Biomarker Of Ischemia Research Articles

Circulating Biomarkers

Cardiovascular diseases (CVD) remain a leading cause of death worldwide. In the past years new biomarkers have drawn the clinician's attention for their use in primary prevention and in the identification of individuals at cardiovascular risk. Biomarkers also provide information on the progression and possible recurrence of cardiovascular events, and include inflammatory markers (C-reactive protein and interleukin-18), endothelial dysfunction markers (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), neurohormonal markers (brain natriuretic peptide and copeptine), ischemia biomarkers (apolipoprotein J) and necrosis markers (troponins). Although biomarkers provide utility for predicting cardiovascular risk, the identification and characterization of new biomarkers to achieve increasing diagnosis and prognostic efficiency in CVD prevention is of high clinical interest. In this review we will discuss on recently discovered biomarkers and their clinical applications.

Obesity Is an Independent Determinant of Ischemia-Modified Albumin

Objective: We have measured ischemia-modified albumin (IMA), total antioxidant status (TAS), total oxidant status (TOS) and high-sensitivity C-reactive protein (hsCRP) levels in obese and normal-weight subjects to investigate if IMA can be used as a biomarker of oxidative stress and inflammation and if IMA was an independent determinant of obesity or not. Methods: The study was performed on 92 obese subjects (20 male, 72 female) aged 38 ± 11 years and 78 normal-weight controls (19 male, 59 female) aged 37 ± 11 years. Serum lipids, IMA, TAS, TOS, and hsCRP levels of the subjects were measured. Results: IMA (p < 0.05), TOS (p < 0.001), and hsCRP (p < 0.001) levels of the obese subjects were significantly higher, whereas TAS levels were significantly lower (p < 0.05) than those of the controls after adjustment for age and gender. In the linear regression analysis, waist circumference (r² = 0.139, p < 0.01), BMI (r² = 0.136, p < 0.01) and insulin (r² = 0.120, p < 0.05) were shown to be significant independent determinants of IMA levels. Conclusions: We have found that oxidative stress and inflammation were increased and antioxidative defense was decreased, which resulted in increased levels of IMA, a biomarker of ischemia, in obese subjects. Also, obesity and insulin were found to be independent determinants of IMA. Thus, obese subjects are under high risk of ischemia, and IMA may be used as a biomarker of oxidative stress and ischemia. Further larger investigations are needed to confirm this opinion.

Perioperative cardiac evaluation, monitoring, and risk reduction strategies in noncardiac surgery patients

Cardiac complications after noncardiac surgery cause significant morbidity and mortality. This review will discuss recent developments in risk stratification, monitoring, and risk reduction strategies. The addition of biomarkers for ischemia, left ventricular function, and atherosclerosis to classic cardiac risk factors improves the prediction of both short-term and long-term outcome after noncardiac surgery. Intraoperative monitoring, using continuous 12-lead ECG assessment and transesophageal echocardiography, may timely identify treatable myocardial ischemia and arrhythmias. A prudent perioperative beta-blocker and statin regimen can reduce cardiac complications and mortality without increasing the risk of stroke in intermediate to high-risk patients. The use of circulatory assist devices might improve outcomes after major surgery in patients with severely reduced left ventricular function. Systematic preoperative assessment can identify patients at high risk of cardiac complications and guide the application of appropriate risk reduction strategies.

Changes of myeloperoxidase (MPO) and ischaemia modified albumin in patients with coronary heart disease

IntroductionMyeloperoxidase (MPO) is an oxidant-generating enzyme expressed in neutrophils and macrophages and involved in the atherosclerosis. Ischaemia modified albumin (IMA) has been demonstrated to be a biomarker of ischaemia associated...

