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Background: Cardiac natriuretic hormones (CNHs) are a family of related peptides, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and other peptides derived from the N-terminal portion of the proANP and proBNP peptide chains. Assays for cardiac natriuretic peptides have been proposed to help assess clinical conditions associated with expanded fluid volume. In particular, the assays can be useful for distinguishing healthy subjects from patients in different stages of heart failure. Measurements of these hormones have also been considered for prognostic indicators of long-term survival in patients with heart failure and/or after acute myocardial infarction. The different CNHs differ in their production/secretion patterns and have different clearance rates. Furthermore, there are numerous proposed assay configurations for each of these hormones, and it is not clear which assay provides the best pathophysiological and/or clinical information. Approach: Here we review recent studies concerning the competitive (such as RIA, enzyme immunoassay, or luminescence immunoassay) and noncompetitive immunoassays (such as two-site IRMA, ELISA, or immunoluminometric assay) for the different cardiac natriuretic peptides to compare the analytical characteristics and clinical relevance of assays for the different CNHs and the different assay formats. Content: Developing sensitive, precise, and accurate immunoassays for cardiac natriuretic peptides has been difficult because of their low concentrations (on average, ∼3–6 pmol/L) in healthy subjects and because of their structural, metabolic, and physiological characteristics. Competitive assays have historically suffered from lack of sensitivity and specificity for the biologically active peptides. These usually require tedious extraction procedures prior to analysis. Recently, immunometric assays have been developed that have improved sensitivity and specificity; it appears these will be the methods of choice. Summary: To date, there is no consensus on the best assay procedure of cardiac natriuretic peptides. To facilitate widespread propagation of determination of these hormones in routine clinical practice, it will be necessary to study the new generation of noncompetitive immunometric methods that are less time-consuming and more sensitive and specific. Although several studies suggest that BNP exhibits better clinical utility than the other CNHs, more studies examining multiple CNHs in the same cohorts of patients will be necessary.

We evaluated the analytical characteristics and clinical usefulness of a commercial immunoradiometric assay (IRMA) kit for brain natriuretic peptide (BNP). Mean (+/-SD) plasma BNP concentrations measured in 129 normal subjects were 2.9+/-2.7 pmol/l (median 2.2 pmol/l; range 0.1-12.4 pmol/l). The mean (+/- SD) value observed in healthy men (2.1 +/- 2.0 pmol/l, n = 49) was significantly (p=0.0009) different to that found in women (3.4 +/- 2.9 pmol/l, n=80). A positive relationship (R=0.214, p=0.0174) was found between BNP values and age. In 65 patients with cardiac diseases, BNP levels increased with the progression of clinical severity of disease; patients with more severe disease [NYHA functional class III-IV, mean (+/- SD) BNP +/- 254 +/- 408 pmol/l, n=22] showed significantly (p

In an attempt to identify and quantify the sites of atrial natriuretic peptide (ANP) degradation, particularly the lungs, a new tracer method to study ANP metabolism in vivo in humans was developed and applied to patients with left ventricular dysfunction. Thirteen male, normotensive, cardiac patients with different degrees of left ventricular myocardial involvement were enrolled in the study. The study protocol required constant infusion (3 patients) or bolus injection (10 patients) of 125I-labeled ANP just upstream of the right atrium and blood sampling from different sites (pulmonary artery, aorta, inferior vena cava, and femoral vein) during the hemodynamic study. Data analysis was based on a kinetic model consisting of three blocks in series (right heart, lungs and left heart, and periphery) supplied by the same plasma flow (plasma cardiac output). Plasma levels of native ANP were measured with a sensitive and specific immunoradiometric assay method. ANP values measured in the aorta (163.9 ± 144.8 pg/mL, n = 80) were superimposable on those measured in the pulmonary artery (161.8 ± 136.5 pg/mL, n = 80). Negligible extraction of 125I-labeled ANP was found in the lungs and left heart block (on average 0.08 ± 3.92%), whereas the peripheral block extraction (46.2 ± 7.8%) accounted for almost total hormone removal from the blood (whole body extraction was 46.4 ± 6.6%). ANP metabolic clearance rate (3.11 ± 1.48, range 1.4–6.8 L/min) declined with the progression of left ventricular dysfunction (plasma cardiac output 3.46 ± 1.08, range 1.2–5.7 L/min), and a close correlation between metabolic clearance rate and cardiac output was evident. Our data suggest that lungs do not extract, or extract only very small amounts, of labeled ANP administered iv to patients with different degrees of left ventricular myocardial involvement, and whole body extraction of labeled ANP remains relatively stable with the progression of disease, and the large reductions in clearance values observed in our patients can be ascribed mainly to the reductions in cardiac output.

In an attempt to identify and quantify the sites of atrial natriuretic peptide (ANP) degradation, a new tracer experiment has been developed.125I-ANP was injected as a bolus just upstream from the right atrium, and blood was sampled from two different sites (pulmonary artery and aorta) in eight cardiac patients. Data were analyzed using a physiologically based circulatory model consisting of three blocks in series (right heart, lungs and left heart, and periphery) supplied by the same flow (cardiac output, measured by thermodilution); the extraction coefficients of the three blocks and of the whole body could be determined from the areas under tracer concentration curves in plasma (AUCs). The values for AUCs (means ± SD) were 64.8 ± 9.4 and 65.5 ± 10.7% dose ⋅ l−1⋅ min−1for pulmonary artery and aorta curves, respectively; the area under the pulmonary artery curve could be subdivided into the area under the first-pass curve (30.6 ± 4.7% dose ⋅ l−1⋅ min−1) and the area under the recirculating curve (34.0 ± 7.7% dose ⋅ l−1⋅ min−1). The metabolic clearance rate of125I-ANP, computed as dose divided by the area under the recirculating curve, was 3.1 ± 0.7 l/min, and the whole body extraction was 47.6 ± 6.6%. In our patients with myocardial dysfunction, neither right heart block nor lungs and left heart block significantly extracted ANP, and periphery block accounted for almost all removal of the hormone from the blood.

