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Aims Gamma-glutamyltransferase (GGT) has been recognized as a cardiovascular risk factor, and its highest molecular weight fraction [big GGT (b-GGT)] is found in vulnerable atherosclerotic plaques. We explored the relationship between b-GGT, computed tomography findings, and long-term outcomes in the general population. Methods and results Between May 2010 and October 2011, subjects aged 45–75 years living in a Tuscan city and without known cardiac disease were screened. The primary endpoint was a composite of cardiovascular death or acute coronary syndrome requiring urgent coronary revascularization. Gamma-glutamyltransferase fractions were available in 898 subjects [median age 65 years (25th–75th percentile 55–70), 46% men]. Median plasma GGT was 20 IU (15–29), and b-GGT was 2.28 (1.28–4.17). Coronary artery calcium (CAC) score values were 0 (0–60), and the volume of pro-atherogenic epicardial fat was 155 mL (114–204). In a model including age, sex, low-density lipoprotein (LDL) cholesterol, current or previous smoking status, hypertension, diabetes, obesity, b-GGT independently predicted epicardial fat volume (EFV) (r = 0.162, P < 0.001), but not CAC (P = 0.198). Over a 10.3-year follow-up (9.6–10.8), 27 subjects (3%) experienced the primary endpoint. We evaluated couples of variables including b-GGT and a cardiovascular risk factor, CAC or EFV. Big GGT yielded independent prognostic significance from age, LDL cholesterol, current or previous smoking status, hypertension, diabetes, obesity, but not CAC or EFV. Conversely, GGT predicted the primary endpoint even independently from CAC and EFV. Conclusion Big GGT seemed at least as predictive as the commonly available GGT assay; therefore, the need for b-GGT rather than GGT measurement should be carefully examined.

Cardiac amyloidosis (CA) is associated with an elevation of natriuretic peptides and troponins, predicting outcome. Nevertheless, the diagnostic yield of these biomarkers has not been extensively investigated. This study aimed to evaluate the diagnostic performance for CA of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT).Patients with suspected CA (n=1,149) underwent a diagnostic work-up in 3 Centers in Italy, France (n=343, derivation cohort), and United Kingdom (n=806, validation cohort). Biomarker values with either 100% sensitivity or ≥95% specificity were selected as rule-out/rule-in cut-offs, respectively. In the derivation cohort, 227 patients (66%) had CA, and presented with higher NT-proBNP and hs-TnT. NT-proBNP 180 ng/L and hs-TnT 14 ng/L were selected as rule-out cut-offs, and hs-TnT 86 ng/L as rule-in cut-off. NT-proBNP180 ng/L or hs-TnT14 ng/L were found in 7% of patients, ruled out without false negatives. In the validation cohort, 20% of patients (2% false negatives) had NT-proBNP180 ng/L or hs-TnT14 ng/L, and 10% showed both biomarkers below cut-offs (0.5% false negatives). These cut-offs refined CA prediction when added to echocardiographic scores in patients with a hematologic disease or an increased wall thickness. In the validation cohort, the 86 ng/L hs-TnT cut-off ruled in 20% of patients (2% false positives). NT-proBNP and hs-TnT cut-offs retained their rule-out and rule-in performance also in cohorts with CA prevalence of 20%, 10%, 5% and 1% derived from the original cohort through bootstrap analysis.Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT-proBNP180 ng/L and hs-TnT14 ng/L reliably exclude the diagnosis, both in the overall population and subgroups referred for either AL-CA or cardiac (pseudo)hypertrophy.

Background and aims Fibroblast growth factor-23 (FGF23) has been associated with left ventricular (LV) hypertrophy, fibrosis, and heart failure (HF). We aimed to investigate the clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients. Methods Patients with systolic HF (left ventricular ejection fraction – LVEF Results We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were 50.9 pg/mL. Patients in the upper iFGF23 tertile had lower LVEF (p=0.014), higher N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.001), and lower peak VO2 (p Conclusions Circulating iFGF23 is associated with renal dysfunction, disease severity and outcome in systolic HF. Figure. Prognostic impact of FGF23 levels in patients with systolic heart failure (HF). In a cohort of HF patients with systolic dysfunction, higher iFGF23 levels (marker of increased cardiac fibrosis and hypertrophy) were associated with a more severe disease, as expressed by lower left ventricular systolic function, higher circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), lower oxygen consumption at cardiopulmonary exercise test and worse renal function. Moreover, iFGF23 elevation identified patients at higher risk for all-cause and cardiac mortality, and HF hospitalization.