Ischemia modified albumin in the differential diagnosis of pleural effusions

The differential diagnosis of pleural effusion often requires invasive procedures. Up to 25 percent of pleural effusions can remain undiagnosed with an unclear pathogenesis. Therefore new biological markers may increase diagnostic yield and provide better understanding of pathogenesis of pleural effusion. We hypothesized that new ischemia biomarker, "ischemia modified albumin (IMA)" would help in both the differentiation of the underlying etiologies and provide a better understanding of pathogenesis of pleural effusions. This study was done between December 2009 and September 2010 in the Department of Pulmonary Diseases of Gaziantep University Hospital. One hundred and sixteen subjects with pleural effusion were included. Pleural and blood IMA levels were measured by ELISA. The underlying etiologies of pleural effusions were as follows: transudates (n = 50), malignancy (n = 32), tuberculosis (n = 12), pulmonary thromboembolism (n = 6), pneumonia (n = 16). The median pleural IMA levels were significantly different between the groups (p < 0.000). There were no such differences in the blood levels of IMA. The most striking difference in the median pleural IMA levels was between transudates and exudates (7986 (25-75%, 5145-56.505) ng/mL; 3376 (25-75%, 1935-4660) ng/mL; respectively, p = 0.000). The area under the ROC curve was 0.837 ± 0.038 for the cut-off level higher than 4711 ng l/mL for the differentiation of transudates from exudates (sensitivity, 82%; specificity, 78%; 95% CI, 0.76 to 0.91; p = 0.0000). In conclusion, the pleural IMA levels are higher in transudates compared to exudates. No such differences were observed in blood levels of IMA suggesting that there are reasons other than ischemia that cause an increase in pleural fluid IMA levels.

Cardiothoracic CT: one-stop-shop procedure? Impact on the management of acute pulmonary embolism.

In the treatment of pulmonary embolism (PE) two groups of patients are traditionally identified, namely the hemodynamically stable and instable groups. However, in the large group of normotensive patients with PE, there seems to be a subgroup of patients with an increased risk of an adverse outcome, which might benefit from more aggressive therapy than the current standard therapy with anticoagulants. Risk stratification is a commonly used method to define subgroups of patients with either a high or low risk of an adverse outcome. In this review the clinical parameters and biomarkers of myocardial injury and right ventricular dysfunction (RVD) that have been suggested to play an important role in the risk stratification of PE are described first. Secondly, the use of more direct imaging techniques like echocardiography and CT in the assessment of RVD are discussed, followed by a brief outline of new imaging techniques. Finally, two risk stratification models are proposed, combining the markers of RVD with cardiac biomarkers of ischemia to define whether patients should be admitted to the intensive care unit (ICU) and/or be given thrombolysis, admitted to the medical ward, or be safely treated at home with anticoagulant therapy.

Myocardial Protective Effect of Human Atrial Natriuretic Peptide in Cardiac Surgery - "hANP Shot" in Clinical Safety Trial -

We studied low-dose human atrial natriuretic peptide (hANP) infusion therapy during cardiac surgery and reported the cardiac and renal protective effects. The efficacy of a bolus injection of hANP (the "hANP shot") simultaneously with induction of cardioplegia has been proven in animal experiments. In the present study the clinical effects of this "hANP shot" were examined. The subjects were 67 patients undergoing Coronary artery bypass grafting. At the time of inducing cardioplegia, 1 group received a simultaneous bolus injection of 100 μg of hANP (hANP group) and the other group received an injection of physiological saline (placebo group). The primary endpoints were (1) operative mortality and complications, and (2) the creatine kinase isoenzyme MB (CPK-MB), troponin-I, and human heart fatty acid binding protein (H-FABP) levels. The secondary endpoints were (1) the incidence of arrhythmia, and levels of (2) atrial and B-type natriuretic peptides, and cyclic guanosine monophosphate (cGMP), and (3) renin, angiotensin II, and aldosterone. Postoperative CPK-MB, troponin-I, and H-FABP levels were significantly lower in the hANP group than in the placebo group. Postoperative arrhythmia was significantly less frequent in the hANP group than in the placebo group. It is possible to achieve cardioprotective effects based on the safety of the "hANP shot", as well as from biomarkers of ischemia and results related to arrhythmia. The "hANP shot" should also be evaluated as a safer and new cardioprotective method for cardiac surgery.

E0235 Study on the primary and secondary protein structure of ischaemia modified albumin

ObjectiveIschaemia-modified albumin (IMA) has been demonstrated to be a biomarker of ischaemia associated with myocardial and skeletal muscle ischaemia, pulmonary embolism and stroke. However there is limited information on the...

Biomarkers of Vulnerable Plaque: The Missing Link With Ischemia

The initial evaluation of chest pain in the emergency department is based on the patient's clinical history, changes in the ECG and necrosis biomarkers. Although management of patients with ST-elevation myocardial infarction or non-ST-elevation myocardial infarction with positive markers of myocardial damage is well defined, exclusion of coronary artery disease or myocardial ischemia in the remaining patients is more challenging. This group represents the majority of patients admitted for chest pain syndromes and that have a substantial risk of an adverse outcome. Given that troponin, as a marker of myocardial damage, detects terminal events in the cascade of acute coronary syndrome, there is a need to search for biomarkers that are able to identify patients at high risk, allowing rapid, bedside stratification. Data suggest that clinical events are prone to occur more frequently in patients with coronary artery stenosis associated with myocardial ischemia. Accordingly, identification of systemic biomarkers of ischemia could facilitate identification of high-risk patients with a high burden of coronary atherosclerosis and plaque rupture. We describe six biomarkers that have been linked to myocardial ischemia. Until now, these biomarkers of ischemia are relevant in order to exclude ischemic heart disease (high negative predictive value) but still lack specificity. Future prospective studies should be performed in larger and more diverse sets of patients presenting with ischemia, and in a complementary fashion in order to provide valuable tools for clinical decision making.