Because little has been published on early effects of treatment with amiodarone on thyroid function, we studied serum total and free thyroid hormone, reverse T3, and TSH levels in patients with cardiac arrhythmias during the first 10 days of treatment with a loading dose of amiodarone by iv infusion. Twenty-four patients were enrolled in the study. A standardized loading regimen for the i.v. infusion of amiodarone was used. The protocol provided the i.v. infusion of 20 mg/kg per day on day 1, the i.v. infusion of 10 mg/kg per day on day 2, then 600 mg/day per os for 7-10 days, and finally, in patients chronically treated with the drug, the dose was gradually reduced to 400-200 mg/day per os. Total and free concentrations of T4 tended to progressively and significantly increase (P < 0.0001 repeated measures ANOVA) starting from the fourth day of therapy, whereas total T3 decreased from the second day progressively (P < 0.0001) throughout the study; free T3 did not significantly change. TSH levels early and significantly (P < 0.001, by ANOVA) increased throughout the study, starting from the first day of therapy and reaching at 10 days a value 2.7 times higher than the basal value. Reverse T3 levels progressively and significantly (after 2 days of treatment) increased and paralleled the TSH values, reaching at the 10th day a value about 2 times higher than basal value. In conclusion, our data suggest that after i.v. treatment with amiodarone: 1) TSH is the first hormone to change significantly followed by reverse T3, T4, and T3; 2) the progressive fall of T3 levels reflects an inhibition of the peripheral conversion of T4 to T3; 3) the observed later increase of total and free T4 levels may be explained by a contribution of direct thyroidal stimulation by TSH and/or by a reduction in T4 clearance.

Over the last 5 years, several immunoassay methods for the measurement of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) became commercially available. Recent studies have confirmed the clinical usefulness of measurements of these cardiac natriuretic peptides for the prognostic stratification of patients with congestive heart failure, for the detection of left ventricular systolic and/or diastolic dysfunction, and for the differential diagnosis of dyspnea (1)(2)(3)(4). However, to answer the most urgent requests of current clinical practice and to allow widespread use of BNP and NT-proBNP assays, some key issues had to be solved, such as increasing the sensitivity, precision, and experimental practicability (5). The aim of the present study was to evaluate and compare the analytical and clinical performance of five commercial natriuretic peptide immunoassays. Throughout this report, the values in healthy individuals and patients are reported as the range, median, and 25th and 75th percentiles. We enrolled 172 healthy adults (89 women and 83 men; age range, 16–73 years; median age, 49.0 years; 25th percentile, 38 years; 75th percentile, 58 years). All participants were nonobese (body mass index, 19.4–27.6 kg/m2, 24 kg/m2, 22.8 kg/m2, and 25.6 kg/m2), normotensive (diastolic blood pressure, 60–85 mmHg, 70 mmHg, 70 mmHg, and 80 mmHg; systolic blood pressure, 90–140 mmHg, 120 mmHg, 102.5 mmHg, and 124.5 mmHg), and free from acute or chronic diseases. All participants had main plasma indices (including creatinine, urea nitrogen, glucose, uric acid, albumin, enzymes, electrolytes, and hemoglobin) within the appropriate reference intervals, and normal erythrocyte and leukocyte counts …

Background: Results collected from the 2010–2012 cycles of the ‘Immunocheck’ external quality assessment scheme for 25-hydroxyvitamin D, conducted by QualiMedLab CNR (Italy) and ProBioQual (France; 250 among Italian and French laboratories) are presented in this article. Methods: Details of how QualiMedLab operates can be found in QualiMedLab website. Results: Interlaboratory imprecision was 19 (2010), 15 (2011) and 13% (2012). The LIAISON® analyzer (DiaSorin, Italy) was the most utilized, followed by Roche (UK), ImmunoDiagnostic Systems methods (UK), ARCHITECT (Abbott, IL, USA), radioimmunoassay (DiaSorin) and others. The within-method variability between laboratories (percentage coefficient of variation) were 15, 12.7 versus 9.8% for LIAISON, 27.8, 16.5 versus 11.7% for Roche, 15, 12 versus 17% for ImmunoDiagnostic Systems and 17.4, 18.6 versus 17.5% for radioimmunoassay in the 2010, 2011 versus 2012 cycles, and 15 versus 8.9% for ARCHITECT in the 2011 versus 2012, respectively. Conclusion: Significant differences in specific samples and discrepancies between laboratories and methods still exist, making the actuation of appropriate external quality assessment schemes mandatory.

OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic accuracy of brain natriuretic peptide assay in neonates and children undergoing surgery for congenital heart disease. DESIGN: Prospective, observational study. SETTING: Single center. PATIENTS: We enrolled 336 consecutive children (median age, 6 mo [range, 0-37 mo]) undergoing cardiac surgery (87 neonates; age, 7 d [5-12]; median, 25th-75th percentile; 24 infants and children; age, 11 mo [4-60]) and 436 healthy controls. INTERVENTIONS: Brain natriuretic peptide was measured preoperatively, on every postoperative day in the ICU, and at discharge. Intubation time was the primary outcome. MEASUREMENTS AND MAIN RESULTS: Preoperative brain natriuretic peptide values in patients with congenital heart disease were higher than those in controls (p < 0.01). Brain natriuretic peptide had a good diagnostic accuracy in discriminating between patients with congenital heart disease and healthy controls with an area under the curve = 0.918 for neonates and area under the curve = 0.894 for older children. The best cutoff values, calculated by receiver operating characteristic analysis, were different for the two age subgroups with cutoff values of 363.5 ng/L for neonates and 23.5 ng/L for older children. At 24 hours after surgery, although brain natriuretic peptide decreased in neonates (baseline 2723 vs 1290 ng/L, p < 0.001), it increased in children (60 vs 365 ng/L at 24 hours, p < 0.001). Multivariable analysis identified the preoperative level of brain natriuretic peptide in infant/children and the difference in brain natriuretic peptide value (baseline 24 hours) in neonates, as independent predictors of intubation time. Furthermore, body surface area, Aristotle score, and cardiopulmonary bypass time had an independent significant effect on the endpoint in either group. CONCLUSIONS: Baseline cardiac endocrine function and its response to surgical stress are dependent on age in neonates and children, undergoing cardiac surgery for congenital heart disease. Brain natriuretic peptide shows a good diagnostic and prognostic accuracy in this setting, with different features in either neonates or infants/children subsets.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) has been suggested as the most promising biomarker of acute kidney injury. However, there are no reliable data on analytical sensitivity and reference limits of urinary NGAL (uNGAL) assay in pediatric age. The aim of the present study is to evaluate the analytical sensitivity and the reference range of uNGAL measured in urine specimens of pediatric age with the fully automated platform ARCHITECT (R) i1000. Methods: A total of 333 urine samples were collected from 25 healthy newborns (16 males and 9 females; age 1-4 days) and 308 children (150 males and 147 females; mean age 80.7 months, range 0.63-248 months) and assayed for uNGAL by two different Italian centers (Department of Laboratory Medicine of the Fondazione Toscana G. Monasterio of Pisa and Massa and the Clinical Pathology Laboratory Unit of Istituto Giannina Gaslini of Genova). Results: The calculated limits of blank (LOB) and detection (LOD) values were 0.5 ng/mL and 0.95 ng/mL, respectively. The distribution of uNGAL values approximated a log-normal distribution (median 5.2 ng/mL, interquartile range 2.5-12.8 ng/mL, 99th percentile 117.6 ng/mL). uNGAL values of the 25 neonates were significantly higher than those of 308 children (neonates: mean 44.2 ng/mL, median 30.3 ng/mL, range 5.2-137.4 ng/mL; children: mean 10.2 ng/mL, median 4.6 ng/mL, range 0.2-146.7 ng/mL; p