Background Cardiac amyloidosis (CA) is associated with an elevation of natriuretic peptides and troponins, predicting outcome. Nevertheless, the diagnostic yield of these biomarkers has not been extensively investigated. Aim To evaluate the diagnostic performance for CA of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT). Methods Patients with suspected CA (n=1,149) underwent a diagnostic work-up in 3 Centers in Italy, France (n=343, derivation cohort), and United Kingdom (n=806, validation cohort). Biomarker values with either 100% sensitivity or ≥95% specificity were selected as rule-out/rule-in cut-offs, respectively. Results In the derivation cohort, 227 patients (66%) had CA, and presented with higher NT-proBNP and hs-TnT. NT-proBNP 180 ng/L and hs-TnT 14 ng/L were selected as rule-out cut-offs, and hs-TnT 86 ng/L as rule-in cut-off. NT-proBNP Conclusions Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT-proBNP

Background An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling, increasing the risk for ventricular arrhythmias and heart failure. Pirfenidone is a drug currently approved for the treatment of idiopathic pulmonary fibrosis, and reduces LV fibrosis in patients with heart failure and preserved ejection fraction. We aimed to characterize the different profiles or protein expression in the infarct zone in rats receiving or not receiving pirfenidone on top of standard therapy for MI. Methods Male Wistar rats were randomized to: sham procedure (group 1; n=13), reperfused MI induced by surgical ligation of the left anterior descending artery (LAD) for 45 minutes (group 2; n=17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta-blocker, and also mineralocorticoid receptor antagonist [MRA]) (group 3; n=17), reperfused MI plus pirfenidone alone (group 4; n=17), reperfused MI plus standard therapy and pirfenidone (group 5; n=17). Rats surviving LAD ligation and reperfusion underwent cardiac magnetic resonance (CMR) after 72 hours and 30 days from MI, and were sacrificed the day after the second CMR exam. The primary endpoint was the change in late gadolinium enhancement (LGE) mass as a percentage of LV mass. Results Forty-six rats survived until the second CMR. Percent changes in LV end-diastolic and end-systolic volume (p=0.370 and 0.423, respectively), ejection fraction (p=0.236) and mass (p=0.815) did not differ significantly between rats on pirfenidone plus standard therapy compared with those receiving standard therapy alone. The decrease in LGE mass was significantly greater in rats on pirfenidone plus standard therapy vs. those on standard therapy alone: -22.0% (interquartile range, -37.1 to -5.7, range -51.1 to +37.5) vs. +1.9% (-7.7 to +12.5, range -19.8 to +56.5), p=0.029. Conclusions Pirfenidone had additive effects to standard therapy for MI (including an MRA) in reducing LV fibrosis in a rat model of reperfused MI, while it did not further improve LV function, volumes or mass.

The cardiac troponins (cTns), cardiac troponin C (cTnC), cTnT, and cTnI are key elements of myocardial apparatus, fixed as protein complex on the thin filament of sarcomere and are involved in the regulation of excitation-contraction coupling of cardiomyocytes in the presence of Ca

Background: Electrocardiographic/echocardiographic abnormalities consistent with early-stage cardiomyopathy were previously reported in creatine transporter (CrT) deficiency. Nevertheless, cardiac involvement has never been accurately characterized. Aim: widen the current knowledge of the cardiac phenotype associated with creatine deficiency in a murine transgenic model and in patients with creatine deficiency syndrome (CDS). Methods: Wild type and transgenic CrT -/y mice (n=20) were serially evaluated in vivo by electrocardiogram (EKG) and echocardiography for 6 months, and ex vivo by histological/biochemical analyses. Nine patients with CDS (n=4 with L-arginine:glycine amidinotransferase - AGAT- deficiency, n=5 with CrT deficiency) underwent blood samples, including cardiac biomarkers, EKG, Holter monitoring, echocardiography and cardiac magnetic resonance (CMR). Results: Compared to wild type, CrT -/y mice showed a prolongation of QT interval (p=0.008) associated with a lower expression of ATPase sarcoplasmic/endoplasmic reticulum Ca 2+ transporting 2, involved in turn in intracellular Ca 2+ homeostasis. The significant reduction in mitochondrial ATP rate production (p Conclusion: Prolonged QT interval is observed in murine model - even with a slightly impaired metabolism - and in subjects with CrT deficiency. Biohumoral signs of neurohormonal activation and an initial replacement fibrosis - the latter suggested by the increase of native T1 - are identified in subjects with AGAT deficiency, but their clinical significance remains to be determined.

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 Fibroblast growth factor-23 (FGF23) has been associated to left ventricular (LV) hypertrophy and heart failure (HF) severity. We aimed to investigate clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients.Methods Patients with systolic HF (left ventricular ejection fraction - LVEFResults We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were 50.9 pg/mL. Patients in the upper iFGF23 tertile had lower LVEF (p=0.014), higher NT-proBNP (p=0.001), and lower peak VO2 (pConclusions Circulating iFGF23 is associated with renal dysfunction, disease severity and outcome in systolic HF.

