac Troponin I (hs-cTnI) during a 12-week exercise training program in patients with chronic symptomatic heart failure with reduced ejection fraction (HFrEF). The changes of biomarkers in plasma levels in an intervention group, performing structured exercise programs, were compared to those in a control group, instructed to perform regular recommended exercise (RRE) according to current guidelines. Methods and results This was a post hoc analysis of the SMARTEX-HF trial in 215 patients with symptomatic heart failure (HF) with Left Ventricular Ejection Fraction (LVEF) &amp;lt;35% and NYHA II-III. The patients were randomly assigned to High Intensity Interval Training (HIIT, n=77), Moderate Continuous Training (MCT, n=65) or RRE, (n=73) for 12 weeks. Measurements and clinical data were acquired before and after the 12-week intervention. In 191 patients, plasma was available for hs-cTnI testing and in 189 patients plasma was available for cMyC testing. Due to the lack of a normal distribution, the values were log transformed. There was a significant association of change in log hs-cTnI and change in log cMyC (Pearson correlation R=0.52 (95% CI 0.37- 0.66) p&amp;lt;0.001) (Figure 1). For any 10% increase in cMyC level, the ratio of the hs-cTnI level increased with approximately 5% (Figure 2). There was no association between the levels of cMyC at baseline and change in hs-cTnI at 12 weeks. Conclusion Changes in levels of the novel biomarker cMyC was significantly associated with hs-cTnI plasma levels in patients with symptomatic chronic HFrEF during a structured 12 week exercise training program. Being more sensitive, it may indicate a role as a future marker of subclinical myocardial damage.Models with adjustmentsMarginal effect at the mean

Clinical application of biomarkers in obstructive hypertrophic cardiomyopathy: insights from SEQUOIA-HCM

Abstract Background Multiple studies show that circulating cardiac biomarkers, N-terminal pro-B type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin I (hs-cTnI) are associated with key pathophysiological processes and clinical outcomes in obstructive hypertrophic cardiomyopathy (oHCM). Herein we describe the impact of aficamten on cardiac biomarkers in SEQUOIA-HCM (NCT05186818). Purpose In this pre-specified analysis, we describe associations between baseline NT-proBNP and hs-cTnI concentrations and assess the relationship between changes after treatment with aficamten and trial endpoints. Methods Patients with oHCM in NYHA Class II-III, were randomized 1:1 to 24 weeks of daily aficamten (5–20 mg, n=142) or placebo (n=140). Aficamten dose was adjusted to achieve Valsalva left ventricular outflow tract gradient (LVOT-G) &amp;lt;30 mmHg while maintaining left ventricular ejection fraction (LVEF) ≥50%. Peak oxygen consumption (pVO2) was measured by cardiopulmonary exercise testing at baseline and week 24. Cardiac biomarkers were measured at baseline, each dose titration (weeks 2, 4, and 6), every 4 weeks during treatment and after 4 weeks drug washout. Multivariable regression analysis was used to identify significant predictors of baseline biomarker values. Joint modeling and mediation analysis was used to determine how much of the treatment effect was indirectly mediated by NT-proBNP and hs-cTnI. Results In 282 symptomatic oHCM patients (mean age 59 years, 41% female), the median (IQR) NT-proBNP was 788 ng/L (346, 1699) and hs-cTnI was 12 ng/L (9, 27). At baseline, LVOT-G modestly correlated with NT-proBNP, rho = 0.26 (p&amp;lt;0.001) but not hs-cTnI, rho = 0.06 (p=0.36). Predictors of baseline biomarker values are summarized in Table 1. Compared to placebo, aficamten treatment was associated with an early relative reduction from baseline at week 8 in NT-proBNP (-79% (95% CI -83%, -76%, p&amp;lt;0.001) and in hs-cTnI -41% (-49%, -32%), p&amp;lt;0.001. This magnitude of change persisted to week 24 with biomarker return to baseline after aficamten washout (Figure 1). The mediation analysis suggested that NT-proBNP reduction over the 24-week treatment period reflected 101% (41%, 195%) of aficamten’s effect on pVO2. In contrast hs-cTnI reduction reflected 3% (-18%, 30%) of aficamten’s effect on pVO2. Conclusions Concentrations of NT-proBNP and hs-cTnI are associated with clinically relevant echocardiographic variables in oHCM. Compared with placebo, aficamten treatment markedly reduced plasma NT-proBNP and hs-cTnI concentrations, evident from week 2 and persisting until the end of treatment. NT-proBNP reduction may link LVOT-G with reduced exercise capacity in oHCM. These data support the use of biomarkers as a tool for managing patients with oHCM in order to monitor response to aficamten therapy.Effect of aficamten on biomarkersPredictors of baseline biomarkers

