Low HDL cholesterol and the eNOS Glu298Asp polymorphism are associated with inducible myocardial ischemia in patients with suspected stable coronary artery disease.

BACKGROUND: The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD). AIM: To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD. METHODS: A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient. RESULTS: In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD. CONCLUSION: In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.

Measurement of Cardiac-Specific Biomarkers in the Emergency Department: New Insight in Risk Evaluation.

The aim of this article review is to analyze some models and clinical issues related to the implementation of accelerated diagnostic protocols based on specific cardiac biomarkers in patients admitted to the emergency department (ED) with symptoms compatible with acute cardiac disorders. Four specific clinical issues will be discussed in detail: (a) pathophysiological and clinical interpretations of circulating hs-cTnI and hs-cTnT levels; (b) the clinical relevance and estimation of the biological variation of biomarkers in patients admitted to the ED with acute and severe diseases; (c) the role and advantages of the point-of-care testing (POCT) methods for cardiac-specific biomarkers in pre-hospital and hospital clinical practice; and (d) the clinical role of specific cardiac biomarkers in patients with acute heart failure (AHF). In order to balance the risk between a hasty discharge versus the potential harms caused by a cardiac assessment in patients admitted to the ED with suspected acute cardiovascular disease, the measurement of specific cardiac biomarkers is essential for the early identification of the presence of myocardial dysfunction and/or injury and to significantly reduce the length and costs of hospitalization. Moreover, specific cardiac biomarkers (especially hs-cTnI and hs-cTnT) are useful predictors of mortality and major adverse cardiovascular events (MACE) in patients admitted to the ED with suspected acute cardiovascular disease. To guide the implementation of the most rapid algorithms for the diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI) into routine clinical practice, clinical scientific societies and laboratory medicine societies should promote collaborative studies specifically designed for the evaluation of the analytical performance and, especially, the cost/benefit ratio resulting from the use of these clinical protocols and POCT methods in the ED clinical practice.

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.

Inflammageing and Cardiovascular System: Focus on Cardiokines and Cardiac-Specific Biomarkers.

The term "inflammageing" was introduced in 2000, with the aim of describing the chronic inflammatory state typical of elderly individuals, which is characterized by a combination of elevated levels of inflammatory biomarkers, a high burden of comorbidities, an elevated risk of disability, frailty, and premature death. Inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and rapid progression to heart failure. The great experimental and clinical evidence accumulated in recent years has clearly demonstrated that early detection and counteraction of inflammageing is a promising strategy not only to prevent cardiovascular disease, but also to slow down the progressive decline of health that occurs with ageing. It is conceivable that beneficial effects of counteracting inflammageing should be most effective if implemented in the early stages, when the compensatory capacity of the organism is not completely exhausted. Early interventions and treatments require early diagnosis using reliable and cost-effective biomarkers. Indeed, recent clinical studies have demonstrated that cardiac-specific biomarkers (i.e., cardiac natriuretic peptides and cardiac troponins) are able to identify, even in the general population, the individuals at highest risk of progression to heart failure. However, further clinical studies are needed to better understand the usefulness and cost/benefit ratio of cardiac-specific biomarkers as potential targets in preventive and therapeutic strategies for early detection and counteraction of inflammageing mechanisms and in this way slowing the progressive decline of health that occurs with ageing.

Variability of cardiac troponin levels in normal subjects and in patients with cardiovascular diseases: analytical considerations and clinical relevance.

In accordance with all the most recent international guidelines, the variation of circulating levels of cardiac troponins I and T, measured with high-sensitivity methods (hs-cTnI and hs-cTnT), should be used for the detection of acute myocardial injury. Recent experimental and clinical evidences have demonstrated that the evaluation of hs-cTnI and hs-cTnT variations is particularly relevant: a) for the differential diagnosis of Acute Coronary Syndromes (ACS) in patients admitted to the Emergency Department (ED); b) for the evaluation of cardiovascular risk in patients undergoing major cardiac or non-cardiac surgery, and in asymptomatic subjects of the general population aged >55 years and with co-morbidities; c) for the evaluation of cardiotoxicity caused by administration of some chemotherapy drugs in patients with malignant tumors. The aim of this document is to discuss the fundamental statistical and biological considerations on the intraindividual variability of hs-cTnI and hs-cTnT over time in the same individual. Firstly, it will be discussed in detail as the variations of circulating levels strictly depend not only on the analytical error of the method used but also on the intra-individual variability of the biomarker. Afterwards, the pathophysiological interpretation and the clinical relevance of the determination of the variability of the hs-cTnI and hs-cTnT values ​​ in patients with specific clinical conditions are discussed. Finally, the evaluation over time of the variation in circulating levels of hs-cTnI and hs-cTnT is proposed for a more accurate estimation of cardiovascular risk in asymptomatic subjects from the general population.

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.

Biomarkers of HFpEF: Natriuretic Peptides, High-Sensitivity Troponins and Beyond.