Background Recent studies suggested that there are marked systematic differences among BNP immunoassays. In this study we compared the BNP data and clinical results obtained with different immunoassays, including a new method (ST-AIA-PACK, TOSOH Corporation). Methods BNP was measured on plasma-EDTA samples of healthy subjects (HS, n = 126) and patients with heart failure (HF, n = 31 NYHA I, II; n = 46 NYHA III, IV) using the ST-AIA-PACK and the Triage Biosite (Beckman Coulter) methods. Control samples distributed in the CardioOrmoCheck external quality assessment were also measured with TOSOH and the most used BNP immunoassays in Italy. Results TOSOH method showed a good correlation (R = 0.976; n = 327) but a mean bias (− 46.9%) compared to Triage Biosite. On the base of the results obtained in 10 samples of the CardioOrmoCheck study, TOSOH method showed a strict agreement with ADVIA Centaur, while it underestimated BNP in comparison with Triage (− 52.5%) and ARCHITECT methods (− 39.4%). The agreement of ST-AIA-PACK and Triage Biosite methods for classification of HF patients was tested using 100 ng/L of BNP; the positive agreement between methods was 65%, overall agreement was 73%. Conclusions Our results confirm that there are marked differences in measured values among commercial methods for BNP assay.

The purpose of this document is to develop recommendations on the use of the latest generation of cardiac troponins in emergency room settings for the diagnosis of myocardial infarction in patients with suspected acute coronary syndrome (ACS) without persistent ST-segment elevation (NSTE-ACS). The main points which have been addressed reaching a consensus are represented by: Suitability and appropriateness of the terminology. Appropriateness of the request. Confirmation of the diagnosis of myocardial infarction (rule-in). Exclusion of the diagnosis of myocardial infarction (rule-out).Each point has been analyzed by taking into account the evidence presented in medical publications. Recommendations were developed using the criteria adopted by the European Society of Cardiology and the American Heart Association/American College of Cardiology (www.escardio.org/guidelines). Each point of the recommendation was submitted for validation to an external audit by a Group of Experts (named above).

The high prevalence of obesity in children may increase the magnitude of lifetime risk of cardiovascular disease (CD). At present, explicit data for recommending biomarkers as routine pre-clinical markers of CD in children are lacking. C-type natriuretic peptide (CNP) is assuming increasing importance in CD; in adults with heart failure, its plasma levels are related to clinical and functional disease severity. We have previously reported five different reference intervals for blood CNP as a function of age in healthy children; however, data on plasma CNP levels in obese children are still lacking. Aim of this study was to assess CNP levels in obese adolescents and verify whether they differ from healthy subjects. Plasma CNP was measured in 29 obese adolescents (age: 11.8 ± 0.4 years; BMI: 29.8 ± 0.82) by radioimmunoassay and compared with the reference values of healthy subjects. BNP was also measured. Both plasma CNP and BNP levels were significantly lower in the obese adolescents compared to the appropriate reference values (CNP: 3.4 ± 0.2 vs 13.6 ± 2.3 pg/ml, p

Background: Interest in hormonal response after pediatric cardiac surgery is growing, but many aspects remain unclear. The aim of this study was to test age-related variations and prognostic values of thyroid hormones, and brain natriuretic peptide (BNP) levels before and after surgery. Methods and Results: A total of 162 children undergoing cardiac surgery were divided into 3 age groups (group 1, n=57 neonates; group 2, n=58 infants; group 3, n=47 toddlers). Free thyroid hormones (fT3 and fT4), thyrotropin (thyroid-stimulating hormone [TSH]) and BNP were measured preoperatively, daily postoperatively in the intensive care unit and after 15 days. The primary outcome was time to extubation (TTE; variable used as time to event by survival analysis). The hormonal response differed among age groups. In older children the TSH nadir occurred at 6–12 h after surgery (0.42 mIU/L, P

We evaluated the analytical characteristics and clinical usefulness of a commercially available IRMA kit for measuring plasma concentrations of atrial natriuretic peptide (ANP) in healthy subjects and in patients with heart failure. The method uses two monoclonal antibodies prepared against sterically remote epitopes of the ANP molecule; the first antibody is coated on the solid-phase beads, and the second is radiolabeled with 125I. Fifty-nine healthy subjects and 77 patients with heart failure were studied. After subjects had rested 20 min in a recumbent position, blood samples were collected from a brachial vein into ice-chilled disposable polypropylene tubes containing aprotinin and EDTA. Plasma samples were immediately separated by centrifugation and stored at -20 degrees C until assay. The working range (CV

Amiodarone, an antiarrhythmic agent, is also known to have important effects on the peripheral metabolism of thyroid hormones; the relationship between these two effects of the drug, however, is not well established. We tested the hypothesis that the antiarrhythmic effect of amiodarone might be mediated by its effect on the metabolism of thyroid hormones. Peripheral thyroid hormone metabolism was investigated using a double-tracer ([125I]-T4 and [131I]-T3) procedure in 10 normal volunteers and 10 euthyroid patients with complex ventricular arrhythmias before and during 6 months' amiodarone treatment. The underlying cardiac disease was coronary artery disease in four cases, dilated cardiomyopathy in three and idiopathic arrhythmias in three. In all but one patient with complex ventricular arrhythmias amiodarone treatment resulted in a reduction of > or = 80% of premature ventricular contractions and complete suppression of episodes of ventricular pairs or ventricular tachycardia. In all cases successful treatment with amiodarone was accompanied by normalization of all kinetic parameters: T4 to T3 conversion ratio and T3/T4 molar ratio of production decreased to mean values of 24.7 +/- 17.5% and 0.35 +/- 0.22% respectively, whereas T4 production rate increased (mean value 75.9 +/- 30.0 nmol day-1 m-2). Our kinetic data indicate that long-term therapy with amiodarone, when effective in suppressing cardiac arrhythmias, also reduces peripheral T4 to T3 conversion, hence restoring the normal peripheral thyroid hormone metabolic pattern. In conclusion, our study confirms that the antiarrhythmic action of amiodarone may be (at least partially) mediated by its action on thyroid hormone metabolism, and may justify the hypothesis that an altered peripheral metabolism of thyroid hormones may play a role in the pathogenesis of complex ventricular arrhythmias.

