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.

Considerations for early acute myocardial infarction rule-out for emergency department chest pain patients: the case of copeptin.

The evaluation of patients admitted at the emergency department (ED) for chest pain is challenging and involves many different clinical specialists including emergency physicians, laboratory professionals and cardiologists. The preferable approach to deal with this issue is to develop joint protocols that will assist the clinical decision-making to quickly and accurately rule-out patients with non life-threatening conditions that can be considered for early and safe discharge or further outpatient follow-up, rule-in patients with acute coronary syndrome and raise the degree of alert of the emergency physicians on non-cardiac life-threatening emergencies. The introduction of novel biomarkers alongside the well-established troponins might support this process and also provide prognostic information about acute short-term or chronic long-term risk and severity. Among the various biomarkers, copeptin measurement holds appealing perspectives. The utility of combining troponin with copeptin might be cost-effective due to the high negative predictive value of the latter biomarker in the rule-out of an acute coronary syndrome. Moreover, in the presence of a remarkably increased concentration (e.g., more than 10 times the upper limit of the reference range), to reveal the presence of acute life-threatening conditions that may not necessarily be identified with the use of troponin alone. The aim of this article is to review current evidence about the clinical significance of copeptin testing in the ED as well as its appropriate placing within diagnostic protocols.

A risk-analysis approach to the evaluation of analytical quality.

BACKGROUND: Setting specifications for analytical quality is always difficult. The risk-management approach might be a way to do so. In this approach, the definition of the required analytical quality is based on the evaluation of patient risk. Risk derives from the probability of error and from the damage that such an error might cause. METHODS: Eight Italian laboratories took part in this experiment. Measurements of glucose and total calcium were taken as examples. Analytical quality was evaluated using a specific ring trial with a frozen serum pool and by means of internal quality-control data. The total allowable error was defined according to biological variation specifications. The probability of error was extracted from the imprecision and comparative bias data of each laboratory. The damage caused by a wrong result was evaluated using the absolute probability judgment approach. RESULTS: According to the iso-risk plots (standardized hyperboles on a graph where the x-axis represents damage and the y-axis represents probability) for glucose, all the laboratories were working with an analytical quality that guaranteed low risk for patients. On the contrary, for total calcium none of the laboratories exhibited sufficient quality to guarantee low risk for patients, the presence of bias being the most relevant problem. CONCLUSIONS: The results seem to demonstrate the applicability of the risk approach to the analytical phase, indicating a new possible way to define analytical quality targets.

The new definition of myocardial infarction: analysis of the ESC/ACC Consensus Document and reflections on its applicability to the Italian Health System.