Improved risk prediction in patients with atrial fibrillation and clinical intermediate-risk CHA2DS2VASc-score utilizing high sensitive troponin T

Abstract Background Guidelines of the European Society of Cardiology recommend risk assessment to identify appropriate candidates for anticoagulation in patients with atrial fibrillation (AF). However, scores such as the CHA2DS2VASc-score show only a modest performance for prediction of adverse events. Methods This retrospective single-center all-comer sub-study from the Heidelberg Registry of Atrial Fibrillation (HERA-FIB) enrolled 9,995 consecutive patients with non-valvular AF, presenting to the emergency department (ED) from June 2009 until March 2020. We tested the performance of the CHA2DS2VASc-score with and without high sensitive cardiac troponin T (hs-cTnT) for prediction of a adverse events such as stroke or major bleedings. Per CHA2DS2VASc, stroke risk was classified as low (0 point in men, ≤1 point in females), intermediate, or high (≥2 points in men and ≥3 points in females). Results Performance of the CHA2DS2VASc-score for the prediction of the composite endpoint consisting of stroke and major bleeding was poor (AUC 0.600, 95%CI: 0.590-0.610) but improved after addition of hs-cTnT as a variable across all risk categories (AUC 0.618 95%CI: 0.608-0.628, ∆AUC 0.0182 95%CI: 0.0124-0.0240, p&amp;lt;0.0001), and particularly in patients at intermediate-risk (∆AUC 0.160 95%CI: 0.0653-0.254, p=0.0009). The absence of detectable hs-cTnT (&amp;lt; LoD) identified a cohort without incident events within patients with intermediate per CHA2DS2VASc. Conclusion Combination of hs-cTnT and clinical-based risk stratification in AF patients presenting to an ED with intermediate CHA2DS2VASc-score is simple and effective. Measurement of hs-cTnT improves prediction of stroke risk in patients with intermediate CHA2DS2VASc-score and may help guide decision for or against anticoagulation.

Biomarkers in early and late period after radiofrequency and pulsed field catheter ablation of atrial fibrillation

Abstract Introduction Biomarkers are routinely used parameters for disease diagnosis, treatment control and risk stratification. In connection with atrial fibrillation (AF), the importance of GDF-15 (growth differentiation factor 15), NT-proBNP (N-terminal fragment brain natriuretic factor) and hs-TnT (high sensitivity cardiac troponin T) is discussed. Catheter ablation is an established treatment method in selected population with AF. However, biomarker response to radiofrequency catheter ablation (RFCA) and pulsed field ablation (PFA) of AF has not been precisely described. Purpose Purpose of the study was to describe early and late dynamics of GDF-15, hs-TnT and NT-proBNP in different ablation technologies. Methods We prospectively enrolled 48 patients (median (IQR) age 62 (55; 70) years, 30 males) undergoing RFCA, which we compared with 30 patients (median (IQR) age 64 (56; 71) years, 18 males) undergoing PFA. All patients underwent 6 sequential blood takes: before ablation (baseline), right after ablation (0h), 24 and 48 hours after procedure (24h and 48h), 90 and 180 days after procedure. Levels of GDF-15, hs-TnT and NT-proBNP were analyzed. Results Out of all patients, 19 (40 %) and 20 (67 %) patients had paroxysmal AF in RFCA and PFA group, respectively. Additional ablation lesions over pulmonary vein isolation were done in 26 (54 %) patients in RFCA group and 11 (43 %) patients in PFA group. Median procedural time was significantly longer in RFCA than in PFA group (155 (130; 190) vs. 80 (70; 90) min; p &amp;lt; 0.01). Early dynamics of GDF-15 and cardiac hs-TnT are visualised in Figure 1 and 2. GDF-15 level peak was registered 48 hours after ablation with median (IQR) 1183 (824; 1988) ng/l. Compared to baseline, GDF-15 values sustained elevated up to 90 days after ablation in both groups and decreased to baseline levels after 180 days. No significant differences were found in GDF-15 levels between patients treated with RFCA and PFA. Maximal values of hs-TnT were significantly higher in PFA group than in RFCA group (1001±589 vs. 458±202 ng/l; p &amp;lt; 0.001). We have recognised decrease of NT-proBNP between baseline and 90 days after procedure in both groups: 338 (112; 613) vs. 209 (101; 545) ng/l; p &amp;lt; 0.05. Conclusion Eventhough GDF-15 is considered as a nonspecific biomarker reflecting general condition of patient, the levels are significantly affected by catheter ablation of AF for several months irrespective to ablation technology. PFA is associated with advanced elevation of hs-TnT.Dynamics of GDF-15 (median; IQR)Dynamics of hs-TnT (median; IQR)

Association of Vascular endothelial factor D with pulmonary hypertension in heart failure: the PREHOSP-CHF Study

