Troponin Research Articles

Troponin Test, Not Only a Number: An Unusual Case of False Positive

Heterophile antibodies, which can arise from infections, autoimmune disorders, or exposure to animal antigens, can interfere with immunoassays. These antibodies can cross-react with the test reagents used in troponin assays, causing a false elevation in troponin levels. The paper describes a case of a 37-year-old male drug abuser admitted to the emergency room with chest pain. A series of troponin measurements performed using different assays gave discrepant results. Only thanks to the use of Scantibodies HBT tubes, which remove heterophile antibodies, was it possible to make a correct diagnosis of troponin negativity. In conclusion, a correct laboratory/clinical approach to the identification of heterophile antibody interference is essential for accurate troponin testing in order to avoid false positive results. Implementing neutralizing tests can significantly improve the reliability of these diagnostic assays, ensuring better patient outcome.

Randomized trial of early exercise rehabilitation and its effects on patients with acute coronary syndrome

To assess the psychological and physiological benefits of early exercise rehabilitation in patients with acute coronary syndrome (ACS). Among 559 ACS-diagnosed patients at Fuzhou University Affiliated Provincial Hospital from January to December 2021, 200 eligible participants were assigned to two groups. The control group received standard care, while the experimental group received early exercise rehabilitation in addition to standard care. The outcomes measured included changes in depression levels (PHQ-9), fasting blood glucose, and troponin I (TnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Data were analyzed using SPSS, with t tests and chi-square tests for group comparisons. In comparison to the control group, the experimental group demonstrated significant improvements in PHQ-9 scores (P < 0.001) and lower fasting blood glucose levels before discharge (P = 0.046). Additionally, the experimental group had notably reduced TnI levels at 72 h after admission (P = 0.001), especially among non-diabetic NSTEMI patients over 60 years old, who showed decreased TnI levels at the 48-hour mark (P = 0.016). However, there were no significant differences in NT-ProBNP change values between the two groups (P > 0.05). Subgroup analysis revealed enhanced outcomes in the intervention group for ACS patients without smoking or drinking history and no heart failure (P = 0.025,P = 0.014,P = 0.018). Early exercise rehabilitation has notable benefits for ACS patients, including reduced depression, improved blood glucose control, and enhanced myocardial protection, especially in nondiabetic NSTEMI patients aged 60 and above.

Troponin I and Its Clinical Significance

Troponin I is one of the regulatory proteins of the troponin complex (troponin I, troponin C and troponin T) found in both cardiac and skeletal muscle. The letter I stands for its inhibitory character as binding is prevented between actin and myosin in relaxed muscle. It plays a significant role in holding actin-tropomyosin complex in place by binding actin in thin myofilaments. Binding of calcium to troponin C causes certain conformational changes, leading to troponin I dislocation and thus exposing binding site of myosin on actin, which leads to muscle contraction. It is frequently used in the diagnosis of acute coronary syndrome and myocardial infarction, and also serves as a prognostic marker in their management (1). There are three distinct forms of troponin I with tissue-specific expression patterns: 1. Slow-twitch skeletal muscle isoform troponin I, 2. Fast-twitch skeletal muscle isoform troponin I and 3. Cardiac troponin I.

Effects of the restrictive cardiomyopathy-associated cardiac troponin I K178E mutation on cAMP signalling at the myofilament

Abstract Background Catecholaminergic stimulation of cardiac β-adrenergic receptors (β-ARs) and subsequent cAMP signalling control cardiac inotropy and lusitropy. cAMP signalling is known to be compartmentalised to optimise sympathetic control by producing heterogeneous cAMP signals and protein kinase A (PKA) activation at distinct subcellular sites. This signalling may be disrupted in diseases such as restrictive cardiomyopathy (RCM) characterised by diastolic dysfunction, which is associated with certain mutations including the K178E missense mutation in cardiac troponin I (TPNI). The impaired ventricular relaxation associated with this mutation is thought to arise from myofilament calcium hypersensitivity, which can be modulated by PKA-dependent TPNI phosphorylation. However, a detailed understanding of the pathological effects mediated by the K178E-TPNI mutation is lacking. Purpose This study aims to determine whether the K178E-TPNI mutation alters local cAMP/PKA signalling at TPNI, potentially affecting myofilament calcium sensitivity and cardiac myocyte relaxation. Methods Real-time imaging of cAMP was carried out using the Fluorescence Resonance Energy Transfer (FRET)-based sensor CUTie (cAMP Universal Tag for imaging experiments) [1] fused to wild type (WT)- or K178E-TPNI. The sensors were expressed by transfection in neonatal rat ventricular myocytes (NRVMs) and FRET-changes were recorded at the myofilament on application of the β-AR stimulant isoproterenol (ISO). We further assessed the involvement of cAMP hydrolysing phosphodiesterases (PDEs) in the regulation of cAMP levels selectively at TPNI. Results The peak FRET-change and FRET-change after 5mins on ISO application were significantly higher in NRVMs expressing the mutant compared to the WT sensor, as was the rate of cAMP accumulation. A strong trend showed that the rise in FRET following PDE4 inhibition was larger in NRVMs expressing the WT compared to the mutant sensor, suggesting the involvement of this isoform in degrading cAMP locally at TPNI and reduced PDE4 activity in the presence of the K178E mutation. Co-immunoprecipitation analysis in HEK293 cells demonstrated interaction between WT-TPNI and a PDE4D isoform, and a weaker interaction of this isoform with the K178E-TPNI mutant. Conclusions This study shows that the K178E-TPNI mutation attenuates the TPNI/PDE4D interaction and alters the magnitude and kinetics of the local cAMP response at the myofilament. This mechanistic insight may aid the development of therapeutics targeting the TPNI/PDE4D interaction to treat RCM-associated diastolic dysfunction.The TPNI-CUTie SensorFRET Response Trace