Aims Amyloid transthyretin cardiomyopathy (ATTR-CM) has become treatable. Wild-type ATTR-CM is an age-related disorder. Establishing the exact prevalence of ATTR-CM in elderly subjects from the general population may be useful for healthcare providers and policy makers alike. Methods and results The characterizing the burden of Amyloid Transthyretin CardiomyopatHy in the elderly (CATCH) study is a population screening on all subjects aged ≥65 years followed by general practitioners working at the Casa della Salute in Terricciola, in an area of Tuscany where there is no cluster of variant ATTR. The study started on 12 March 2021 and is ongoing. The first step of the evaluation includes clinical history and physical examination, electrocardiogram, transthoracic echocardiogram, and blood sampling with measurement of N-terminal pro-B-type natriuretic peptide and high-sensitivity (hs) troponin T. The following elements are searched: (i) any clinical red flag of amyloidosis (history of carpal tunnel syndrome, lumbar spine stenosis, etc.), (ii) interventricular septal thickness ≥12 mm or other echocardiographic red flags, and (iii) hs-troponin T higher than the upper reference limit (14 ng/l). Patients with any of these elements are referred to a second step including diphosphonate scintigraphy and the search for a monoclonal protein in the serum and urine. The standard diagnostic workup for CA is then followed until the diagnosis is confirmed or discarded. As of 31 October 2021, 514 subjects ≥65 years have been evaluated for possible participation. Among them, 135 (26%) could not be contacted, were reluctant to enter the study, died before being contacted, or were bedridden. Out of the other 379 subjects, 329 (87%) have already undergone the first step. Forty percent of individuals (n = 132) have been referred to the second step. Thirteen subjects have declined (10%); 69 patients have undergone diphosphonate scintigraphy, and the search for a monoclonal protein (while the other 50 are awaiting these exams). Two subjects showed an intense myocardial uptake of the diphosphonate tracer (Perugini score 2–3) and no monoclonal protein, and were then diagnosed with ATTR-CM. They were both women, aged 83 and 78 years, both mildly symptomatic for dyspnoea (New York Heart Association II) and with unexplained hypertrophy. The search for TTR gene mutation was negative in the first case and is still ongoing in the second. Based on these preliminary data, the prevalence of ATTR-CM in the elderly population can be calculated as 2/266 = 0.8% (Figure). Conclusions The CATCH study is expected to enroll at least 1000 subjects and will provide the first data on the epidemiology of ATTR-CM in elderly subjects. Based on an interim analysis, almost 1 in 100 individuals ≥65 years has ATTR-CM.

Background The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined. Methods and Results We included all patients diagnosed with amyloid light‐chain (AL) or transthyretin cardiac amyloidosis at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular endomyocardial biopsy. Patients (n=37) were more often men (92%), with a median age of 72 years (interquartile range, 68–81). Lambda‐positive AL was found in 14 of 19 AL cases (38%) and kappa‐positive AL in 5 of 19 (14%), while transthyretin was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10%–30%), without significant differences between AL and transthyretin amyloidosis. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10%–23%; range, 5%–60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between transthyretin amyloidosis and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance, the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume ( r =0.661, P =0.001). The combined amyloid and fibrosis extent correlated with high‐sensitivity troponin T ( P =0.035) and N‐terminal pro‐B‐type natriuretic peptide ( P =0.002) serum levels. Conclusions Extracellular spaces in cardiac amyloidosis are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased extracellular volume at cardiac magnetic resonance and circulating biomarkers than amyloid extent alone.

Serial measurements of cardiac troponin are recommended by international guidelines to diagnose myocardial infarction (MI) since 2000. However, some relevant differences exist between the three different international guidelines published between 2020 and 2021 for the management of patients with chest pain and no ST-segment elevation. In particular, there is no agreement on the cut-offs or absolute change values to diagnose non-ST-segment elevation MI (NSTEMI). Other controversial issues concern the diagnostic accuracy and cost-effectiveness of cut-off values for the most rapid algorithms (0 h/1 h or 0 h/2 h) to rule-in and rule-out NSTEMI