Abstract Background Pulmonary hypertension (PH) complicated with heart failure (HF) is associated with increased morbidity and mortality. Vascular endothelial growth factor D (VEGF-D), one of key regulators of lymphangiogenesis, was reported to be higher in HF patients with pulmonary congestion on chest X-ray. Furthermore, we previously reported that HF patients with high VEGF-D had higher incidence of major adverse cardiovascular events (MACE), defined as cardiovascular death or heart failure hospitalization. Purpose To investigate the association of VEGF-D with pulmonary hypertension in patients with HF. Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in HF. A total of 1,024 patients (mean age 75.5±12.6 years; 58.7% male) admitted to acute decompensated HF were included in the analyses. Serum levels of VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitivity C reactive protein (hs-CRP), were measured at the time of discharge. PH was assessed by tricuspid regurgitation velocity (TRV) in echocardiography. Patients were followed-up over two years. Results Data on PH was obtained in 932 patients. Of these, 44 (4.7%) and 223 (23.9%) patients showed PH (TRV&amp;gt;3.4 m/s) and borderline PH (TRV&amp;gt;2.8 m/s), respectively. Patients with PH/borderline PH were significantly older and had lower body mass index. Prevalence of prior HF hospitalization, HF with preserved ejection fraction, atrial fibrillation, anemia, and chronic kidney disease were higher in patients with PH/borderline PH. Levels of NT-proBNP and VEGF-D, but not hs-cTnI or hs-CRP, were higher in patients with PH/borderline PH (Figure). Levels of NT-proBNP and VEGF-D had weak but significant correlation with TRV (NT-proBNP, R2=0.04, P&amp;lt;0.001; VEGF-D, R2=0.05, P&amp;lt;0.001). After adjustment for these factors, VEGF-D levels were significantly correlated with TRV (β, 3.29; SEM, 0.85, P&amp;lt;0.001). During the follow-up, 12 in PH, 34 in borderline PH, and 53 in no PH patients developed MACE. Unadjusted Hazard ratios [95% confidence intervals] for MACE compared to no PH were 2.44 [1.58-3.60] in PH, and 1.62 [1.26-2.05] in borderline PH. When we divided each PH group into two groups based on the median of VEGF-D levels of each group (no PH, 387 pg/ml; borderline PH, 479 pg/ml; PH, 549 pg/ml), patients with high VEGF-D showed significantly higher incidence of MACE in no PH (unadjusted hazard ratio, 1,70; 95% confidence intervals, 1.29-2.26), and tended to show high incidence of MACE in borderline PH group (unadjusted hazard ratio, 1,39; 95% confidence intervals, 0.93-2.09) and PH group (unadjusted hazard ratio, 1,83; 95% confidence intervals, 0.84-4.18). Conclusions VEGF-D levels were independently associated with PH in patients with HF, and might serve as a predictive biomarker for PH, as well as prognostic biomarker for MACE among patients with HF.

Baseline C-reactive protein as a predictor of non-ischemic LGE in myocarditis

Abstract Background Identifying reliable early indicators of myocardial injury in myocarditis is a pressing concern in cardiology. Despite their established role in detecting myocardial necrosis, traditional markers like high-sensitivity cardiac troponin (hs-cTn) may not fully capture the extent of myocardial damage identified by non-ischemic late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) Purpose To identify early admission biomarkers associated with non-ischemic LGE in patients with myocarditis, offering the potential for improved risk stratification and therapeutic targeting. Methods In this retrospective study, we analyzed 59 myocarditis patients admitted to a high-volume medical center from 2017 to 2023, who underwent CMR to evaluate LGE. 41 patients (69.5%) exhibited non-ischemic LGE and 18 (30.5%) did not. We assessed baseline laboratory and echocardiographic parameters, employing Pearson correlation, logistic regression, and ROC curve analyses to elucidate the potential association of baseline biomarkers with non-ischemic LGE, while also discerning subepicardial from midwall patterns. Results Baseline C-reactive Protein (CRP) levels were significantly correlated with non-ischemic LGE (Pearson's r=0.301, p&amp;lt;0.05). Logistic regression analysis substantiated CRP as a predictor of non-ischemic LGE (OR=1.41, p&amp;lt;0.05), corroborated by a multivariate approach even after accounting for age and sex (OR=1.33; p&amp;lt;0.05). Among non-ischemic patterns, subepicardial LGE exhibited the strongest correlation with CRP (Pearson's r=0.321, p&amp;lt;0.05). In contrast, hs-cTn levels showed no significant association with non-ischemic LGE. The ROC analysis revealed that while both CRP and hs-cTn provide valid predictive values for non-ischemic LGE, with AUCs of 0.7333 and 0.6898 respectively, CRP demonstrated a higher discriminative performance, indicating that CRP may offer a more reliable assessment in this clinical context. Additionally, diabetic status emerged as the most significant condition associated with increased CRP levels, with diabetic patients presenting a substantial elevation in baseline CRP compared to non-diabetic patients (8.75 mg/dl vs 3.21 mg/dl; p&amp;lt;0.05). Conclusion CRP appears as a key early biomarker for non-ischemic LGE in myocarditis, with its predictive value being particularly evident in the subepicardial pattern and notably more pronounced among diabetic patients who demonstrate an increased inflammatory burden. These findings suggest a critical role for CRP in risk stratification right from the point of hospital admission and underline the potential for tailored therapeutic approaches that warrant further investigations. Figure 1: ROC curves comparison for CRP and hs-cTn in predicting non-ischemic LGE in myocarditis patients. Figure 2: Patients with diabetes (DM) exhibit significantly higher CRP levels (mean 8.75 mg/dl, SE = 5.54 mg/dl) than those without DM (mean 3.21 mg/dl, SE = 0.49 mg/dl).ROC curves comparisonCPR in patients with and without DM

