Objective: To evaluate the diagnostic and prognostic role of the Immulite cTnI assay for the detection of acute coronary syndromes (ACS).Population: 150 males and 63 females with a median age of 63 years, range 28 to 88, and an interquartile range of 18 years were admitted within 24 It of chest pain and non-ST segment elevation ACS were studied. The median onset of symptoms was 3 It (range 0-23).Methods: Venous samples were taken on admission (t = 0) and at 24 h (t = 24). The serum samples were assayed for CK, CK-MB and cTnT on an Elecsys 1010 (Roche Diagnostics, Lewes, UK). The cTnT assay CV was 5.5% at 0.32 mu g/L and 5.4% at 6.0 mu g/L, and the detection limit was 0.01 mu g/L with an upper limit of 25 mu g/L. For cTnI using the Immulite (DPC, Gwynedd, Wales), the detection limit was 0.1 mu g/L, and the upper limit was 180 mu g/L. Final diagnostic categorization was performed by both WHO and European Society of Cardiology criteria using cTnT as the diagnostic cardiac biomarker. Patients were followed for the major adverse cardiac events (MACE), endpoints cardiac death, AMT or need for urgent revascularization. ROC curves were constructed using final diagnosis. Outcome prediction was assessed by ROC curves and Kaplan-Meier survival curves.Results: Both methods had equivalent diagnostic efficiency using WHO criteria for AMI. When ESC criteria were used the AUC for admission and 24 h cTnT and cTnI values were 0.945 vs. 0.910, P = 0.20 and 0.998 vs. 0.937, P = 0.005, respectively. Both methods predicted outcome as either death or MI or MACE and were not significantly different.Conclusion: The Immulite cTnI assay can be used for diagnosis and risk stratification in patients admitted with non-ST segment elevation acute coronary syndromes. (c) 2006 The Canadian Society of Clinical Chemists. All rights reserved.

Objective: To assess the diagnostic efficiency of the third generation cardiac troponin T assay in routine clinical practice. Design: Prospective observational study of unselected consecutive admissions. Setting: Multicentre study in 43 teaching and non-teaching hospitals in 13 countries. Subjects: 1105 hospital admissions, median age 67 years (range 15–96 years, 63.7% male) with suspected acute coronary syndromes (72.3% of cases) or other non-specific symptoms where cardiac disease required exclusion (27.7%). Interventions: Over the study period, myoglobin, creatine kinase MB isoenzyme (CK-MB), and cardiac troponin T where measured in parallel with conventional diagnostic tests. Final diagnostic classification involved standard ECG changes and CK-MB mass exceeding 5.0 μg/l. Main outcome measures: Diagnostic efficiency was assessed by receiver operator characteristic curve analysis including and excluding patients with unstable angina. Results: Measurement of cardiac troponin T was diagnostically equivalent to CK-MB and both were better than myoglobin, with areas under the curve at 12 hours of 0.94, 0.99, and 0.80, respectively. Diagnostic criteria using CK-MB were inadequate and showed bias when patients with unstable angina were included. Elevations of cardiac troponin T did not occur when cardiac disease could be categorically excluded but were found in clinical conditions other than suspected acute coronary syndromes. Conclusions: CK-MB is unsuitable as a diagnostic gold standard even at the proposed lower threshold. A lower cut off for cardiac troponin T of 0.05 μg/l should be used for diagnosis of acute myocardial infarction. Diagnosis of acute myocardial infarction cannot be made solely on the basis of a cardiac troponin T result.