Increased ischaemia modified albumin following coronary artery bypass grafting

Background: Any increase of cardiac biomarkers after coronary artery bypass grafting (CABG) indicates myocyte necrosis and is likely to be related to an impaired outcome. We investigated whether ischaemia-modified albumin (IMA), a biomarker of ischaemia, is also raised following CABG. Methods: We studied 50 stable consecutive patients undergoing elective isolated CABG on cardiopulmonary bypass, of whom 46 were men and four women, aged 64 ± 9 years. Blood samples were obtained the day before the operation (pre-op) as well as immediately after the operation, 24 h postoperatively (post-op) and the fourth day post-op and assayed for creatine kinase, the MB isoenzyme of creatine kinase, cardiac troponin-I, albumin and IMA. Results: The typical rising and falling pattern of myocardial necrosis of all three cardiac enzymes was observed post-op (p <0.0001). IMA increased significantly following CABG at all three time points (113 ± 43, 106.7 ± 22.6 and 110.2 ± 12.5 U ml−1, respectively) compared with pre-op values (91.7 ± 10.5 U ml−1), (p <0.0001); the sample immediately post-op was significantly higher compared with the following samples (immediately post-op vs 24 h, p = 0.008 and immediately post-op vs 4 days, p = 0.03, with no significant difference between the last two). IMA level changes during the study course were independent of the albumin changes. Haemoglobin decreased significantly post-op (p <0.0001 vs baseline) whereas serum creatinine did not differ during the study period. Conclusions: IMA increases significantly following CABG but whether or not this carries a prognostic significance remains to be elucidated.

Effects of remote ischemic preconditioning on myocardial oxidative stress and cardiac ischemia biomarkers in off-pump coronary artery bypass graft surgery

Effects of remote ischemic preconditioning on myocardial oxidative stress and cardiac ischemia biomarkers in off-pump coronary artery bypass graft surgery

HPLC assay with UV detection for determination of RBC purine nucleotide concentrations and application for biomarker study in vivo

ATP and other purine nucleotides are important biomarkers for ischemia and may have considerable potential as targets for management of ischemic heart disease and stroke. The main objective of the study is to develop a rapid HPLC assay, which has adequate sensitivity and specificity for measuring concentrations of ATP, ADP, AMP, GTP, GDP and GMP in erythrocytes (RBC). The assays used ion-pair chromatography coupled with ultraviolet detection at 254 nm to separate and detect the purine nucleotides. Using 50–100 μL of RBC lysate as blank biologic matrix, the assay was linear from 100 to 2000 μg/mL for ATP and ADP, and 20–400 μg/mL for AMP, GTP, and GDP with coefficients of determination ( r 2) >0.99. GDP and GMP were not measurable in the study because of low concentrations and interference from endogenous materials, respectively. The intra-assay and inter-assay variations over a period of 1 year were less than 10% and 20%, respectively for most of the nucleotides. The assay was successfully applied to two pilot biomarker studies to measure RBC concentrations of the purine nucleotides in rats under restraining and exercise conditions. Preliminary results showed that the RBC concentrations of ATP and GTP were higher in the spontaneously hypertensive rats (SHR) compared to the Sprague–Dawley (SD) rats, and that exercise increased RBC concentrations of ATP in rats treated with the calcium channel blocker diltiazem.

Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia

Recognition of myocardial ischemia is critical both for the diagnosis of coronary artery disease and the selection and evaluation of therapy. Recent advances in proteomic and metabolic profiling technologies may offer the possibility of identifying novel biomarkers and pathways activated in myocardial ischemia. Blood samples were obtained before and after exercise stress testing from 36 patients, 18 of whom demonstrated inducible ischemia (cases) and 18 of whom did not (controls). Plasma was fractionated by liquid chromatography, and profiling of analytes was performed with a high-sensitivity electrospray triple-quadrupole mass spectrometer under selected reaction monitoring conditions. Lactic acid and metabolites involved in skeletal muscle AMP catabolism increased after exercise in both cases and controls. In contrast, there was significant discordant regulation of multiple metabolites that either increased or decreased in cases but remained unchanged in controls. Functional pathway trend analysis with the use of novel software revealed that 6 members of the citric acid pathway were among the 23 most changed metabolites in cases (adjusted P=0.04). Furthermore, changes in 6 metabolites, including citric acid, differentiated cases from controls with a high degree of accuracy (P<0.0001; cross-validated c-statistic=0.83). We report the novel application of metabolomics to acute myocardial ischemia, in which we identified novel biomarkers of ischemia, and from pathway trend analysis, coordinate changes in groups of functionally related metabolites.