Heart failure risk assessment using biomarkers in patients with atrial fibrillation: analysis of 32,041 patients from the COMBINE-AF study

Abstract Introduction Heart failure (HF) is one of the most common comorbidities in patients with AF, resulting in a clinical need for robust risk assessment. Purpose To investigate the incremental value of adding NTproBNP, high-sensitivity cardiac troponin T (hs-cTnT), and growth-differentiation factor-15 (GDF-15) to clinical predictors for HF risk stratification in patients with AF, and the individual contribution of each biomarker accounting for inter-biomarker correlation. Methods We used pooled individual patient data from 3 large RCTs investigating DOACs versus VKAs (ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY) from the COMBINE-AF cohort and included all patients with available biomarkers at baseline. The composite primary endpoint was hospitalization for HF (HHF) or CV death (CVD), with HHF as secondary endpoint. We employed analyses of absolute risk and Cox-regression adjusting for clinical factors to assess the association of the individual biomarkers with both endpoints, testing incremental discrimination with the likelihood ratio test from nested models. To address the inter-biomarker correlation, weighted quantile sum (WQS) regression analysis summarizing the adjusted risk of all biomarkers (per quartile) in one index was applied, thereby exploring the individual and additive contribution of each biomarker to risk assessment. Results Data were available in 32,041 patients (median age 71 [IQR 64-77] years, 36.7% female, 23.0% with paroxysmal AF, 41.6% with established HF). Higher biomarker values were associated with a graded increase in absolute risk for HHF/CVD and HHF (Figure 1). In a model adjusting for clinical variables and all biomarkers, hs-cTnT (HR per 1-SD 1.39 [95% CI 1.33-1.44]), NT-proBNP (HR 1.67 [95% CI 1.58-1.76]), and GDF-15 (HR 1.20 [95% CI 1.15-1.25]) were associated with HHF/CVD. The c-index increased with addition of biomarkers (0.70 [0.69, 0.70] to 0.77 [0.76, 0.78]; Likelihood ratio test p&amp;lt;0.001). Results were similar for HHF alone. NTproBNP was significantly correlated with hs-cTnT (r=0.40, p&amp;lt;0.0001) and GDF-15 (r=0.36, p&amp;lt;0.001). To address this correlation, WQS regression analysis was conducted (Figure 2). NTproBNP and hs-cTnT contributed nearly equally to the risk assessment for HHF/CVD and HHF, with GDF-15 providing statistically significant but less contribution to risk assessment (Figure 2). Conclusion Hs-cTnT, NT-proBNP and GDF-15 contribute individually and additively to the risk assessment for HHF/CVD and HHF in patients with AF. Our analysis suggests that hs-cTnT is as important as NTproBNP for HF risk assessment, with significant but less contribution of GDF-15. Our findings support the possible future routine use of biomarkers to distinguish patients with AF at low or high risk for HF and could guide the introduction of therapies to mitigate the risk of HF events in this growing population.Event incidence by biomarker quartilesWeighted quantil sum regression analysis

Enhancing primary prevention: the incremental predictive value of high-sensitivity cardiac troponin T beyond ASCVD risk assessment

