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.

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.

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.

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.

Redesigning the diagnostic pathway for chest pain patients in emergency departments.

Patients presenting with chest pain at an emergency department in the United Kingdom receive troponin tests to assess the likelihood of an acute myocardial infarction (AMI). Until recently, serial testing with two blood samples separated by at least six hours was necessary in order to analyse the change in troponin levels over time. New high-sensitivity troponin tests, however, allow the inter-test time to be shortened from six to three hours. Recent evidence also suggests that the new generation of troponin tests can be used to rule out AMI on the basis of a single test if patients at low risk of AMI present with very low cardiac troponin levels more than three hours after onset of worst pain. This paper presents a discrete event simulation model to assess the likely impact on the number of hospital admissions if emergency departments adopt strategies for serial and single testing based on the use of high-sensitivity troponin. Data sets from acute trusts in the South West of England are used to quantify the resulting benefits.

Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure.

Tissue preconditioning, whereby various short-term stressors initiate organ resistance to subsequent injury, is well recognized. However, clinical preconditioning of the kidney for protection against acute kidney injury (AKI) has not been established. Here we tested whether a pro-oxidant agent, iron sucrose, combined with a protoporphyrin (Sn protoporphyrin), can induce preconditioning and protect against acute renal failure. Mice were pretreated with iron sucrose, protoporphyrin, cyanocobalamin, iron sucrose and protoporphyrin, or iron sucrose and cyanocobalamin. Eighteen hours later, ischemic, maleate, or glycerol models of AKI were induced, and its severity was assessed the following day (blood urea nitrogen, plasma creatinine concentrations; post-ischemic histology). Agent impact on cytoprotective gene expression (heme oxygenase 1, hepcidin, haptoglobin, hemopexin, α1-antitrypsin, α1-microglobulin, IL-10) was assessed as renal mRNA and protein levels. AKI-associated myocardial injury was gauged by plasma troponin I levels. Combination agent administration upregulated multiple cytoprotective genes and, unlike single agent administration, conferred marked protection against each tested model of acute renal failure. Heme oxygenase was shown to be a marked contributor to this cytoprotective effect. Preconditioning also blunted AKI-induced cardiac troponin release. Thus, iron sucrose and protoporphyrin administration can upregulate diverse cytoprotective genes and protect against acute renal failure. Associated cardiac protection implies potential relevance to both AKI and its associated adverse downstream effects.

Serum, milk, and tissue monensin concentrations in cattle with adequate and potentially toxic dietary levels of monensin: pharmacokinetics and diagnostic interpretation.

Used in both beef cattle and dairy cows, monensin can provide many health benefits but can, when unintended overexposures occur, result in adverse effects. Information on serum and tissue concentrations following overexposure and/or overt toxicosis which may aid in diagnostics and clinical outcome is lacking. The aim of this study was to determine concentrations of monensin in biological specimens following oral exposure for 10 days to an approved dose (1 mg/kg) and a higher dose (5 mg/kg) of monensin given daily on a body weight basis to 10 dairy cows. No deaths were reported; cows receiving 5 mg/kg showed early signs of toxicosis including depression, decreased feed intake, and diarrhea after 4 days of exposure. Histopathological findings were minimal in most cows. Pharmacokinetic modeling of the detected serum concentrations for the 1 and 5 mg/kg dose groups determined the Cmax , Tmax, and t1/2λ to be 0.87 and 1.68 ng/mL, 2.0 and 1.0 h, and 1.76 and 2.32 days, respectively. Mixed regression models showed that the dose level and days since last dose were significantly associated with monensin concentrations in all four tissues, and with cardiac troponin levels. The high dose resulted in a significant elevation of monensin in tissues at approximately 4.7 times compared to the monensin concentrations in the tissues of animals from the low-dose group. The cTnI concentrations in the high-dose group were 2.1 times that of cTnI in the low-dose group. Thus, the ability to diagnose monensin overexposure and/or toxicosis will improve from knowledge of biological monensin concentrations from this study.

Troponin in diabetic patients with and without chronic coronary artery disease.