First time evaluation of myocardium microRNA profile in Anderson-Fabry disease: implications in the pathological processes

Abstract Background Anderson Fabry disease (AFD) is an X-linked lysosomal disorder, characterized by progressive sphingolipid storage and organ dysfunction. Cardiac involvement is characterized by left ventricular hypertrophy, inflammation and fibrosis and is leading cause of mortality. MicroRNAs (miRNAs) are emerging as promising biomarkers in medicine, as they are dysregulated in many human diseases, offering opportunities to improve our understanding of disorders and discover new therapeutic targets. However, so far, only a few studies have evaluated the role of miRNAs in Fabry disease, and cardiac tissue miRNAs have never been assessed. Purpose To determine the specific tissue miRNA profile analyzing myocardial tissue of AFD patients and to evaluate their relationship with the severity of cardiac involvement. Methods 19 AFD patients (10 females [53%]; median age 53 years [IQR 43-63]) undergoing right ventricular endomyocardial biopsy (n=15) or surgical septal myectomy (n=4), standard cardiac magnetic resonance (1.5T, cines for maximum wall thickness (MWT) and indexed LV mass (LVMi) calculation) and high-sensitivity Troponin I (TnI) dosage were included and compared to 7 endomyocardial biopsies of controls. Myocardial samples were fixed in formalin and embedded in paraffin. RNA was extracted from 3-5 slides of tissue and used to generate small RNA libraries (Qiagen) for Next Generation Sequencing analysis on Illumina sequencer. Raw data were normalized and analyzed using DEseq2 pipeline. Correlations were performed using Pearson r; a p &amp;lt; 0.05 was considered statistically significant. Results In AFD group median MWT was 13 mm [IQR 8-17], LVMi was 72 g/m2 [IQR 46-97]. TnI was increased in 9 patients (47%) and NT-proBNP in 8 (42%). 6 patients were on specific AFD treatment. We identified 9 miRNAs differentially expressed in AFD patients compared to controls; miRPath analysis revealed that these miRNAs are associated to pathways involved in AFD pathogenesis (autophagy and mTOR signalling, HIF-1, apoptosis, TGF-beta signalling and inflammation) (figure 1). Moreover, we found 10 miRNAs that were differentially expressed in maximal wall thickness (&amp;lt;10 mm, 10-15 mm, &amp;gt;15 mm) groups (figure 2), in particular 3 miRNAs that progressively increased at the increasing of thickness. Among these miRNAs, miR-21-5p showed the strongest correlation with myocardial hypertrophy (r=0.869, p value&amp;lt;0.001 for MWT; r=0.905, p&amp;lt;0.001 for LVMi) and with cardiac damage (r=0.831, p&amp;lt;0.001 for TnI). Additionally, miR-21-5p had a modest correlation with age (r=0.518, p=0.05) and did not differ between patients on specific AFD treatment and patients not treated (p=0.660). Conclusions This study for the first time evaluated the myocardial miRNA profile in AFD patients and identified miR-21-5p as a cardiac biomarker correlating with clinical heart involvement, both in terms of left ventricular hypertrophy (MWT, LVMi) and myocardium damage (troponin).Figure 1Figure 2

T2 mapping as a marker of active myocardial injury in Anderson-Fabry disease patients

Abstract Background In Anderson-Fabry Disease (AFD) with cardiac involvement, left ventricular hypertrophy (LVH) is often associated with myocardial scarring by cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging. Myocardial inflammation, detected as increased T2 weighted/T2 mapping (T2m) signal, has also been reported, although its role in disease progression is still unclear. Purpose To investigate the relationship between T2m and LGE/LVH progression in AFD patients. Methods 67 paired CMR scans (1.5T) from 30 AFD patients were included. Three groups were defined according to LGE: no LGE at either scan (LGE-/-); LGE at baseline, unchanged at follow-up (LGE+/-); LGE at follow-up, appeared or increased compared to baseline (LGE+/+). T2m was measured in the infero-lateral basal segment in all scans; in LGE+ scans only, LGE was also manually contoured (ROI_LGE), and the ROI_LGE copied and pasted on the matching T2m image (T2m_ROI_LGE). See Figure 1. Troponin I (TnI) was also dosed at each scan. A univariate repeated measures analysis of variance was used to compare the groups and Tukey-Kramer correction was applied. Results As expected, the presence of LGE was strongly associated with older age, higher global and regional T2m, left ventricular (LV) mass and TnI values. As a novelty, in the LGE+/+ scans (scar appearance/progression) T2m in the ROI_LGE was higher than in the LGE+/- scans (scar unchanged) (p value 0.02). None of the other parameters, such as LV mass, TnI and global T2m values, differ between the the LGE+/+ compared to the LGE +/- group. See Table 1. Conclusions In our AFD patients’ cohort, scar progression was associated with focal increase in T2m values, i.e. T2m may identify patients with active myocardial injury. The potential implication on management/disease progression monitoring needs to be tested in future research, with longer follow-up. The role of sex, with females known to have higher average T2m values, will also need to be explored in a wider patient’s cohort.

