Peter J. Stubbs

Prospective study of the role of cardiac troponin T in patients admitted with unstable angina

Abstract Objective: To examine the prognostic significance and role in risk stratification of the biochemical marker troponin T in patients admitted with unstable angina. Design: Single centre, blinded, prospective study of patients admitted with chest pain. Setting: Coronary care unit of a district general hospital. Subjects: 460 patients admitted with chest pain and followed up for a median of three years. 183 patients had a final diagnosis of unstable angina. Main outcome measures: Cardiac death, need for coronary revascularisation, or readmission with non-fatal myocardial infarction as first events. Results: 62 (34%) unstable angina patients were troponin T positive. This group had significantly increased incidence rates of subsequent cardiac death (12 cases (19%) v 14 (12%)), coronary revascularisation (22 (35%) v 26 (21%)), death or revascularisation (33 (53%) v 40 (33%)), and death or non-fatal myocardial infarction (18 (29%) v 21 (17%)) compared with the troponin T negative group. In multiple logistic regression troponin T status was a highly significant predictor for the end points coronary revascularisation and cardiac death or revascularisation as first events. Conclusion: Troponin T in the serum of patients with unstable angina identifies a subgroup at higher risk of subsequent cardiac events and its measurement aids in risk factor stratification. The increased risk extends to two years after admission. Prospective randomised trials are required to identify optimum therapeutic strategies for this subgroup. Key messages Stratifying patients with unstable angina for risk remains a difficult clinical problem A new cardiac specific protein, troponin T, can now be measured in serum The detection of troponin T 12-24 hours after admission identifies a high risk subgroup of patients with unstable angina Prospective trials are required to identify optimum therapeutic strategies for this subgroup

Effect of Plasma Homocysteine Concentration on Early and Late Events in Patients With Acute Coronary Syndromes

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.

Relationships Between Homocysteine, Factor VIIa, and Thrombin Generation in Acute Coronary Syndromes

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.

Elevated homocysteine levels are associated with increased ischemic myocardial injury 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 microg/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 microg/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 microg/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) micromol/liter, respectively, p = 0.002. CONCLUSIONS Elevated homocysteine levels are associated with a higher risk of ischemic myocardial injury in patients presenting with ACS.

Measurement of Serum Troponin T, Creatine Kinase MB Isoenzyme, and Total Creatine Kinase following Arduous Physical Training

We have compared measurement of cardiac troponin T by enzyme linked immunosorbent assay with creatine kinase MB isoenzyme (CK-MB) concentration measurement in 219 Royal Marine commandos with no evidence of cardiovascular disease who have elevated creatine kinase (CK) produced by arduous physical training. CK was elevated up to 22.6 times and CK-MB mass up to 6.6 times the upper reference limit. Only two commandos had detectable cardiac troponin T, with neither exceeding the upper reference limit of 0.2 μg/L. At decision thresholds optimized for diagnosis of acute myocardial infarction in previous published work, 58.3% of the total CK activity, 13.8% of the CK-MB concentration/CK activity ratio and 1.6% of CK-MB concentration measurements showed elevated values but no elevations in cardiac troponin T occurred. Cardiac troponin T is currently the investigation of choice for the differential diagnosis of patients with an elevated CK due to skeletal muscle trauma to exclude myocardial damage.

Acute and convalescent changes in plasma homocysteine concentrations in acute coronary syndromes

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) μmol/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) μmol/l and 12.3 (7.7 to 14.9) μmol/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.

Significance of an index of insulin resistance on admission in non-diabetic patients with acute coronary syndromes

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 non-diabetic 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) v 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.

Efficacy and Safety of d-Sotalol, a Pure Class III Antiarrhythmic Compound, in Patients With Symptomatic Complex Ventricular Ectopy Results of a Multicenter, Randomized, Double-blind, Placebo-Controlled Dose-Finding Study

Background There is increasing interest in pure class III antiarrhythmic compounds, ie, drugs in which the electrophysiological effect is confined to the propensity for producing an isolated lengthening of action potential duration. d -Sotalol represents the prototype of such pure class III agents. This double-blind, placebo-controlled, randomized dose-finding study evaluated the antiarrhythmic efficacy and safety of d -sotalol in patients with symptomatic chronic ventricular ectopy. Methods and Results A total of 233 patients presenting with ≥30 premature ventricular contractions (PVCs) per hour during drug-free Holter monitoring randomly received placebo or d -sotalol at dosages of 50, 100, or 200 mg BID. Drug efficacy was assessed by repeat Holter monitoring at the end of double-blind therapy. There was a dose-dependent increase in QT and QT c duration, indicating class III activity. A dose-related decrease in hourly PVC counts was observed, reaching statistical significance for patients receiving 200 mg d -sotalol BID (311 PVCs/h during baseline compared with 135 PVCs/h during active treatment, P d -sotalol dose, with 8 patients (14%) meeting this criterion. Eighteen patients reported side effects, which led to drug discontinuation in 5. One sudden death and one nonfatal cardiac arrest occurred in patients with dilative cardiomyopathy receiving 200 mg d -sotalol BID. No incidence of torsade de pointes was reported. Conclusions d -Sotalol exerts dose-dependent class III activity in patients with symptomatic ventricular ectopy. Its PVC-suppressing activity is modest and becomes evident predominantly at dosages of 200 mg administered BID. The observation of drug-associated serious adverse arrhythmic events emphasizes the need for individualized careful dose titration, particularly in patients with advanced organic heart disease.