Preconditioning of mesenchymal stem cells with ghrelin exerts superior cardioprotection in aged heart through boosting mitochondrial function and autophagy flux.

Application of mesenchymal stem cells (MSCs) is considered as a promising cell-based therapy to induce cardioprotection against ischemia-reperfusion (IR) injury. Preconditioning of MSCs is the key strategy to improve MSCs functions in vitro and their efficacy in vivo, especially in elderly subjects in whom cardioprotection is lost. This study investigated the effects of preconditioning of human umbilical cord-derived MSCs with ghrelin and their combination with nicotinamide-mononucleotide (NMN) on cardioprotection, and the role of autophagy flux and mitochondrial function in aged hearts subjected to IR injury. Aged Sprague Dawley rats (20-22 months old) were subjected to LAD occlusion-induced myocardial IR injury and treated with ghrelin-preconditioned or unconditioned-MSCs at early reperfusion. NMN (500 mg/kg, i.p) was also administered at early reperfusion and repeated 12 h later. Intra-myocardial injection of ghrelin-preconditioned MSCs reduced infarct size and cardiotroponin release of aged myocardium, and improved cardiac function following IR injury. MSCs preconditioning with ghrelin restored IR-induced mitochondrial reactive oxygen species and membrane potential depolarization and enhanced ATP production. To reveal possible mechanism, preconditioned-MSCs increased autophagy flux by downregulating the overexpression of Beclin-1 and P62 proteins and increasing the LC3-II expression and LC3-II/LC3-I ratio. Moreover, combining NMN to ghrelin-preconditioned MSCs synergistically augmented its protective effects on infarct size and mitochondrial function. All above effects were abolished by autophagy flux inhibitor, chloroquine. Thus, ghrelin may serve as a promising candidate to improve the cardioprotective efficacy of MSC-based therapy via autophagy/mitochondrial pathway and that NMN serves as a good booster in combination therapy in aged hearts.

High sensitivity troponin, analytical advantages, clinical benefits and clinical challenges - An update.

The measurement of cardiac troponin (cTn) by a high sensitivity method now represents the standard method for cTn measurement in the laboratory. High sensitivity method are not measuring a novel form of troponin but have undergone methodological improvement in assay sensitivity to allow both very low level detection and repeat measurements at low levels with very low degrees of analytical imprecision. The methods identify additional patients with myocardial injury who would benefit from evidence-based interventions. Rapid predictive algorithms utilising measurement on admission as well as short sampling periods (1-2 h) allow much more rapid categorisation of patients to appropriate clinical pathways. The shift in the diagnosis from traditional "cardiac enzymes" to troponin based on the 99th percentile has accounted for the majority of the detection of myocardial injury in patients without acute coronary syndromes. These patients have a worse prognosis irrespective of the underlying cause of their hospital admission. The appropriate management strategy in this group, beyond managing the underlying problem, remains to be defined. Measurement of cTn in otherwise asymptomatic individuals may have a role for patient selection for preventive treatment or for patients monitoring. Clinical trials in this area are awaited.

External validation of the clinical chemistry score.

BACKGROUND: Combining high-sensitivity cardiac troponin (hs-cTn) with estimated glomerular filtration rate and glucose within the Clinical Chemistry Score (CCS) could help in the assessment of patients with suspected acute myocardial infarction (AMI). METHODS: In patients presenting with suspected AMI to the emergency department, we aimed to externally validate the performance of the CCS in a prospective international multicenter study and to directly compare the diagnostic and prognostic performance of the CCS with hs-cTnT and hs-cTnI baseline levels alone using a single cut-off approach. The diagnostic endpoint was diagnostic accuracy for AMI as centrally adjudicated by two independent cardiologists including cardiac imaging and serial hs-cTnT/I measurements. The prognostic endpoint was 30-day AMI or death. RESULTS: AMI was the final diagnosis in 620/3827 patients (16.2%) adjudicated with hs-cTnT and 599 patients (15.7%) adjudicated with hs-cTnI. The CCS resulted in high diagnostic accuracy for AMI and prognostic accuracy for 30-days AMI/death as quantified by the area under the receiver-operating characteristic curve (AUC), using hs-cTnT 0.90 (95%CI 0.89-0.91) and 0.89 (95%CI 0.88-0.90), using hs-cTnI 0.91 (95%Cl 0.90-0.92) and 0.90 (95%CI 0.89-0.91) respectively. E.g. a CCS of 0 points resulted in a sensitivity of 99.8% (95%CI 99.1-100%) for rule-out of index AMI and 99.5% (95%CI 98.5-100%) for AMI/death at 30 days for hs-cTnT and 99.8% (95%CI 98.9-100%) and 99.6% (95%CI 98.6-100%) using hs-cTnI. Overall, the single hs-cTnT/I measurement approach provided comparable diagnostic (sensitivity 99.5-99.7%) and prognostic (sensitivity 98.9-99.5%) performance versus the CCS. INTERPRETATION: The CCS provided high diagnostic and prognostic performance also in this independent large validation cohort. A single hs-cTnT/I measurement approach for rule-out MI yielded similar estimates.