Comparison of two anthracycline regimens for treatment of breast cancer and the incidence of cardiac injury

Abstract Background Anthracycline based breast cancer treatment regimens have evolved over time. Whether the risk of myocardial injury is different between regimens is unclear. Purpose To compare the incidence and significance of high sensitivity troponin-I (TpI) levels immediately post anthracycline therapy in women with breast cancer treated with two different anthracycline regimens. Methods We prospectively recruited women with early-stage breast cancer who received either dose-dense doxorubicin and cyclophosphamide (ddAC) or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) with or without subsequent HER2 therapy. The ddAC regimen comprises 4 cycles of doxorubicin given every 2 weeks (240mg/m2), whereas FEC consists of 3 cycles of epirubicin given every 3 weeks (total epirubicin dose of 300mg/m2, which is doxorubicin equivalent dose of 240mg/m2 using a cardiovascular toxicity dose ratio of 0.80 as per the 2022 ESC Cardio-oncology guidelines). Clinical characteristics were collected and TpI levels were measured before anthracyclines and 4-6 weeks post last dose. Comprehensive echocardiograms were conducted at baseline and post-therapy. Results 236 female participants were enrolled; 103 (43.6%) received ddAC and 133 (56.4%) received FEC. Compared to FEC, patients receiving ddAC were older (mean age 58.1±10.2 vs 51.0±9.3 years; p &amp;lt; 0.001) received similar cumulative doxorubicin equivalent dose (237.4±23.4 vs 239.9 ± 11.9 mg/m2; p=0.30), had similar baseline LVEF (62.1 ± 4.8 vs 61.3 ± 3.6%, p=0.14), and TpI levels (median (IQR) 2.0 (2.0-2.0) vs 2 (2.0-3.0) ng/L, p=0.12) respectively. Baseline risk factors were similar (hypertension 21% vs 17%, p=0.34; diabetes 7% vs 5%, p=0.44; dyslipidemia 15% vs. 8%, p=0.12). Post-anthracycline, the ddAC group had higher TpI level compared to patients in the FEC group (median (IQR) 12 (7-29) vs 6 (4-11) ng/L; p&amp;lt;0.001). The proportion of patients with abnormal TpI levels (&amp;gt;99th percentile, &amp;gt;16.0 ng/L) was higher in the ddAC group (43.7% vs 15.0%; p &amp;lt; 0.001). In a multivariable linear regression model that included age, treatment regimen, baseline TpI, hypertension, diabetes mellitus and dyslipidemia, ddAC remained significantly associated with higher post anthracycline TpI levels (β=15.5, 95%CI: 8.7-22.3; p&amp;lt;0.001). There was no significant difference in the mean LVEF post-anthracycline (59.9 ± 5.1 vs 60.0 ± 3.8; p=0.91). No patients developed clinical heart failure. Conclusion Despite similar doxorubicin equivalent doses, the incidence of abnormal TpI levels was ~3 fold higher with DD-AC than FEC. Given that DD-AC is now more commonly used especially with immunotherapy this knowledge is clinically relevant. The difference in proportion with troponin elevation could be due to differences in the number of cycles (3 vs 4) and the frequency of chemotherapy administration (every 2 vs 3 weeks) between the regimens. However, this did not translate into a larger reduction in LVEF. But longer-term follow-up is needed.

Cardiac troponin fragmentation in marathon runners. The MaraCat2 study

Abstract Background Cardiac troponins(cTn) are in a key role in the diagnosis of acute myocardial infarction (MI). Minor cardiac troponin elevations are also common after strenuous exercise, while limited evidence suggests this elevation consists mostly of smaller cTn fragments. Purpose We aimed to determine if our novel cardiac troponin assay, measuring long molecular forms of cardiac troponin (long cTnT) can differentiate cardiac troponin elevation associated with strenuous exercise from that seen in MI. Methods In a Proof-of-Principle study, we developed a simple time-resolved immunofluorometric assay based on europium chelate labels for the measurement of long cardiac troponin T molecules, which showed high accuracy in discriminating between cTn elevations in MI and end-stage renal failure. In the present study, we compared the characteristics of cTn release after a marathon race and Type 1 MI using an improved version of the long troponin test and a commercially available cTnT test. Troponin composition was analyzed in heparin plasma samples taken from 45 runners &amp;lt;1h after marathon race and from 45 patients with Type 1 MI. The concentration of long cTnT was measured with a novel immunofluorometric assay, total cTnT was measured with a commercial high-sensitivity cTnT assay, and the ratio of long to total cTnT (troponin ratio) was determined. Results Conventional cTnT exceeded the upper reference limit in 37 (82%) runners with a median concentration of 25.0 (IQR 16-36)ng/l. Median long cTnT concentration was 4.1 (IQR 2.4-5.8)ng/l. The median total and long cTnT concentration and the troponin ratio were higher in patients with MI than in marathon runners (p&amp;lt;0.001). Troponin ratio decreased (r=-0.497, p&amp;lt;0.001) in marathon runners and increased (r=0.466, p=0.001) in patients with MI with increasing troponin release (Figure 1). In the receiver operating characteristics curve analyses of all patients with cTnT release &amp;gt;14ng/l, long cTnT showed good predictive power with area under curve 0.969 (CI95% 0.939-1.000) in discriminating marathon runners from MI patients. Conclusions Our novel highly sensitive long cTnT immunoassay shows that the troponin release after strenuous exercise is composed mainly of smaller troponin fragments. Our test could be useful in separating benign cTnT elevations caused by exercise from those of acute MI.