The recent document of the ESC/ACC Committee for the redefinition of myocardial infarction (MI) has introduced the measurement of cardiac troponin as the biochemical standard for the diagnosis of MI. This change has been mainly driven by the demonstration that any amount of myocardial damage, as detected by cardiac troponins, implies a worse long-term outcome of the patient. The results of several studies consistently show that there is a continuous relationship between the degree of troponin elevation and the patient's prognosis. The new definition has important consequences on the diagnostic and therapeutic approaches to patients with acute coronary syndromes; in fact, patients with increased troponins, i.e. patients with MI, necessitate more aggressive treatment than those without troponin elevations, i.e. patients with unstable angina. The application of the new definition is expected to increase the number of cases of MI by about 30% and to decrease mortality. We believe that several aspects of the new definition need to be discussed before the new criteria for MI are used in clinical practice in Italy. The most relevant issues are the following: 1) the definition of troponin elevation should meet the analytical performance of the available assays, the diagnostic cutoff of which is frequently too imprecise. We propose that troponin elevations be defined as values exceeding the concentration corresponding to a total analytical imprecision of 10%. We disclose such a concentration for the currently available assays and suggest its use in clinical practice to mitigate the possibility of false-positive values; 2) the number of samples required for the diagnosis should be sufficient for the assessment of the changes in concentration over time. When only one sample is available, or when the temporal pattern of the changes in marker concentration is not consistent with the time elapsed from the onset of symptoms, we suggest that objective evidence that myocardial ischemia is the likely cause of myocardial damage should be obtained; 3) the diagnosis of MI after a percutaneous coronary intervention represents a unique situation. In contrast with myocardial damage occurring during spontaneous ischemia, available data do not support the concept that any troponin elevation is associated with an adverse prognosis. In the absence of conclusive studies, we suggest that the diagnosis of MI after a percutaneous coronary intervention be based on conventional criteria. Finally, we propose this summary with the aim of overcoming some of the more controversial aspects of the ESC/ACC redefinition of MI: Criteria for acute, evolving or recent MI. Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: 1) elevation of biochemical markers of myocardial necrosis (preferably troponin) with at least one of the following: a) ischemic symptoms; b) development of pathologic Q waves on the ECG; c) ECG changes indicative of ischemia (ST segment elevation or depression); d) coronary artery intervention (e.g., coronary angioplasty). Marker elevations should be accompanied by objective evidence that myocardial ischemia is the likely cause of myocardial damage when: a) only one blood sample is available; b) marker changes over time are not consistent with the onset of symptoms; 2) pathologic findings of an acute MI. Criteria for established MI. Anyone of the following criteria satisfies the diagnosis for established MI: 1) development of new pathologic Q waves on serial ECGs. The patient may or may not remember previous symptoms. Biochemical markers of myocardial necrosis may have normalized, depending on the length of time that has passed since the infarct developed; 2) pathologic findings of a healed or healing MI.

Management of patients with low-risk chest pain at the time of admission: a prospective study on a non-selected population from the Emergency Department.

BACKGROUND: The management of patients with acute chest pain is a common and difficult challenge from the epidemiological, clinical, organizational and malpractice points of view. Our purpose was to test and implement a simple clinical protocol for the management of patients with acute chest pain and at low-risk for an acute coronary syndrome (ACS) at the time of admission to the Emergency Department (ED). METHODS: During a 5-month study period, 570 consecutive patients were admitted to the ED with acute chest pain: 224 patients were excluded owing to the presence of a clear diagnosis of an ACS or of high-risk factors. The remaining 346 were considered, at the time of admission, as being at low risk for an ACS and constituted the study group (208 males, 138 females, mean age 65 years). These 346 patients were evaluated in the ED area by means of multiple ECGs and multiple blood sampling for the creatine kinase-MB mass and troponin I serum levels at the time of admission and 6 and 12 hours later. In selected cases a treadmill stress test was requested in order to further clarify the diagnosis. RESULTS: The ECG at the time of admission was normal or nearly normal in 79% of the patients. Stress testing was performed in 79 patients (25%). Sixty-six/346 low-risk patients (19%) were admitted to the coronary care unit during ED observation: 38 patients because of positive markers, 10 because of a positive ECG, 13 because of positive markers and ECG, and 5 because of a positive stress test. Two hundred and eighty low-risk patients without evidence of acute ischemia were definitively discharged and classified as having non-ischemic chest pain. At 1 month of follow-up, 1 patient underwent coronary artery bypass grafting, 1 patient was again admitted to the ED for acute pulmonary edema, and 2 patients had acute extracardiac events. Within 1 year of follow-up 4 deaths occurred: 2 were cancer-related and 2 were sudden deaths. CONCLUSIONS: The tested strategy, based on integrated clinical, ECG and multimarker data, and on a short "test of time" period of low-risk patient observation, can allow the identification of patients having an ACS on the one hand and of those for whom a safe, rapid and early discharge is possible on the other, in a low-cost environment.

[Two cases of false troponin I increase in patients with heterophile antibodies]. / Due casi di incremento spurio di troponina I in pazienti con anticorpi eterofili.