Background Patients with acute heart failure (AHF) show high levels of fibroblast growth factor-23 (FGF23) on admission. We examined if plasma FGF23 changes during an episode of AHF, and if FGF23 holds prognostic significance in this setting. Methods Consecutive AHF patients were enrolled. Blood samples were collected on admission and at discharge. Patients were then followed for all-cause death or HF hospitalization. Results Patients (n=125; median age 76 years [interquartile interval 71–83], 63% men, left ventricular ejection fraction 35% [25–56%]) had median admission FGF23 70 ng/L (47–100), N-terminal pro-B-type natriuretic peptide (NT-proBNP) 5,844 ng/L (2,503–10,468), high-sensitivity troponin T (hs-TnT) 40 ng/L (25–72), and soluble suppression of tumorigenesis-2 (sST2) 26 ng/mL (17–37). While other biomarkers decreased, FGF23 increased by 15% from admission to discharge (p=0.033), with a significant correlation with percent changes in estimated glomerular filtration rate (rho=0.306, p=0.001). Over a 12-month follow-up, 64 patients (51%) experienced the endpoint. They were more often men, older, with higher systolic pulmonary artery pressure (sPAP), higher NT-proBNP, hs-TnT and discharge FGF23. The best FGF23 cut-off at discharge from receiver operating characteristics analysis was 78 ng/L. Both discharge FGF23 and the 78 ng/L cut-off independently predicted outcome in models including gender, sPAP, age, and 1) admission NT-proBNP, 2) discharge NT-proBNP, 3) admission NT-proBNP and hs-TnT, 4) discharge NT-proBNP and hs-TnT. The 78 ng/L cut-off also refined risk reclassification. Conclusions During an AHF episode, FGF23 increases from admission to discharge, and patients with higher discharge FGF23 have a higher risk of worse outcome. Funding Acknowledgement Type of funding sources: None.

Background The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined. Methods We included all patients diagnosed with amyloid light-chain or transthyretin (AL/ATTR) CA at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular (LV) endomyocardial biopsy (EMB). Results Patients (n=37) were more often male (92%), with a median age of 72 years (68–81). Lambda+ AL was found in 14/19 AL cases (38%) and kappa+ AL in 5/19 (14%), while TTR was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10–30%), without significant differences between AL and ATTR. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10–23%, range 5–60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between ATTR and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance (CMR), the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume (ECV; r=0.661, p=0.001). The combined amyloid and fibrosis extent correlated with high-sensitivity troponin T (p=0.035) and N-terminal pro-B-type natriuretic peptide (p=0.002) serum levels. Conclusions Extracellular spaces in CA are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased ECV at CMR and circulating biomarkers than amyloid extent alone. Funding Acknowledgement Type of funding sources: None.

Heart failure (HF) has a complex pathophysiology including neurohormonal activation, inflammation and oxidative stress that, together with comorbidities, promote progressive myocardial damage and cardiac remodeling. Over the years the study of these pathogenic mechanisms has led to the identification of several analytes potentially useful as biomarkers in HF. High-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification of HF, with independent value to natriuretic peptides. Other biomarkers currently being evaluated as predictors of adverse outcome in HF are galectin-3, growth differentiation factor 15, mid-regional pro-adrenomedullin as well as makers of renal dysfunction. The use of multi-marker scores as well as the application of genomics, transcriptomics, proteomics and metabolomics could further refine the management of HF.

Heart failure (HF) is the final common pathway of many cardiovascular diseases and is associated with increased morbidity and mortality. Natural history of HF patients can be improved when early diagnosis is achieved, and a timely treatment is initiated. Circulating biomarkers, reflecting pathophysiological pathways involved in HF development and progression, help clinicians diagnose and manage patients with HF. Natriuretic peptides are cardioprotective hormones released by cardiomyocytes in response to pressure/volume overload. B-type natriuretic peptides, namely B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide, have been widely validated as tools for diagnosis and risk stratification of HF, and their use appears promising also for screening the population at risk and as a guide for preventive measures halting progression towards HF. Conversely, there is conflicting evidence regarding their role as a guidance for HF therapy.

Despite advances in treatment of acute myocardial infarction (AMI), many patients suffer significant myocardial damage with cardiac dysfunction. Sympathetic renal denervation (RD) may reduce adrenergic activation following AMI. To investigate the potential role of RD limiting myocardial damage and remodeling when performed immediately after AMI. Sixteen farm pigs underwent 90 min left anterior descending artery balloon occlusion. Eight pigs underwent RD immediately after reperfusion. LV function, extent of myocardium at risk, and myocardial necrosis were quantified by cardiac magnetic resonance 5 and 30 days after AMI. 123I-MIBG scintigraphy was performed 31 days after AMI to image myocardial sympathetic innervation. Heart norepinephrine was quantified (from necrotic, border and remote zone). RD and control did not differ in myocardium at risk extent (59 ± 9 vs 55 ± 11% of LV mass) at 5 days. At 30 days CMR, RD pigs had smaller necrotic areas than control as assessed by gadolinium delay enhancement (18 ± 7 vs 30 ± 12% of LV mass, p = 0.021) resulting in improved myocardial salvage index (60 ± 11 vs 44 ± 27%, p

