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

The use of serial measurement of cardiac troponin (cTn) is recommended by international guidelines for the diagnosis of myocardial infarction (MI) since 2000. This article focuses on factors influencing temporal changes in high-sensitive cTn (hs)-cTn and the impact of these factors on the diagnosis of non-ST-segment elevation MI (NSTEMI). The recommendations proposed by three different international guidelines published in 2020–2021 for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation (NSTE) show some discrepancies. In particular, there is no agreement among these guidelines about cut-off or absolute change values to be used for the rule-in, especially regarding the use of sex-specific cut-off values. Furthermore, there are no sufficient evidences on the diagnostic accuracy and cost effectiveness related to cut-off values suggested for algorithms to be used by some hs-cTnI methods.

The most recent international guidelines recommend the measurement of cardiac troponin I (cTnI) and cardiac troponin T (cTnT) using high-sensitivity methods (hs-cTn) for the detection of myocardial injury and the differential diagnosis of acute coronary syndromes. Myocardial injury is a prerequisite for the diagnosis of acute myocardial infarction, but also a distinct entity. The 2018 Fourth Universal Definition of Myocardial Infarction states that myocardial injury is detected when at least one value above the 99th percentile upper reference limit is measured in a patient with high-sensitivity methods for cTnI or cTnT. Not infrequently, increased hs-cTnT levels are reported in patients with congenital or chronic neuromuscular diseases, while the hs-cTnI values are often in the normal range. Furthermore, some discrepancies between the results of laboratory tests for the two troponins are occasionally found in individuals apparently free of cardiac diseases, and also in patients with cardiac diseases. In this review article, authors discuss the biochemical, pathophysiological and analytical mechanisms which may cause discrepancies between hs-cTnI and hs-cTnT test results.

An enormous amount of experimental and clinical evidence has clearly shown that the measurement of cardio-specific biomarkers is able to significantly and independently improve the diagnostic accuracy and risk stratification in cardiovascular diseases. Furthermore, many recent studies have reported that the measurement of cardio-specific biomarkers has a positive impact also on the management and outcome of patients with cardiovascular diseases. Considering the significant and independent information associated with cardio-specific biomarkers, several studies have recently reported that the combined dosage of natriuretic peptides and cardiac troponins may be convenient not only for the diagnosis, prognosis, and treatment of heart disease, but also for general screening of the population for individuals with high cardiovascular risk. Due to the higher cost of cardio-specific biomarkers compared with other laboratory tests, the clinical adequacy of the combined measurement of natriuretic peptides and cardiac troponins must be carefully evaluated. Consequently, an increase in the clinical use of a laboratory test should be based not only on the favorable pathophysiological characteristics of a biomarker, but also on the high performance of the methods used for biomarker dosing. The purpose of this review is to discuss the clinical relevance and the possible cost efficiency of the combined dosage of natriuretic peptides and cardiac troponins in some clinical conditions, in particular those most frequently observed in patients with critical illnesses admitted to the emergency room.

Background Postexercise release of cardiac troponin (cTn) is a well-known phenomenon, although the influence of various confounders remains unclear. The aim of this critical review was to analyze the postexercise release of cTn according to age, sex, different types of sport, exercise intensity and duration, and training level. Data sources A literature search was performed within the National Library of Medicine using the following keywords: cTn, peak, release, and exercise. The search was further refined by adding the keywords athletes, children/adolescents, and sport. Main results For final analysis, 52 studies were included: 43 adult studies, 4 pediatric studies, and 5 with a mixed population of adults and children. Several studies have investigated the kinetics of cTn response after exercise with different biomarkers. The current evidence suggests that sport intensity and duration have significant effects on postexercise cTn elevation, whereas the influence of the type of sport, age, and sex have been not completely defined yet. Most data were obtained during endurance races, whereas evidence is limited (or almost absent), particularly for mixed sports. Data on young adults and professional athletes are limited. Finally, studies on women are extremely limited, and those for non-White are absent. Conclusions Postexercise release of cTn can be observed both in young and master athletes and usually represents a physiological phenomenon; however, more rarely, it may unmask a subclinical cardiac disease. The influence of different confounders (age, sex, sport type/intensity/duration, and training level) should be better clarified to establish individualized ranges of normality for postexercise cTn elevation.

We assessed whether high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, expressed by an increased TG/HDL-C ratio, predict coronary atherosclerotic disease (CAD) outcomes in patients with stable angina. We studied 355 patients (60 ± 9 years, 211 males) with stable angina who underwent coronary computed tomography angiography (CTA), were managed clinically and followed for 4.5 ± 0.9 years. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. At baseline, the proportion of males, patients with metabolic syndrome, diabetes and obstructive CAD increased across TG/HDL-C ratio quartiles, together with markers of insulin resistance, hepatic and adipose tissue dysfunction and myocardial damage, with no difference in total cholesterol or LDL-C. At follow-up, the global CTA risk score (HR 1.06, 95% confidence interval (CI) 1.03–1.09, P = 0.001) and the IV quartile of the TG/HDL-C ratio (HR 2.85, 95% CI 1.30–6.26, P Trial registration. EVINCI study: ClinicalTrials.gov NCT00979199, registered September 17, 2009; SMARTool study: ClinicalTrials.gov NCT04448691, registered June 26, 2020.