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a global health challenge, prompting widespread use of conventional risk assessment tools (SCORE2 in Europe and the ASCVD Risk calculator in the United States) to guide preventive strategies. Emerging evidence indicates that high-sensitivity cardiac troponin (hsTn) may refine risk stratification. Objective We investigate whether measuring hsTnT in primary prevention correlates with mortality and enhances prediction compared to conventional risk score stratification. Methods Utilizing National Health and Nutrition Examination Survey (NHANES) data (1999 to 2004) linked to the National Death Index, our cohort included individuals without a history of CVD at baseline and suitable for assessment of the ASCVD ACC/AHA risk score. Individuals were grouped based on computed 10-year risk (low: &amp;lt;5%; borderline: 5-7.5%; intermediate: 7.5-20%; high: ≥ 20%). hsTroponin T levels were measured (Roche assay, 99 th percentile 22ng/L for men and 17ng/L for women). Cox regression estimated association between ASCVD risk categories, with or without hsTnT, and all-cause and cardiovascular mortality. Results Among 5257 adults, 47% male, mean age 54 ± 9.1 years, the mean 10-year ASCVD risk was 8.17 ± 8.2%, grouped as: low: 53.3%; borderline: 11.5%; intermediate: 23.9%; and high: 11.3%. hsTnT above the 99 th percentile was measured in 1.1%, 2.7%, 4.9% and 13.4%, respectively (p &amp;lt; 0.001). Over 16.2 ± 3.4 years, all-cause and cardiovascular death was 22.3% and 5.6%, respectively. Compared to low-risk, the hazard ratio (HR) for all-cause death increased to 2.85 (2.2-3.7), 5.6 (4.2-7.5), and 15.3 (11.7-19.9) for borderline, intermediate, and high-risk, respectively. A significant interaction with hsTnT above 99 th percentile was observed (low: HR 3.5 (1.3-9.2); borderline: HR 4.75 (2.1-10.8); intermediate: HR 2.6 (1.8-3.7), high: HR 2.2 (1.7-2.9), p&amp;lt;0.01 for all interactions, see Fig. 1). For cardiovascular death, a significant interaction occurred in intermediate (HR 3.3 (2-5.4), p&amp;lt;0.001) and high-risk (HR 3.6 (2.2-6), p&amp;lt;0.001) groups. Conclusion Our findings suggest that hsTnT provides incremental predictive value, at least doubling the hazard of all-cause death across all risk categories, and tripling the hazard of CV death in intermediate and high-risk groups, compared to ASCVD risk stratification alone. The integration of troponin measurements into risk assessment strategies could refine primary prevention approaches.

Identifying low-risk chest pain in out-of-hours primary care: the diagnostic performance of preHEAR and preHEART scores based on two European cohorts

Abstract Background Distinguishing cardiac from non-cardiac acute chest pain presents a diagnostic challenge. Risk stratification tools, such as the HEART score, have been developed for decision support for hospital-based settings. For prehospital settings, the preHEART score was developed as an alternative to the HEART score, with refinements made to meet prehospital conditions, as illustrated in Figure 1. While promising for use by emergency medical services, the diagnostic performance in primary care is unknown. Purpose In this study, we aim to evaluate the preHEART score (with and without high-sensitivity cardiac troponin (hs-cTn)) as a risk stratification tool to rule out acute myocardial infarction (MI) in patients evaluated in out-of-hours primary care. Methods We relied on retrospective data from two cohorts, namely, the OUT-ACS study involving 1,711 consecutive patients (47.7% female, median age: 56 (25th-75th percentiles: 45-68)) evaluated at a Norwegian primary care emergency centre from 2016-2018; and the TRACE study involving 664 consecutive patients (56.9% female, median age: 48 (25th-75th percentiles: 32-67) from a Dutch primary care emergency centre in 2017. We evaluated the preHEAR (OUT-ACS &amp; TRACE without hs-cTn) and preHEART scores (OUT-ACS). The threshold of ≤3 points was considered low-risk and previously determined as optimal for rule-out purposes. The primary outcome was the diagnostic performance for ruling out MI at the index episode, and the secondary outcome was the composite of 90-day all-cause death or MI. Results In the OUT-ACS cohort, 61 (3.6%) patients were diagnosed with an MI; for the TRACE study, MI was diagnosed in 20 (3.0%) patients. The percentage of patients deemed at low risk by preHEAR was 49.3% (n=843) and 82.7% (n=549) for OUT-ACS and TRACE, respectively. For preHEART, only 33.6% (n=575) of OUT-ACS patients were deemed low-risk. As shown in Figure 2, the corresponding sensitivity/specificity indices for index MI were 63.9%/49.8% (OUT-ACS) and 65.0%/84.2% (TRACE) for preHEAR and 93.4%/34.6% for preHEART. Positive predictive values were low (preHEAR 5.0-11.3%, preHEART 5.0%), whereas negative predictive values were high (preHEAR 97.4-98.7%, preHEART 99.3%). For the secondary outcome, similar diagnostic performance metrics were found. All missed MI cases (n=4) in the low-risk preHEART group were female. Conclusion The preHEAR and preHEART scores did not result in adequate rule-out safety for an emergency primary care setting despite a low a priori MI risk. Moreover, the score appears to underestimate the risk for MI in females.preHEAR(T) risk scoresPerformance of the risk scores

Comparing combined testing of cMyBP-C and hs-cTnT with other algorithms for rapid rule-out of acute myocardial infarction in suspected acute coronary syndrome patients