The use of a point of care high sensitivity troponin in the investigation of patients presenting to the Emergency Department with undifferentiated chest pain

Abstract Background In 2012 in a hospital, New Zealand, a chest pain pathway was instituted for the use in patients presenting to the Emergency Department (ED) with undifferentiated chest pain. This reduced hospital admissions and ED length of stay (LOS) without adversely affecting outcomes. The pathway consists of risk stratification combined with ECG and troponin testing. The pathway suggests, but does not enforce, that low risk patients can be discharged after a single troponin, intermediate risk patients are for serial troponins (which can be done in ED or the next day in the community), with further testing if appropriate, and high risk patients are reviewed by Cardiology or General medicine. In August 2023, Siemens point of care high sensitivity troponin I (POC-hsTnI) was introduced for the use in ED, although Beckman laboratory troponin I (Lab–hsTnI) is still available. A POC test reduces result turnaround times but until recently there has been a lack of POC assays fulfilling criteria for "high sensitivity". Purpose To ascertain whether the availability of a POC-hsTnI in the ED is a viable option for use in the chest pain pathway Methods A 1 month "snap shot" of all consecutive patients presenting to the ED with chest pain was undertaken and the patients followed for adverse events using electronic notes review. October 2023 was selected for the post POC-hsTnI period and compared with April 2022. Results There were 688 patients presenting to ED with undifferentiated chest pain during October 2023 with a type 1 acute myocardial infarction (AMI) rate of 80 (11.6%), median age 58 (41-72), female 335 (48.7%). POC-hsTnI was used in isolation in 377 (54.8%), in conjunction with Lab-hsTnI in 218 (31.7%) and Lab-hsTnI was used alone in 93 (13.5%). The median turnaround time for POC-hsTnI was 11 minutes (10-11) compared with Lab-hsTnI 87 minutes (61-129). The POC-hsTnI was less sensitive for AMI than the Lab-hsTnI on presentation using the upper reference limit, 72.1% (60.6-81.6) versus 91.5% (83.0-96.4). However, when used with risk stratification, there were no excess adverse events (cardiac death or AMI) at 4 months in patients discharged with a diagnosis of non-cardiac chest pain – 7 (1.4%) (n=495) versus 5 (1.2%), (n=424) in 2022. Median LOS in the ED was 4.4 hours (2.9-6.2) versus 4.0h (3.0-5.9) in 2022. However, a higher proportion of patients had a second cTn: 414 (60.2%) versus 309 (48.4%) and a lower proportion had their second troponin the next day in the community, 28 (6.7%) versus 56 (18.1%). Conclusion The use of a POC-hsTnI is a practical solution to reduce turnaround times for troponin results and has the potential to reduce LOS or allow serial troponins to be measured in a timely manner during their ED visit, obviating the need for a next day community troponin. Whilst POC-hsTnI has a lower early sensitivity for AMI, the use of POC-hsTnI as part of a pathway does not adversely affect outcomes.

Comparison of rapid test for high-sensitivity troponin I with laboratory high-sensitivity troponin T in patients with acute chest pain - a prospective monocentric study