Cardiac troponin T and I are highly sensitive and specific biochemical markers for the detection of myocardial damage and they are now considered the preferred markers for the diagnosis of myocardial infarction. Despite this, in some cases elevations in the serum levels of cardiac troponin T and I are not associated with a final diagnosis of cardiac necrosis. These false-positive results are to be related to different interferences in immunometric assays. We report 2 cases of false-positive troponin I results due to heterophilic antibodies. Two women admitted to the Emergency Department with acute chest pain persistently showed, in serial blood samples, elevated and constant values of troponin I serum levels. The results were confirmed as being false positives by treatment of the samples with heterophilic blocking reagent (Scantibodies Laboratory, Santee, CA, USA). Coronary artery disease was excluded at coronary angiography and at stress testing in the first case and at stress myocardial perfusion imaging in the second case. In clinical practice, in case of persistently elevated but constant values of cardiac troponin without the time interval of release characteristic of acute syndromes, it is important to bear in mind the possible occurrence of false-positive cardiac troponin results due to the presence of heterophilic antibodies.

[New definition of myocardial infarction: analysis of the consensus document ESC/ACC and thoughts about applicability to the Italian health situation]. / La nuova definizione di infarto miocardico: analisi del documento di consenso ESC/ACC e riflessioni sull'applicabilità alla realtà sanitaria italiana.

The recent document of the ESC/ACC Committee for the redefinition of myocardial infarction (MI) has introduced the measurement of cardiac troponin as the biochemical standard for the diagnosis of MI. This change has been mainly driven by the demonstration that any amount of myocardial damage, as detected by cardiac troponins, implies a worse long-term outcome of the patient. The results of several studies consistently show that there is a continuous relationship between the degree of troponin elevation and the patient's prognosis. The new definition has important consequences on the diagnostic and therapeutic approaches to patients with acute coronary syndromes; in fact, patients with increased troponins, i.e. patients with MI, necessitate more aggressive treatment than those without troponin elevations, i.e. patients with unstable angina. The application of the new definition is expected to increase the number of cases of MI by about 30% and to decrease mortality. We believe that several aspects of the new definition need to be discussed before the new criteria for MI are used in clinical practice in Italy. The most relevant issues are the following: 1) the definition of troponin elevation should meet the analytical performance of the available assays, the diagnostic cut-off of which is frequently too imprecise. We propose that troponin elevations be defined as values exceeding the concentration corresponding to a total analytical imprecision of 10%. We disclose such a concentration for the currently available assays and suggest its use in clinical practice to mitigate the possibility of false-positive values; 2) the number of samples required for the diagnosis should be sufficient for the assessment of the changes in concentration over time. When only one sample is available, or when the temporal pattern of the changes in marker concentration is not consistent with the time elapsed from the onset of symptoms, we suggest that objective evidence that myocardial ischemia is the likely cause of myocardial damage should be obtained; 3) the diagnosis of MI after a percutaneous coronary intervention represents a unique situation. In contrast with myocardial damage occurring during spontaneous ischemia, available data do not support the concept that any troponin elevation is associated with an adverse prognosis. In the absence of conclusive studies, we suggest that the diagnosis of MI after a percutaneous coronary intervention be based on conventional criteria. Finally, we propose this summary with the aim of overcoming some of the more controversial aspects of the ESC/ACC redefinition of MI: Criteria for acute, evolving or recent MI. Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: 1) elevation of biochemical markers of myocardial necrosis (preferably troponin) with at least one of the following: a) ischemic symptoms; b) development of pathologic Q waves on the ECG; c) ECG changes indicative of ischemia (ST segment elevation or depression); d) coronary artery intervention (e.g., coronary angioplasty). Marker elevations should be accompanied by objective evidence that myocardial ischemia is the likely cause of myocardial damage when: a) only one blood sample is available; b) marker changes over time are not consistent with the onset of symptoms; 2) pathologic findings of an acute MI. Criteria for established MI. Anyone of the following criteria satisfies the diagnosis for established MI: 1) development of new pathologic Q waves on serial ECGs. The patient may or may not remember previous symptoms. Biochemical markers of myocardial necrosis may have normalized, depending on the length of time that has passed since the infarct developed; 2) pathologic findings of a healed or healing MI.

Diagnosis of alterations of serum calcium metabolism.