Neurohormonal activation has never been investigated in patients with cardiac amyloidosis (CA). Forty-seven patients with amyloid light-chain (AL)-CA and 61 with transthyretin (ATTR)-CA were matched to non-amyloidotic heart failure (HF) patients based on age, sex, left ventricular ejection fraction ranges, renal function and HF therapies. N-terminal pro-B-type natriuretic peptide (NT-proBNP), norepinephrine and renin were dosed. The primary and secondary endpoints were 1-year cardiovascular death or HF hospitalisation, and 5-year cardiovascular death, respectively. Patients with AL-CA had a 10-fold higher NT-proBNP than HF patients (6548 ng/L [2059���15,097] vs. 692 [243���2241], p p = 0.047). Patients with ATTR-CA had higher NT-proBNP (3984 ng/L [2275���9505] vs. 1751 [470���4768], p = 0.006), norepinephrine (552 ng/L [344���855] vs. 441 [323���601], p = 0.020), and renin (14 mU/L [8���80] vs. 10 [4���34], p = 0.017). Patients with AL- or ATTR-CA had more often 2 or 3 neurohormones above the corresponding upper reference limits than matched HF patients. NT-proBNP and aldosterone were univariate predictors of the primary endpoint in patients with ATTR-CA, but not in matched controls. NT-proBNP and renin predicted the secondary endpoint in patients with AL-CA, but not in matched controls. Patients with CA display a neurohormonal activation, with some prognostic significance.

Aims Clinical trials and observational cohorts show that beneficial effects of sacubitril/valsartan are less strong in an appreciable proportion of patients with heart failure with reduced ejection fraction (HFrEF). Lower blood pressure and impaired renal function predict suboptimal sacubitril/valsartan titration and a less favourable response. Circulating renin encompasses neurohormonal activation, intravascular volume, and renal function. We hypothesized that renin may predict response to sacubitril/valsartan, assessed by changes in N‐terminal fraction of pro‐brain natriuretic peptide (NT‐proBNP). Methods and results We performed a prospective, open‐label, real‐life cohort study. The study population consisted of 80 consecutive HFrEF patients (age 66 ± 10 years, 83% men) planned to initiate sacubitril/valsartan. Clinical and biohumoral assessment, including a full neurohormonal panel, was performed at baseline and at 1, 3, and 6 month follow‐up. Response to sacubitril/valsartan was defined as ≥30% reduction in NT‐proBNP levels from baseline to 6 months. Patients in the lower renin tertile had higher blood pressure and plasma sodium concentration (all P

Background Patients with acute heart failure (AHF) show high levels of fibroblast growth factor-23 (FGF23) on admission. We examined if plasma FGF23 changes during an episode of AHF, and if FGF23 holds prognostic significance in this setting. Methods Consecutive AHF patients were enrolled. Blood samples were collected on admission and at discharge. Patients were then followed for all-cause death or HF hospitalization. Results Patients (n = 125; median age 76 years [interquartile interval 71–83], 63% men, left ventricular ejection fraction 35% [25%–56%]) had median admission FGF23 70 ng/L (47–100), N-terminal pro-B-type natriuretic peptide (NT-proBNP) 5844 ng/L (2,503-10,468), high-sensitivity troponin T (hs-TnT) 40 ng/L (25–72), and soluble suppression of tumorigenesis-2 (sST2) 26 ng/mL (17–37). While other biomarkers decreased, FGF23 increased by 15% from admission to discharge (p = 0.033), with a significant correlation with percent changes in estimated glomerular filtration rate (rho = 0.306, p = 0.001). Over a 12-month follow-up, 64 patients (51%) experienced the endpoint. They were more often men, older, with higher systolic pulmonary artery pressure (sPAP), higher NT-proBNP, hs-TnT and discharge FGF23. The best FGF23 cut-off at discharge from receiver operating characteristics analysis was 78 ng/L. Both discharge FGF23 and the 78 ng/L cut-off independently predicted outcome in models including gender, sPAP, age, and 1) admission NT-proBNP, 2) discharge NT-proBNP, 3) admission NT-proBNP and hs-TnT, 4) discharge NT-proBNP and hs-TnT. The 78 ng/L cut-off also refined risk reclassification. Conclusions During an AHF episode, FGF23 increases from admission to discharge, and patients with higher discharge FGF23 have a higher risk of worse outcome.