Despite the progressive improvements in diagnosis and therapy during the first 20 years of this century, the morbidity and mortality of patients with heart failure (HF) remain high, resulting in an enormous health and economic burden. Only a further improvement in understanding the pathophysiological mechanisms related to the development of cardiac injury and dysfunction can allow more innovative and personalized approaches to HF management. The renin-angiotensin system (RAS) has a critical role in cardiovascular physiology by regulating blood pressure and electrolyte balance. The RAS is mainly regulated by both angiotensin converting enzyme (ACE) and type 2 angiotensin converting enzyme (ACE2). However, the balance between the various peptides and peptidases constituting the RAS/ACE pathway remains in great part unraveled in patients with HF. This review summarizes the role of the RAS/ACE axis in cardiac physiology and HF pathophysiology as well as some analytical issues relevant to the clinical and laboratory assessment of inter-relationships between these two systems. There is evidence that RAS peptides represent a dynamic network of peptides, which are altered in different HF states and influenced by medical therapy. However, the mechanisms of signal transduction have not been fully elucidated under physiological and pathophysiological conditions. Further investigations are necessary to explore novel molecular mechanisms related to the RAS, which will provide alternative therapeutic agents. Moreover, monitoring the circulating levels of active RAS peptides in HF patients may enable a personalized approach by facilitating assessment of the pathophysiological status of several cardiovascular diseases and thus better selection of therapies for HF patients.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): The EVINCI study was supported by a grant from the European Union FP7-CP-FP506 2007 project (GA 222915). The SMARTool study was supported by a grant from the European Union H2020-PHC-30-2015 (GA 689068). This study was also partially supported by a grant from AMGEN (Protocol N. 20167781, 2017). Background. High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) characterize an atherosclerotic cardiovascular disease (CAD) risk condition defined as atherogenic dyslipidemia. Aim. To assess whether atherogenic dyslipidemia defined by TG/HDL-C ratio predicts CAD related outcomes in patients with stable angina, independently of other risk factors and treatments. Methods. We studied 355 patients (60 ± 9 y, 211m) with stable angina from the EVINCI Outcome study. Patients were characterized for clinical, bio-humoral and imaging profiles, managed clinically, and followed for 4.5 ± 0.9 years. A computed tomography angiography (CTA) coronary risk score was obtained at baseline in all patients, and at follow-up in 154 of them. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. CTA scan was repeated at follow-up in 154 patients to assess CAD progression. Results. The median value of TG/HDL-C ratio was 2.095 (2.079IQR). At baseline, the proportion of males, smoking, diabetes and metabolic syndrome, as well as circulating bio-markers of abnormal glucose metabolism and myocardial damage progressively increased across quartiles of TG/HDL-C ratio. The CTA score was significantly higher in the IV quartile of the TG/HDL-C ratio and both were the only independent predictors of the primary (CTA Score: HR 1.06, 95%CI 1.03-1.09, p = 0.001; TG/HDL-C IV quartile: HR 2.85, 95%CI 1.30-6.26, p Conclusions. In patients with stable angina, the TG/HDL-C ratio expresses a cardio-metabolic atherogenic disorder which is progressive over time and is associated with CAD related outcomes independently of LDL-C levels and treatments.

Important advances achieved in pharmacological cancer treatment have led progressively to a reduction in mortality from many forms of cancer, and increasing numbers of previously incurable patients can now hope to become cancer-free. Yet, to achieve these improved outcomes a high price has been paid in terms of untoward side effects associated with treatment, cardio-toxicity in particular. Several recent studies have reported that cardiac troponin assay using high-sensitivity methods (hs-cTn) can enable the early detection of myocardial injury related to chemotherapy or abuse of drugs that are potentially cardiotoxic. Several authors have recently suggested that changes in hs-cTn values enable the early diagnosis of cardiac injury from chemotherapy, thus potentially benefitting cancer patients with increased troponin values by initiating early cardioprotective therapy. However, large randomised clinical trials are needed in order to evaluate the cost/benefit ratio of standardised protocols for the early detection of cardiotoxicity using the hs-cTn assay in patients treated with chemotherapy.

The measurement of cardiac troponin (cTn) is recommended by all guidelines as the gold standard for the differential diagnosis of Acute Coronary Syndromes. The aim of this review is to discuss in details some key issues regarding both analytical and clinical characteristics of the high-sensitivity methods for cTn (hs-cTn), which are still considered controversial or unresolved. In particular, the major clinical concern regarding hs-cTn methods is the difficulty to differentiate the pathophysiological mechanism responsible for biomarker release from cardiomyocytes after reversible or irreversible injury, respectively. Indeed, recent experimental and clinical studies have demonstrated that different circulating forms of cTnI and cTnT can be respectively measured in plasma samples of patients with reversible or irreversible myocardial injury. Accordingly, a new generation of hs-Tn methods should be set up, based on immunometric immunoassays or chromatographic techniques, specific for circulating peptide forms more characteristics for reversible or irreversible myocardial injury. It is conceivable that this new generation of hs-cTn methods will complete the mission regarding the laboratory tests for specific cardiac biomarkers, started more than 20 years ago, which has already revolutionized the diagnosis, prognosis and management of patients with cardiac diseases.