Biomarkers of Ischemia in Patients With Known Coronary Artery Disease

A fundamental understanding of the mediators and mechanisms associated with the pathophysiological process of reversible myocardial ischemic injury would be a substantial advancement in our basic understanding of this process and would speed the translation from “bench to bedside.” For example, elucidation of the chemical signals that both indicate the presence and extent of reversible ischemia and have a putative role in cellular dysfunction and injury would clearly have potential as a valuable biomarker for the development of diagnostic tools, in the clinical management of patients, and perhaps as a guide for the development of viable therapeutic targets. Focusing on the inflammatory process would seem to have a high likelihood for success because ischemic events, infection, and mechanical cell injury are known to activate numerous pluripotent pathways, cascades, and networks, including the cytokine and coagulation systems. These systems are highly integrated and redundant because of their critical role in the survival of the organism. Inflammatory cytokines such as interleukin-6 (IL-6) are low-molecular-weight pluripotent glycoproteins with a dynamic range of local and systemic actions and a wide range of target cells and organs.1 In many instances, individual cytokines have multiple biological activities that confer functional redundancy during inflammation and tissue repair; different cytokines can also have the same activity. Inflammatory cytokines and cytokine networks are also intimately associated with other injury response systems, including the coagulation system that controls for fibrinogenesis and fibrinolysis, with all its associated matrices, proteases, and metabolites, including fibrin, thrombin, plasmin, fibrinopeptides, and fibrin metabolites, to name a few. Central to the coagulation system is the transmembrane glycoprotein known as tissue factor, which controls clot formation via the extrinsic pathway. The coordinated integration of cytokine networks and coagulation cascades is essential in controlling inflammation and repair. For example, cytokines such as IL-1, tissue necrosis factor, and …

Usefulness of Biomarkers for Predicting Long-Term Mortality in Patients With Diabetes Mellitus and Non–ST-Elevation Acute Coronary Syndromes (A GUSTO IV Substudy)

The present study evaluated whether biomarkers of ischemia, inflammation, myocardial damage, and dysfunction are equally useful in patients who have diabetes mellitus (DM) for prediction of cardiac events in non-ST-elevation acute coronary syndrome (ACS). DM was present in 1,677 of 7,800 patients (21.5%) who had non-ST-elevation ACS and were included in the Fourth Global Utilization of Strategies To Open Occluded Arteries (GUSTO IV) trial. Creatinine, N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), troponin T, C-reactive protein, and interleukin-6 were analyzed in serum samples that were obtained at a median of 9.5 hours from symptom onset. One-year mortality rates were 13.5% among patients who had DM (n = 227) and 6.9% among those who did not (n = 418, p < 0.001). The median level of NT-pro-BNP was 2 times as high in patients who had DM, whereas troponin T levels did not differ by DM status. Mortality increased with ascending quartiles of NT-pro-BNP, with 1-year mortality rates of 3.9% (n = 11) in the bottom quartile and 29% (n = 103) in the top quartile. In multivariable analyses, factors that were predictive of 1-year mortality in patients who did not have DM were also significant for those who did. Presence of ST depression > 0.5 mm had the highest odds ratio of 2.3 (95% confidence interval 1.2 to 4.6). NT-pro-BNP levels > 669 ng/L (odds ratio 2.0, 95% confidence interval 1.1 to 3.6) and interleukin-6 levels > 10 ng/L (odds ratio 1.9, 95% confidence interval 1.2 to 3.0) were significant biomarker predictors. In conclusion, DM confers a high long-term mortality in non-ST-elevation ACS. Despite a larger proportion of ST depression and increased levels of NT-pro-BNP and interleukin-6 at admission, these factors provide independent prognostic information that may improve risk stratification and guidance of treatment.