Abstract Background We aimed to compare the diagnostic accuracy of a dual-marker strategy (DMS), incorporating cardiac myosin-binding protein C (cMyBP-C) and high-sensitivity cardiac troponin T (hs-cTnT) testing, against other rapid rule-out algorithms for acute myocardial infarction (AMI). Methods We enrolled 2059 patients presenting to the emergency department with suspected AMI and compared diagnostic measures using the DMS (cMyBP-C &amp;lt;10 ng/L and hs-cTnT≤14 ng/L), serial hs-cTnT sampling (hs-cTnT&amp;lt;14ng/L at different time points within 1-3h), modified European Society of Cardiology (ESC) 0/1h- or 0/3h-protocol (hs-cTnT&amp;lt;5ng/L or &amp;lt;12ng/L &amp; ∆hs-cTnT&amp;lt;3ng/L at 1h or &amp;lt;7ng/L at 3h if hs-cTnT at 1h was not available), as well as the hs-cTnT limit-of-blank (LoB, &amp;lt;3ng/L) and -detection (LoD, &amp;lt;5ng/L) were compared. Negative predictive values (NPV) and sensitivities for AMI rule-out were assessed. Results True-negative rule-out rates using the DMS ranged from 38.1% to 51.6% across all patients, surpassing rates of 6.2%, 17.4%, 45%, and 50.8% achieved by LoB, LoD, serial hs-cTnT sampling, and ESC 0/1h or 0/3h algorithms, respectively. The DMS demonstrated an NPV of 99.7%, similar to serial hs-cTnT sampling and ESC 0/1h or 0/3h algorithms, and 100% for both LoB and LoD. Sensitivities were 98.9%, 98.9%, 100%, and 100%, respectively. Conclusions The DMS - incorporating cMyBP-C and hs-cTnT - effectively rules out AMI, showing non-inferiority to hs-cTnT-only-based rapid rule-out algorithms and offers a promising alternative, potentially enhancing clinical decision-making in emergency settings.

Effect of heart failure and atrial fibrillation on cardiorespiratory fitness in hemodialysis patients.

Heart failure (HF) and atrial fibrillation (AF) are highly prevalent in hemodialysis. They are well-known significant modifiers of the disease associations with cardiovascular outcomes, but there is a lack of evidence regarding the effects of HF and AF on cardiorespiratory fitness. This study is the first to examine the possible association of the presence of HF and AF with exercise intolerance in patients undergoing hemodialysis. This analysis included 40 sex- and age-matched participants [10 hemodialysis patients with HF or AF, 10 hemodialysis patients without HF or AF, 10 patients with HF or AF without chronic kidney disease (CKD) and 10 healthy controls] that underwent CPET and spirometry examinations. The total of patients with HF had preserved ejection fraction. VO2peak(ml/kg/min) showed a graded increase between hemodialysis patients with HF or AF, hemodialysis patients without HF or AF, non-CKD patients with HF or AF and controls (13.17 ± 2.45 vs 15.26 ± 3.29 vs 19.64 ± 5.84 vs 25.11 ± 6.94ml/kg/min, p < 0.001); VO2peak(ml/min) followed the same pattern (1172 ± 197 vs 1269 ± 314 vs 1817 ± 583 vs 1952 ± 592ml/min respectively, p = 0.001). VO2peak(%predicted), VO2AT(ml/kg/min), VO2AT(ml/min) and maximal work load significantly differed between the study groups, with a tendency for higher values from hemodialysis patients to non-CKD patients with HF or AF and to healthy controls. FEV1 and FVC levels were similar between the study groups. In the whole population, VO2peak(ml/kg/min) showed a positive correlation with hemoglobin (r = 0.663, p < 0.001) and negative correlations with high-sensitivity cardiac troponin I (r = -0.493, p = 0.001) and BNP (r = -0.479, p = 0.002). Hemodialysis patients have low exercise tolerance, and the presence of HF or AF is associated with further decreased values of VO2peak, the most important determinant of cardiorespiratory fitness.

Diagnosis of acute myocardial infarction in patients with renal failure using high-sensitivity cardiac troponin T