Heart failure (HF) is a significant cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) is a complex syndrome, often participated by several cardiac and extracardiac conditions, including chronic kidney disease, pulmonary disease, anaemia and advanced age. Circulating biomarkers reflecting pathophysiological pathways involved in HFpEF development and progression may assist clinicians in early diagnosis and management of this condition. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload and in response to activation of neuro-endocrine-immune system. The relevance of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification has been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the value of NPs to guide HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, predicting outcome independently from NPs. In this review, some novel biomarkers are being tested in such clinical scenario, more tightly linked to specific pathophysiological processes of cardiac damage.

Evaluation of the cardiovascular risk in patients undergoing major non-cardiac surgery: role of cardiac-specific biomarkers.

Major adverse cardiovascular events are frequently observed in patients undergoing major non-cardiac surgery during the peri-operative period. At this time, the possibility to predict cardiovascular events remains limited, despite the introduction of several algorithms to calculate the risk of adverse events, mainly death and major adverse cardiovascular events (MACE) based on the clinical history, risk factors (sex, age, lipid profile, serum creatinine) and non-invasive cardiac exams (electrocardiogram, echocardiogram, stress tests). The cardiac-specific biomarkers natriuretic peptides (NPs) and cardiac troponins (cTn) have been proposed as additional tools for risk prediction in the peri-operative period, particularly for the identification of myocardial injury in patients undergoing major non-cardiac surgery. The prognostic information from the measurement of BNP/NT-proBNP and hs-cTn is independent and complementary to other important indicators of risk, also including ECG and imaging techniques. Elevated levels of cardiac-specific biomarkers before surgery are associated with a markedly higher risk of MACE during the peri-operative period. BNP/NT-proBNP and hs-cTn should be measured in all patients during the clinical evaluation before surgery, particularly during intermediate- or high-risk surgery, in patients aged >65 years and/or with comorbidities. Several questions remain to be assessed in dedicated clinical studies, such as how to optimize the management of patients with raised cardiac specific biomarkers before surgery, and whether a strategy based on biomarker measurement improves patient outcomes and is cost-effective.

Natriuretic Peptides and Troponins to Predict Cardiovascular Events in Patients Undergoing Major Non-Cardiac Surgery.

Patients undergoing major surgery have a substantial risk of cardiovascular events during the perioperative period. Despite the introduction of several risk scores based on medical history, classical risk factors and non-invasive cardiac tests, the possibility of predicting cardiovascular events in patients undergoing non-cardiac surgery remains limited. The cardiac-specific biomarkers, natriuretic peptides (NPs) and cardiac troponins (cTn) have been proposed as additional tools for risk prediction in the perioperative period. This review paper aims to discuss the value of preoperative levels and perioperative changes in cardiac-specific biomarkers to predict adverse outcomes in patients undergoing major non-cardiac surgery. Based on several prospective observational studies and six meta-analyses, some guidelines recommended the measurement of NPs to refine perioperative cardiac risk estimation in patients undergoing non-cardiac surgery. More recently, several studies reported a higher mortality in surgical patients presenting an elevation in high-sensitivity cardiac troponin T and I, especially in elderly patients or those with comorbidities. This evidence should be considered in future international guidelines on the evaluation of perioperative risk in patients undergoing major non-cardiac surgery.

High-sensitivity troponins for outcome prediction in the general population: a systematic review and meta-analysis.

BACKGROUND: High-sensitivity (hs) assays allow to measure cardiac troponin T and I (cTnT/I) even in healthy individuals. The higher hs-cTn values, the higher the ongoing cardiomyocyte damage, and then reasonably the risk of developing symptomatic cardiac disease. METHODS: We retrieved all studies evaluating the prognostic value of hs-cTnT or I in the general population. We calculated pooled hazard ratio (HR) values for all-cause and cardiovascular death, cardiovascular events and heart failure (HF) hospitalization. RESULTS: We included 24 studies for a total of 203,202 subjects; 11 studies assessed hs-cTnT and 14 hs-cTnI. One standard deviation (SD) increase in baseline hs-cTn was associated with a 23% higher risk of all-cause death (HR 1.226, 95% CI 1.083-1.388, p<0.001, I2=88.5%); all these studies measured hs-cTnI. In an exploratory analysis on 3 studies with 25,760 subjects, hs-cTn predicted cardiovascular death (HR 1.822, 95% CI 1.241-2.674, p=0.002, I2=87.2%). After synthesizing 9 studies with 58,565 subjects, hs-cTn predicted cardiovascular events (HR 1.328, 95% CI 1.167-1.513, p<0.001, I2=93.8%). Both hs-cTnT (HR 1.627, 95% CI 1.145-2.311, p<0.001) and hs-cTnI (HR 1.260, 95% CI 1.115-1.423, p<0.001; p for interaction <0.001). Furthermore, in 10 studies with 61,467 subjects, hs-cTn predicted HF hospitalization (HR 1.493, 95% CI 1.368-1.630, p<0.001, I2=76.6%). Both hs-cTnT (HR 1.566, 95% CI 1.303-1.883, p<0.001) and hs-cTnI (HR 1.467, 95% CI 1.321-1.628, p<0.001) were associated with HF hospitalization (p for interaction <0.001). CONCLUSIONS: hs-cTn values hold strong prognostic value in subjects from the general population, predicting the risk of all-cause and cardiovascular mortality, cardiovascular events, and HF hospitalization.