Reverse remodeling (R2) in non-ischemic dilated cardiomyopathy (NIDCM) is associated with reduced morbidity, improved quality of life and survival. There is still scarce knowledge on predictors of R2, relevant for guide to treatment and device implantation. We aimed to identify predictors of R2

We evaluated the performance and diagnostic accuracy of an electrochemiluminescence immunoassay (ECLIA) method for N-terminal pro-B-type natriuretic peptide (NT-proBNP) in healthy persons and in patients with cardiac disease, and then compared the results obtained with the ECLIA method with results from IRMA methods for BNP and atrial natriuretic peptide (ANP). We studied 58 healthy individuals [mean (SD) age, 58 (8) years; 19 women and 39 men] and 148 consecutive patients [mean age, 64 (13) years; range, 20–80 years; 47 women and 101 men] with cardiomyopathy, admitted to the Department of Cardiovascular Medicine of our Institute. The study was done from November 2001 to October 2002. All healthy participants were nonobese, normotensive, and free from acute diseases, and all denied the use of any drug during the 4 weeks before the study. All had normal values for the main plasma indices and nonpathologic erythrocyte and leukocyte counts and urine analysis. In all of the participants, a complete cardiologic examination, including electrocardiogram and echocardiographic investigation (left ventricular ejection fraction >55%), was performed; in patients >50 years of age, an effort stress test was …

Recent studies reported that many different biochemical forms of B-type-related peptides circulate in human blood. In particular, a significant amount of the prohormone peptide (i.e., proBNP108) can be detected in plasma of patients with heart failure. These data indicate that the posttranslational maturation processing of the B-type natriuretic peptide (BNP) precursor may not be efficient in heart failure. The aim of this chapter is to describe the biochemical pathways of proBNP108 maturation and to discuss the pathophysiological relevance of alteration of the posttranslational maturation mechanisms in heart failure. An impaired cardiac endocrine function was proposed to explain the altered electrolyte and fluid homeostasis occurring in chronic heart failure. Recent studies demonstrated that a great part of BNPs assayed by immunoassay methods in healthy subjects and in patients with cardiovascular disease is devoid of biological activity. These findings suggest that an alteration in posttranslational maturation of BNP precursor may promote the resistance to biological action of BNP in patients with heart failure at a prereceptor level. These studies also open a new and more complex scenario regarding the circulating BNPs. The active hormone (i.e., BNP1-32) may be produced even in vivo from the circulating precursor proBNP108 by plasma enzyme degradation, such as the soluble form of corin, possibly able to process the circulating intact precursor of natriuretic hormones. As a future perspective, the simultaneous measurement of the proBNP1-108 and the active peptide BNP1-32 with more specific methods could allow a more accurate estimation of both production/secretion of B-type-related peptides from cardiomyocytes and the true activity of the cardiac endocrine function.

The aim of this review is to analyze in detail some possible pathophysiological mechanisms linking obesity and cardiac endocrine function, in order to try to explain the negative association previously observed between BMI and BNP values in both healthy subjects and patients with cardiovascular diseases. In particular, we discuss the hypothesis that the response of the cardiac endocrine system is the integrated resultant of several and contrasting physiological and pathological interactions, including the effects of peptide and steroid hormones, cytokines, cardiovascular hemodynamics, clinical conditions, and pharmacological treatment. Several studies suggested that gonadal function regulates both body fat distribution and cardiac endocrine function. Visceral fat expansion can increase the clearance of active natriuretic peptides by means of an increased expression of clearance receptors on adipocytes, and in this way, it may contribute to decrease the activity of the cardiac endocrine system. Moreover, obesity is associated with ectopic lipid deposition even in the heart, which may directly exert a lipotoxic effect on the myocardium by secreting in loco several cytokines and adipokines. Obese subjects are frequently treated for hypertension and coronary artery disease. Pharmacological treatment reduces plasma level of cardiac natriuretic peptides, and this effect may explain almost in part the lower BNP levels of some asymptomatic subjects with increased BMI values. At present time, it is not possible to give a unique and definitive answer to the crucial question concerning the inverse relationship between the amount of visceral fat distribution and BNP levels. Our explanation for these unsatisfactory results is that the cardiac endocrine response is always the integrated resultant of several pathophysiological interactions. However, only few variables can be studied together; as a result, it is not possible to perform a complete evaluation of pathophysiological mechanisms under study. We are still not able to well integrate these multiple information together; therefore, we should learn to do it.

Cardiopulmonary exercise test (CPT) has a prominent value in assessing clinical severity in chronic heart failure (HF) patients. Reduced free triiodothyronine (fT3) plasma level is associated with a more severe disease and prognosis. The aim of this study was to evaluate the relationship between low fT3 plasma level and reduced exercise capacity in chronic HF, and to determine the influence of a low T3 status in subsets of patients with different functional impairment.240 HF patients (79% males; age 62 ± 12 years, mean ± standard deviation; left ventricular ejection fraction, EF, 30 ± 9%) underwent a CPT, clinical and neurohormonal characterization (assay for plasma brain natriuretic peptide, BNP, norepinephrine, aldosterone, renin activity, fT3, free T4, thyroid-stimulating hormone). At multivariate analysis in the whole population, age, gender and BNP level were independently associated with peak VO2, whereas in patients with severe functional impairment (peak VO214 ml/min/kg) fT3 resulted independently related to peak VO2, together with gender and BNP. When patients with peak VO214 ml/min/kg were divided according to fT3 levels, patients with low T3 syndrome showed reduced exercise capacity and worse ventilatory efficiency.BNP and fT3 are independently associated with exercise capacity in severely compromised HF patients.

article Objectives: We analyzed the platelet proteome of circulating platelets during the onset of clopidogrel therapy in patients with stable angina underwent percutaneous coronary intervention in order to investigate the mechanisms that control platelet reactivity and clopidogrel response in this context. Design & methods: Twenty patients were enrolled in this study. Blood samples were collected before coronary angiography (T0), 12 h after 600 mg of clopidogrel (T1) and 24 h after percutaneous coronary intervention (PCI) (T2). Platelet reactivity, Clopidogrel response and proteomic analysis were examined. Results: Clopidogrel loading dose produced a significant inhibition in all markers of platelet activation in both flow cytometry and aggregation tests. Among the proteins found differentially expressed, eighteen were identified by MS/MS analysis and they resulted involved in the cytoskeleton rearrangement (profilin-1, calpain, α-soluble NSF attachment protein, thrombospondin), in the energetic metabolism (ubiquitin-like modifier-activating enzyme 1, protein-L-isoaspartate-(D-aspartate) O-methyltransferase and nucleoside diphosphate kinase B) and in the oxidative stress (heat shock 70 kDa protein 5 and anti-stress induced phosphoprotein 1. Conclusions: The present study provides novel information on platelet proteome changes associated with platelet activation and clopidogrel response. This investigation supports the development of further proteomic studies for the identification of novel platelet biomarkers.