The cardiospecificity and sensitivity of cardiac troponin measurement has proved to be a two edged sword for the laboratory and the clinician The ability to measure the cardiac specific markers, cardiac troponin T (cTnT) and cardiac troponin I (cTnI) (the cardiac troponins), has produced a paradigm shift in the assessment of patients with suspected acute coronary syndromes (ACS). Elevations of creatine kinase (CK) and its MB isoenzyme (CK-MB) resulting from skeletal muscle damage can now reliably be distinguished from those caused by acute myocardial infarction (AMI).1 In the ACS patient, measurement of cTnT and cTnI identified prognostically significant myocardial damage when myocardial infarction was excluded by conventional tests.2 This confirmed and extended previous work showing that minor but non-diagnostic elevations of CK-MB in ACS patients indicated myocardial damage and were prognostic.3 The evidence that cTnT and cTnI elevations predict prognosis in patients with and without ST elevation ACS is comprehensive and led to the proposed redefinition of AMI.4 This recognised cTnT and cTnI measurement as the biochemical diagnostic “gold standard”. The role of cardiac biomarkers to guide treatment has also been recognised and incorporated into management guidelines.5 The cardiospecificity and sensitivity of cardiac troponin measurement has proved to be a two edged sword for the laboratory and the clinician. The laboratory must now produce analytically precise and accurate cardiac marker measurements by immunoassay on a 24 hour, seven day a week basis. The individual laboratory methods for cTnI show differing sensitivities and do not give equivalent answers.1 The clinician has found that evidence of cardiac damage can be readily (and unsurprisingly) detected in a range of other clinical conditions.6,7 Is this a problem of the test or the clinical interpretation of the test result? There is no evidence that these are “false …

Background-Raised plasma homocysteine is a risk factor for coronary artery disease. Patients with myocardial infarction or unstable angina show greater activation of coagulation, greater troponin release, and a worse outcome.Objective-To examine variations in plasma homocysteine concentration in relation to C reactive protein (CRP) in patients presenting with acute coronary syndromes.Methods-Consecutive patients presenting with acute myocardial infarction (22) and unstable angina pectoris (12) were studied. Plasma samples were obtained on admission (before clinical intervention), on days 2, 7, and 28, and again six months after admission. Plasma homocysteine, assayed by high performance liquid chromatography, and CRP were both determined at the same time points. Changes were assessed by analysis of variance.Results-CRP concentrations showed a classical rise on day 2, followed by a gradual decline to normal values taken at six months from admission in both myocardial infarction (p < 0.0001) and unstable angina (p = 0.02). Homocysteine concentrations in myocardial infarction (median, 25th to 75th interquartile range) were: 11.9 (10.7 to 12.6), 11.5 (9.1 to 13.4), 12.1 (11.4 to 14.1), 12.4 (11.1 to 14.4), and 12.1 (11.2 to 14.0) mol/l, for days 1, 2, 7, 28, and 180, respectively (p = 0.02). Significant differences were observed only between day 2 and day 7 (p < 0.05). The final homocysteine measurement was not different from the admission level. Homocysteine concentrations in unstable angina did not differ between admission and convalescence (12.5 (9.1 to 14.5) mol/l and 12.3 (7.7 to 14.9) mu mol/l, respectively).Conclusions-Plasma homocysteine concentrations are minimally influenced by acute phase variations with reliable measurements obtained on admission in patients with myocardial infarction and unstable angina.

BACKGROUND:Insulin-like growth factor 1 (IGF-1) promotes favorable cardiac remodeling in heart failure. However, the relation of plasma IGF-1 in patients with various degrees of heart failure is not known.METHODS:Venous plasma samples were collected from patients with clinically documented heart failure (n = 24) and from control subjects (n = 21) for measurements of IGF-1 levels. In the heart failure group, functional assessment of the physical capacity was determined by means of the New York Heart Association (NYHA) score. Objective determination of ventricular performance was made by transthoracic echocardiographic measurement of left ventricular fractional shortening (FS).RESULTS:IGF-1 levels were higher in patients with heart failure (mean age, 67 +/- 2 years; 17 men) than in control subjects (age, 71 +/- 2 years; 9 men) (20.2 +/- 2 mU/L, 14.1 +/- 2 mU/L, respectively, P <.05). However, the elevated IGF-1 levels were demonstrated only in patients with mild-to-moderate symptoms (NYHA classes I and II) of heart failure (24.7 +/- 3.3 mU/L, n = 12, P =.005 vs control subjects) but not in patients with severe symptoms (NYHA classes III and IV) (15.7 +/- 2.3 mU/L, n = 12). There was a strong positive correlation between IGF-1 levels and left ventricular FS (%) (r = 0.58, P =.003, n = 24). Adjustments for other potential confounders including age, sex, treatment received, and underlying cause of heart failure did not alter the relation between IGF-1 and left ventricular FS (odds ratio, 2.01; 95% confidence interval, 1.26 to 6.24; P =.01).CONCLUSIONS:Plasma levels of IGF-1 show distinct variations with the severity of heart failure and may play a vital role in compensated heart failure.