The high-sensitivity immunoassays for cardiac troponin I (hs-cTnI) and cardiac troponin T (hs-cTnT) are recommended by all the most recent international guidelines as gold standard laboratory methods for the detection of myocardial injury and diagnosis of acute myocardial infarction (AMI). In this review article, the Authors aimed at discussing the relevant biochemical, physiological, and clinical issues related to biological variability of cTnI and cTnT. Cardiac troponins, measured with hs-cTn methods, show a better clinical profile than the other cardio-specific biomarkers (such as the natriuretic peptides, BNP and NT-proBNP). In particular, the hs-cTn methods are characterized by a low intra-individual index of variation (30% can be considered statistically significant. These favourable biological characteristics and analytical performance of hs-cTn methods significantly improved the accuracy in the diagnostic process of acute coronary syndromes (ACS) in patients admitted to emergence department. In addition, several studies have demonstrated the clinical usefulness of cardiovascular risk evaluation with hs-cTn methods in some groups of patients with clinical conditions at high cardiovascular risk (such as systemic hypertension, severe obesity, diabetes mellitus, renal insufficiency, and chronic obstructive pulmonary disease). However, screening programs in the general population with hs-cTn methods for cardiovascular risk stratification require further investigation to define the optimal target populations, timing of measurement, and preventive interventions.

Bakground The aim of this study was to evaluate both analytical characteristics and clinical results of a new chemiluminescent method for the measurement of cardiac troponin I (cTnI), named VITROS ® High Sensitivity Troponin I Assay, using the VITROS® 3600 automated platform. The results found with this new method were compared to those observed with hs-cTnI ARCHITECT and ECLIA hs-cTnT ELECSYS methods. Methods For evaluation of analytical performance and comparison of clinical results, plasma samples (lithium-heparin), were collected from apparently healthy subjects and patients with cardiovascular diseases. Results The hs-cTnI VITROS method showed values for limit of blank (LoB 0.33 ng/L), limit of detection (LoD, 0.91 ng/L), limit of quantifications at 20% (LoQ 20% CV, 1.82 ng/L), and 10% (LoQ 10% CV, 4,74 ng/L), which are comparable to those previously reported for other hs-cTnI methods. Moreover, the clinical results of the hs-cTnI VITROS method were found to be closely correlated to those of hs-cTnI ARCHITECT (R = 0,9883, N = 198) and ECLIA hs-cTnT Elecsys (R = 0,9704, N = 293) methods. Conclusions The hs-cTnI VITROS method shows analytical performance comparable to other cTnI and cTnT assay. The results of this study confirm that there are significant systematic differences among hs-cTnI methods. Further multicenter studies using larger reference populations are needed in order to obtain a better estimation, especially of the 99° percentile URL values categorized for sex and age of hs-cTnI and hs-cTnT methods.

Cardiac troponins (cTn) are the preferred biomarkers for the evaluation of myocardial injury and play a key role in the diagnosis of acute myocardial infarction (MI). Pre-analytical or analytical issues and interferences affecting troponin T and I assays are therefore of major concern given the risk of misdiagnosis. False positive troponin results have been related to various interferences including anti-troponin antibodies, heterophilic antibodies, or elevated alkaline phosphatase level. On the other hand, false negative results have been reported in the case of a large biotin intake. These interferences are characterized with erroneous but reproducible troponin results. Of interest, non-reproducible results have also been reported in the literature. In other words, if the sample is reanalyzed a second time, a significant difference in troponin results will be observed. These interferences have been named “fliers” or “outliers”. Compared to the biotin interference that received major attention in the literature, troponin outliers are also able to induce harmful clinical consequences for the patient. Moreover, the prevalence of outliers in recent studies was found to be higher (0.28–0.57%) compared to the biotin interference. The aim of this systematic review is to warn clinicians about these non-reproducible results that may alter their clinical judgment. Four case reports that occurred in the Clinique of Saint-Luc Bouge are presented to attest this point. Moreover, we aimed at identifying the nature of these non-reproducible troponin results, determining their occurrence, and describing the best way for their identification.

All the latest international guidelines recommend that cardiac troponin (cTn) I and T should be considered the preferred biomarkers for diagnosis of acute myocardial infarction. However, only in the last 5 years, a progressive improvement in analytical performance of immunometric assays has allowed the measurement of circulating levels of cTnI and cTnT in the large part of apparently healthy adult subjects. The routine use of these high-sensitivity methods for cardiac troponin (hs-cTn) assay has in a short time demonstrated that cardiac troponin concentrations frequently increase after strenuous prolonged exercise in healthy athletes. This acute response of hs-cTn assay following exercise was at first considered to be physiological and without long-term adverse consequences. More recent studies have suggested that exercise-induced increases in hs-cTn values may not be always a physiological response to exercise, but, conversely, it should sometimes be considered as an early cardiovascular risk marker. The aim of this review is to provide an overview of acute and chronic effects of strenuous physical exercise on hs-cTn circulating levels and also to discuss the potential pathophysiological and clinical implications of biomarker responses.

