Effects of pirfenidone on scar size and ventricular remodeling after myocardial infarction: a preclinical study.

BACKGROUND: An intense fibrotic response after myocardial infarction (MI) may lead to scar expansion and left ventricular (LV) remodeling. We investigated the effects of the antifibrotic drug pirfenidone in this setting. METHODS: Male Wistar rats were randomized to: sham procedure (n = 13), reperfused MI-induced by ligating the left anterior descending artery (LAD) for 45 min (n = 17), reperfused MI plus standard therapy (aspirin, angiotensin-converting enzyme inhibitor, beta blocker, and mineralocorticoid receptor antagonist) (n = 17), reperfused MI plus pirfenidone alone (n = 17), or reperfused MI plus standard therapy and pirfenidone (n = 17). Rats surviving MI induction underwent cardiac magnetic resonance scans after 72 h and 30 days from MI, and were sacrificed on day 31. RESULTS: Rats completing the whole protocol numbered 11 in the sham group, 9 in the untreated MI group, 8 in the standard treatment group, 9 in the pirfenidone alone group, and 9 in the standard treatment plus pirfenidone group. No significant differences emerged between LV volumes, ejection fraction or mass at 30 days or the differences from 72 h to 30 days. Small, nonsignificant differences between rats on pirfenidone alone vs. those on standard therapy emerged. The total extent of LV fibrosis, quantified as area and percentage of the tissue sample, did not differ significantly between rats on pirfenidone alone vs. those on standard therapy alone. CONCLUSION: Pirfenidone does not have additional effects on LV remodeling or fibrosis compared with standard therapy, but its effects are similar to standard therapy alone.

Colchicine added to standard therapy further reduces fibrosis in pigs with myocardial infarction.

BACKGROUND: The anti-inflammatory drug colchicine improves the outcome of patients with myocardial infarction (MI). As an intense inflammatory and fibrotic response after MI may lead to scar expansion and left ventricular (LV) remodeling, the clinical benefit of colchicine could be related to a positive effect on the infarct scar and LV remodeling. METHODS: Pigs underwent left anterior descending artery occlusion through an angioplasty balloon for 90 min and were then randomized into two groups: standard therapy [ACE inhibitor, beta blocker, mineralocorticoid receptor antagonist (MRA), aspirin] plus colchicine (n = 14) or standard therapy alone (n = 13). The pigs were treated for 30 days and underwent two cardiac magnetic resonance (CMR) scans at 72 h and 30 days. The pigs were then sacrificed the day after the second CMR. The primary efficacy end point was the extent of fibrosis in the infarct zone (calculated on eight samples from this zone and averaged). RESULTS: In the hearts explanted after 31 days, pigs in the colchicine group had less fibrosis in the infarct zone than the other animals [41.6% (20.4-51.0) vs. 57.4% (42.9-66.5); P = 0.022]. There was a trend toward a higher myocardial salvage index (MSI; an index of the efficacy of revascularization) in pigs on colchicine (P = 0.054). Conversely, changes in LV volumes, ejection fraction and mass did not differ between groups. CONCLUSION: Colchicine therapy for 1 month after reperfused MI further reduces myocardial fibrosis when added to standard therapy, while it does not have additional effects on LV remodeling.

Intact fibroblast growth factor 23 in heart failure with reduced and mildly reduced ejection fraction.

BACKGROUND: Fibroblast growth factor-23 (FGF23) has been associated to left ventricular (LV) hypertrophy and heart failure (HF) severity. We aimed to investigate the clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients. METHODS: Patients with stable HF and left ventricular ejection fraction (LVEF) < 50% were prospectively enrolled, managed according to current recommendations and followed over time. iFGF23 was measured at baseline with a fully automated immuno-chemiluminescent assay. RESULTS: We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were < 35.2 pg/mL, 35.2-50.9 pg/mL, and > 50.9 pg/mL. LVEF decreased from the first iFGF23 tertile to the third tertile (p = 0.014). N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased from the first to the third tertile (p = 0.001), while peak oxygen consumption decreased (p < 0.001). Thirty-five patients (23%) experienced the primary endpoint (all-cause death or HF hospitalization at 5 years), and 26 (17%) the secondary endpoint (all-cause death at 5 years). On multivariable analysis, iFGF23 independently predicted the primary endpoint on top of age, gender and LVEF (HR 4.6 [95% CI 2.1-10.3], p < 0.001), age, gender and eGFR (HR 4.1 [95% CI 1.6-10.3], p = 0.003), as well as age, gender and NT-proBNP (HR 3.6 [95% CI 1.6-8.2], p = 0.002). iFGF23 even reclassified patient risk on top of all the 3 models, with NRI values of 0.65 (95% CI 0.30-1.01), 0.55 (95% CI 0.25-0.88), and 0.60 (95% CI 0.24-0.96), respectively (both p < 0.001). CONCLUSIONS: Circulating iFGF23 is associated with disease severity and outcome in HF patients with reduced and mildly reduced ejection fraction.

N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T hold diagnostic value in cardiac amyloidosis.