Abstract Background and purpose High-sensitivity troponin (hs-Tn) assays are recommended for routine clinical use for diagnosis of acute coronary syndrome (ACS). However, laboratory hs-TnT can be elevated due to non-cardiac conditions, such as pulmonary embolism, skeletal muscle injury or chronic kidney disease. The aim of our study was to compare the diagnostic accuracy of the bed-side rapid hs-troponin I (hs-TnI) assay with hs-TnT measured by routine laboratory. Methods This prospective monocentric study was conducted at a tertiary hospital outpatient cardiac unit with an emergency clinic for patients with acute symptoms. A total of 129 patients were included between May 2021 and August 2022. Hs-TnI was measured via a bed-side test from whole blood directly in the emergency room, while hs-TnT was measured from plasma through the routine laboratory. Definite ACS was confirmed by coronary angiography. Patients were compared by grouping them into definitive diagnosis of ACS or no ACS. Hs-TnI as well as hs-TnT values were compared for accuracy and predictive values. Routine clinical parameters and comorbidities were documented and compared as well. Agreement between hs-TnI and hs-TnT was assessed by likelihood ratios and Bland Altman plot. Results Overall, 129 patients (65.1% male, 61.8 ± 15.6 years) with acute chest pain were analysed. Median hs-TnI was 7.0 ng/L (IQR: 2.7-15.8), while median hs-TnT was 14 ng/L (IQR: 7.0-31.0). Results for TnI were available faster (average: 1:14 h ± 0:54) compared to TnT. Coronary angiography confirmed ACS in 17 patients (13.2%) displaying significant coronary stenoses requiring intervention. The relative risk of ACS patients to have an elevated hs-TnI result was 6.59 compared to that of 2.29 for the hs-TnT test, meaning that a positive hs-TnI test was a better classifier for validated ACS than that of hs-TnT. Hs-TnI exhibited equivalent negative predictive value to hs-TnT (99%) for definite ACS diagnosis, but had comparatively higher positive predictive value (50.0 vs. 25.8%). Bland Altman plot of hs-TnI versus hs-TnT showed an average difference of -4.6 ng/L (95% CI: -12.4 to 3.2) between the tests. In 39 patients with chronic kidney disease (minimum stage 3a CKD) median hs-TnT (27.0 ng/L, IQR: 16.0-55.0) values were higher than hs-TnI (11.2 ng/L, IQR: 7.5-30.7). Conclusion Bed-side hs-TnI is comparable to hs-TnT with a high degree of agreement. Measurement of troponin I using the rapid bed-side hs-TnI assay possesses a shorter blood-draw-to-result-time than routine troponin T measurement.

Fastidious adherence to 0/1-hour high-sensitivity troponin T testing reduces emergency department length of stay in patients presenting with suspected acute coronary syndromes

Abstract Background High-sensitivity cardiac troponins (hs-cTn) are key clinical biomarkers in patients presenting with suspected acute coronary syndromes (ACS) to Emergency Departments (EDs). They have facilitated rapid 0h/1h troponin testing protocols, leading to safe, effective, and efficient triage of patients. However, early distinction of myocardial infarction (MI), which has a reported frequency of less than 10% in most cohorts, from the apparently stable hs-cTn elevations of chronic myocardial injury (CMI) remains a challenge. Often CMI patients require confirmation by further testing and observation, prolonging patient length of stay. Further, reliably obtaining serial hs-cTn samples at 60-minutes in a busy ED setting may be difficult. A potential explanation for only 5-6% of Australian sites adopting 0h/1h hs-cTn testing. Methods and Results We undertook a case-control study between March and August 2023 among patients with suspected ACS presenting to Liverpool Hospital ED (Sydney, Australia). 185 patients (cases) underwent hs-cTnT sampling at 30- and 60-minutes (± 5 minutes) after baseline. Diagnosis of MI was made in 8.6%, 35.7% were placed into a further observation group and MI ruled-out in 55.7%. The latter two groups were matched to 169 patients (controls) who received ‘usual’ care, which was a 0h/1h hs-cTnT testing protocol. The case and control arms were matched by age, gender, time from symptom onset and main presenting symptom. Control patients had a median sampling interval of 118 [85 to 174] minutes, rather 60 minutes as the protocol directs. When comparing the paired differences between the case and control arms, there was a mean reduction in length of stay of 104 (95% CI: 41 to 186, P = 0.01) and 47 (95% CI: 11 to 84, P = 0.01) minutes, for the observation and rule-out MI groups respectively. The figure shows the distribution of lengths of stay by group. Among the rule-out group, Wilcoxon signed rank test indicated the control arm had a longer median length of stay of 6.3 [5.1 to 8.4] hours, compared to 5.0 [4.5 to 7.1] hours in the case arm (P=0.005). Similarly, in the further observation group, control patients also had a longer median length of stay of 9.2 [6.9 to 10.4] hours compared to case patients of 8.1 [5.1 to 10.3] hours (P = 0.009). At 30-days, ED representation rates were 10.7% in controls and 8.3% in cases, rehospitalisation 3.6% in controls and 5.3% in cases, cardiac death 0% in both arms and non-cardiac death 1% in both arms. There were no differences in event rates between each arm (P &amp;gt; 0.05). Conclusion Accurate 0h/1h hs-cTnT testing reduces patient length of stay in ED and offers more personalised prediction of MI risk. The importance of adherence to protocol-directed sampling times is clear, where further studies are required regarding routine implementation in a busy ED setting.Exact 60 min TnT and LOSOutcomes at 30 days

The safety of standardized management of suspected cardiovascular immune-related events in patients treated by immunecheckpoints inhibitors