BACKGROUND:It has been suggested by clinical, epidemiological, and experimental in vitro studies that homocysteine potentiates thrombin generation. This prothrombotic effect however has not previously been demonstrated in patients presenting with acute coronary syndromes (ACS).METHODS AND RESULTS:Patients with ACS (n =117) presenting with confirmed acute myocardial infarction (MI) (n =57) or unstable angina pectoris (UAP) (n =60) were consecutively recruited together with patients (n =18) in whom the presenting chest pain was not of cardiac origin (NCP), included as controls. Plasma samples were collected on admission and before clinical intervention. Homocysteine was assayed by high performance liquid chromatography, and both Factor VIIa and prothrombin fragment F1+2 were analyzed by ELISA. There were significant elevations in F1+2 in MI (P<0.001) and UAP (P=0.003), and modest elevations in Factor VIIa in UAP (P<0.05) compared with NCP but no differences in homocysteine levels among those groups. On dividing patients with ACS into quartiles of homocysteine, there was a stepwise increase in F1+2 (P<0.0001) and of Factor VIIa (P<0.05). There were significant correlations in ACS between homocysteine and F1+2 (r=0.46, P<0.0001), homocysteine and Factor VIIa (r=0.24, P<0.01), and F1+2 and Factor VIIa (r=0.41, P<0.0001). There was no correlation between homocysteine and either F1+2 (r=-0.15, P=0.57) or Factor VIIa (r=0. 22, P=0.37) in the NCP patients.CONCLUSIONS:Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS.

Thrombomodulin is an endothelial cell receptor for thrombin. It functions as a natural anticoagulant by greatly accelerating activation of protein C by thrombin. Using a direct gene screening strategy we identified a frameshift insertion mutation, insT 1689, in the thrombomodulin gene of a patient with myocardial infarction. The mutation predicts an elongated gene product because of substitution of the 12 C-terminal amino acids by 61 abnormal residues. Pedigree analysis showed that the mutation was also likely to have been present in a sibling who had had fatal myocardial infarction. Carriers of the mutant allele express significantly lower amounts of thrombomodulin on the surface of their monocytes detected by flow cytometry and have lower levels of soluble thrombomodulin in plasma. Wild type and the mutant thrombomodulin were expressed in COS-7 cells. Cellular distribution of the expressed proteins was evaluated by immunofluorescence microscopy, which showed reduced cell surface expression and intense juxtanuclear localization of the abnormal protein. This suggests impaired translocation through the endoplasmic reticulum/Golgi apparatus. Cells expressing abnormal thrombomodulin had reduced ability ( approximately 2.5-fold) to accelerate the thrombin mediated activation of protein C. This is the first demonstration of reduced expression arising from a natural thrombomodulin gene mutation. The results provide support for the suggestion that gene mutation of thrombomodulin may be important in the pathogenesis of some cases of occlusive thrombotic disease. (Blood. 2000;95:569-576)