BACKGROUND: Cardiac-specific troponin detected with the new high-sensitivity assays can be chronically elevated in response to cardiovascular comorbidities and confer important prognostic information, in the absence of unstable coronary syndromes. Both diabetes mellitus and coronary artery disease are known predictors of troponin elevation. It is not known whether diabetic patients with coronary artery disease have different levels of troponin compared with diabetic patients with normal coronary arteries. To investigate this question, we determined the concentrations of a level 1 troponin assay in two groups of diabetic patients: those with multivessel coronary artery disease and those with angiographically normal coronary arteries. METHODS: We studied 95 diabetic patients and compared troponin in serum samples from 50 patients with coronary artery disease (mean age = 63.7, 58 % male) with 45 controls with angiographically normal coronary arteries. Brain natriuretic peptide and the oxidative stress biomarkers myeloperoxidase, nitrotyrosine and oxidized LDL were also determined. RESULTS: Diabetic patients with coronary artery disease had higher levels of troponin than did controls (median values, 12.0 pg/mL (95 % CI:10-16) vs 7.0 pg/mL (95 % CI: 5.9-8.5), respectively; p = 0.0001). The area under the ROC curve for the diagnosis of CAD was 0.712 with a sensitivity of 70 % and a specificity of 66 %. Plasma BNP levels and oxidative stress variables (myeloperoxidase, nitrotyrosine, and oxidized LDL) were not different between the two groups. In a multivariate analysis, gender (p = 0.04), serum glucose (0.03) and Troponin I (p = 0.01) had independent statistical significance. CONCLUSION: Troponin elevation is related to the presence of chronic coronary artery disease in diabetic patients with multiple associated cardiovascular risk factors. Troponin may serve as a biomarker in this high-risk population. TRIAL REGISTRATION: http://www.controlled-trials.com REGISTRATION NUMBER: ISRCTN26970041.

Cardiotoxicity due to Chemotherapy: the Role of Biomarkers.

An ever-increasing array of chemotherapeutic agents is being used in the treatment of solid organ or hematologic malignancies. The success of many of these agents has led to an increasing survival of patients with cancer. However, many of these agents, particularly anthracyclines and trastuzumab, are associated with the development of cardiotoxicity. The current standard for the evaluation of chemotherapy-associated cardiotoxicity typically involves the use of serial measurements of left ventricular (LV) function by echocardiogram (Echo) and radionuclide ventriculogram (MUGA). Unfortunately, this time-honored method offers low sensitivity to the early prediction or detection of cardiac events. Frequently, by the time cardiotoxicity is detected, significant LV dysfunction has occurred and ultimately this may not respond to standard cardioprotective treatment. Cardiac biomarkers, troponin I and B-type natriuretic peptide, may allow a more accurate and timely monitoring strategy. The current data and a summarized understanding of how to utilize cardiac biomarkers for the prevention and early detection of cardiac dysfunction during chemotherapy are presented.

RIPC Remains a Promising Technique for Protection of the Myocardium during Open Cardiac Surgery: A Meta-Analysis and Systematic Review.

BACKGROUND: Remote ischemic preconditioning (RIPC) is the process of inducing brief ischemia in a tissue to prevent ischemic damage in another. This preconditioning can be induced simply by inflating a blood pressure cuff on a limb. Previous randomized controlled trials (RCT) have suggested that RIPC may infer myocardial protection during open cardiac surgery. One method of assessing the degree of myocardial damage incurred in these studies is to assay troponin concentration. Troponin is a cardiac enzyme released by damaged myocardiocytes. With the recent publication of several large RCTs in this area, a meta-analysis of the evidence was undertaken. METHODS: A systematic search of PubMed, EMBASE, and clinicaltrials.gov.uk was conducted using MeSH terms "ischaemic preconditioning" and "cardiac surgery." RCTs that examined post-surgery troponin concentrations were included in this review. The primary outcome investigated was troponin levels at six hours post-cardiac surgery. Secondary outcomes included six to eight hour and twenty-four hour troponin release. RESULTS: Thirteen RCTs, comprising 1398 participants, were identified for inclusion in this meta-analysis. Twelve hour postoperative troponin was significantly reduced by RIPC, standardized mean difference 1.29 (95% CI 0.34-2.24). Six to eight and twenty-four hour troponin were also significantly reduced, standardized mean differences 1.23 (95% CI 0.62-1.84) and 1.25 (95% CI 0.31-2.19) respectively. CONCLUSIONS: The reduction in troponin concentration suggests that RIPC reduces myocardial damage during open cardiac surgery, however, the degree of bias in the studies assessed may have had a significant impact on this result.

Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation*.