Recent studies reported that many different biochemical forms of B-type-related peptides circulate in human blood. In particular, a significant amount of the prohormone peptide (i.e., proBNP108) can be detected in plasma of patients with heart failure. These data indicate that the posttranslational maturation processing of the B-type natriuretic peptide (BNP) precursor may not be efficient in heart failure. The aim of this chapter is to describe the biochemical pathways of proBNP108 maturation and to discuss the pathophysiological relevance of alteration of the posttranslational maturation mechanisms in heart failure. An impaired cardiac endocrine function was proposed to explain the altered electrolyte and fluid homeostasis occurring in chronic heart failure. Recent studies demonstrated that a great part of BNPs assayed by immunoassay methods in healthy subjects and in patients with cardiovascular disease is devoid of biological activity. These findings suggest that an alteration in posttranslational maturation of BNP precursor may promote the resistance to biological action of BNP in patients with heart failure at a prereceptor level. These studies also open a new and more complex scenario regarding the circulating BNPs. The active hormone (i.e., BNP1-32) may be produced even in vivo from the circulating precursor proBNP108 by plasma enzyme degradation, such as the soluble form of corin, possibly able to process the circulating intact precursor of natriuretic hormones. As a future perspective, the simultaneous measurement of the proBNP1-108 and the active peptide BNP1-32 with more specific methods could allow a more accurate estimation of both production/secretion of B-type-related peptides from cardiomyocytes and the true activity of the cardiac endocrine function.

Background: Third generation troponin assays should aid in the rule-out of acute myocardial infarction (AMI). The study aim was to assess the capability of admission measurement of ultra-sensitive troponin I (TnI-Ultra) to exclude AMI from other myocardial injury. Methods: The fi rst TnI-Ultra sample from 856 patients at presentation to the Emergency Department and subsequent admission to the Cardiac Care Unit were considered in this case series. Myoglobin was simultaneously detected in 684 patients. Results: The sensitivity of the fi rst single TnI-Ultra level was 82.5 % in overall AMI, and similar in ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarc-tion (NSTEMI), admitted, respectively at 3 and 8 h from symptoms. The diagnostic capability of a fi rst single TnI-Ultra level was poor for both STEMI and NSTEMI to dis-criminate and rule-out overall AMI from myocardial injury, with an area under the receiver-operating curve of 0.65 and a negative likelihood ratio of 0.55. Adopting an optimal test threshold or adding myoglobin detection did not improve TnI-Ultra performances. Conclusions: The capability of a fi rst single TnI-Ultra level to exclude AMI from other myocardial injury in early and late presenters is poor. Addition of myoglobin assay offered no further improvement and was not considered useful. Keywords: acute myocardial infarction; biomarkers; diagno-sis; sensitivity; troponin.

Acute kidney injury (AKI) is a common and serious condition, currently diagnosed by functional biomarkers, such as serum creatinine measurements. Unfortunately, creatinine increase is a delayed and unreliable indicator of AKI. The lack of early biomarkers of structural kidney injury has hampered our ability to translate promising experimental therapies to human AKI. The recent discovery, translation and validation of neutrophil gelatinase-associated lipocalin (NGAL), possibly the most promising novel AKI biomarker, is reviewed here. NGAL may be measured by several methods both in plasma and urine for the early diagnosis of AKI and for the prediction of clinical outcomes, such as dialysis requirement and mortality, in several common clinical scenarios, including in the intensive care unit, cardiac surgery and renal damage due the exposition to toxic agent and drugs, and renal transplantation. Furthermore, the predictive properties of NGAL, may play a critical role in expediting the drug development process. A systematic review of literature data indicates that further studies are necessary to establish accurate reference population values according to age, gender and ethnicity, as well as reliable and specific decisional values concerning the more common clinical settings related to AKI. Furthermore, proper randomized clinical trials on renal and systemic outcomes comparing the use of NGAL vs. standard clinical practice are still lacking and accurate cost-benefit and/or cost-utility analyses for NGAL as biomarker of AKI are also needed. However, it is important to note that NGAL, in the absence of diagnostic increases in serum creatinine, is able to detect some patients affected by subclinical AKI who have an increased risk of adverse outcomes. These results also suggest that the concept and definition of AKI might need to be reassessed.

Objective Adiponectin is a protein secreted by adipose tissue and involved in inflammatory process as well as in metabolic regulation. The aim of this study was to examine the response of plasma adiponectin to cardiac surgery in children with congenital defects to determine whether its measurement is associated to the response to injury. Design and methods Twenty-five pediatric patients undergoing heart surgery for correction of congenital defects were studied. Adiponectin plasma levels, obtained pre- and three times postoperatively, were determined by dedicated ELISA. Brain natriuretic peptide (BNP) plasma levels were also determined. Results Adiponectin levels are highest in the first month of life (p = 0.004 newborns vs. children) with a progressive fall in the next few years. After surgery, adiponectin increased slowly over a 1-month period, following an initial decrease in the first 3 days. Conclusions Adiponectin could be involved in the acute response to injury although further investigation into the relationship between adiponectin, glucose regulation and inflammatory process is necessary to examine the issue of the adiponectin decrease after surgery from a more integrated prospective.

The effects of age on atrial natriuretic factor (ANF) metabolism were studied in male Sprague Dawley rats by standard radioimmunological procedures, transmission electron microscopy, and ultrastructural morphometry. Plasma atrial natriuretic peptide (ANP) levels increased during growth (1- month- old rats: 64± 8.7 pg/mL; 2- month- old rats: 105± 8.1 pg/mL) and did not change thereafter. Immunoreactive (ir)-ANP concentration increased significantly in senescent rats, both in the right (12- month- old rats: 254± 33 ng/mg; 24 month- old: 415+- 77 ng/mg) and left atrium (226± 30 and 498± 60 respectively). The ultrastructural morphological features of the endocrine cardiocytes of senescent rats were the presence of a few lysosomal structures and atrial specific granules of higher electrondensity. Ultrastructural morphometry studies did not reveal any significant increase in the number or in the mean individual volume of atrial specific granules, compared with young adult rats. In conclusion, unlike younger rats, morphometric data in older and senescent rats show that atrial granularity may not necessarily change together with atrial ir-ANP contents; ir-hormone assay findings show that senescent rats have ANP plasma levels within the norm, and a much larger hormone store in atrial tissue. (Aging Clin. Exp. Res. 6: 167–174, 1994)