BACKGROUND:Although a raised plasma homocysteine is a risk factor for vascular disease, it is not known whether it is associated with an adverse cardiac outcome in patients admitted with acute coronary syndromes. We evaluated the relationship between plasma homocysteine and short-term (28 days) and long-term (median 2.5 years) prognosis in acute coronary syndromes.METHODS AND RESULTS:We evaluated the relationship of quintiles of homocysteine to fatal and nonfatal coronary disease early (28 days) and late (29 days to a median of 2. 5 years) after admission to a single unit of patients with unstable angina (n=204) and myocardial infarction (n=236). The end points studied were cardiac death (n=67) and/or myocardial (re)infarction (n=30). Cox regression and logistic regression were used to estimate the relationship of homocysteine to coronary events. The event rate within the first 28 days (22 cardiac deaths and 5 nonfatal infarctions) was not related to the admission homocysteine level. In the 203 unstable angina and 214 myocardial infarction survivors, an apparent threshold effect was seen on long-term follow-up, with a significant step-up in the frequency of events between the lowest 3 quintiles (14 cardiac deaths and 11 nonfatal infarctions) and the upper 2 quintiles (31 fatal and 12 nonfatal events). Patients in the upper 2 quintiles (>12.2 micromol/L) had a 2.6-fold increase in the risk of a cardiac event (95% CI, 1.5 to 4.3, P<0.001).CONCLUSIONS:Elevated total homocysteine levels on admission strongly predict late cardiac events in acute coronary syndromes.

OBJECTIVES This study was conducted to determine whether the amount of myocardial damage during acute coronary syndromes (ACS) is related to the admission plasma homocysteine concentration.BACKGROUND Elevated homocysteine levels are associated with increased thrombosis in patients presenting with ACS. It is not known whether this association is reflected in the degree of myocardial injury in those patients.METHODS We studied consecutive patients presenting with acute myocardial infarction (MI) (n = 205) and unstable angina pectoris (UAP) (n = 185). Plasma samples were collected on admission and prior to clinical intervention and were assayed for homocysteine by high performance liquid chromatography (HPLC). Myocardial necrosis was assessed by measurements of cardiac troponin T (cTnT) on admission and 12 h after admission (peak cTnT). The patients were studied by quintiles of homocysteine concentration.RESULTS There was a significant increase in peak cTnT in the 5th homocysteine quintile in MI (analysis of variance [ANOVA], p = 0.005), the levels being 4.10, 3.86, 4.13, 6.20 and 7.85 mu g/liter for quintiles 1 to 5, respectively (p < 0.0001, for top vs, bottom quintile). Similarly, there was a step-up in peak cTnT levels in the top homocysteine quintile in UAP (ANOVA, p < 0.0001), the levels being 0.03, 0.03, 0.02, 0.04 and 0.15 mu g/liter, (p < 0.0001 for top vs, bottom quintile). In a multivariate regression model, the association between peak cTnT and the top homocysteine quintile remained strong after adjustment of other confounders including age, gender, final diagnosis and thrombolysis treatment (odds ratio [OR]: 2.92 (1.75-4.87) p < 0.0001). The patients with UAP were further examined according to peak cTnT levels below (cTnT negative) or above (cTnT positive) 0.1 mu g/liter. Homocysteine levels were significantly higher in cTnT positive than cTnT negative patients; 13.8 (11.7-15.3) vs. 10.3 (9.4-11.3) mu mol/liter, respectively, p = 0.002.CONCLUSIONS Elevated homocysteine levels are associated with a higher risk of ischemic myocardial injury in patients presenting with ACS. CT Am Coil Cardiol 2000;36:1217-22) (C) 2000 by the American College of Cardiology.

Background-Insulin resistance is associated with ischaemic heart disease and has been proposed as a risk factor for subsequent myocardial infarction.Aim-To investigate the potential use of a recently proposed insulin resistance index in identifying insulin resistance in patients admitted with an acute coronary syndrome.Methods-Single centre study of 441 nondiabetic patients admitted with chest pain to a coronary care unit and followed prospectively for a median of three years for outcome. Admission glucose and insulin concentrations were measured and from these values an admission index of insulin resistance (AIRI) calculated. Its association with other known factors in the insulin resistance syndrome, and subsequent outcome, was examined.Results-The AIRI was greater in patients with myocardial infarction than in a control group without myocardial infarction (p < 0.0001). A Cox regression model for subsequent cardiac death identified previous myocardial infarction (p < 0.0001), infarct size (p < 0.0001), and AIRI (p = 0.0033) as positive risk predictors. Patients of Indian subcontinent ethnic origin had greater AIRI values than white patients: mean (SD) 7.5 (1.3) upsilon 4.:6 (0.2), p < 0.001.Conclusions-A simple index of insulin resistance measured on patients admitted with myocardial infarction provides an important predictive measure of poor outcome and is superior to admission glucose measurement. It may be useful in identifying patients admitted with myocardial infarction who could benefit from alternative early management strategies.