Abstract Background Immune checkpoint inhibitors (ICIs) treatment carries a risk of immune-related adverse events (irAEs), including cardiovascular (CV) events. Current guidelines recommend troponin testing to detect early CV irAEs, especially myocarditis, prompting hospital admission. However, high volumes might hinder hospital admission for all suspected CV irAEs patients. Purpose To assess the safety of standardized management in outpatients with suspected irAEs. Methods A prospective single-center cohort study was conducted, including all adults referred to our unit for suspected CV irAEs. Patients exhibiting CV symptoms, receiving double ICIs, or showing ECG changes were referred to cardiology or intensive care based on severity. Patients with no CV symptoms or ECG changes, on single ICI therapy, and no other immune disorder were assessed in a day stay within 8 working days. Patients underwent serial serum testing, ECG, transthoracic echocardiogram, and cardiac magnetic resonance imaging (cMRI) and were assessed by a multidisciplinary team (MDT) including cardiology and internal medicine specialists. Coronary artery imaging and endomyocardial biopsy were performed when deemed necessary (Figure 1). The primary endpoint was CV mortality at 30 days after referral. Secondary endpoints included identifying factors associated with the diagnosis of CV irAEs at referral. Events were adjudicated by a panel of experts (FC, MM, SH) who reviewed the MDT's weekly meeting conclusions. Results 175 patients were enrolled from March 2022 to October 2023; 40 (22.89%) were male, median age 61 (IQR 48.0-72.0) years. 146 (83.4%) were seen in the outpatient clinic. No CV deaths occurred within the initial 30 days. 95 patients (54.1%) had CV irAEs at referral, including 72 (41.1%) with myocarditis; 10 (5.7%) with acute coronary syndromes; 9 (5.1%) with pericarditis; 7 (4.0%) with heart failure; 4 (2.3%) with high-degree conduction or ventricular arrhythmias; and 1 (0.6%) with Tako-Tsubo. 8 (4.6%) had a combination of CV irAEs. The majority of patients admitted to the hospital had CV irAEs (24, 82.7%). On multivariable regression analysis(Figure 2), CV or muscle symptoms(OR 2.677 [CI 1.207-5.937], p=0.015), prior CV disease history(OR 3.668 [CI 1.486-9.057], p=0.0048), and abnormal ECG (OR 2.855 [CI 1.074-7.589], p=0.035) remained associated with CV irAEs at referral. Including global longitudinal strain (GLS) in the model, we identified prior CV disease history. (OR 7.011 [CI 2.217-22.167], p=0.0009) and GLS &amp;lt;16% (OR 2.774 [CI 1.07-7.17], p=0.035) as significant. Conclusions We demonstrate the safety of a standardized outpatient management approach for most patients referred for suspected CV irAEs, mainly triggered by asymptomatic elevation of troponin. No patient experienced CV death at 30 days. When suspecting a CV irAEs, CV or muscle symptoms, previous history of CV disease, and abnormal ECG should prompt speedy assessment given the higher likelihood of CV irAEsFigure 1

Safety and efficiency of implementation of high-sensitivity troponin T in the assessment of emergency department patients with cardiac chest pain.

For emergency department (ED) patients with cardiac chest pain, introduction of high-sensitivity troponin (hsTnT) pathways has been associated with reductions in length of stay of less than 1h. At two urban Canadian sites, we introduced hsTnT on January 26, 2016. While the prior diagnostic algorithm required troponin testing at 0 and 6h, serial hsTnT serial testing was conducted at 0 and 3h. We identified consecutive patients who presented with cardiac chest pain from January 1, 2015, to March 31, 2017, along with 30-day outcomes. The primary outcome was a missed 30-day major adverse cardiac event, (MACE) defined as death, revascularization, or readmission for myocardial infarction occurring in a patient-discharged home with a minimizing diagnosis and without cardiac-specific follow-up. Secondary outcomes included admission rate, ED length of stay, and MACE. We compared pre- and post- implementation periods using descriptive methods and repeated this analysis in patients with noncardiac chest pain. We collected 5585 patients with cardiac chest pain, (2678 pre- and 2907 post-introduction) and 434 had (7.8%, 95% CI 7.1 to 8.5%) MACE, with 1 missed MACE. (0.2%, 95% CI 0.04 to 1.3%). Admission rate was stable at 24.1% pre- and 23.7% while median length of stay decreased from 464 to 285 min, a difference of 179 min. (95% CI 61 to 228 min). For 11,611 patients with noncardiac chest pain, admission rate (9%) and length of stay (191 versus 193 min) remained constant. Implementation of hsTnT for evaluation of ED chest pain patients was safe and associated with a 3-h decrease in length of stay.

Temporal trends in concordance between ICD-coded and cardiac biomarker-classified hospitalisation rates for acute coronary syndromes: a linked hospital and biomarker data study

BackgroundSince 2000, the definition of myocardial infarction (MI) has evolved with reliance on cardiac troponin (cTn) tests. The implications of this change on trends of acute coronary syndrome (ACS) subtypes...

Structural dynamics of the intrinsically disordered linker region of cardiac troponin T.

Troponin plays a central role in regulating heart contraction, and mutations in troponin can cause human cardiomyopathies. There are several functionally-significant regions of troponin that have not been structurally resolved, including the troponin T linker region that contains multiple cardiomyopathy mutations. In these unresolved regions, it is not possible to understand how changes in sequence affect function. We used computational and experimental techniques to demonstrate that this linker is dynamic and intrinsically disordered both in isolation and in the fully regulated thin filament. Moreover, we show how a cardiomyopathy mutation in this region affects function via allosteric disruption of intermolecular interactions. Our results highlight the need to consider how key mutations affect troponin disorder rather than the structure-function relationship.

Myocarditis: Differences in Clinical Expression between Patients with ST-Segment Elevation in Electrocardiogram vs. Patients without ST-Segment Elevation.