Abstract Background Diagnosing myocardial infarction (MI) in patients with chronic kidney disease (CKD) is difficult as these patients often have elevated baseline high-sensitivity cardiac troponin T (hs-cTnT) concentrations. Methods Observational U.S. cohort study of emergency department (ED) patients undergoing hs-cTnT measurement. Cases with &amp;gt;1 hs-cTnT increase &amp;gt;99th percentile were adjudicated following the Fourth Universal Definition of MI. Diagnostic performance of baseline and serial 2- and 6-hour hs-cTnT thresholds for ruling-in acute MI was compared between those without and with CKD (eGFR &amp;lt;60 ml/min/1.73m2). Results The study cohort included 1992 patients, amongst whom 501 (25%) had CKD. There were 701 (82%) patients with myocardial injury, 64 (7.5%) with type 1, and 91 (11%) with type 2 MI. In CKD patients with baseline hs-cTnT thresholds of &amp;gt;52, &amp;gt;100, &amp;gt;200 or &amp;gt;300 ng/L, PPVs for acute MI were 37% [95% CI 28-46], 53% (95% CI 39-67), 73% (95% CI 50-89) and 80% (95% CI 44-98), and in those without CKD, 64% (95% CI 50-77), 69% (95% CI 49-85), 59% (95% CI 33-82) and 54% (95% CI 25-81). In CKD patients with a 2-hour hs-cTnT delta of &amp;gt;10, &amp;gt;20 or &amp;gt;30 ng/L, the corresponding PPVs were 65% (95% CI 50-78), 86% (95% CI 68-96) and 88% (95% CI 68-97), and in those without CKD, 65% (95% CI 51-78), 73% (95% CI 57-86) and 75% (95% CI 58-88) (Figure). Conclusion Diagnostic performance of standard baseline and serial 2-hour hs-cTnT thresholds to rule-in MI is suboptimal in patients with CKD. It significantly improves when using higher baseline thresholds and delta values.

Impact of discordance in cardiac troponin T versus I on the performance of triage pathways for myocardial infarction

Abstract Background Biological, analytical, and regulatory differences between high-sensitivity cardiac troponin T (hs-cTnT) and hs-cTnI could lead to an underestimation of the performance of a hs-cTnT-based triage-algorithm if evaluated against a hs-cTnI-based reference standard, and vice versa. Unfortunately, the impact of hs-cTnT/hs-cTnI-discordance on diagnostic performance measures is largely unknown. Methods We quantified the impact of hs-cTnT/hs-cTnI-discordance on the diagnostic performance of the three most widely used and guideline recommended hs-cTnT/I-based triage algorithms for patients presenting with symptoms suggestive of myocardial infarction (MI): the ESC 0/1h-algorithm, the ESC 0/2h-algorithm and the High-STEACS pathway. For the central adjudication of the final diagnosis (reference standard), two independent cardiologists had access to all available clinical information and applied the 4th universal definition of MI, one time with serial hs-cTnT-Elecsys measurements (gold standard T) and a second time with serial hs-cTnI-Architect measurements (gold standard I). The primary diagnostic endpoint for the rule-out of NSTEMI was sensitivity, while for rule-in of NSTEMI specificity. Results Among 7728 eligible patients, the final diagnosis was NSTEMI in 1463 patients (18.9%). Of these, NSTEMI was diagnosed with only one of the two adjudication methods (either gold standard T or I) in 167 (11.4%) patients. When the three hs-cTnT-based early-triage algorithms were evaluated using gold standard T and gold standard I, sensitivity was very high and comparable. In contrast, when the three hs-cTnI-based early-triage algorithms were evaluated using gold standard T and gold standard I, sensitivity was again very high, but consistently lower when using gold standard T as compared to gold standard I. The difference in sensitivity was 1.1% (95%CI, 0.6–1.7) for ESC hs-cTnI-0/1h (Table 1A), 1.0% (95% CI, 0.5—1.6) for ESC hs-cTnI-0/2h (Table 1B), and 2.6% (95%CI, 1.7—3.5) for High-STEACS (Table 2). The differences observed in specificity mirrored those for sensitivity, i.e. always lower specificity when using the other hs-cTnT/I-assay for adjudication. Conclusion The impact of hs-cTnT/hs-cTnI-discordance on the diagnostic performance of hs-cTnT/I-based triage algorithms is modest, but large enough to result in a fallacious underestimation of the rule-out safety when evaluating hs-cTnI-based strategies using a hs-cTnT-based reference standard.

Acute kidney injury in relation to high-sensitivity cardiac troponin T levels in the emergency department