C-type natriuretic peptide (CNP) is assuming increasing importance in cardiovascular disease, and in adults its plasma levels are related to clinical and functional disease severity. Data are scarce regarding the reference values for CNP in infancy. Aim of this study was to assess the reference intervals for CNP in human healthy newborns and infants. Plasma CNP was measured in 121 healthy children divided into: 41 newborns (age 0-3 days), 24 newborns (4-30 days), 22 infants (1-12 months) and 32 children (1-12 years). A group of 32 healthy adult subjects (age 64 ± 1 years) was also studied. CNP was measured by a specific radioimmunoassay. Between- and within-assay variability resulted ≤ 30 and 20%, respectively and analytical sensitivity 0.77 ± 0.05 pg/tube. Plasma CNP resulted significantly higher in children than in adult subjects (13.6 ± 1.2 pg/ml vs. 7.4 ± 1.0 pg/ml, p=0.030). When the results were analyzed as a function of the age the reference intervals for plasma CNP resulted: 11.6 ± 2.1 pg/ml for newborns (0-3 days), 16.4 ± 3.7 pg/ml for newborns (4-30 days), 15.4 ± 2.7 pg/ml for infants (1-12 months), 13.6 ± 2.3 pg/ml for children (1-12 years) [p=0.01 newborns (4-30 days) vs. adults; p=0.03 infants (1-12 months) vs. adults]. CNP showed the highest concentrations after 12h of life with a peak between 4 and 5 days of life and with a progressive decline afterwards. According to these data at least five different reference intervals for CNP determinations should be used. These observations may be helpful for future clinical application of CNP in human children.

Recent studies demonstrated that large amounts of the pro-hormone peptide of brain natriuretic peptide (proBNP) can be detected in plasma of healthy subjects and in particular of patients with heart failure. As a result, a great part of B-type natriuretic peptides measured in patients with cardio-vascular disease may be devoid of biological activity. These findings stimulated the set up of specific immunoassay methods for the measurement of the intact proBNP peptide. The aim of this review article is to discuss the methodological characteristics and the possible clinical relevance of specific immunoassay methods for the measurement of the proBNP peptide. From an analytical point of view, a fully automated immunoassay of proBNP has some theoretical advantages (e.g., a more stable molecule with higher molecular weight than the derived peptides) compared to the active hormone BNP. Recent studies supported the concept that the precursor proBNP might be actually considered a circulating prohormone, which can be cleaved by specific plasma proteases in BNP, the active hormone, and NT-proBNP, an inactive peptide. The peripheral processing of circulating proBNP could likely be submitted to regulatory rules, which might be impaired in patients with heart failure, opening new perspectives in the treatment of heart failure (e.g., by studying drugs inducing the cleavage of the prohormone into active BNP). Furthermore, as a future perspective, the specific assay in the same plasma sample of the intact precursor proBNP and of the biologically active peptide BNP, could allow a more accurate estimation of the production/secretion of B-type related peptides from cardiomyocytes and of the global cardiac endocrine function.

BACKGROUND In order to evaluate whether there is still present a very large variability in measured values and analytical performance among different free thyroid (FT) hormone immunoassays, we considered the results derived from an External Quality Assessment (EQA) scheme, named Immunocheck. METHODS The EQA Immonocheck study enrolled about 1000 participant laboratories, which measured the 54 quality control samples distributed in the three annual cycles (2007, 2008 and 2009). Participant laboratories produced a total of 30,476 results for FT3 and 31,351 for FT4, respectively. RESULTS The results recovered during the EQA cycles allowed the estimation of assay imprecision (i.e., within-method and between-laboratories variability). On average, control samples with lower free triiodothyronine (FT3) and free thyroxine (FT4) concentrations showed higher imprecision values (CV%) than those with levels within or above the normal range. The agreement among the results produced by different methods was estimated by computing the percent differences (i.e., percent bias values) between the concentrations measured by the methods and the mean of all collected results (i.e., consensus mean). CONCLUSIONS The results of our study demonstrate that a large variability in measured values is still present among different free thyroid hormone immunoassays. Indeed, some immunoassays for both FT3 and FT4 measurement showed percent bias values compared to the consensus mean >20%. Laboratories should inform the clinicians about analytical performance and reference limits of the method used. Furthermore, the clinicians should avoid the use of different methods in the follow-up of patients.

We read with interest the paper of Eindhoven et al. [(1)][1] underscoring the clinical usefulness of N-terminal pro–B-type natriuretic peptide (NT-proBNP) in adult patients with different congenital heart diseases (CHDs), even corrected or palliated. Plasma levels of NT-proBNP differing by

At the dawn of the new century, the advent of more specific myocardial tissue markers, such as cardiac troponin I (cTnI) and T (cTnT), has led to a new definition of acute myocardial infarction (AMI) by international guidelines. If we accept the concept that AMI is the portion of acutely necrotic myocardial tissue (irrespective of size), some patients previously diagnosed with severe angina may be currently considered to present minimal (even microscopic) quantities of myocardial necrosis. Although increased cTnI or cTnT values always indicate myocardial tissue damage, a positive test is not able to identify the mechanism responsible for that cardiac damage (which could be not due to ischemia). New cTnI and cTnT immunoassays with increased analytical sensitivity may increase "false positive" results in patients with cardiovascular disease, especially those with advanced age, heart failure (HF), severe comorbidities (such as chronic renal insufficiency), or assuming potential cardiotoxic drugs. Hence, it may be not clear for most patients and physicians whether high-sensitivity cTnI and cTnT methods will lead to more clarity or confusion. The aim of this review is to update the present knowledge in the field of cTnI and cTnT with particular attention on the impact of immunoassays with increased analytical sensitivity on both laboratory and clinical practice.

Background: We organized and conducted a proficiency testing study (CardioOrmocheck) to evaluate the differences in analytical performance of brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) immunoassays. Methods: Approximately 90 Italian laboratories were involved in the 2005–2007 proficiency testing cycles, while 112 laboratories took part in the 2008 cycle (from January to May 2008). A total of 28 study samples were measured by participating laboratories for a total of 2354 determinations. Results: The mean total variability for BNP (50.6 %CV) was significantly higher than that for NT-proBNP (8.4 %CV). In addition, the mean variability due to differences between-methods (46.4 %CV) comprised the majority of the total variability for BNP. Between-method variability for BNP comprised, on average, 84% of total variability, while the within-method variability comprised an average of 20.2 %CV. On the contrary, for NT-proBNP the within-method variability (7.3 %CV) represented the majority of total variability (average 75%), while between-method variability was smaller (4.1 %CV). Imprecision around the cut-off value showed marked differences among methods, especially for BNP immunoassay methods. In addition, BNP methods were affected by large systematic differences, for example an average 2.7-fold difference between Access and ADVIA Centaur methods, while agreement between NT-proBNP methods was better (an average 1.2-fold difference between Dimension and ECLIA on the Elecsys methods). Conclusions: This multicenter collaborative study demonstrates that there are significant differences in analytical characteristics and measured values among the most popular commercial methods for BNP and NT-proBNP. Clinicians should be very careful when comparing results obtained by laboratories that use different methods. Clin Chem Lab Med 2009;47:762–8.