AIMS: 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). METHODS AND RESULTS: Patients with suspected CA (n = 1149) underwent a diagnostic work-up in three centres 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-proBNP <180 ng/L or hs-TnT <14 ng/L were found in 7% of patients, and ruled out CA without false negatives. In the validation cohort, 20% of patients (2% false negatives) had NT-proBNP <180 ng/L or hs-TnT <14 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 haematologic 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. CONCLUSIONS: Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT-proBNP <180 ng/L and hs-TnT <14 ng/L reliably exclude the diagnosis, both in the overall population and subgroups referred for either AL-CA or cardiac (pseudo)hypertrophy.

Cardiac troponins: Mechanisms of release and role in healthy and diseased subjects.

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 Ca2+ . Circulating cTnT and cTnI (cTns) increase following cardiac tissue necrosis, and they are consolidated biomarkers of acute myocardial infarction (AMI). However, the use of high sensitivity (hs)-immunoassay tests for cTnT and cTnI has made it possible to identify a multitude of other clinical conditions associated with increased circulating levels of cTns. cTns can be measured also in the peripheral circulation of healthy subjects or athletes, suggesting that different mechanisms are involved in the release of cTns in the blood independently of cardiac cell necrosis. In this review, the molecular/cellular mechanisms involved in cTns release in blood and the exploitation of cTnI and cTnT as biomarkers of cardiac adverse events, in addition to cardiac necrosis, are discussed.

Big gamma-glutamyltransferase is associated with epicardial fat volume and cardiovascular outcome in the general population.

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.

Use of high-sensitivity cardiac troponins in the emergency department for the early rule-in and rule-out of acute myocardial infarction without persistent ST-segment elevation (NSTEMI) in Italy.

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.

Amyloid Deposits and Fibrosis on Left Ventricular Endomyocardial Biopsy Correlate With Extracellular Volume in Cardiac Amyloidosis.

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.

Patients with cardiac amyloidosis have a greater neurohormonal activation than those with non-amyloidotic heart failure.

BACKGROUND: Neurohormonal activation has never been investigated in patients with cardiac amyloidosis (CA). METHODS: 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. RESULTS: 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 < 0.001), and slightly higher norepinephrine (595 ng/L [383-869] vs. 416 [250-693], 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. CONCLUSIONS: Patients with CA display a neurohormonal activation, with some prognostic significance.

[Biomarkers for the diagnosis and management of heart failure: new frontiers]. / Biomarcatori per la diagnosi e la gestione dello scompenso cardiaco: nuove frontiere.

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.

Discharge FGF23 level predicts one year outcome in patients admitted with acute heart failure.

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.

Evaluation and Comparison with Other High-Sensitivity Methods of Analytical Performance and Measured Values of a New Laboratory Test for Cardiac Troponin I Assay.

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.

[Biomarkers for the diagnosis and management of heart failure: natriuretic peptides]. / Biomarcatori per la diagnosi e la gestione dello scompenso cardiaco: i peptidi natriuretici.

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.

Myocardial salvage is increased after sympathetic renal denervation in a pig model of acute infarction.

RATIONALE: 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. OBJECTIVE: To investigate the potential role of RD limiting myocardial damage and remodeling when performed immediately after AMI. METHODS AND RESULTS: 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 < 0.001). RD pigs had higher cardiac output (3.7 ± 0.8 vs 2.66 ± 0.7 L/min, p < 0.001) and lower LV end diastolic volume (98 ± 16 vs 113 ± 31 ml, p = 0.041). 123I-MIBG defect extension was smaller in RD than control (60 ± 28 vs 78 ± 17%, p < 0.05) with significant reduction in the difference between innervation and perfusion defects (25 ± 12 vs 36 ± 30%, p = 0.013). NE content from necrotic area (238; IQR 464 vs 2546; IQR 1727 ng/g in RD and control, respectively, p < 0.001) and from border zone (295; IQR 264 vs 837; IQR 207 in RD and control, respectively, p = 0.031) was significantly lower in RD than control. CONCLUSIONS: RD results in increased myocardial salvage and better cardiac function, when performed immediately after AMI. Reduction of sympathetic activation with preservation of cardiac sympathetic functionality warranted by RD may sustain these effects.

Renin profiling predicts neurohormonal response to sacubitril/valsartan.

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 < 0.05). At follow-up, 38 patients (48%) were classified as responders. Circulating renin was lower in the responder group compared with non-responders (19.8 mU/L, IQR 3.7-78.0 mU/L vs. 55.0 mU/L, IQR 16.4-483.1 mU/L; P = 0.004). After adjustment for age, renal function, and blood pressure, renin was independently associated to response to sacubitril/valsartan (P = 0.018). CONCLUSIONS: In our preliminary study, we show that circulating renin predicts reduction in NT-proBNP levels after sacubitril/valsartan initiation in HFrEF patients. Renin assessment might be useful to discriminate potential responders from the subgroup with a weaker expected benefit, thus needing a closer, tailored management strategy.

The combined measurement of high-sensitivity cardiac troponins and natriuretic peptides: a useful tool for clinicians?

: 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.

Early evaluation of myocardial injury by means of high-sensitivity methods for cardiac troponins after strenuous and prolonged exercise.

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.

Harmonization of two hs-cTnI methods based on recalibration of measured quality control and clinical samples.

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.

Evaluation of analytical performance of immunoassay methods for cTnI and cTnT: From theory to practice.

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.