Cardiovascular disease is the primary cause of death in westernizedpopulation. However, a number of cardiovascular fatalities may be preventable if wehave biomarkers upstream from markers of necrosis such as inflammatory cytokines,acute-phase reactants, biomarkers of ischemia and of myocardial stretch, which mayprovide an earlier assessment of overall patient risk. Recently ischemia modifiedalbumin (IMA) has been proposed as a biomarker in clinical conditions related toischemia associated with oxidative stress, such as cardiac ischemia, or persistentperipheral ischemia (chronic kidney disease, systemic sclerosis, hypercholesterolemia,type 2 diabetes). IMA represents the in vivo modification of human serum albuminamino-terminal end by reactive oxygen species (ROS). The N-terminal end (aminoterminal end) of albumin molecule is a binding site for transition metals. As a result ofROS generated by hypoxia, free-radical injury or membrane disruption, the Nterminalof albumin molecule undergoes a decrease in binding capacity in thepresence of ischemia. This alteration can be measured by the albumin cobalt bindingtest (ACB test).Aim: The aim of the present study was to investigate serum levels of IMA, as apotential marker of presence and/or severity of coronary artery disease (CAD) insubjects with documented CAD and without documented CAD in association withmenopause and obesity conditions that are associated with an increase ofcardiovascular risk.Methods and Results: The study included 429 individuals divided into 3 Groups.Group A: consists of 12 hypertensive patients undergoing exercise stress test (EST).IMA, albumin and NT-proBNP kinetics were investigated in 12 hypertensive patientsduring the EST. An hour after stress, IMA and NT-proBNP serum levels weresignificantly higher than baseline suggesting a myocardial ischemic burden and aventricular myocyte stretch respectively. There was not any change of albumin serumlevels an hour after stress. At maximum exercise, there was a decrease of IMA serumlevels as compared to baseline values, attributed probably to the increase of lacticserum levels that generates an analytical interference on ACB test.Group B: consists of 114 patients (88 men and 30 women) aged 43-80 years withdocumented CAD without evidence of acute coronary syndrome (ACS) undergoingcoronary angiography (CA) and 163 controls (131 men and 32 women) of similaraged. Serum IMA levels were measured before CA. Serum levels of high-sensitivityC-reactive protein (hsCRP), cardiac troponin T (cTnT), CK-MB concentration and Nterminalpro brain natriuretic peptide (NT-proBNP), which represent biomarkers ofinflammation, of myocardial ischemia, damage or necrosis as well as serum totalantioxidant status (TAS) were also evaluated. The results indicated that IMA levelswere higher (p<0.001) while TAS was lower (p<0.001) in patients than in controls.IMA and TAS were negatively correlated in all subjects (p<0.001). Among patients,there was no correlation between IMA and the number of diseased vessels (severity ofCAD). Serum levels of hsCRP and NT-proBNP were higher (p<0.001 and p=0.008for NT-proBNP) in patients than in controls. However, although the studied patientswere at high risk of ACS based upon CA documentation, only 8 (7%) of those hadhsCRP levels above the cut-off of 3mg/L, which indicates elevated vascular risk. Inpatients, serum NT-proBNP levels were elevated (above 161 pg/mL) only in thosebelonging to the two upper quartiles of NT-proBNP distribution. The observed cTnTlevels did not suggest myocardial necrosis. Serum IMA determination seems toprovide an index of the presence of CAD before any elevation of cTnT and/or NTproBNP.For CAD diagnosis the best cut-off point for IMA was 101.5 KU/L with asensitivity and a specificity of 87.7% and negative predictive value 83.3%. IMA wasassociated with an increased risk for CAD (OR=1.23, 95% CI: 1.16-1.31; p<0.001).Albumin serum levels, although within the normal range, were decreased in patientsin comparison to controls.Group C: consists of 130 non-smoker postmenopausal women aged 43-80 years, 40with BMI 26-32 kg/m2 (overweight), 60 with BMI 21-25 (non-overweight), and 30with documented CAD and BMI 23-29. Serum IMA, albumin, hsCRP and NTproBNP,glucose and insulin were measured. Homeostasis assessment model score(HOMA) and Quantitative insulin sensitivity index (QUICKI) were co-estimated.Serum IMA levels were significantly elevated in overweight as compared to nonoverweight(p<0.001) women but were similar to those with CAD. hsCRP and NTproBNPdid not differ between overweight and non-overweight while they were lowerin comparison to those with CAD (p<0.001). Glucose, insulin and HOMA wereelevated in overweight compared to non-overweight (p<0.001) while QUICKI waslower (p<0.001). In overweight women, IMA was positively correlated with BMI,hsCRP, insulin, HOMA and negatively with QUICKI. Multivariable regressionanalysis revealed that in postmenopausal women obesity was the strongest significantpredictor (determinant) of circulating IMA levels (p<0.001) contributing, therefore, tothe elevated serum IMA concentration.Conclusions: It is worth pointing out that IMA was measured by the ACB assay and the determinants of the ACB assay mechanism of action include, apart from the proportion of intact N-terminus of serum albumin, serum albumin concentration, thestate of oxidation of cys34 of serum albumin, the plasma pH and the plasmacysteine/cystine ratio encountered with oxidative stress, conditions that are associatedor predispose to atherosclerosis and vascular disease.In conclusion our results suggest that:1. IMA determination may provide earlier information of CAD presence before hsCRP or NT-proBNP elevation, contributing to early assessment of overall patient risk.2. Postmenopausal obesity is associated with elevated serum IMA possibly due to obesity-associated oxidative stress and IMA measurement could provide an assessment of global atherosclerotic burden in postmenopausal women.3. Increased serum IMA levels after EST suggest a large myocardial ischemic burden.Whether that elevation may be useful for predicting the severity of myocardialischemia and/or improve the accuracy of EST remains to be elucidated.IMA measurement might provide alone or in contribution with other serumbiomarkers an earlier assessment of global atherosclerotic burden andcardiovascular risk.
EndoScreen Chip: Serum Complement C9 Immunoassays Improve Risk Prediction and Early Diagnosis of Esophageal Adenocarcinoma