BACKGROUND High sensitivity cardiac troponins I (hs-cTnI) and T (hs-cTnT) and natriuretic peptides (BNP and NT-proBNP) are universally recognized as cardiac reference biomarkers in patients with acute coronary syndromes and heart failure respectively. However, while on one hand the high sensitivity methods of cardiac biomarkers have provided answers to fundamental pathophysiological and clinical questions in patients with heart disease, less information is available on their assessment in paraphysiological conditions, such as high intensity exercise in healthy athletes. The aim of this study was to evaluate hs-cTnI and NT-proBNP in highly trained runners after a 50 km ultramarathon. METHODS We have enrolled 20 highly trained male athletes who have run a 50 km ultramarathon. Blood samples were collected 2 hours before the start of the race (T0) and 20 minutes after the end of the race (T1). The blood concentrations of hs-cTnI and NT-proBNP measured before the race were within reference intervals in all runners. RESULTS Hs-cTnI significantly increased after the end of the race (median: 19 ng/L [IQR: 12.5-25.75] versus 6 ng/L [IQR: 4.25-8.0]; P

Background The study aim was to evaluate whether is possible to harmonize the results of two hs-cTnI methods using a recalibration procedure based on linear regression models and measured values of external quality assessment (EQA) and clinical samples. Methods A two-step experimental approach was used. The preliminary step was performed using 16 EQA samples. The harmonization procedure was then validated by using 2530 heparinized plasma samples collected by 12 Italian University and Regional Hospitals from apparently healthy volunteers and patients admitted to emergency department with cardiac diseases. Two hs-cTnI methods were tested: Architect Stat High Sensitive Troponin-I, and the Access hs-cTnI using DxI platform. Linear regression models based on mean values measured with the two hs-cTni methods were used. Results A significant reduction in the measurement bias between the two methods was found after recalibration procedure. The agreement between-methods improved of about 2.5 folds after recalibration, as assessed by reduction in mean CV values from 38.4% (SD 25.9%) before recalibration to 15.0% (SD 10.6%) after recalibration for hs-cTnI values ≤ 500 ng/L (n = 13, P = 0.0111 by non-parametric test for paired data). Conclusions A recalibration procedure based on means of measured concentrations with hs-cTnI methods, which use monoclonal antibodies with similar binding characteristics, can be used to significantly reduce systematic bias and so to improve harmonization between methods. The results of this study can aid laboratorians and clinicians to better compare the concentrations respectively measured with the Architect and Access hs-cTnI methods.

In recent years, the formulation of some immunoassays with high-sensitivity analytical performance allowed the accurate measurement of cardiac troponin I (cTnI) and T (cTnT) levels in reference subjects. Several studies have demonstrated the association between the risk of major cardiovascular events and cardiac troponin concentrations even for biomarker values within the reference intervals. High-sensitivity cTnI and cTnT methods (hs-cTn) enable to monitor myocardial renewal and remodelling, and to promptly identify patients at highest risk ofheart failure. An early and effective treatment of individuals at higher cardiovascular risk may revert the initial myocardial remodelling and slow down heart failure progression. Specific clinical trials should be carried out to demonstrate the efficacy and efficiency of the general population screening by means of cost-benefit analysis, in order to better identify individuals at higher risk for heart failure (HF) progression with hs-cTn methods.

Drug-induced cardiotoxicity is a major clinical problem; cardiotoxic drugs may induce both cardiac dysfunction and myocardial injury. Several recent studies reported that cardiac troponins measured with high-sensitivity methods (hs-cTn) can enable the early detection of myocardial injury related to chemotherapy or abuse of drugs that are potentially cardiotoxic. Several authors have some concerns about the standard definition of cardiotoxicity, in particular, regarding the early evaluation of chemotherapy cardiotoxicity in cancer patients. Several recent studies using the hs-cTn assay indicate that myocardial injury may precede by some months or years the diagnosis of heart failure (HF) based on the evaluation of left ventricular ejection fraction (LVEF). Accordingly, hs-cTn assay should considered to be a reliable laboratory test for the early detection of asymptomatic or subclinical cardiotoxic damage in patients undergoing cancer chemotherapy. In accordance with the Fourth Universal Definition of Myocardial Infarction and also taking into account the recent experimental and clinical evidences, the definition of drug-cardiotoxicity should be updated considering the early evaluation of myocardial injury by means of hs-cTn assay. It is conceivable that the combined use of hs-cTn assay and cardiac imaging techniques for the evaluation of cardiotoxicity will significantly increase both diagnostic sensitivity and specificity, and also better prevent chemotherapy-related left ventricular (LV) dysfunction and other adverse cardiac events. However, large randomized clinical trials are needed to evaluate the cost/benefit ratio of standardized protocols for the early detection of cardiotoxicity using hs-cTn assay in patients receiving chemotherapy for malignant diseases.