Optimal cut-off value of elevated cardiac troponin concentrations for myocardial injury predicts clinical outcomes in adult patients with COVID-19: a dose-response analysis protocol for systematic review.

INTRODUCTION: Acute myocardial injury in patients with COVID-19 infection has been recognised as one important complication associated with in-hospital mortality. The potential dose-response effect of cardiac troponin (cTn) concentrations on adverse clinical outcomes has not been systematically studied. Hence, we will conduct a comprehensive dose-response meta-analysis to quantitatively evaluate the relationship between elevated cTn concentrations and in-hospital adverse clinical outcomes in patients with COVID-19. METHODS: We will search PubMed, EMBASE, Cochrane Library and ISI Knowledge via Web of Science databases, as well as preprint databases (medRxiv and bioRxiv), from inception to October 2021, to identify all retrospective and prospective cohorts and randomised controlled studies using related keywords. The primary outcome will be all-cause mortality during hospitalisation. The secondary outcome will be major adverse event (MAE). To conduct a dose-response meta-analysis of the potential linear or restricted cubic spline regression relationship between elevated cTn concentrations and all-cause mortality or MAE, studies with three or more categories of cTn concentrations will be included. Univariable or multivariable meta-regression and subgroup analyses will be conducted to compare elevated and non-elevated categories of cTn concentration. Sensitivity analyses will be used to assess the robustness of our results by removing each included study at one time to obtain and evaluate the remaining overall estimates of all-cause mortality or MAE. ETHICS AND DISSEMINATION: In accordance with the Institutional Review Board/Independent Ethics Committee of Fuwai Hospital, ethical approval was waived for this systematic review protocol. This meta-analysis will be disseminated through a peer-reviewing process for journal publication and conference communication. PROSPERO REGISTRATION NUMBER: CRD42020216059.

Cardiac Troponin Composition Characterization after Non ST-Elevation Myocardial Infarction: Relation with Culprit Artery, Ischemic Time Window, and Severity of Injury.

BACKGROUND: Troponin composition characterization has been implicated as a next step to differentiate among non-ST elevation myocardial infarction (NSTEMI) patients and improve distinction from other conditions with troponin release. We therefore studied coronary and peripheral troponin compositions in relation to clinical variables of NSTEMI patients. METHODS: Samples were obtained from the great cardiac vein (GCV), coronary sinus (CS), and peripheral circulation of 45 patients with NSTEMI. We measured total cTnI concentrations, and assessed both complex cTnI (binary cTnIC + all ternary cTnTIC forms), and large-size cTnTIC (full-size and partially truncated cTnTIC). Troponin compositions were studied in relation to culprit vessel localization (left anterior descending artery [LAD] or non-LAD), ischemic time window, and peak CK-MB value. RESULTS: Sampling occurred at a median of 25 hours after symptom onset. Of total peripheral cTnI, a median of 87[78-100]% consisted of complex cTnI; and 9[6-15]% was large-size cTnTIC. All concentrations (total, complex cTnI, and large-size cTnTIC) were significantly higher in the CS than in peripheral samples (P < 0.001). For LAD culprit patients, GCV concentrations were all significantly higher; in non-LAD culprit patients, CS concentrations were higher. Proportionally, more large-size cTnTIC was present in the earliest sampled patients and in those with the highest CK-MB peaks. CONCLUSIONS: In coronary veins draining the infarct area, concentrations of both full-size and degraded troponin were higher than in the peripheral circulation. This finding, and the observed associations of troponin composition with the ischemic time window and the extent of sustained injury may contribute to future characterization of different disease states among NSTEMI patients.