OBJECTIVE: Serum troponin concentrations predict mortality in almost every clinical setting they have been examined, including sepsis. However, the causes for troponin elevations in sepsis are poorly understood. We hypothesized that detailed investigation of myocardial dysfunction by echocardiography can provide insight into the possible causes of troponin elevation and its association with mortality in sepsis. DESIGN: Prospective, analytic cohort study. SETTING: Tertiary academic institute. PATIENTS: A cohort of ICU patients with severe sepsis or septic shock. INTERVENTIONS: Advanced echocardiography using global strain, strain-rate imaging and 3D left and right ventricular volume analyses in addition to the standard echocardiography, and concomitant high-sensitivity troponin-T measurement in patients with severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Two hundred twenty-five echocardiograms and concomitant high-sensitivity troponin-T measurements were performed in a cohort of 106 patients within the first days of severe sepsis or septic shock (2.1 ± 1.4 measurements/patient). Combining echocardiographic and clinical variables, left ventricular diastolic dysfunction defined as increased mitral E-to-strain-rate e'-wave ratio, right ventricular dilatation (increased right ventricular end-systolic volume index), high Acute Physiology and Chronic Health Evaluation-II score, and low glomerular filtration rate best correlated with elevated log-transformed concomitant high-sensitivity troponin-T concentrations (mixed linear model: t = 3.8, 3.3, 2.8, and -2.1 and p = 0.001, 0.0002, 0.006, and 0.007, respectively). Left ventricular systolic dysfunction determined by reduced strain-rate s'-wave or low ejection fraction did not significantly correlate with log(concomitant high-sensitivity troponin-T). Forty-one patients (39%) died in-hospital. Right ventricular end-systolic volume index and left ventricular strain-rate e'-wave predicted in-hospital mortality, independent of Acute Physiology and Chronic Health Evaluation-II score (logistic regression: Wald = 8.4, 6.6, and 9.8 and p = 0.004, 0.010, and 0.001, respectively). Concomitant high-sensitivity troponin-T predicted mortality in univariate analysis (Wald = 8.4; p = 0.004), but not when combined with right ventricular end-systolic volume index and strain-rate e'-wave in the multivariate analysis (Wald = 2.3, 4.6, and 6.2 and p = 0.13, 0.032, and 0.012, respectively). CONCLUSIONS: Left ventricular diastolic dysfunction and right ventricular dilatation are the echocardiographic variables correlating best with concomitant high-sensitivity troponin-T concentrations. Left ventricular diastolic and right ventricular systolic dysfunction seem to explain the association of troponin with mortality in severe sepsis and septic shock.

"Troponin elevation in coronary ischemia and necrosis".

Detection of a rise and/or fall of cardiac troponin (cTn) is the cornerstone in the diagnosis of myocardial infarction (MI). For the acute risk, it is hypothesized that cTn mirrors activated coagulation and platelet reactivity and indicates the presence of a ruptured plaque, which may help to identify patients at high risk who benefit particularly from aggressive pharmacological treatment and early invasive strategy. High-sensitivity assays using the 99th percentile as the threshold for positivity can achieve sensitivity at presentation of 90 % or more, and performance further improves with subsequent measurements within 3 to 6 h. By 3 h, negative predictive values of almost 100 % have been reported. However, use of assays with higher sensitivity lead ultimately to a loss of clinical specificity. Thus, other conditions than MI, such as stroke, pulmonary embolism, sepsis, acute perimyocarditis, Takotsubo, acute heart failure and tachycardia also can go with elevated troponin levels. The detection of brief rise and subsequent fall of troponin concentration in marathon runners, and even in healthy subjects, after a standardized exercise test has cast doubts on the hypothesis that troponin is released only upon irreversible damage. This kind of troponin leakage may originate from a cytosolic compartment of the cells and not from the necrosis of thin filaments.

Metabolic derangement and cardiac injury early after reperfusion following intermittent cross-clamp fibrillation in patients undergoing coronary artery bypass graft surgery using conventional or miniaturized cardiopulmonary bypass.

Myocardial ischemic stress and early reperfusion injury in patients undergoing coronary artery bypass grafting (CABG) operated on using intermittent cross-clamp fibrillation (ICCF) are not presently known. The role of mini-cardiopulmonary bypass (mCPB) versus conventional CPB (cCPB) during ICCF has not been investigated. These issues have been addressed as secondary objective of randomised controlled trial (ISRCTN30610605) comparing cCPB and mCPB. Twenty-six patients undergoing primary elective CABG using ICCF were randomised to either cCPB or mCPB. Paired left ventricular biopsies collected from 21 patients at the beginning and at the end of CPB were used to measure intracellular substrates (ATP and related compounds). Cardiac troponin T (cTnT) and CK-MB levels were measured in plasma collected from all patients preoperatively and after 1, 30, 60, 120, and 300 min after institution of CPB. ICCF was associated with significant ischemic stress as seen by fall in energy-rich phosphates early after reperfusion. There was also a fall in nicotinamide adenine dinucleotide (NAD(+)) indicating cardiomyocyte death which was confirmed by early release of cTnT and CK-MB during CPB. Ischemic stress and early myocardial injury were similar for cCPB and mCPB. However, the overall cardiac injury was significantly lower in the mCPB group as measured by cTnT (mean ± SEM: 96 ± 14 vs. 59 ± 8 µg/l, p = 0.02), but not with CK-MB. ICCF is associated with significant metabolic derangement and early myocardial injury. This early outcome was not affected by the CPB technique. However, the overall cardiac injury was lower for mCPB only when measured using cTnT.