Objectives The aims of this paper were to evaluate the levels of Vitamin D (VitD) in patients with heart failure (HF), compared to a control group, to assess the effects of VitD on HF outcome and to compare VitD measurement between LIAISON immunoassay and HPLC-MS-MS methods in this population. Design and Methods We collected clinical, biochemical and outcome data from 247 patients with HF and in a subgroup of 151 patients, we measured VitD both with LIAISON and HPLC-MS-MS. Results HF patients had statistically lower 25OHD levels (45.2 ± 23.7 nmol/L vs 58.2 ± 24.0 nmol/L, P P P P = 0.02), confirmed in a multivariate adjusted analysis. Kaplan–Meier survival analyses showed that VitD insufficiency was associated with reduced survival in HF patients (log rank P = 0.017). There was a good agreement between LIAISON and HPLC-MS-MS (Cohen’s kappa coefficient 0.70), but the prevalence of VitD insufficiency was significantly higher with the former compared to the latter method (58.3%, n = 88 vs 55.6%, n = 84, P Conclusions 25OHD levels adequately measured by HPLC-MS-MS showed to be low in HF population and to be correlated with HF-related risk of death.

To the Editor: Vigorous endurance-type exercise causes cardiac troponin T (cTnT)1 elevations that often exceed the diagnostic cutoff value for acute myocardial infarction (AMI) (1). It remains to be investigated whether exercise-induced cTnT release reflects a physiological or pathological process. Our recent studies utilizing multiple protein analysis techniques allowed determination of circulating cTnT forms, and it appeared that these are different in acute vs chronic pathologies (2, 3). In sera of AMI patients, cTnT is degraded from its intact form (estimated molecular weight by SDS-PAGE; MW est, 40 kDa) to primary ( MW est, 29 kDa) and subsequent secondary ( MW est, 14–18 kDa) fragments in a time-dependent manner (2). Only …

OBJECTIVE Pharmacologically induced glycosuria elicits adaptive responses in glucose homeostasis and hormone release, including decrements in plasma glucose and insulin levels, increments in glucagon release, enhanced lipolysis, and stimulation of ketogenesis, resulting in an increase in ketonemia. We aimed at assessing the renal response to these changes. RESEARCH DESIGN AND METHODS We measured fasting and postmeal urinary excretion of glucose, β-hydroxybutyrate (β-HB), lactate, and sodium in 66 previously reported patients with type 2 diabetes and preserved renal function (estimated glomerular filtration rate ≥60 mL · min−1 · 1.73 m−2) and in control subjects without diabetes at baseline and following empagliflozin treatment. RESULTS With chronic (4 weeks) sodium–glucose cotransporter 2 inhibition, baseline fractional glucose excretion ( CONCLUSIONS We conclude that the sodium–glucose cotransporter 2 inhibitor–induced increase in β-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.

C-type natriuretic peptide (CNP) is an endogenous adipogenesis regulator whose plasma levels in childhood are known, while no data are available on its expression. Our aim was to evaluate both CNP plasma levels and CNP system expression in whole blood obtained from normal-weight (N, n = 24) and obese (O, n = 16) adolescents (age:13.5 ± 0.4 years). Endothelial function was assessed measuring reactive hyperemia index (RHI). CNP plasma levels, evaluated with specific RIA, resulted significantly lower in O than in N (6.1 ± 0.8 vs.15.2 ± 1.3 pg/mL; p 0.0001), while CNP/NPR-B/NPR-C mRNA, measured by Real-Time PCR, resulted similar in N (4.1 ± 1.7; 5.0 ± 1.6; 2.2 ± 0.9) and in O (4.3 ± 1.6; 3.5 ± 1.1; 2.3 ± 0.8). RHI was significantly lower in O than in N (1.4 ± 0.08 vs.2.1 ± 0.04, p 0.0001). Dividing all subjects according to the RHI median value, irrespective of the presence or absence of obesity (Group 1 1.9, n = 23, Group 2 1.9, n = 17), CNP plasma concentrations resulted significantly (p = 0.014) higher in Group 1 (14.6 ± 1.6) than in Group 2 (7.5 ± 1.0), showing a significant correlation with RHI (p = 0.0026), while CNP mRNA expression was, surprisingly, higher in Group 2 (7.0 ± 2.3) than in Group 1 (1.8 ± 0.4; p = 0.02). NPR-B mRNA resulted similar in both Groups (4.3 ± 1.6; 4.7 ± 1.3) and NPR-C significantly higher in Group 2 (p = 0.02). Our data suggest different trends between CNP plasma levels and expression, assessed for the first time in whole blood, that could reflect changes occurring both at CNP transcriptional level in activated leukocytes due to inflammation, and at circulating levels, due to CNP paracrine/autocrine activities. This could represent an interesting area for new therapies able to modulate endothelial dysfunction.