In cases of myocarditis, electrocardiograms (ECGs) may suggest a pattern of ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI). NSTEMI patterns are less frequent in myocarditis cases, but it remains unclear if the presence of ST-segment elevation in myocarditis cases is related to a more severe condition and more damage in the myocardium. This is a retrospective study involving 38 patients admitted to hospital with myocarditis. Patients were divided into two groups: patients with ST-segment elevation (STE) patterns in the ECG (25), and patients without ST-segment elevation (non-STE) patterns (13). The data compared included results from epidemiological, laboratory, and instrumental tests. Data were analysed using IBM SPSS Statistics v26.0. A p value of <0.05 was established as the threshold for statistical significance. C-reactive protein (CRP) levels were higher in the STE group (103.40 ± 82.04 mg/L vs. 43.54 ± 61.93 mg/L, p = 0.017). The left ventricle ejection fraction (LVEF) was significantly higher in the non-STE pattern group (49.71 ± 4.14 vs. 56.58 ± 3.99, p < 0.001). A lower LVEF correlates with higher TnI levels (r= -0.353, p = 0.032) and higher CRP levels (r = -0.554, p < 0.001). Lower left ventricle (LV) strain correlates with higher levels of Troponin I (TnI) (r = -0.641, p = 0.013). LVEFs in the STE group were lower compared to those in the non-STE pattern group. STE pattern was associated with higher CRP levels. Higher TnI levels in cases of myocarditis were associated with lower LV strain and lower LVEF; higher CRP levels also correlated with lower LVEF. Based on a 6-month echocardiographic follow-up, the prognosis of myocarditis was favourable.

Validation and correlation of high-sensitive troponin I and troponin T in the emergency department

BackgroundTroponin elevation is frequently observed in various scenarios in the Emergency Department (ED), yet there is a paucity of studies investigating simultaneously measured high-sensitivity cardiac troponin T (hs-cTnT) and troponin I (hs-cTnI) within a diverse cohort in a clinical setting.MethodsAll patients who underwent troponin testing at a single center were eligible for this study. Only patients with simultaneous samples with hs-cTnI (Siemens) and hs-cTnT (Roche) were included, regardless of chief complaint.ResultsAnalysis of 1987 samples from 1134 patients showed a significant correlation between hs-cTnT and hs-cTnI (r = 0.86, p < 0.01). Of these samples, 65% exceeded the upper reference limit (URL) for hs-cTnT, and 30% for hs-cTnI with 39% who exhibited elevated hs-cTnT levels alongside normal hs-cTnI levels. The area under the curve (AUC) for acute myocardial infarction (AMI) for the index visit was 0.80 (95% CI; 0.75–0.85) for hs-cTnT and 0.87 (95% CI; 0.83–0.91) for hs-cTnI. Sensitivity and specificity were 91% and 39% for hs-cTnT, and 80% and 80% for hs-cTnI. Positive predictive value (PPV) and negative predictive value (NPV) was 9.3% and 98.5% for hs-cTnT respectively, corresponding for hs-cTnI was 21.3% and 98.3% respectively. Hazard ratios for 1-year mortality were 1.52 (95% CI; 1.40–1.66) for hs-cTnT and 1.26 (95% CI; 1.18–1.34) for hs-cTnI.ConclusionElevated troponins above the URL were very common in this diverse cohort, particularly for hs-cTnT, which was twice as frequent compared to hs-cTnI, resulting in low specificity and PPV for AMI.

Elevated Cardiac Troponin Levels as a Predictor of Increased Mortality Risk in Non-Cardiac Critically Ill Patients Admitted to a Medical Intensive Care Unit.

Background: Cardiac troponin I (TnI) is a specific marker of myocardial damage used in the diagnosis of acute coronary syndrome (ACS). TnI levels can also be elevated in patients without ACS, which is linked to a worse prognosis and mortality. We evaluated the clinical implications and prognostic significance of serum TnI levels in critically ill non-cardiac patients admitted to the intensive care unit (ICU) at a tertiary-level hospital. Materials and Methods: A three-year retrospective study including the years 2017-2020 was conducted to evaluate in-hospital mortality during ICU stay and mortality rates at 28 and 90 days, as well as one and two years after admission, in 557 patients admitted to the medical ICU for non-cardiac causes. Results: TnI levels were elevated in 206 (36.9%) patients. Patients with elevated TnI levels were significantly older and had higher rates of comorbidities, including chronic heart failure, coronary heart disease, and chronic kidney disease (p < 0.05 for all). Patients with elevated TnI levels required more invasive mechanical ventilation, vasopressor infusion, and dialysis in the ICU and experienced more shock within the first 72 h (p = 0.001 for all). High TnI levels were associated with higher Acute Physiological and Chronic Health Evaluation (APACHE) II (27.6 vs. 20.3, p = 0.001) and Sequential Organ Failure assessment (8.8 vs. 5.26, p = 0.001) scores. Elevated TnI levels were associated with higher mortality rates at 28 days (58.3% vs. 19.4%), 90 days (69.9% vs. 35.0%), one year (78.6% vs. 46.2%), and two years (82.5% vs. 55.6%) (p < 0.001 for all). Univariate logistic regression analysis revealed that high TnI levels were a strong independent predictor of mortality at all time points: 28 days (OR = 1.2, 95% CI: 1.108-1.3, p < 0.001), 90 days (OR = 1.207, 95% CI: 1.095-1.33, p = 0.001), one year (OR = 1.164, 95% CI: 1.059-1.28, p = 0.002), and two year (OR = 1.119, 95% CI: 1.026-1.22, p = 0.011). Multivariate analysis revealed that age, albumin level, APACHE II score, and requirements for dialysis and vasopressor use in the ICU were important predictors of mortality across all timeframes, but elevated TnI levels were not. Conclusions: Elevated TnI levels in critically ill non-cardiac patients are markers of disease severity. While elevated TnI levels were significant predictors of mortality in the univariate analysis, they lost significance in the multivariate model when adjusted for other factors. Patients with elevated TnI levels had higher mortality rates across all timeframes, from 28 days to two years.