High-sensitivity cardiac troponins in pediatric population.

Apparently healthy children often complain of chest pain, especially after physical exercise. Cardiac biomarker levels are often measured, but the clinical relevance of these assays in children is still debated, even when a cardiac disease is present. Coronary artery disease is exceedingly rare in children, but elevated circulating levels of cardiac troponin I (cTnI) and T (cTnT) in an acute setting may help detect heart failure due to an unknown cardiac disorder, or worsening heart failure, particularly in combination with other biomarkers such as B-type natriuretic peptides. However, the interpretation of biomarkers is often challenging, especially when institutions transition from conventional cTn assays to high-sensitivity (hs-cTn) methods, as well demonstrated in the emergency setting for adult patients. From a clinical perspective, the lack of established reference values in the pediatric age is the main problem limiting the use of hs-cTn methods for the diagnosis and managements of cardiac diseases in infants, children and adolescents. This review aims to discuss the possibility to use hs-cTnI and hs-cTnT to detect cardiac disease and to explore age-related differences in biomarker levels in the pediatric age. We start from some analytical and pathophysiological considerations related to hs-cTn assays. Then, after a systematic literature search, we discuss the current evidence and possible limitations of hs-cTn assay as indicators of cardiac disease in the most frequently cardiac disease in pediatric setting.

Cardiac Troponin-T Release After Sport and Differences by Age, Sex, Training Type, Volume, and Intensity: A Critical Review.

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

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.

Association of Circulating Heme Oxygenase-1, Lipid Profile and Coronary Disease Phenotype in Patients with Chronic Coronary Syndrome.

BACKGROUND: The NF-E2-related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) pathway has an emerging role in atherosclerosis. Activated by oxidative stress, it is deemed to exert athero-protective effects. We aimed at evaluating the relationships between plasma HO-1, clinical/molecular profiles and coronary disease patterns in patients with chronic coronary syndromes (CCS). METHODS: HO-1 was measured in 526 patients (60 ± 9 years, 318 males) with CCS. Coronary computed tomography angiography (CTA) and stress imaging were used to assess the disease phenotype (coronary atherosclerosis and myocardial ischemia) in a subgroup of 347 patients. RESULTS: In the overall population, HO-1 median value (25-75 percentile) was 5.195 (1.75-8.25) ng/mL. Patients with higher HO-1 were more frequently male, had a higher BMI and lower LVEF%, but otherwise similar risk factors than the other patients. Their bio-humoral profile was characterized by higher markers of endothelial/myocardial dysfunction, but lower levels of cholesterol lipoproteins. Coronary artery disease was characterized by more diffuse atherosclerosis, with mainly non-obstructive and calcified plaques, and a higher prevalence of functional ischemia. CONCLUSION: In patients with CCS, higher plasma HO-1 levels are associated with lower cholesterol and a more diffuse but mainly non-obstructive coronary atherosclerosis, confirming a potential role for the Nrf2/HO-1 pathway as a protective feedback.

Triglycerides and low HDL cholesterol predict coronary heart disease risk in patients with stable angina.

We assessed whether high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, expressed by an increased TG/HDL-C ratio, predict coronary atherosclerotic disease (CAD) outcomes in patients with stable angina. We studied 355 patients (60 ± 9 years, 211 males) with stable angina who underwent coronary computed tomography angiography (CTA), were managed clinically and followed for 4.5 ± 0.9 years. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. At baseline, the proportion of males, patients with metabolic syndrome, diabetes and obstructive CAD increased across TG/HDL-C ratio quartiles, together with markers of insulin resistance, hepatic and adipose tissue dysfunction and myocardial damage, with no difference in total cholesterol or LDL-C. At follow-up, the global CTA risk score (HR 1.06, 95% confidence interval (CI) 1.03-1.09, P = 0.001) and the IV quartile of the TG/HDL-C ratio (HR 2.85, 95% CI 1.30-6.26, P < 0.01) were the only independent predictors of the primary outcome. The TG/HDL-C ratio and the CTA risk score progressed over time despite increased use of lipid-lowering drugs and reduction in LDL-C. In patients with stable angina, high TG and low HDL-C levels are associated with CAD related outcomes independently of LDL-C and treatments.Trial registration. EVINCI study: ClinicalTrials.gov NCT00979199, registered September 17, 2009; SMARTool study: ClinicalTrials.gov NCT04448691, registered June 26, 2020.

Evaluation of pathophysiological relationships between renin-angiotensin and ACE-ACE2 systems in cardiovascular disorders: from theory to routine clinical practice in patients with heart failure.

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

Diagnostic algorithms for non-ST-segment elevation myocardial infarction: open issues.

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