Background The Italian Society of Clinical Biochemistry (SIBioC) and the Italian Section of the European Ligand Assay Society (ELAS) have recently promoted a multicenter study (Italian hs-cTnI Study) with the aim to accurately evaluate analytical performances and reference values of the most popular cTnI methods commercially available in Italy. The aim of this article is to report the results of the Italian hs-cTnI Study concerning the evaluation of the 99th percentile URL and reference change (RCV) values around the 99th URL of the Access cTnI method. Materials and methods Heparinized plasma samples were collected from 1306 healthy adult volunteers by 8 Italian clinical centers. Every center collected from 50 to 150 plasma samples from healthy adult subjects. All volunteers denied the presence of chronic or acute diseases and had normal values of routine laboratory tests (including creatinine, electrolytes, glucose and blood counts). An older cohort of 457 adult subjects (mean age 63.0 years; SD 8.1 years, minimum 47 years, maximum 86 years) underwent also ECG and cardiac imaging analysis in order to exclude the presence of asymptomatic cardiac disease. Results and conclusions The results of the present study confirm that the Access hsTnI method using the DxI platform satisfies the two criteria required by international guidelines for high-sensitivity methods for cTn assay. Furthermore, the results of this study confirm that the calculation of the 99th percentile URL values are greatly affected not only by age and sex of the reference population, but also by the statistical approach used for calculation of cTnI distribution parameters.

Background The aims of this study were: (1) to calculate reliable thyroid stimulating hormone (TSH) reference intervals using laboratory databases; (2) to evaluate the relationship between TSH, sex and age values in different large Italian populations. Methods The TSH values stored in the laboratory information system of clinical laboratories of four Italian city hospitals, including 146,801 TSH measurements (with the respective age and sex data of individuals) were taken in consideration. Assuming a log-normal distribution, to log-transformed TSH values were applied the Dixon’s iterative principle in order to exclude the outliers. At the end of this iterative process 142,821 log-transformed TSH results remained. The four clinical laboratories measured serum TSH concentrations using the same TSH immunoassay method (Access TSH 3rd IS, using UniCel DxI platform). Results The TSH reference interval calculated in the present study (0.362–5.280 mIU/L) is similar to that suggested by the manufacturer for the Access TSH 3rd IS assay (0.45–5.33 mIU/L). TSH values in females were significantly higher than in males (females: mean=2.06 mIU/L; standard deviation [SD]=1.26 mIU/L; n=101,243; males: mean=1.92 mIU/L; SD=1.19 mIU/L; n=41,578; p Conclusions The results of the present multicenter study confirm that data mining techniques can be used to calculate clinically useful reference intervals for TSH. From a pathophysiological point of view, our results suggest that some Northern populations of Italy might still suffer some harmful effects on the thyroid gland due to mild to moderate iodine intake deficiency. Specific clinical trials are needed to confirm these results.

Rigid bronchoscopy has historically been introduced more than 100 years ago and has successfully passed the test of time reaching present with renewed interest and usefulness. For long time it was mainly performed for therapeutic interventions of foreign bodies removal and dilation of stenosis. In the mid-1960s, the flexible bronchoscope appeared on the scene, bringing with its important changes: the audience of actors for bronchoscopic procedures expanded from surgeons to pneumologists too; the lower invasiveness of the procedure determined a clear reduction in the number of rigid bronchoscopies performed. A renewed interest in rigid bronchoscopy occurred around the mid-1980s: the need to provide the increasingly frequent diagnosis of lung cancer on the one hand, technological development and the subsequent advent of new endobronchial therapies on the other, have led to the genesis of a new specialty, interventional pneumology. Today, rigid bronchoscopy is used primarily as a means of access to central airways for the management of patients with difficult benign and malignant airway disorders. In this review we will analyse the different applications of rigid bronchoscopy in children, with a particular focus on interventional endoscopic procedures.

Background C-peptide and insulin are widely used in clinical practice for the diagnosis for several conditions, including hypoglycaemia and diabetes. However, the lack of method harmonization represents an important analytical limitation. Aims of this study were to evaluate new Mindray CL-2000i C-peptide and insulin methods for precision and comparability with Tosoh AIA-CL2400 and Siemens Immulite 2000 systems. Methods Mindray CL-2000i precision was evaluated by the CLSI EP15-A3 protocol and compared with the manufacturer's claimed values. A series of one hundred sixty-five specimens were used for comparing C-peptide and immunoreactive insulin (IRI) between Mindray CL-2000i, Tosoh AIA-CL2400 and Siemens Immulite 2000. Results Mindray CL-2000i repeatability results were 1.7% and 1.35% for C-peptide and 2.1% and 1.2% for IRI. Intermediate precisions were 2.6% and 1.4% for C-peptide and 4.6% and 2.3% for IRI. For C-peptide, Mindray CL-2000i performed similarly to Tosoh AIA-CL2400; for IRI a good agreement between Mindray C-2001 and Siemens Immulite 2000was found. Conclusions Mindray CL-2000i shows a low imprecision while a satisfactory for IRI between Mindray 2000i and Siemens Immulite 2000 was onbserved. Overall, results emphasize the need for standardization/harmonization efforts for both C-peptide and IRI measurement.