We re-examined, in the context of modern practice, plasma insulin and stress hormone concentrations in patients admitted to hospital with acute coronary syndromes. Venous blood sampling was carried out prior to anti-thrombotic therapy in 148 patients with myocardial infarction (MI); 76 patients with unstable angina (UA) pectoris were also studied, together with 27 patients with non-cardiac chest pain (NCP). There were significant progressive increases in the concentrations of catecholamines, cortisol, glucose and insulin from NCP to UA to MI patients. Hyperglycaemia (glucose > 8 mmol/l) was present in over 50% of MI patients. The plasma cortisol and insulin levels were both significantly positively correlated with the glucose concentration on admission. Only the cortisol concentration was correlated with peak cardiac enzyme levels. The glucose and insulin concentrations on admission in 141 MI and UA patients were related to insulin resistance, as judged from subsequent insulin and glucose concentrations measured while fasting and during a glucose tolerance test. The product of admission insulin×glucose (divided by 25; the admission insulin-resistance index, or AIRI) was significantly correlated with indices of insulin resistance, and was significantly higher (approximately double) in the MI group (7.81±0.76) and the UA group (6.88±1.19) than in the control NCP group (3.59±0.06; Kuskul–Wallis: P = 0.0001), implying that the insulin levels in the first two groups were approximately twice as high as is appropriate for the glucose levels. The ethnic origin of 20% of the patients was the Indian subcontinent; admission insulin and glucose levels in this subgroup were higher than in the non-Asians across all the groups with chest pain. Cortisol was the only stress hormone that was raised in proportion to the size of the infarct, and is a likely partial cause of the elevation in blood glucose. The high insulin levels were related to the prevalence of insulin resistance, and this was particularly important in the Asian subgroup presenting with MI and UA. Thus it appears feasible to identify acute coronary syndrome patients who are insulin-resistant at a time (on admission) when alternative early therapeutic strategies can be instituted.

SummaryThrombomodulin is an endothelial cell surface receptor that transforms the procoagulant thrombin into an anticoagulant. A mutation in the thrombomodulin gene is a potential risk factor for venous and arterial thrombosis.We screened a region within the coding sequence of the thrombomodulin gene by single-strand conformation polymorphism analysis (SSCP) in a pilot study of 104 patients with myocardial infarction and 104 age, sex and race matched controls. We identified a 127G to A mutation in the gene, which predicts an Ala25Thr substitution, in 2 out of 104 patients (1 man and 1 woman) with myocardial infarction but in no controls. We assessed the risk of myocardial infarction associated with the mutation in a larger “Study of Myocardial Infarctions Leiden” (SMILE). Among 560 men with a first myocardial infarction before the age of 70, 12 were carriers of the Ala25Thr substitution. In a control group of 646 men, frequency-matched for age, seven were carriers of the Ala25Thr substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls suggesting risk associated with the mutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1]. In patients aged below 50, the predicted risk was almost seven times increased (OR 6.5, CI 0.8-54.2). In the presence of additional risk factors, such as smoking and a metabolic risk factor, the predicted risk increased to 9-fold (OR 8.8, CI 1.8-42.2) and 4-fold (OR 4.4, CI 0.9-21.3), respectively.While not conclusive, these results strongly suggest that the Ala25Thr substitution is a risk factor for myocardial infarction, especially in young men, and when in the presence of additional risk factors.