Calcium is essential to homeostasis and functioning of multiple organ systems. Its circulating concentration is maintained within a very tight physiologic range: 2.25 and 2.50 mmol/L. Under physiological conditions, the ionized calcium concentration is regulated by the parathyroid hormone (PTH), and 1,25(OH)(2) vitamin D through interactions on target organs such as kidney, bone and intestine. In mild, moderate, and severe hypercalcemia, laboratory findings are essential in assessing and monitoring disease course and therapy. The main tools are specific standard biochemical tests able to assess calcium balance and renal function, and some specific biochemical tests, such as PTH, 25(OH) vitamin D, and genetic sequencing, used to clarify the cause of hypercalcemia and, subsequently, to determine appropriate therapy. Once hypercalcemia is confirmed by ionized calcium measurement, the intact PTH assay plays a crucial role to differentiate PTH-mediated from non-PTH-mediated hypercalcemia. Mild hypercalcemia is also present in up to 10-20% of patients treated with lithium for bipolar disorders, in 7-8% of those treated with thiazide diuretics, and in patients with prolonged immobilization, while very high (>3.5 mmol/L) serum calcium levels, together with low PTH, and a rapid increase of hypercalcemia, usually suggest a malignancy-associated hypercalcemic syndrome. The measurement of PTH-related protein, a tumor product that mimics certain action of PTH, is useful only in selected cases. The role of biochemical markers of bone turnover for predicting metastatic bone disease, and monitoring bone metabolic changes, and their usefulness as a predictive mean of the likelihood of bone loss or fractures risk is still unclear.

Treatment of chronic hypercalcemia.

Hypercalcemia is a relatively frequent alteration, mostly associated to primary hyperparathyroidism (PHPT) and malignancy-associated hypercalcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hypercalcemia. The antireabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hypercalcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy- associate hypercalcemia is broadly divided into two categories: humoral MAH and osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The receptor activator of nuclear factor-κ ligand (RANKL) has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results .

Prognostic value of ventricular-arterial coupling and B-type natriuretic peptide in patients after myocardial infarction: a five-year follow-up study.

BACKGROUND: The aim of this study was to determine the prognostic role of ventricular-arterial coupling compared with B-type natriuretic peptide (BNP) in patients after myocardial infarctions. METHODS: Forty-one consecutive patients with history of myocardial infarctions were enrolled. Ventricular-arterial coupling was assessed as the ratio between arterial elastance (E(a)) and end-systolic ventricular elastance (E(es)). E(a) and E(es) were calculated using systolic and diastolic blood pressure, echocardiographically derived stroke volume, left ventricular ejection fraction, and the ratio between aortic preejection time and total systolic time. Cardiovascular mortality was the prespecified endpoint, with 5-year follow-up. RESULTS: BNP was significantly correlated with New York Heart Association class and known echocardiographic parameters of systolic and diastolic left ventricular function and also with the E(a)/E(es) ratio (P = .001), which emerged as an independent correlate of BNP in multivariate analysis. The E(a)/E(es) ratio demonstrated good accuracy in predicting long-term cardiovascular mortality (area under the receiver operating characteristic curve, 0.73; P = .019), comparable with that of BNP in patients after myocardial infarctions. CONCLUSION: Ventricular-arterial coupling assessed using the E(a)/E(es) ratio is an independent echocardiographic correlate of BNP levels in patients with previous myocardial infarctions and has a significant role in predicting long-term cardiovascular mortality in this setting.

Heart failure in patients with aortic stenosis: clinical and prognostic significance of carbohydrate antigen 125 and brain natriuretic peptide measurement.