Puerarin alleviates coronary heart disease via suppressing inflammation in a rat model.

BACKGROUND: Puerarin shows inhibitory effects on inflammation in chronic heart failure (CHF), but its efficacy in coronary heart disease (CHD) remained vague. METHODS: Rat CHD model was constructed, and serum parameters were determined using a blood liquid biochemical analyzer. Also, contents of creatine kinase (CK), creatine kinase MB isoenzyme (CK-MB), lactate dehydrogenase (LDH) and cardiac troponin (cTnT) were measured using colorimetry. Histological examination was conducted with Hematoxylin-Eosin (H&E) staining, and cardiac function was assessed by Echocardiography. Cell apoptosis was detected using Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Relative expressions were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot as needed. RESULTS: In CHD rats, the levels of TC, LDL and TG and the expressions of matrix metalloproteinase-9 (MMP-9), CD40 ligand (CD40L), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were increased while HDL level was decreased, accompanied with inflammatory cell infiltration and cardiac malfunction. Also, the contents of CK, CK-MB, LDH and cTnT, the percentage of apoptotic cells, the expressions of Bcl-2 associated X protein (Bax), cleaved Caspase-3, TNF-α, Interleukin-ß (IL-ß), IL-6 and Lipoprotein-associated Phospholipase A2 (Lp-PLA2) expressions and the levels of oxidized-(ox-)LDL and malondialdehyde (MDA) were upregulated, while the level of super oxidase dismutase (SOD) and the expressions of B cell lymphoma-2 (Bcl-2) and vascular endothelial growth factor (VEGF) were downregulated. However, Puerarin ameliorated the effects of CHD model construction, suppressed nuclear factor-(NF-)κB expression, and enhanced the expressions of Farnesoid X Receptor (FXR), phosphorylated-AKT (p-AKT) and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3). CONCLUSION: Puerarin alleviated CHD in rats via inhibiting inflammation, providing possible method for CHD treatment.

Interpretation of elevated high-sensitivity cardiac troponin I in elite soccer players previously infected by severe acute respiratory syndrome coronavirus 2.

OBJECTIVES: To clarify the meaning of elevated cardiac troponin in elite soccer athletes previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and screened for cardiovascular involvement in the wake of competitive sport resumption. METHODS: We designed a retrospective cohort study with the collaboration of two Italian Serie A teams. Soccer players from both rosters (58 athletes) were systematically analysed. For every SARS-CoV-2 positive athlete, the Italian Soccer Federation protocol requested full blood tests including high-sensitivity cardiac troponin I (hs-cTnI), along with a complete cardiovascular examination. We extended the analysis to SARS-CoV-2 negative athletes. RESULTS: A total of 13/58 players (22.4%) suffered from SARS-CoV-2infection: all had a negative cardiovascular examination and 2/13 (15%) showed increased hs-cTnI values (120.8 pg/ml and 72,6 pg/ml, respectively; upper reference level 39.2 pg/ml), which did not track with inflammatory biomarkers. Regarding the 45/58 (77.6%) non infected athletes, a slight increase in hs-cTnI was observed in 2 (4.5%) subjects (values: 61 pg/ml and 75 pg/ml respectively). All hs-cTnI positive athletes (4/58, 7%) underwent cardiac magnetic resonance (CMR), that excluded any cardiac injury. CONCLUSIONS: In our retrospective study, SARS-CoV-2 infection in elite soccer athletes was not associated to clinical or biomarkers abnormalities. Increased hs-cTnI was rare and not significantly associated with previous SARS-COV2 infection nor with pathological findings at CMR, albeit elevated hs-cTnI was numerically more prevalent in the infected group.

Differential expression of MAP3K7 and TROPONIN C proteins and related perturbations in renal amyloidosis.