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

Current guidelines worldwide recommend cardiac troponins I (cTnI) and T (cTnT) as the biomarkers of choice for the differential diagnosis of acute coronary syndrome (ACS), and the measurement of the 99th upper reference population limit (URL) value for cardiac troponins, with an imprecision of ≤10 CV%. Measuring the 99th URL of cTnI and cTnT is a challenging analytical task due to low biomarker concentrations present in healthy subjects. Therefore, since the year 2006, several manufacturers have established new generation cTnI and cTnT immunoassays with an improved analytical sensitivity in accordance with the quality specifications described in international guidelines, the more recent of which state that only immunoassays that meet the required quality specifications should be considered "high-sensitivity" methods. For the early diagnosis of ACS, and for the stratification of cardiovascular risk in cardiac patients and the general population, high-sensitivity methods should be employed. It is therefore important for laboratory professionals and clinicians to gain a thorough understanding of the analytical performances of immunoassay methods for cTnI and cTnT, especially at low to normal concentration ranges. The aim of the present study was to analyze critical aspects related to definition, analytical performance, pathophysiological interpretations, and the clinical relevance of high-sensitivity cardiac troponin assays.

Over the past 10years cardiac troponin (cTn) immunoassays have been improved in analytical sensitivity and precision thereby allowing the measurement of cTn in adult healthy subjects. However, there are currently substantial gaps in our knowledge on circulating levels of cTn in healthy children. The aim of this study is to evaluate the distribution of plasma troponin concentration in apparently healthy pediatric subjects using a high sensitive immunoassay for cTnI measurement (hs-cTnI). Blood samples were obtained from 357 healthy pediatric subjects [204 males; age range 0-18years; mean (SD): 8.7(6) years], including 36 subjects aged

Background Ventricular Assist Device (VAD) as bridge to transplantation is a common therapy for adult with heart failure (HF), but VAD use is increasing also in children. Cardiac and inflammatory biomarkers have an important role in the diagnosis and prognosis of HF in adults, but their role in paediatric setting is unknown. The aim of this study was to examine changes in cardiac and inflammatory biomarkers, both in HF paediatric and adult patients, before and following VAD. Methods Cardiac (NT-proBNP, cTnI, sST2,Gal-3) and inflammatory (IL-6,IL-8) biomarkers were determined in plasma collected from 12 paediatric patients and 7 adult patients with HF, before and at 4 h,1,3,7,14 and 30 days after VAD implant. Results All biomarkers increased up to 1 day after VAD implant and then decreased at pre-VAD levels in 1 month in both groups. Only in children, NT-proBNP decreased significantly after 30 days Post-VAD treatment compared to pre-VAD levels. During the post-operative time-course, NT-proBNP and sST2 were significantly higher in children than adults, while IL-6 was lower. Conclusions Cardiac and inflammatory biomarkers were differently modified by VAD implant in children compared to adults. These preliminary data could suggest that different molecular pathways may underlie HF patho-physiology of the two groups, possibly paving the way to a specific and targeted therapeutic intervention in the near future.

The international guidelines “on the Redefinition of AMI”, published in 2000 by the Joint European Society of Cardiology/American College of Cardiology (ESC/ACC) Committee, for the first time recommended that an increase of cardiac troponin I (cTnI) or T (cTnT) values over the 99 th percentile upper reference limit (99 th URL) should be considered as clinically significant, and they also specifically indicated that this thresholds value should be measured with an imprecision ≤10 coefficient of variation (CV%) (1).

noBackground & Objectives: The postoperative Low T3 syndrome has been considered as a possible source of reduced myocardial contractility, resulting in increased mortality after CABG. Effect of preoperative Low T3 has not been well studied in patients undergoing CABG surgery. Aim of our study is to evaluate effect of preoperative Low T3 syndrome in patients undergoing CABG surgery.Materials & Methods: Six hundred and six patients undergoing CABG were included in this prospective study. The impact of the base-line FT3 concentration and of preoperative low T3 syndrome on the risk of postoperative low cardiac output and hospital death was analyzed.Results: Fifteen patients (2.3%) postoperatively and 159 (26.2%) developed major complications. At univariate analysis a reduced EF, the presence of peripheral vascular disease, the NYHA class, the surgical urgency, the aortic cross-clamp time, the CPB time and the FT3 concentration at admission were significantly associated with low CO and higher mortality. At multivariate analysis, the CPB time, an emergency procedure, a reduced LVEF, and the fT3 concentration were independently related to the development of low CO. However, in multivariate analysis low EF, and the fT3 concentration were the only predictors of hospital death.Conclusion: We conclude that preoperative low EF and low T3 syndrome independently causes low cardiac output and higher mortality in patients undergoing CABG. Therefore, all patients undergoing CABG should be evaluated for low T3 syndrome and patients with low T3 syndrome should be considered at increased risk. Appropriate preoperative T3 replacement therapy could decrease the postoperative complications in patients undergoing CABG.JCMS Nepal. 2015; 11(2):1-7