Light chain amyloidosis 2012: a new era.

AL amyloidosis patients with multi-organ and particularly cardiac involvement have historically been considered to have a bad prognosis. The introduction of autologous stem cell transplantation was associated with unacceptable toxicity in high-risk patients, but responding patients have prolonged overall survival. Toxicities can be decreased by careful patient selection, but this reduces the applicability of this treatment modality to a limited number of patients. Efforts are therefore needed to design novel more effective regimens, with the use of new medications, such as thalidomide, lenalidomide and bortezomib, next generation immunomodulatory drugs and proteasome inhibitors. Their combination with dexamethasone and alkylating agents show promising results, allowing a high percentage of remission and subsequent event-free and overall survival, even in a significant proportion of high risk, poor prognosis populations. This review includes the state-of-the-art treatment for AL amyloidosis patients as of 2012, in light of the progress in management of this disease during recent years.

Myocardial performance index and biochemical markers for early detection of doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukaemia.

BACKGROUND: Despite significant improvements in the prognosis of childhood acute lymphoblastic leukaemia (ALL), the risk of anthracycline-induced cardiovascular disease remains a major concern. This study was designed to investigate the role of the myocardial performance index (MPI) and serum concentrations of biomarkers (cTnT and NT-pro-BNP) in the early detection of subclinical anthracycline-induced functional alterations in children with ALL. METHODS: All children consecutively admitted to our Pediatric Oncologic Department from January 2009 to October 2010 with a diagnosis of ALL were enrolled in this study. cTnT and NT-pro-BNP were evaluated in all patients at diagnosis, before doxorubicin therapy and 2 and 24 h following each anthracycline administration. ECG and echocardiography were performed at diagnosis and 24 h after each anthracycline course. RESULTS: Nineteen children with standard-risk ALL were evaluated. The mean age was 6 years. The cumulative doxorubicin dosage was 240 mg/m(2) according to the AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) ALL 2000 protocol. None of the 19 patients developed congestive heart failure. With increasing cumulative dosages of anthracyclines a significant increase was observed in MPI. This increase was statistically significant starting from the cumulative dosage of 120 mg/m(2) compared to baseline, while the median NT-pro-BNP level did not change significantly during treatment and cTnT levels never exceeded the cut-off value for cardiac injury. CONCLUSION: MPI value is a sensitive and accurate parameter, allowing subclinical cardiac dysfunction to be detected in children receiving anthracyclines. Lifelong cardiac surveillance of these patients is warranted in order to determine the clinical implications of increased MPI on long-term cardiac status.

Troponin.

Troponin T and I can be found within the myocardial filaments. Measuring these cardiac troponin levels in full-term newborns and premature infants has not become a common practice in the neonatal intensive care unit and newborn nurseries. Research studies are discovering that an elevation in troponin T and I levels can be directly correlated with the severity of the infant's illness, and it can be potentially prognostic of morbidity. This literature analysis discusses what can be considered normal cardiac troponin levels along with what elevated levels are and possible conditions associated with those elevations.

Influence of adaptive analysis on unnecessary patient recruitment: reanalysis of the RATPAC trial.

STUDY OBJECTIVE: Recruitment to clinical trials is a challenging but essential activity in emergency medicine. Conventional fixed-sample trials may continue to recruit patients after efficacy has been demonstrated or when further recruitment is futile. Adaptive trials make use of emerging information to modify aspects of a trial or terminate it prematurely, potentially resulting in savings in terms of sample size, time, and cost. We aim to use sequential testing procedures to reanalyze data from a fixed-sample trial, the Randomised Assessment of Treatment Using Panel Assay of Cardiac Markers (RATPAC) trial, and investigate the potential for adaptive designs to reduce unnecessary recruitment. METHODS: The trial was reanalyzed with a triangular group sequential design, with interim analyses planned every 3 months. Patients were analyzed in the order in which they entered the original trial. RESULTS: We found that the RATPAC trial could potentially have stopped 1 year earlier, with 722 patients enrolled compared with 2,243 patients in the original trial, making a potential saving of approximately $390,000. Estimates of effect were similar, and the qualitative conclusions of the original and group sequential RATPAC trials were in agreement. However, the group sequential approach is not without limitations and would have resulted in less precise estimates of effect and less information available for the subsequent evaluation of secondary endpoints. CONCLUSION: Sequential designs are well suited in emergency medicine because of the rapidly obtained outcomes and the need to avoid unnecessary recruitment. We recommend that group sequential designs be considered for clinical trials in emergency medicine.