OBJECTIVES: Renal amyloidosis (RA) is a rare protein misfolding disorder that prompts progressive renal insufficiency. This study aimed to decipher proteomic changes in human sera to understand the pathophysiology and molecular mechanisms underlying the disease development, hence assisting in the diagnosis of RA. METHODS: Serum proteomic analysis was performed using a gel-based approach followed by MALDI-TOF MS. RA patients with age and sex matched healthy volunteers were recruited from Max Super Speciality Hospital, New Delhi, India. RESULTS: Proteome profiles of serum revealed eight differentially expressed proteins namely, Zinc finger protein 624, Protein FAM183A, Calcium-binding mitochondrial carrier protein Scamc-3, V-type proton ATPase 116 kDa subunit A isoforms 2, Protein TXNRD3NB, ATP - dependent RNA helicase, Troponin C and Mitogen-activated protein kinase kinase kinase 7. These proteins were reported first time in RA. The increased levels of MAP3K7 and TROPONIN C were validated by bio-layer interferometry and their diagnostic accuracy was evaluated by ROC curve analysis. The differentially expressed proteins were predominantly associated with vesicular trafficking, transcriptional regulation, metabolic processes, apoptotic process and mitochondrial metabolism. CONCLUSION: The results indicate that these proteomic signatures may be considered as potential molecular targets for RA diagnostics and therapeutics subject to validation on large sample size. Abbreviations: AßP= Amyloid-beta protein, Aß=Amyloid-beta, AL= Light chain amyloidosis, AA= Amyloid A, ALECT2= LECT2 amyloidosis, APS= Ammonium persulfate CKD= Chronic Kidney Diseases, EBRT= external beam radiation therapy, ESRD= End-Stage Kidney Disease, Glis2= Gli-similar 2, JNK= c-Jun NH 2-terminal kinase, MAPK= Mitogen-Activated Protein Kinase, MM=Multiple Myeloma, PHD= Prolyl hydroxylase, RA = Renal Amyloidosis, SAA= Serum Amyloid A, SD= Standard Deviation, Sepp= Selenoprotein, SCC= Squamous cell carcinoma, SDS= Sodium dodecyl sulfate, TEMED = tetramethyl ethylenediamine, TGF-Beta-1=Transforming growth factor- Beta-1, Trx = Thioredoxin, TrxR= Thioredoxin reductase.

Meta-analysis of preoperative high-sensitivity cardiac troponin measurement in non-cardiac surgical patients at risk of cardiovascular complications.

BACKGROUND: Patients undergoing major non-cardiac surgery are at risk of cardiovascular complications. Raised levels of high-sensitivity troponin are frequently detected before operation among these patients. However, the prognostic value of high-sensitivity troponin in predicting postoperative outcomes remains unclear. METHODS: A systematic search of PubMed, Embase and Science Citation Index Expanded was undertaken for observational studies published before March 2018 that reported associations between raised preoperative levels of high-sensitivity troponin and postoperative major adverse cardiac events and/or mortality after non-cardiac surgery. Meta-analyses were performed, where possible, using random-effects models. RESULTS: Seven cohort studies with a total of 4836 patients were included. A raised preoperative high-sensitivity troponin level was associated with a higher risk of short-term major adverse cardiac events (risk ratio (RR) 2·92, 95 per cent c.i. 1·96 to 4·37; I2  = 82·6 per cent), short-term mortality (RR 5·39, 3·21 to 9·06; I2  = 0 per cent) and long-term mortality (RR 2·90, 1·83 to 4·59, I2  = 74·2 per cent). The addition of preoperative high-sensitivity troponin measurement provided improvements in cardiovascular risk discrimination (increase in C-index ranged from 0·058 to 0·109) and classification (quantified by continuous net reclassification improvement) compared with Lee's Revised Cardiac Risk Index alone. There was substantial heterogeneity and inadequate risk stratification analysis in the included studies. CONCLUSION: Raised preoperative levels of high-sensitivity troponin appear to represent a risk for postoperative major adverse cardiac events and mortality. Further study is required before high-sensitivity troponin can be used to predict risk stratification in routine clinical practice.