Elevation of resting high-sensitivity troponin (hs-Tn) holds prognostic value in heart failure (HF), but its pathophysiological meaning is unclear. We aimed to investigate hs-Tn elevation after maximal exercise in patients with systolic HF and its neurohormonal and hemodynamic correlates: 30 patients diagnosed with systolic HF (left ventricular ejection fraction 32 ± 8%, mean ± SD), on guideline-directed medical therapy and not recognized inducible ischemia, underwent maximal cardiopulmonary stress test, with assay of plasma N -terminal proB-type natriuretic peptide (NT-proBNP), norepinephrine (NE), and hs-TnT (hs-TnT) at baseline, peak, and 1 and 4 hours after exercise. Cardiac output (CO) was measured during effort, with a rebreathing technique. The natural logarithm of the ratio between percentage (%) increase in CO and NT-proBNP (ln[CO%/NT-proBNP% increase]) was evaluated, as a noninvasive estimate of Frank–Starling adaptation to effort, with NT-proBNP variation considered as a surrogate of end-diastolic left ventricular pressure variation. Hs-TnT increased during exercise with a 4-hour peak (p = 0.001); 10 patients had hs-TnT increase >20%. Patients with Hs-TnT increase >20% were more symptomatic at rest (p = 0.039) and showed greater NE at peak exercise (p = 0.003) and less ln[CO%/NT-proBNP% increase] (p = 0.034). A lower ln[CO%/NT-proBNP% increase] correlated with greater NE at peak exercise ( r = −0.430, p = 0.018). In conclusion, acute troponin elevation after maximal exercise was detected in 1/3 of this series. The association of troponin release with NE, CO, and NT-proBNP changes after effort suggests a pathophysiological link among transient hemodynamic overload, adrenergic activation, and myocardial cell damage, likely identifying a clinical subset at greater risk for HF progression.

Recently, adrenomedullin (ADM) was defined as a new member of the adipokine family. ADM secreted by adipocytes, through its vasodilator and antioxidant actions, might be protective against metabolic syndrome-associated cardiovascular complications. The aim of the study was to assess plasma mid-regional (MR)-proADM levels in obese adolescents compared to normal-weight subjects and its relation with BMI, body composition and metabolic indices. Plasma MR-proADM was measured in 32 healthy adolescents [BMI z-score (mean ± SEM) = 0.6 ± 0.09 and 0.8 ± 0.07 in females and males, respectively] and in 51 age-matched obese adolescents [BMI z-score (mean ± SEM) = 2.8 ± 0.12 and 2.9 ± 0.08 in female and males, respectively] by a time-resolved amplified cryptate emission technology assay. Plasma MR-proADM levels resulted significantly higher in obese than in normal-weight adolescents (MR-proADM: 0.33 ± 0.1 vs 0.40 ± 0.1 nmol/L, p

Ventricular remodeling occurs progressively in untreated patients after large myocardial infarction and in those with cardiomyopathy. The pathologic changes of increased left ventricular (LV) volume and perturbation in the LV chamber geometry involve not only the myocytes, but also the non-myocyte cells and the extracellular matrix. Inflammation, fibrosis, neuro-hormonal activation, and ongoing myocardial damage are the mechanisms underlying remodeling. The detection of an ongoing remodeling process by means of biomarkers such as cytokines, troponins, neurohormones, metalloproteinases, galectin-3, ST-2 and others, may hold a clinical value and could, to some extent, drive the therapeutical strategy in patients after a myocardial infarction or with heart failure. For this reason, there is an increasing interest in the development of new biomarkers and a great number of laboratory tests have been recently proposed, whose clinical usefulness, however, is not fully established yet.

It is well known that the results of immunoassay methods can be affected by specific or non-specific interferences, ranging from 0.4% to 4.0%. The presence of interference may greatly compromise the accuracy of immunoassay analyses causing an error in the measurement, producing false-positive or false-negative results. From a clinical point of view, these analytical errors may have serious implications for patient care because they can cause misdiagnosis or inappropriate treatment. Unfortunately, it is a very difficult task to identify the irregular analytical errors related to immunoassay methods because they are not detectable by normal laboratory quality control procedures, are reproducible within the test system, may be clinically plausible and are relatively rare. The first line of defense against erroneous results is to use in laboratory practice only immunoassay systems with the highest level of robustness against interference. The second line of defense is always taking into account the possibility of interference in immunoassay results. A correct approach should be addressed on identification of samples at high risk of interference. The attainment of this goal requires a critical review of the test result in relation to patient’s clinical conditions and literature data, taking into account the analytical characteristics of the immunoassay system. The experts in immunoassay systems should make every effort to find some specific and reliable quality indicators for irregular analytical errors in order to better detect and monitor erroneous immunoassay results due to specific or non-specific interferences.

The results of several recent experimental studies using animal models and clinical trials suggested that obesity is not merely an epiphenomenon or a prominent comorbidity in patients with heart failure (HF). Indeed, recent studies suggest that obesity is intimately involved in the pathogenesis of HF with preserved ejection fraction (HFpEF). The most recent studies indicate that approximately 50% of HF patients have HFpEF. As standard pharmacological treatment usually shows only a weak or even neutral effect on primary outcomes in patients with HFpEF, treatment strategies targeted to specific groups of HFpEF patients, such as those with obesity, may increase the likelihood of reaching substantial clinical benefit. Considering the well-known inverse relationship between body mass index (BMI) values and B-type natriuretic peptide (BNP) levels, it is theoretically conceivable that the measurement of natriuretic peptides, using cutoff values adjusted for age and BMI, should increase diagnostic and prognostic accuracy in HFpEF patients. However, further experimental studies and clinical trials are needed to differentiate and better understand specific mechanisms of the various HFpEF phenotypes, including obese HFpEF.