Serial measurements of cardiac troponin are recommended by international guidelines to diagnose myocardial infarction (MI) since 2000. However, some relevant differences exist between the three different international guidelines published between 2020 and 2021 for the management of patients with chest pain and no ST-segment elevation. In particular, there is no agreement on the cut-offs or absolute change values to diagnose non-ST-segment elevation MI (NSTEMI). Other controversial issues concern the diagnostic accuracy and cost-effectiveness of cut-off values for the most rapid algorithms (0 h/1 h or 0 h/2 h) to rule-in and rule-out NSTEMI. Finally, another important point is the possible differences between demographic and clinical characteristics of patients enrolled in multicenter trials compared to those routinely admitted to the Emergency Department in Italy. The Study Group of Cardiac Biomarkers, supported by the Italian Scientific Societies Società Italiana di Biochimica Clinica, Italian Society of the European Ligand Assay Society, and Società Italiana di Patolgia Clinica e Medicina di Laboratorio decided to revise the document previously published in 2013 about the management of patients with suspected NSTEMI, and to provide some suggestions for the use of these biomarkers in clinical practice, with a particular focus on the Italian setting.

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.

Background Cardiac amyloidosis (CA) is caused by the extracellular deposition of misfolded proteins into insoluble amyloid fibrils, the 2 most common forms being transthyretin (ATTR) and immunoglobulin light chain (AL) amyloidosis. Chronic elevation of cardiac troponins and natriuretic peptides is common in CA and predicts worse outcome. The diagnostic yield of biomarkers of cardiac damage for CA has been less investigated. Purpose We aimed to evaluate the ruling-in/out values for the diagnosis of CA of high-sensitivity cardiac troponin T (hs-cTnT) and of N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP). Methods We studied 275 consecutive patients referred to two tertiary Centers in Italy (n=184) and France (n=91) with the clinical suspicion of CA due to the presence of a plasma cell dyscrasia or an unexplained left ventricular (pseudo)hypertrophy. CA was confirmed by the combination of suggestive features on imaging techniques (echocardiography, cardiac magnetic resonance, diphosphonate scintigraphy) and biopsy examination. All patients underwent a full baseline characterization including hs-cTnT and NT-proBNP. Biomarkers values corresponding to a negative likelihood ratio 10 were respectively chosen as rule-out and rule-in cut-offs for CA. Results CA was confirmed in 161 (59%) patients, who had either AL amyloidosis (n=96, 60%) or ATTR amyloidosis (n=65, 40%). At time of evaluation, 97 (35%) patients (34 CA vs. 63 controls, p=0.112) were hospitalized for decompensated heart failure. Patients with CA showed higher hs-cTnT (65 ng/L [44–122] vs. 31 [18–42], p Conclusions Plasma hs-cTnT and NT-proBNP have diagnostic value in patients with suspected CA. Stand-alone hs-cTnT levels Figure 1 Funding Acknowledgement Type of funding source: None

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 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.

Background The study aim was to evaluate and compare analytical performances and clinical results of ADVIA BNP and PBNP methods using the Centaur XPT platform with those of Access BNP, using the DxI platform and the ECLIA NT-proBNP method, using the Cobas e411 platform, respectively. Methods Limits of blank (LoB), detection (LoD) and quantitation (LoQ) at 20% CV and 10% CV were evaluated according to international standardized protocols. The analytical parameters were assessed throughout a 90-working-day period using three curve calibrations. Results LoB, LoD and LoQ at 20% CV and 10% values of the ADVIA BNP method were 1.0 ng/L, 2.0 ng/L, 3.7 ng/L and 10.2 ng/L, respectively; while those of the ADVIA PBNP method were 1.3 ng/L, 3.0 ng/L, 9.7 ng/L and 22.3 ng/L, respectively. The ADVIA BNP and PBNP methods were able to measure the clinical decision values suggested by international guidelines for diagnosis of heart failure (HF) with an imprecision ≤6%. BNP concentrations measured with the ADVIA and Access methods showed a close linear regression (R=0.9923, n=200); a close linear regression was also found between NT-proBNP concentrations measured with the ADVIA and ECLIA methods (R=0.9954, n=202). However, the ADVIA method measured significantly lower BNP values than the Access method (on average −20.9%), while ADVIA PBNP method measured significantly higher NT-proBNP concentrations than the ECLIA method (on average +17.8%). Conclusions Analytical performances of the BNP and PBNP ADVIA methods are well in accordance with the quality specifications required by international guidelines for diagnosis and follow-up of patients with HF.

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 …

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.

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.