ANTECEDENTES: Los pacientes a los que se realiza una cirugía mayor no cardíaca tienen riesgo de presentar complicaciones cardiovasculares. En estos pacientes se observan con frecuencia niveles preoperatorios elevados de troponina de alta sensibilidad (high-sensitivity troponin, hs-cTn). Sin embargo, el valor pronóstico de la hs-cTn para predecir los resultados postoperatorios no está bien definido. MÉTODOS: Se realizó una búsqueda sistemática en las bases de datos PubMed, EMBASE y Science Citation Index Expanded de estudios observacionales publicados antes de marzo de 2018 que analizasen la posible relación de los niveles elevados preoperatorios de hs-cTn y los efectos adversos graves de tipo cardíaco (major adverse cardiac events, MACE) postoperatorios y/o la mortalidad después de la cirugía no cardíaca. Se realizó el metaanálisis utilizando modelos de efectos aleatorios siempre que fuera posible. RESULTADOS: Se incluyeron siete estudios de cohortes con un total de 4.836 pacientes. La elevación preoperatoria de hs-cTn se asoció con un mayor riesgo de MACE a corto plazo (tasa de riesgo, risk ratio, RR 2,92, i.c. del 95% 1,96-4,37, I2 = 82,6%) y con la mortalidad a corto plazo (RR 5,39, i.c. del 95 % 3,21-9,06, I2 = 0%) y a largo plazo (RR 2,90, i.c. del 95% 1,83-4,59, I2 = 74,2%). Añadir la medición preoperatoria de hs-cTn mejoró la capacidad discriminativa para el riesgo cardiovascular (aumento de 5,8% a 10,9% en el índice C) y también la clasificación de los pacientes (cuantificada mediante el índice de reclasificación neta continua) en comparación con el uso de solo el índice de riesgo cardíaco revisado de Lee. En los estudios incluidos, hubo gran heterogeneidad y análisis inadecuado de la estratificación del riesgo. CONCLUSIÓN: Los niveles preoperatorios elevados de troponina de alta sensibilidad parecen ser un marcador de riesgo de efectos adversos graves de tipo cardíaco en el postoperatorio y de mortalidad. Se requieren más estudios antes de utilizar la troponina de alta sensibilidad para la estratificación del riesgo en la práctica clínica rutinaria.

Association of High-Sensitivity Troponin with Cardiac CT Angiography Evidence of Myocardial and Coronary Disease in a Primary Prevention Cohort of Men: Results from MACS.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) elevations are associated with incident cardiovascular disease events in primary prevention samples. However, the mechanisms underlying this association remain unclear. METHODS: We studied 458 men without known cardiovascular disease who participated in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study and had cardiac CT angiography. We used multivariable linear and logistic regression models to examine the cross-sectional associations between coronary artery stenosis, coronary artery plaque, indexed left ventricular mass (LVMi), and the outcome of hs-cTnI. We also evaluated the associations between HIV serostatus or use of highly active antiretroviral therapy (HAART) and hs-cTnI. RESULTS: The mean age was 54 years, 54% were white, and 61% were HIV infected. In multivariable-adjusted logistic models, comparing the highest quartile of LVMi with the lowest quartile, the odds ratio (OR) of hs-cTnI ≥75th percentile was 2.59 (95% CI, 1.20-5.75). There was no significant association between coronary stenosis severity or plaque type and hs-cTnI in linear models; however, in logistic regression models, coronary artery stenosis ≥70% (8% of sample) was marginally associated with a higher likelihood (OR, 2.75 [95% CI, 1.03, 7.27]) of having hs-cTnI ≥75th percentile. There were no associations between HIV serostatus or HAART use and hs-cTnI in either linear or logistic models. CONCLUSION: Among primary prevention men with or at risk for HIV, hs-cTnI concentrations were strongly associated with LVMi but were not associated with HIV infection or treatment status or with coronary plaque type or stenosis until the extremes of severity (≥70% stenosis).

Ascending Defibrillation Waveform Significantly Reduces Myocardial Morphological Damage and Injury Current.

OBJECTIVES: This study tested the hypothesis that a biphasic defibrillation waveform with an ascending first phase (ASC) causes less myocardial damage by pathology and injury current than a standard biphasic truncated exponential (BTE) waveform in a swine model. BACKGROUND: Although lifesaving, defibrillation shocks have significant iatrogenic effects that reduce their benefit for patient survival. METHODS: An ASC waveform with an 8-ms linear ramp followed by an additional positive 0.5-ms decaying portion with amplitudes of 20 J (ASC 20J) and 25 J (ASC 25J) was used. The control was a 25-J BTE conventional waveform (BTE 25J) RESULTS: The ASC 20J and ASC 25J shocks were both successful in 6 of 6 pigs, but the BTE 25J was successful in only 6 of 14 pigs (p < 0.05). Post-shock ST-segment elevation (injury current) in the right ventricular electrode was significantly greater with BTE 25J than with ASC 20J and ASC 25J. With a blinded pathology reading, hemorrhage, inflammation, thrombi, and necrosis 24 h post-shock were significantly greater with BTE 25J than with ASC 20J and ASC 25J. Troponin levels were also markedly lower at 3, 4, 5, and 6 h post-shock. CONCLUSIONS: Defibrillation shocks cause electrophysiological, histological, and biochemical signs of myocardial damage and necrosis. These signs of damage are markedly less for an ASC waveform than for a conventional BTE waveform.