Ischemia-modified albumin levels in cord blood: A case-control study in uncomplicated and complicated deliveries

Background In the past few years ischemia modified albumin (IMA) has emerged as a new biomarker of ischemia in the area of monitoring acute coronary syndromes. We hypothesized that reduced blood flow, such as that resulting from vascular compression in complicated labors or placental ischemia, may increase IMA. IMA level in cord blood could then serve as an indicator of fetal hypoxia and fetal tissue ischemia and serve as a biomarker of the severity of these conditions. Methods We performed a case-control study with 26 newborns (12 normal term deliveries, Apgar 8–9; and 14 complicated labors or pre-term deliveries, Apgar 5–8). Complications were: prematurity (3), fetal distress (6), premature rupture of membranes (6), intrauterine growth retardation (3), pre-eclampsia (1). We also studied 30 healthy adults. IMA was measured in serum from cord blood (or venous blood for adults) by the decrease in cobalt 2+ binding. Results IMA levels in neonates from non-complicated deliveries are significantly higher (45%, p < 0.005) than those of an adult control population, suggesting that IMA may increase as a consequence of labor. This increased IMA in neonates could not be accounted for by the changes in albumin concentration. It is conceivable that a transient increase in IMA reflects, in part, transient localized tissue ischemia due to the external forces exerted on the fetus during the mechanism of labor. IMA levels in cord blood from neonates from complicated deliveries are 50% higher than in neonates from uneventful deliveries ( p < 0.05) while their albumin values are not significantly different (32 ± 3 vs. 33 ± 2 g/l). Moreover, IMA seems to be responsive to hypoxic fetal distress, showing values more than 300% higher in cases of severe fetal hypoxia (Apgar 5 n = 2: 2.19 ± 0.01 AU vs. 0.64 ± 0.24 for controls). IMA values did not correlate significantly with either lipoperoxides or CRP levels. Conclusions This is the initial reporting of IMA levels in cord blood from normal deliveries compared to healthy adult ranges and neonates from complicated deliveries. Cord blood IMA levels may be an indicator of fetal ischemia and/or hypoxia. This test could become an additional biomarker to be used in conjunction with other markers and/or clinical scores aimed at determining risk of neurological complications of fetal distress.

Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome

Evaluation of patients who present to the hospital with a complaint of chest pain or other signs or symptoms suggestive of acute coronary syndrome (ACS) is time-consuming, expensive, and problematic. Recent investigations have indicated that increases in biomarkers upstream from biomarkers of necrosis (cardiac troponins I and T), such as inflammatory cytokines, cellular adhesion molecules, acute-phase reactants, plaque destabilization and rupture biomarkers, biomarkers of ischemia, and biomarkers of myocardial stretch may provide earlier assessment of overall patient risk and aid in identifying patients with higher risk of an adverse event. The purpose of this review is to provide an overview of the pathophysiology and clinical and analytical characteristics of several biomarkers that may have potential clinical utility to identify ACS patients. These biomarkers (myeloperoxidase, metalloproteinase-9, soluble CD40 ligand, pregnancy-associated plasma protein A, choline, ischemia-modified albumin, unbound free fatty acids, glycogen phosphorylase isoenzyme BB, and placental growth factor) have demonstrated promise and need to be more thoroughly evaluated for commercial development for implementation into routine clinical and laboratory practice. Specifications that have been addressed for cardiac troponins and natriuretic peptides will need to be addressed with the same scrutiny for the biomarkers discussed in this review. They include validating analytical imprecision and detection limits, calibrator characterization, assay specificity and standardization, pre-analytical issues, and appropriate reference interval studies. Crossing boundaries from research to clinical application will require replication in multiple settings and experimental evidence supporting a pathophysiologic role and, ideally, interventional trials demonstrating that monitoring single or multiple biomarkers improves outcomes.

Identification of post-mortem cerebrospinal fluid proteins as potential biomarkers of ischemia and neurodegeneration.

Only few biological markers are currently available for the routine diagnosis of brain damage-related disorders including cerebrovascular, dementia, and other neurodegenerative diseases. In this study, post-mortem cerebrospinal fluid samples were used as a model of massive brain insult to identify new markers potentially relevant for neurodegeneration. The protein pattern of this sample was compared to the one of cerebrospinal fluid from healthy subjects by two-dimensional gel electrophoresis. Using gel imaging, N-terminal microsequencing, mass spectrometry, and immunodetection techniques, we identified 13 differentially expressed proteins. Most of these proteins have been previously reported to be somehow associated with brain destruction or with the molecular mechanisms underlying certain neurodegenerative conditions. These data indicate that the identified proteins indeed represent potential biomarkers of brain damage. We recently showed that H-FABP, a protein highly homologous to E-FABP and A-FABP identified in this study, is a potential marker of Creutzfeldt-Jakob disease and stroke.