BACKGROUND: Brain natriuretic peptide (BNP) is related to symptomatic status and outcome in aortic stenosis (AS) patients. Carbohydrate antigen 125 (CA125) demonstrated recently a BNP-like behaviour in patients with congestive heart failure (CHF) but has never been studied in AS patients. We aimed to assess the role of CA125 and BNP in AS patients. METHODS: CA125 and BNP blood levels, transthoracic echocardiography and independent evaluation of CHF symptoms were obtained in 64 consecutive patients (76+/-9 years; 35 males) with AS (valve area 0.9+/-0.3 cm(2)). A pre-specified combined end-point consisting of cardiac mortality, urgent aortic valve replacement and hospitalization for CHF was considered. The median follow-up was 8 months (interquartile range 4.5-10 months). RESULTS: Both CA125 and BNP have accurately identified patients with III-IV NYHA class: area under the ROC curve was 0.85 for CA125 and 0.78 for BNP (best cut-offs of 10.3 U/mL and 254.64 pg/mL respectively) and were independently correlated to left ventricular ejection fraction. Fifty-two percent of patients with CA125>or=10.3 U/mL vs. 13% with CA125<10.3 U/mL (p<0.01) and 65% patients with BNP>or=254 pg/mL vs. 7% with BNP<254 pg/mL (p<0.001) have reached the end-point. CONCLUSIONS: Both CA125 and BNP levels are significantly correlated with NYHA class and outcome in patients with AS. CA125 blood level assessment (less expensive) may improve the clinical management in this setting.

National survey on critical values reporting in a cohort of Italian laboratories.

BACKGROUND: Critical values' reporting is an essential requisite for clinical laboratories. Local policies were investigated within an indicative cohort of Italian laboratories to monitor the situation and establish a performance benchmark. METHODS: A five-point questionnaire was administered to 150 laboratory specialists attending the SIMEL (Italian Society of Laboratory Medicine) National Meeting in June 2006. RESULTS: A total of 107 questionnaires (71.3%) were returned with a 100% individual question response rate. Only 55% of the participants acknowledge critical values reporting as an essential practice, 80% admit that a comprehensive list of critical values is unavailable in the laboratory and 4% do not promptly communicate critical values. The list of critical values is variable among laboratories, ranging from none to 20 analytes included. The requesting physician or his/her office staff receives the great majority (97%) of notifications by telephone for outpatients. Critical values for inpatients are notified directly by telephone (81%) and in a minority of cases by either fax or computer (19%). In the inpatient setting, the information is notified to physicians (77%), nurses (15%) or other healthcare staff in the clinic (8%). It was found that 49% of the participants adopt a standard (digital or written) policy for routine recording of notifications; in 32% of the cases the registration is left to individual attitudes, whereas in 20% of the cases the notification is not recorded. No laboratory has yet adopted a read-back verification of the complete test result by the person receiving the information. CONCLUSIONS: The importance of critical value reporting is still poorly recognized in Italy and uniform or internationally accredited practices for communication and recording are not currently implemented.

Prognostic role of left atrial volume in elderly patients with symptomatic stable chronic heart failure: comparison with left ventricular diastolic dysfunction and B-type natriuretic peptide.

BACKGROUND: Left atrial (LA) volume and B-type natriuretic peptide (BNP) represent powerful outcome predictors in patients with heart failure (HF). AIM: To assess the comparative prognostic role of LA volume (indexed to body surface area, LAVi), left ventricular diastolic dysfunction (LVDD) and BNP levels on long-term outcome in patients with symptomatic but stable chronic HF. methods: We studied consecutively 46 patients with symptomatic stable chronic HF (73 +/- 10 years, 30 men), in sinus rhythm, without significant valvular disease. Echocardiographic measurements included: LV mass, LV volumes and ejection fraction, and LAVi. LVDD was graded using a comprehensive Doppler algorithm. Blood taken before echocardiography was assayed for BNP levels. Primary end point was combined: all-cause mortality and hospitalization for worsening HF. RESULTS: During 20 +/- 14 months of follow-up 19 events occurred: 8 deaths, and 11 hospitalizations for HF. In univariate analyses LAVi, LVDD, BNP levels, LV ejection fraction, LV volumes, and LV mass were significant outcome predictors (P < 0.05). At multivariate regression LAVi was the only independent predictor of outcome (hazard ratio: 1.03 per 1 ml/m(2) increase, 95% CI: 1.01-1.06, P = 0.02). CONCLUSION: Although directly related to LVDD and to BNP levels, only LAVi emerged as an independent outcome predictor in this cohort of elderly patients with symptomatic stable chronic HF.