Multi-Site Coronary Vein Sampling Study on Cardiac Troponin T Degradation in Non-ST-Segment-Elevation Myocardial Infarction: Toward a More Specific Cardiac Troponin T Assay.

Background Cardiac troponin T ( cTnT ) is seen in many other conditions besides myocardial infarction, and recent studies demonstrated distinct forms of cTnT . At present, the in vivo formation of these different cTnT forms is incompletely understood. We therefore performed a study on the composition of cTnT during the course of myocardial infarction, including coronary venous system sampling, close to its site of release. Methods and Results Baseline samples were obtained from multiple coronary venous system locations, and a peripheral artery and vein in 71 non- ST -segment-elevation myocardial infarction patients. Additionally, peripheral blood was drawn at 6- and 12-hours postcatheterization. cTnT concentrations were measured using the high-sensitivity- cTnT immunoassay. The cTnT composition was determined via gel filtration chromatography and Western blotting in an early and late presenting patient. High-sensitivity - cTnT concentrations were 28% higher in the coronary venous system than peripherally (n=71, P<0.001). Coronary venous system samples demonstrated cT n T-I-C complex, free intact cTnT , and 29 kD a and 15 to 18 kD a cTnT fragments, all in higher concentrations than in simultaneously obtained peripheral samples. While cT n T-I-C complex proportionally decreased, and disappeared over time, 15 to 18 kD a cTnT fragments increased. Moreover, cT n T-I-C complex was more prominent in the early than in the late presenting patient. Conclusions This explorative study in non- ST -segment-elevation myocardial infarction shows that cTnT is released from cardiomyocytes as a combination of cT n T-I-C complex, free intact cTnT , and multiple cTnT fragments indicating intracellular cTnT degradation. Over time, the cT n T-I-C complex disappeared because of in vivo degradation. These insights might serve as a stepping stone toward a high-sensitivity- cTnT immunoassay more specific for myocardial infarction.

Nobiletin protects against myocardial injury and myocardial apoptosis following coronary microembolization via activating PI3K/Akt pathway in rats.

It has been found that use of drugs which upregulate the PI3K/Akt pathway can effectively reduce cardiomyocyte apoptosis which has been induced by coronary microembolization (CME). However, whether this functional protein is able to be modified through pretreatment via nobiletin (NOB) in models of CME has not yet been investigated. Therefore, this study set out to explore the cardioprotective effect of NOB on rats with myocardial injuries induced by CME and also explored the potential mechanism which underlies this cardioprotective effect. The study used 40 Sprague-Dawley (SD) rats, which were randomized into four groups: the sham, CME, CME+NOB, and CME+NOB+LY294002 (LY) groups. Twelve hours after surgery, levels of microinfarct, serum c-troponin I (cTnI), cardiac function, apoptotic index, and oxidative stress [superoxide dismutase (SOD) and malondialdehyde (MDA)] were measured for rats in each group. Western blot analysis was performed to detect any protein involved in the PI3K/Akt pathway. Nobiletin improved cardiac dysfunction which had been induced by CME, decreased serum level of cTnI and MDA, and increased serum SOD activities. In addition, nobiletin inhibited myocardial apoptosis, which may be connected to downregulated apoptotic index, upregulated Bcl-2, and cleaved caspase-3 and Bax, while it increased protein levels in phosphorylated Akt. However, when nobiletin was co-administered with LY294002, a PI3K (phosphatidylinositol 3-kinase)/Akt inhibitor, all of the previously mentioned effects were blocked. Nobiletin is able to inhibit cardiomyocyte apoptosis and can consequently attenuate CME-induced myocardial injuries. These functions are realized through the activation of the PI3K/Akt signaling pathway as well as by reducing oxidative stress.

Appropriateness of Cardiac Troponin Testing: Insights from the Use of TROPonin In Acute coronary syndromes (UTROPIA) Study.