Abstract Background The clinical implications of high-sensitivity cardiac troponin T (hs-cTnT) measurements in all-comers with AKI in the emergency department (ED) is largely unknown. Purpose To investigate the prevalence of myocardial injury, associations between serum-creatinine concentrations (SCC) and hs-cTnT kinetics, and the accuracy of established hs-cTnT-based myocardial infarction (MI) risk stratification algorithm criteria in patients with AKI. Methods This observational cohort study was based on patient visits to 7 EDs in Sweden from December 9, 2010 to August 31, 2017. All visits by patients ≥18 years fulfilling criteria for AKI with ≥1 hs-cTnT measurement and the exposure was dynamic change in SCC (ΔSCC) during the visits. Linear mixed models were used to estimate linear predictors of kinetic change in hs-cTnT (Δhs-cTnT). Logistic regression models were applied to calculate odds ratios (ORs) for Δhs-cTnT indicative of acute myocardial injury (Δhs-cTnT &amp;gt;20% and elevated hs-cTnT) in relation to ΔSCC among patients without MI, and to assess the diagnostic performance of hs-cTnT for MI in a subgroup of patients presenting with chest pain. Results A total of 15,211 visits by patients with AKI were included, of whom 1174 (8%) had an MI. Four of five (81%) patients without MI had myocardial injury (hs-cTnT &amp;gt;14 ng/l), and almost one of three (31%) had acute myocardial injury. These entities were common in both cardiac and non-cardiac conditions. The Δhs-cTnT in non-MI patients was 1.8-fold (β: 1.78, 95% CI: 1.62-1.96) in the highest quartile of ΔSCC and was paralleled by a 2-fold risk of acute myocardial injury (OR: 2.32, 95% CI: 2.08-2.59), compared with the lowest ΔSCC quartile. Using a 0 h hs-cTnT cut-off ≥52 ng/l assigned 627 (26%) patients to a high-risk group in whom the specificity and positive predictive value (PPV) for MI was low (78.5% (95% CI: 76.7-80.2) and 27.6% (95% CI: 24.1-31.3), respectively). Conclusions Hs-cTnT concentrations indicative of acute myocardial injury are frequently observed among all-comers with AKI in the ED and are associated with dynamic changes in SCC. These observations are accompanied by poor performance of recommended hs-cTnT-based algorithms for MI risk stratification in patients with chest pain.

Serum amyloid A-low-density-lipoprotein complex and cause-specific mortality in patients with suspected or known coronary artery disease: The ANOX Study

Abstract Background Serum amyloid A-low-density-lipoprotein (SAA-LDL) is a complex formed from the oxidative interaction between SAA and LDLs. A relatively small-scale study has shown that circulating SAA-LDL levels may serve as a prognostic marker in patients with stable coronary artery disease (CAD). However, the association between SAA-LDL and cause-specific mortality in patients with suspected or known CAD is unknown. Methods Serum SAA-LDL levels were measured in 2416 patients with suspected or known CAD undergoing elective coronary angiography. The outcomes were all-cause death, cardiovascular (CV) death, non-CV death, cancer death, and other non-CV death. Patients were followed up over a 3-year period. Results During the follow-up, 254 (10.5%) deaths occurred, including 88 (3.6%) CV deaths, 151 (6.3%) non-CV deaths, 66 (2.7%) cancer deaths, 85 (3.5%) other non-CV deaths, and 15 (0.6%) undetermined deaths. Stepwise regression analysis including baseline data on potential clinical confounders and established CV biomarkers (i.e., N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein [hs-CRP]) revealed that the strongest independent determinant of SAA-LDL levels was hs-CRP (partial regression coefficient, 0.248; standard error, 0.010; p&amp;lt;0.001). After adjusting for potential clinical confounders and established CV biomarkers, the highest quartile of SAA-LDL levels (vs. the lowest quartile) was significantly associated with all-cause death (adjusted hazard ratio [aHR], 1.56; 95% confidence interval [CI], 1.05–2.34) and non-CV death (aHR, 1.76; 95% CI, 1.02–3.11), but not with CV death (aHR, 1.16; 95% CI, 0.62–2.20), cancer death (aHR, 1.68; 95% CI, 0.71–4.34), or other non-CV death (aHR, 1.65; 95% CI, 0.82–3.45) in the entire cohort. In patients with low hs-CRP levels (≤1.0 mg/L, n=1253), the highest quartile of SAA-LDL levels was significantly associated with all-cause death (aHR, 2.19; 95% CI, 1.11–4.57), non-CV death (aHR, 2.78; 95% CI, 1.05–8.79), and cancer death (aHR, 4.65; 95% CI, 1.12–31.9), but not with CV death (aHR, 1.22; 95% CI, 0.39–3.92) or other non-CV death (aHR, 1.68; 95% CI, 0.42–8.35). In contrast, the highest quartile of SAA-LDL levels was not significantly associated with all-cause death (aHR, 1.18; 95% CI, 0.72–1.96), CV death (aHR, 1.02; 95% CI, 0.45–2.31), non-CV death (aHR, 1.46; 95% CI, 0.75–2.91), cancer death (aHR, 1.35; 95% CI, 0.43–4.58), or other non-CV death (aHR, 1.38; 95% CI, 0.60–3.25) in patients with high hs-CRP levels (&amp;gt;1.0 mg/L, n=1163). Conclusions Elevated SAA-LDL levels were independently associated with all-cause and non-CV mortality, but unexpectedly not with CV mortality, in patients with suspected or known CAD. These associations were pronounced in patients with low hs-CRP levels (≤1.0 mg/L). The association between the SAA-LDL level and cancer mortality suggests its predictive utility in patients with low hs-CRP levels (≤1.0 mg/L).