Cardiac Troponins (cTnI, cTnT), NT-proBNP, and galectin-3 (GAL-3) mirror cardiomyocyte injury, stretch, and fibrosis. However, although these biomarkers has been thoroughly studied in marathon or ultramarathon, the effects occurring running shorter distances, as half-marathon, are less known and data are generally limited to immediately post-race evaluation. Moreover, significant variation of alpha-1 antitrypsin (AAT), an anti-protease factor with anti-inflammatory properties, has been recently observed in heart failure, but not investigated in paraphysiological settings. The aim of the study was to evaluate these biomarkers concentration and trends in trained runners before half-marathon run and during a 48-h recovery period. In 18 half-marathon runners (15 males, 46 ± 6 years), cTnI, GAL-3 (Architect, Abbott), cTnT, NT-proBNP (Cobas e411, Roche), and AAT (Abcam, Cambridge, UK) were evaluated at rest, immediately post-run, and at 24 and 48-h recovery period. cTnT, NT-proBNP, and GAL-3 transiently increased after post-race, but normalized at 24 h (GAL-3 p

Background:The study aim was to evaluate and compare the analytical performance of the new chemiluminescent immunoassay for cardiac troponin I (cTnI), called Access hs-TnI using DxI platform, with those of Access AccuTnI+3 method, and high-sensitivity (hs) cTnI method for ARCHITECT platform.Methods:The limits of blank (LoB), detection (LoD) and quantitation (LoQ) at 10% and 20% CV were evaluated according to international standardized protocols. For the evaluation of analytical performance and comparison of cTnI results, both heparinized plasma samples, collected from healthy subjects and patients with cardiac diseases, and quality control samples distributed in external quality assessment programs were used.Results:LoB, LoD and LoQ at 20% and 10% CV values of the Access hs-cTnI method were 0.6, 1.3, 2.1 and 5.3 ng/L, respectively. Access hs-cTnI method showed analytical performance significantly better than that of Access AccuTnI+3 method and similar results to those of hs ARCHITECT cTnI method. Moreover, the cTnI concentrations measured with Access hs-cTnI method showed close linear regressions with both Access AccuTnI+3 and ARCHITECT hs-cTnI methods, although there were systematic differences between these methods. There was no difference between cTnI values measured by Access hs-cTnI in heparinized plasma and serum samples, whereas there was a significant difference between cTnI values, respectively measured in EDTA and heparin plasma samples.Conclusions:Access hs-cTnI has analytical sensitivity parameters significantly improved compared to Access AccuTnI+3 method and is similar to those of the high-sensitivity method using ARCHITECT platform.

According to recent international guidelines, including the 2012 Third Universal Definiton of Myocardial Infarction by the Joint ESC/ACCF/AHA/WHF Task Force, an increase in cardiac troponin (cTn) levels over the 99th percentile upper reference limit (99th URL) should be considered clinically relevant, this cut-off being measured with an imprecision ≤10 CV%. In theory 99th URL values strongly depend not only on demographic and physiological variables (i.e. criteria for considering the reference population “healthy”), but also on the analytical performance of cTn methods and mathematical algorithms used for the calculation. The aim of the present article was therefore to review the methodological and pathophysiological factors affecting the evaluation and calculation of the 99th URL for cTn assay. The critical analysis made showed that no uniform procedure is followed, and nor have experts or regulatory bodies provided uniform guidelines for researchers or cTn assays manufacturers as an aid in “their quest to define normality”. In particular, little attention has been paid to the way in which a healthy reference population is to be selected, or the criteria for calculating the 99th URL value for cTn assays, thus highlighting the need for international recommendations not only for demographic and physiological variables criteria for defining a healthy reference population, but also for calculating mathematical algorithms for establishing/calculating clinical decision values. An expert consensus group, comprising laboratory and clinical scientists, biomedical statisticians, industrial and regulatory representatives, should be responsible for drawing up these guidelines.

Background:Systematic difference between thyroid-stimulating hormone (TSH) immunoassays may produce misleading interpretation when samples of the same patients are measured with different methods. The study aims were to evaluate whether systematic differences are present among TSH immunoassays, and whether it is possible to obtain a better harmonization among TSH methods using results obtained in external quality assessment (EQA) schemes.Methods:Seven Italian clinical laboratories measured TSH in 745 serum samples of healthy subjects and patients with thyroid disorders. These samples were also re-measured by two reference laboratories of the study with the six TSH immunoassays most popular in Italy after 2 months of storage at −80 °C. Moreover, these data were compared to 53,823 TSH measurements, obtained by laboratories participant to 2012–2015 EQA annual cycles in 72 quality control samples (TSH concentrations from about 0.1 mIU/L to 18.0 mIU/L). TSH concentrations were recalibrated using a mathematical approach based on the principal component analysis (PCA).Results:Systematic differences were found between the most popular commercially available TSH immunoassays. TSH concentrations measured by the clinical laboratories were very closely correlated to those measured with the same method by reference laboratories after 2 months of storage at −80 °C. After recalibration using the PCA approach the variation of TSH values significantly decreased from a median pre-calibration value of 13.53% (10.79%–16.53%) to 9.63% (6.90%–13.21%) after recalibration.Conclusions:Our data suggest that EQA schemes are useful to improve harmonization among TSH immunoassays and also to produce some mathematical formulas, which can be used by clinicians to better compare TSH values measured with different methods.