OBJECTIVE: Our objective was to examine the appropriateness of cardiac troponin (cTn) testing among patients with cTn increases. METHODS: This is a planned secondary analysis of the Use of TROPonin In Acute coronary syndromes (UTROPIA, NCT02060760) observational cohort study. Appropriateness of cTn testing was adjudicated for emergency department patients with cTn increases >99th percentile and analyzed using both contemporary and high-sensitivity (hs) cTnI assays according to sub-specialty, diagnoses, and symptoms. RESULTS: Appropriateness was determined from 1272 and 1078 adjudication forms completed for 497 and 422 patients with contemporary and hs-cTnI increases, respectively. Appropriateness of cTnI testing across adjudication forms was 71.5% and 72.0% for cTnI and hs-cTnI, respectively. Compared with emergency physicians, cardiologists were less likely to classify cTnI orders as appropriate (cTnI: 79% vs 56%, P < .0001; hs-cTnI: 82% vs 51%, P < .0001). For contemporary cTnI, appropriateness of 95%, 70%, and 39% was observed among adjudication forms completed by cardiologists for type 1 myocardial infarction, type 2 myocardial infarction, and myocardial injury, respectively; compared with 90%, 86%, and 71%, respectively, among emergency physicians. Similar findings were observed using hs-cTnI. Discordance in appropriateness adjudication forms occurred most frequently in cases of myocardial injury (62% both assays) or type 2 myocardial infarction (cTnI 31%; hs-cTnI 23%). CONCLUSIONS: Marked differences exist in the perception of what constitutes appropriate clinical use of cTn testing between cardiologists and emergency physicians, with emergency physicians more likely to see testing as appropriate across a range of clinical scenarios. Discordance derives most often from cases classified as myocardial injury or type 2 myocardial infarction.

Universal definition of MI: Above 99 percentile of upper reference limit (URL) for hs-cTn: Yes, but which URL?

The definition of myocardial infarction (MI) is based on the detection of high-sensitive cardiac troponin (hs-cTn) levels above the 99th percentile of upper reference limit (URL) value for a healthy reference population. In the era of hs-cTn assay and the 4th definition for MI, the distinction between the injury and infarction is crucial for the clinician. Measurable troponin is present in the blood of healthy adult subjects. Thus, the calculation of the 99th percentile URL depends on the selected reference population. There is no consensus in the definition of 'reference population' among hs-cTn manufacturing companies. For example, gender, age, ethnic and populational differences affect the URL for hs-cTn assay. The URL level is substantially higher in elderly as compared with younger patients. Elevated levels of cTn are found in up to 22% of persons living in the community who are 70 years of age or older. Similarly, men have significantly higher URL levels compared to women. Using the same URL for men and women causes underdiagnosis of MI in women. Finally, the definition of MI covers a wide variety of systemic conditions that can affect the myocardium through injury or infarction. Professional societies have published their recommendations to solve the pre-analytic and analytic contraversies in hs-cTn assay. In conclusion, hs-cTn assays have revolutionized the practice of cardiology. Universal healthy normal pool and consideration of different cut off levels for different populations (i.e. elderly) can potentially help to standardize the interpretation of the hs-cTn test.

Serum cardiac troponins as prognostic markers in patients with traumatic and non-traumatic brain injuries: A meta-analysis.

OBJECTIVE: The association between brain injury and elevated serum cardiac troponin (cTn) remains poorly understood. We conducted a systematic review and meta-analysis to evaluate whether elevated cTn increases the risk of mortality in patients with traumatic (TBI) or non-traumatic brain injury (NT-BI). METHODS: Cochrane Library, MEDLINE, PubMed, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and Google scholar databases, and clinicaltrials.gov were searched for a retrospective, prospective and randomized clinical trials (RCT) or quasi-RCT studies that assessed the effect of elevated cTn (conventional or high sensitive assay) on the outcomes of brain injury patients. The main outcome of interest was mortality. Two authors independently abstracted the data using a data collection form. Results from different studies were pooled for analysis, whenever appropriate. The total number of patients pooled was 2435, of which 916 had elevated cTn and 1519 were in control group. RESULTS: Out of 691 references identified through the search, 8 analytical studies met inclusion criteria. Among both types of brain injuries, an elevated cTn was associated with a higher mortality with an overall pooled odd ratio (OR) of 3.37 (95% CI 2.13-5.36). The pooled OR for mortality was 3.31 (95% CI 1.99-5.53) among patients with TBI and 3.36 (95% CI 1.32-8.6) among patients with NT-BI. CONCLUSIONS: Pooled analysis indicates that elevated cTn is significantly associated with a high mortality in patients with TBI and NT-BI. Prospective clinical trials are needed to support these findings and to inform a biomarker risk stratification regardless of the mechanism of injury.