1. Abstract The measurement of circulating brain natriuretic peptide (BNP) and its related peptide, the N‐terminal fragment of proBNP (NT‐proBNP), have a high degree of diagnostic accuracy and clinical relevance both in acute and chronic heart failure (HF). However, the role of measurement of BNP/NT‐proBNP in the follow‐up of treated HF patients is still debated. In this chapter, authors have studied the clinical impact of B‐type natriuretic peptide assay in the follow‐up of patients with heart failure, and, in particular, the possible role of the measurement of its circulating levels in guiding the treatment. A relatively small number of randomized studies were designed to specifically evaluate the clinical use of BNP/NT‐proBNP assay in monitoring and tailoring the medical therapy in HF patients. A meta‐analysis of results reported in these studies indicate that the inefficacy to improve the mortality rate of the peptide‐guided compared to the control group found in some studies, may depend on to the inability of current therapeutic strategies to modify prognosis, especially in the elderly subset of patients, who are characterized by more advanced disease and comorbidities. Further prospective and randomized clinical studies are necessary to definitively demonstrate whether BNP/NT‐proBNP‐guided therapy is able to significantly improve the outcome of patients with HF.

At the dawn of the new century, the advent of more specific myocardial tissue markers, such as cardiac troponin I (cTnI) and T (cTnT), has led to a new definition of acute myocardial infarction (AMI) by international guidelines. If we accept the concept that AMI is the portion of acutely necrotic myocardial tissue (irrespective of size), some patients previously diagnosed with severe angina may be currently considered to present minimal (even microscopic) quantities of myocardial necrosis. Although increased cTnI or cTnT values always indicate myocardial tissue damage, a positive test is not able to identify the mechanism responsible for that cardiac damage (which could be not due to ischemia). New cTnI and cTnT immunoassays with increased analytical sensitivity may increase "false positive" results in patients with cardiovascular disease, especially those with advanced age, heart failure (HF), severe comorbidities (such as chronic renal insufficiency), or assuming potential cardiotoxic drugs. Hence, it may be not clear for most patients and physicians whether high-sensitivity cTnI and cTnT methods will lead to more clarity or confusion. The aim of this review is to update the present knowledge in the field of cTnI and cTnT with particular attention on the impact of immunoassays with increased analytical sensitivity on both laboratory and clinical practice.

Heart failure (HF) may be considered as the fatal finishing line of all cardiovascular disorders. There is not a single diagnostic test for HF, and its diagnosis relies on clinical judgment based on a combination of history, physical examination, and appropriate investigations. For these reasons, the accuracy of diagnosis by clinical means alone is often inadequate. Despite the enormous advances in understanding and treatment that have taken place during the last 50 years, HF continues to have a poor prognosis. Diagnosis and risk stratification of patients with HF depend on the availability of specific, accurate, and effective disease or risk markers. Thus, there is an increasing interest in the development of new cardiovascular biomarkers, and, consequently, a great number of laboratory tests have recently been proposed for their assay. In this review, we briefly discuss the characteristics of an ideal HF biomarker and describe the analytical performance and clinical relevance of available biomarker assay methods, comparing their performances with that of an ideal biomarker for HF. Finally, we present a scheme to search for more efficient diagnostic and prognostic biomarkers for HF.

The increased analytical sensitivity of the new generation of methods for cardiac troponin I (cTnI) and T (cTnT) has demonstrated that measurable troponin is present in the blood of healthy adult subjects. These data are not in accordance with the prevailing opinion that any reliably detected increase in cardiac troponins should be considered abnormal and potentially caused by cardiac necrosis. The goal of the present review is to discuss the hypothesis that cardiac troponins can be released from cardiomyocytes, even in healthy adult subjects as a result of a process related to "physiological renewal" of the human myocardium and possibly enhanced by physical exercise or aging. The latest generation of high-sensitive cTnI and cTnT immunoassays are characterized by detection limits (DLs) as low as a few picograms. This clearly represents a greater increase in discrimination than that obtained by the most sophisticated cardiac imaging techniques that are commercially available at present. However, the critical question is whether high-sensitive troponin assays are clinically useful and in particular, whether some specific laboratory biomarkers (such as cTnI and cTnT) yield better diagnostic (or prognostic) accuracy and cost-effectiveness when compared with echocardiography in patients with cardiovascular disease. Only specific and well-designed clinical trials will answer this important question.

Background We evaluated the analytical characteristics of electrochemiluminescence (ECLIA) immunoassay for NT-proBNP (proBNP II, Roche Diagnostics, Germany) and compared its analytical performance to that of the previous polyclonal method. Methods We measured NT-proBNP in EDTA plasma samples of 177 consecutive cardiac patients (69 females and 108 males; mean age 62.2 ± 16.4 years, range 13 to 96 years) with monoclonal and polyclonal ECLIA methods following manufacturer's instructions using an Elecsys® 2010 analyzer. Results Monoclonal ECLIA method for NT-proBNP assay showed an imprecision (CV%) lower than 3% at the cut-off value (i.e., 150 ng/L). No significant interference was found in plasma samples containing high levels of hemoglobin, triglycerides or bilirubin. EDTA plasma showed slightly, but significantly lower NT-proBNP values than serum (on average − 6.3%) and lithium-heparinized plasma (on average − 3.9%) samples. Finally, a very close linear regression was found between the NT-proBNP values found by either monoclonal or polyclonal ECLIA method (monoclonal ECLIA = − 72.17 + 1.04 polyclonal ECLIA, n = 177, R = 0.993). Conclusions The monoclonal ECLIA method showed very similar analytical characteristics with slightly lower NT-proBNP results (on average − 2.5%) than the polyclonal ECLIA method. The difference between monoclonal and polyclonal methods seems to be too slight to change the reference range and decisional values for NT-proBNP assay, as previously assessed by the polyclonal ECLIA method.