Aim of the study Recently, Beckman Coulter Diagnostics set up a new TSH immunoassay for the automated DxI platform. The aim of this study was to evaluate and compare the analytical performance and clinical results of this method with those of previous method. Material and methods A multicenter study (named TSH ELAS Study) was organized using 593 serum samples, collected from healthy subjects and patients with thyroid disorders, and 13 control samples, circulated in an External Quality Assessment (EQA) scheme. Results The values of LoB and LoD, and LoQ at 20% CV were 0.0004 mIU/L, 0.001 mIU/L and 0.0023 mIU/L, respectively. Moreover, TSH concentrations > 0.01 mIU/L actually show imprecision values lower than 5% CV. This new TSH assay showed a systematic underestimation (on average of 6.25%) compared to old method, which is mainly due to larger differences between methods for samples with low TSH concentrations, related to the better analytical sensitivity of new compared to old method. In a reference population, including 279 apparently healthy adult subjects, Caucasian volunteers (mean age 43.6 years, age 20–63 years, 138 women and 141 males) the distribution of TSH concentrations was: mean (CI 95%) 1.694 mIU/L (1.588–1.779), median 1.495 mIU/L (1.412–1.588 mIU/L), 97.5th percentile 3.707 mIU/L. Conclusions The new TSH immunoassay for DxI platform shows some relevant improvements compared to the previous one: use of the most recent WHO 3rd IRP 81/563 standard and monoclonal antibodies (instead of polyclonal antibodies of the old method), and better analytical sensitivities and reproducibility.

Background Cardiomyocyte apoptosis increases in heart failure (HF) and is implicated in disease progression. The apoptotic cell is not inevitably committed to death, and appropriate therapy like left ventricular assist device (LVAD) support could offer a rescue of cellular functions. Literature data regarding the modulation of the apoptotic process during LVAD support are still controversial. Methods To assess whether LVAD implantation modifies the apoptotic profile in the heart, cardiac tissue was collected from end-stage HF patients before LVAD implant (pre-LVAD, n =22) and at LVAD removal (post-LVAD, n =6) and from stable HF patients on medical therapy without prior circulatory support (HTx, n =7) at heart transplantation as control. Caspase (Casp)-3, Bax, Bcl-2, and Hsp72 cardiac mRNA and protein expression were evaluated by real-time polymerase chain reaction and Western blotting (WB) in the three groups of patients. Immunohistochemical analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and DNA laddering analysis were performed; cellular size and interstitial fibrosis content were also determined. Results All the apoptotic indices were increased in the post-LVAD group compared to pre-LVAD, specially antiapoptotic Hsp72 and proapoptotic Bax (Hsp72: 3.27±0.41 vs. 0.76±0.14, P P =.035; post-LVAD vs. pre-LVAD, respectively). The significant increase in Hsp72 was confirmed by WB and immunohistochemical analysis. Conclusion LVAD appears to induce an activation of apoptotic mediators, mainly at the mitochondrial level, while the following activation of Casp-3 is reduced by the significant increase of Hsp72, whose enhancement could be an important factor in cardiac remodeling associated with LVAD support.

It is well known that adult fertile women have about two-fold higher circulating levels of cardiac natriuretic peptides (NPs) than men of the same age. Conversely, men have on average higher circulating levels of cardiac troponin I (cTnI) and T (cTnT) than women. Furthermore, the circulating levels of both cardiac NPs and troponins progressively increase after 65 years of age in both sexes. From a physiological point of view, these differences in circulating levels between cardiac NPs and troponins are closely related to production, secretion and peripheral degradation of these biomarkers; these complex physiological mechanisms are differently regulated in men and women. Some cardiac and extra-cardiac diseases with sex-related prevalence can also affect these physiological mechanisms, and in this way to allow more difficult the clinical interpretations of cardiac biomarker measurement with immunoassay methods. The aim of this review article is to discuss the available evidence of the possible different mechanisms related to production, secretion and degradation of cardiac NPs and cardiac troponins in men and women.

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 aged1month (neonates), 57 between 1 and 12months (infants), 65 between 1 and 10years (toddlers), and 223 between 10 and 18years (adolescents). The percentages of healthy population with cTnI values equal or less than the calculated and LOD value were 13.1%. cTnI plasma levels were highest in the first month of life with a progressive decline in the next years and were lower in female. At multivariate analysis, only age was predictor of hs-cTnI plasma levels. The age and sex of children influence normal and physiologically released circulating concentrations of hs-cTnI, suggesting the need of reference intervals specific for age and sex.