Unrecognised myocardial infarction and its relationship to outcome in critically ill patients with cardiovascular disease.

PURPOSE: To establish the incidence of myocardial infarction (MI) in ICU patients with co-existing cardiovascular disease (CVD), and explore its association with long-term survival. METHODS: In a multi-centre prospective cohort study in 11 UK ICUs, we enrolled 273 critically ill patients with co-existing CVD. We measured troponin I (cTnI) with a high sensitivity assay for 10 days; ECGs were carried out daily for 5 days and analysed by blinded cardiologists for dynamic changes. Data were combined to diagnose myocardial 'infarction', 'injury' or 'no injury' according to the third universal definition of MI. Patients were followed-up for 6 months. Regression and mediation analyses were used to explore relationships between acute physiological derangements, MI, and mortality. RESULTS: cTnI was detected in all patients, with a rise/fall pattern consistent with an acute hit. In 73% of patients, this peaked on days 1-3 [median 114 ng/l (first, third quartiles: 27, 393)]. Serial ECGs indicated 24.2% (n = 66) of patients experienced MI, but > 95% were unrecognized by clinical teams. Type 2 MI was the most likely aetiology in all cases. A further 46.1% (n = 126) experienced injury (no ECG changes). Injury and MI were both associated with 6-month mortality (reference: no injury): OR injury 2.28 (95% CI 1.06-4.92, p = 0.035), OR MI 2.70 (95% CI 1.11-6.55, p = 0.028). Mediation analysis suggested MI partially mediated the relationship between acute physiological derangement and 6-month mortality (p = 0.002), suggesting a possible causal association. CONCLUSIONS: Undiagnosed MI occurs in around a quarter of critically ill patients with co-existing CVD and is associated with lower long-term survival.

Possible mechanisms behind cardiac troponin elevations.

Cardiac-specific troponins are elevated in blood following cardiac injury and are the preferred diagnostic biomarkers when acute myocardial infarction is suspected clinically. Cardiac troponin (cTn) elevations are also observed in clinical conditions without obvious connection to cardiac injury. Irrespective of the underlying condition, cTn elevation is linked to a poor prognosis, even if the elevation is stable over time. Here, we explore mechanisms that may lead to cTn elevations, including necrosis, apoptosis, necroptosis, cell wounds and decreased clearance. The aim is to broaden the perspective of how we interpret unexpected cTn elevations in patients. The cTn elevations may not be able to serve as direct proof of myocardial necrosis especially in the absence of a clear-cut reason for its release. Abbreviations: AMI: acute myocardial infarction; cTn: cardiac troponin; cTnI: cardiac troponin I; cTnT: cardiac troponin T; MLKL: mixed lineage kinase domain-like; TUNEL: terminal deoxynucleotidyl transferase nick end labeling.

Diagnostic and prognostic value of H-FABP in acute coronary syndrome: Still evidence to bring.

The assessment of chest pain patients presenting to the emergency area (EA) is still a clinical challenge, as the majority of patients are not diagnosed with acute coronary syndrome (ACS). New generation high sensitivity c-Tn (hs-cTn) assays have showed better performances compared to the standard c-Tn. However, hs-Tn still presents some limitations. Hence, novel, early biomarkers are needed in this setting. Among all, heart-type fatty acid binding protein (H-FABP) has been largely investigated. This article reviews the studies evaluating H-FABP performance in diagnosing acute myocardial infarction (AMI) and stratifying chest pain patients by risk. H-FABP optimal performances in ACS have been reported by studies that used low threshold for positivity, or compared the biomarker to cTn at 3-6 h, or by studies with small sample size. Literature review allows stating that H-FABP is clearly not a reliable marker in ACS, as it is unable to diagnose AMI, neither as a stand-alone test nor combined with hs-cTn. Few evidence supports its incremental value in ruling-out AMI and its risk stratification ability for chest pain patients presenting to EA. Thus, available data may not encourage going on investigating.

Anthracycline-induced cardiotoxicity: A multicenter randomised trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial.

BACKGROUND: Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit. METHODS: The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; 'prevention' arm), and enalapril started only in patients with an increase in troponin during or after CT ('troponin-triggered' arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold. FINDINGS: Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270-360] and 240 [240-240] mg/m2, respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%. INTERPRETATION: Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.