Summary Objective We evaluated and compared the analytical and clinical performance of the TnI-Ultra immunoassay for cardiac Troponin I (cTnI) measurement, carried out on the fully automated ADVIA Centaur and ADVIA Centaur CP ® platforms (Siemens Medical Solutions Diagnostics SrL), and that of Access AccuTnI™, carried out on the UniCell ® DxI 800 platform (Beckman Coulter, Inc., Fullerton). Methods We assayed 645 plasma Li-heparin samples of healthy subjects and 230 of patients with cardiovascular diseases (70 with a cTnI value higher than the decision level for acute myocardial infarction) by TnI-Ultra and Access AccuTnI™ immunoassays. Results The total imprecision (CV) profile of TnI-Ultra method was determined by repeatedly measuring 19 plasma pools, with different concentrations of TnI, in 20 different runs using two reagent lots; the CV ranged from 25% (at 0.02 μg/L) to less than 5% (for levels greater than 0.4 μg/L). On average, functional sensitivity (i.e. concentration measured with an imprecision of 10% CV) of TnI-Ultra method was 0.057 μg/L. The 99th percentile of normal distribution, calculated by enrolling a control group of 645 healthy subjects (278 males and 367 females; mean age of 47.4 ± 16.2 years, range 15–89 years), was 0.072 μg/L. Therefore, the ratio between functional sensitivity and 99th percentile values was less than 1 (i.e., 0.057/0.072 = 0.79), while for Access AccuTnI™ resulted 0.07/0.06 = 1.16. A close linear regression was found between the cTnI values obtained with the two methods only when the samples of patients with cardiac disease were taken into account (TnI-Ultra = −0.192 + 1.434 AccuTnI T ; R = 0.976; n = 230). A significant bias was found between the two methods by means of Bland-Altman plot (mean difference 38.9%), but when 368 healthy subjects were considered, no significant linear regression was found between these two methods ( R = 0.002, p = 0.9624). Conclusion Our results indicate that the TnI-Ultra immunoassay carried out on the fully automated ADVIA Centaur platforms shows analytical characteristics well in agreement with the quality specifications recommended for cardiac troponin assay.

The practice of cardiology is in continual evolution, in parallel with the progress achieved by medical research in understanding the pathophysiology of cardiovascular disease and in developing new therapeutic procedures. Consequently, manufacturers of cardiac biomarkers are pressed with new demands to improve the performance of the existing and the development of novel ones. Several highly sensitive and/or specific assays for myocardial ischemic damage and myocardial function detection have already become commercially available. Moreover, an increasing number of novel risk factors have been added to the classical risk factors of cardiovascular disease. Finally, the recent surge of genetic analysis procedures will likely soon provide the clinical cardiologist with a number of laboratory tests for defining the molecular diagnosis, assessing new risk factors, and better targeting the pharmaceutical approaches in patients with cardiovascular disease. In this review, we first present the general characteristics of a biomarker followed by the analytical and clinical performance of assay methods.

There is evidence that natriuretic peptide (namely atrial and/or B-type natriuretic peptides) plasma concentration may be elevated in many clinical conditions besides cardiovascular diseases, the most frequent being lung diseases, renal and liver failure, acute cerebrovascular events, acute and chronic inflammatory diseases and certain metabolic and endocrine disorders. In general, increased circulating levels of natriuretic peptides (compared to the normal range of a healthy population) may be considered expression of activation of the neuro-endocrine system, which can be the cause or consequence of cardiac stressor events. Furthermore, some variables, such as gender and obesity, may affect natriuretic peptide secretion and plasma concentration by completely extra-cardiac mechanisms. Increased expression of the natriuretic peptide system, counteracting neuro-hormonal and immunological activation, may occur in many clinical conditions, as witnessed by the considerable number of diseases in which the natriuretic peptide system has been found to be altered. Several studies have demonstrated that higher circulating levels of natriuretic peptides represent a strong independent risk factor for major cardiovascular complications and/or death, even in extra-cardiac diseases. Because several of these diseases may be present in patients with left ventricular dysfunction, the possible influence on diagnostic and prognostic accuracy of natriuretic peptides in heart failure will be discussed.

BACKGROUND The aim of this study was to evaluate the distribution of cardiac troponin I (cTnI) values, measured by the ADVIA TnI-Ultra method (Siemens Medical Solutions Diagnostics SrL) in healthy subjects and to characterize its relation to gender, age, as well as to N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). METHODS A Caucasian population of 692 healthy subjects (311 males and 381 females) with a mean (SD) age of 45.3 (17.3) years [range 11-89 years; females 46.5 (17.3) years, males 43.8 (17.1) years] was enrolled. The presence of cardiac or systemic acute or chronic diseases was excluded by history and accurate clinical evaluation. RESULTS A significant difference was found between the cTnI values in men and women (men: median 0.012 microg/L, range from undetectable values to 0.196 microg/L; women: median 0.008 microg/L, range from undetectable values to 0.130 microg/L; p

The evaluation of cardiac endocrine function by means of automated robust assays has permitted the introduction of a cheap and powerful clinical tool. Plasma concentration of B-type-related natriuretic peptides is a marker of either hemodynamic or neurohormonal stress on the heart and has been validated within the diagnostic and prognostic domain in patients with suspected or ascertained heart failure, mostly in the in-hospital setting. Evidence is growing, supporting an out-of-hospital use, namely in primary care. Its implementation in this setting in screening programs and diagnostic algorithms might contribute to decrease the apparent disparity between the general practitioner and the specialist approach to disease management.

The study investigates the response of atrial natriuretic peptide (ANP) to different cardiac pacing modes in comparison with hemodynamic changes. Ten patients underwent Swan-Ganz catheterization during pacemaker implant. Atrioventricular and ventricular pacing were performed consecutively at three pacing rate levels (80, 100, and 110 ppm). Blood samples were taken from the pulmonary artery for ANP determination, both basally and at the end of each pacing period. Concomitantly, mean pulmonary capillary wedge pressure (PCWP) and mean pulmonary artery pressure (PAP) were measured. Cardiac output (CO) was determined by thermodilution both basally and during the 110 ppm steps. During atrioventricular pacing, whereas no significant changes were observed for ANP, PCWP and PAP, CO increased significantly (P less than 0.0005). At the beginning of ventricular pacing hemodynamic parameters and ANP levels were comparable with those of baseline conditions. During subsequent ventricular pacing PCWP and ANP increased significantly at the 110 ppm rate step (P less than 0.05). PAP did not change significantly, whereas CO decreased in all cases (P less than 0.01). A positive correlation was observed between ANP and PCWP during ventricular (P less than 0.001), but not atrioventricular pacing. The results, while confirming the hemodynamic advantages of atrioventricular pacing, point to a major stimulation of ANP secretion during ventricular pacing. This fact, together with the observed drop in CO and the correlation between ANP and PCWP, suggest that the increase of ANP in ventricular pacing may be the expression of a compensatory mechanism to the hemodynamic disadvantages of atrioventricular asynchrony.