Utility of the AngelMed Guardian System in myocardial bridging: a case report

BackgroundMyocardial bridging (MB) is a known congenital anomaly in which a segment of the coronary artery transverses from the epicardium through the myocardium. MB may clinically manifest as recurrent angina, acute coronary syndrome, ventricular dysrhythmia, and even sudden cardiac death. On electrocardiogram (EKG), MB can present with findings consistent with significant ST-segment changes. The AngelMed Guardian System (the Guardian device) was developed in an effort to optimize the time from the onset of myocardial ischemia to intervention. The device analyzes myocardial electrical changes and alerts the patient to seek emergent medical evaluation if an acute ST-segment deviation is detected. We describe the first documented case of the Guardian device detecting acute ST-segment changes secondary to myocardial bridging.Case PresentationA 50-year-old male, with a history of percutaneous coronary intervention of the proximal left anterior descending (LAD) artery, presented to his cardiologist’s office with reports of recurrent, atypical chest pain. The Guardian device was implanted. One month after implantation, the patient experienced chest pain and was alerted by the Guardian device to seek emergent medical evaluation. Initial EKG and high-sensitivity troponins were negative for acute ischemia. Guardian device interrogation revealed significant ST depressions, encouraging further ischemic evaluation. The exercise myocardial perfusion imaging revealed an apical reversible defect. Left heart catheterization revealed a large segment of mid-LAD MB with the patient’s previous LAD stent noted to be widely patent along with no evidence of new obstructive coronary disease. Following the identification of the MB, medication regimen adjusted and the patient denied recurrence of chest pain or Guardian alerts.ConclusionsWe describe the first documented case of the Guardian device detecting acute ST-segment changes that were secondary to myocardial bridging. The Guardian device appropriately documented an ischemic event not appreciated with initial EKG or troponin testing. With the assistance of the Guardian device, we were able to rapidly identify MB as the cause for the ischemic EKG changes and subsequent abnormal stress test, optimize medical management, and prevent recurrent atypical chest pain along with office and hospital visits.

NUPR1 modulates pulmonary embolism progression via smooth muscle cells phenotypic transformation

ObjectiveThis study aimed to investigate the role of Nuclear Protein 1 (NUPR1) in pulmonary embolism (PE) and its impact on the phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs). MethodsA PE model was established via autologous pulmonary emboli infusion into the jugular vein. Partial Pressure of Oxygen (PaO2), Oxygenation Index (OI), Brain Natriuretic Peptide (BNP), and Troponin I (TnI) were measured, and lung tissue was subjected to hematoxylin-eosin (HE) staining. NUPR1 expression was assessed through Immunofluorescence and Western blot analyses. To investigate role of NUPR1, PE rats were treated with lentiviral vectors for NUPR1 knockdown (si-NUPR1) or overexpression (ov-NUPR1), and the effects on lung pathology were examined. NUPR1 expression was evaluated in human PASMCs. Additionally, PASMCs from SD rats were cultured under normoxic and hypoxic conditions to evaluate NUPR1 expression. Transfection of NUPR1 expression vectors into PASMCs allowed monitoring of phenotypic transformation-associated protein changes and PASMCs activity. ResultsIncreased NURP1 was observed in human-derived PASMCs. In PE rats, histological examination revealed ruptured pulmonary alveoli, exudate accumulation, interstitial edema, and infiltration of inflammatory cells, concomitant with elevated NUPR1 expression levels. Knockdown of NUPR1 in PE rats significantly improved lung tissue structure, reducing alveolar rupture and interstitial edema. Conversely, NUPR1 overexpression exacerbated lung damage, leading to increased inflammatory infiltration. NUPR1 expression in rat PASMCs remained stable under normoxic conditions; however, under hypoxic conditions, NUPR1 protein expression increased progressively over time. Subsequent upregulation of NUPR1 expression led to a decrease in the levels of contractile phenotype markers α-SMA and SM22α in PASMCs, accompanied by increased expression of synthetic phenotype markers Vimentin and OPN. This phenotypic shift was associated with enhanced cellular proliferation, invasion, and migration. ConclusionsElevated NUPR1 expression in PE exacerbates abnormal PASMCs proliferation by promoting their phenotypic transformation, thereby fostering the pathological progression of PE.