Circulating trimethyllysine and risk of acute myocardial infarction in patients with suspected stable coronary heart disease.

BACKGROUND: The carnitine precursor trimethyllysine (TML) is associated with progression of atherosclerosis, possibly through a relationship with trimethylamine-N-oxide (TMAO). Riboflavin is a cofactor in TMAO synthesis. We examined prospective relationships of circulating TML and TMAO with acute myocardial infarction (AMI) and potential effect modifications by riboflavin status. METHODS: By Cox modelling, risk associations were examined amongst 4098 patients (71.8% men) with suspected stable angina pectoris. Subgroup analyses were performed according to median plasma riboflavin. RESULTS: During a median follow-up of 4.9 years, 336 (8.2%) patients experienced an AMI. The age- and sex-adjusted hazard ratio (HR) (95% CI) comparing the 4th vs. 1st TML quartile was 2.19 (1.56-3.09). Multivariable adjustment for traditional cardiovascular risk factors and indices of renal function only slightly attenuated the risk estimates [HR (95% CI) 1.79 (1.23-2.59)], which were particularly strong amongst patients with riboflavin levels above the median (Pint  = 0.035). Plasma TML and TMAO were strongly correlated (rs  = 0.41; P < 0.001); however, plasma TMAO was not associated with AMI risk in adjusted analyses [HR (95% CI) 0.81 (0.58-1.14)]. No interaction between TML and TMAO was observed. CONCLUSION: Amongst patients with suspected stable angina pectoris, plasma TML, but not TMAO, independently predicted risk of AMI. Our results motivate further research on metabolic processes determining TML levels and their potential associations with cardiovascular disease. We did not adjust for multiple comparisons, and the subgroup analyses should be interpreted with caution.

Association of plasma neopterin with risk of an inpatient hospital diagnosis of atrial fibrillation: results from two prospective cohort studies.

BACKGROUND: Link between inflammation and atrial fibrillation (AF) has been increasingly recognized. Neopterin, a biomarker of cellular immune activation, may be associated with incident AF. OBJECTIVE: To investigate the association between plasma neopterin levels and risk of an inpatient hospital diagnosis of AF, and to evaluate a joint association of neopterin and a nonspecific inflammatory marker C-reactive protein (CRP) in two prospective cohorts. METHODS: We performed a prospective analysis from a community-based cohort (the Hordaland Health Study (HUSK), n = 6891), and validated the findings in a cohort of patients with suspected stable angina pectoris (the Western Norway Coronary Angiography Cohort (WECAC), n = 2022). RESULTS: In both cohorts, higher plasma levels of neopterin were associated with an increased risk of incident AF after adjustment for age, sex, body mass index, current smoking, diabetes, hypertension and renal function. The multivariable-adjusted hazard ratio (HR) (95% CI) per one SD increment of log-transformed neopterin was 1.20 (1.10-1.32) in HUSK and 1.26 (1.09-1.44) in WECAC. Additional adjustment for CRP did not materially affect the risk association for neopterin. The highest risk of AF was found among individuals with both neopterin and CRP levels above the median (HR: 1.54; 95% CI: 1.16-2.05 in HUSK and HR: 1.67; 95% CI: 1.11-2.52 in WECAC). CONCLUSIONS: Our findings indicate an association of plasma neopterin with risk of an inpatient hospital diagnosis of AF, which remains after adjustment for traditional risk factors as well as for CRP. This study highlights a role of cellular immune activation, in addition to inflammation, in AF pathogenesis.

Cosinor modelling of seasonal variation in 25-hydroxyvitamin D concentrations in cardiovascular patients in Norway.

BACKGROUND/OBJECTIVES: Seasonal variation may reduce the validity of 25-hydroxyvitamin D (25OHD) as a biomarker of vitamin D status. Here we aimed to identify potential determinants of seasonal variation in 25OHD concentrations and to evaluate cosinor modelling as a method to adjust single 25OHD measurements for seasonal variation. SUBJECTS/METHODS: In Caucasian cardiovascular patients (1999-2004), we measured 25OHD by liquid chromatography tandem mass spectrometry in 4116 baseline and 528 follow-up samples. To baseline values, we fitted a cosinor model for monthly concentrations of 25OHD. Using the model, we estimated each patient's adjusted annual 25OHD value. Further, we studied how covariates affected the annual mean 25OHD concentration and seasonal variation of the study cohort. To evaluate the model, we predicted follow-up measurements with and without covariates and compared accuracy with carrying forward baseline values and linear regression adjusting for season, common approaches in research and clinical practice, respectively. RESULTS: The annual mean (59.6 nmol/l) was associated with participants' age, gender, smoking status, body mass, physical activity level, diabetes diagnosis, vitamin D supplement use and study site (adjusted models, P<0.05). Seasonal 25OHD variation was 15.8 nmol/l, and older age (>62 years) was associated with less variation (adjusted model, P=0.025). Prediction of follow-up measurements was more accurate with the cosinor model compared with the other approaches (P<0.05). Adding covariates to cosinor models did not improve prediction (P>0.05). CONCLUSIONS: We find cosinor models suitable and flexible for analysing and adjusting for seasonal variation in 25OHD concentrations, which is influenced by age.

Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials.

OBJECTIVES: In the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, patients were randomly assigned to homocysteine-lowering B-vitamins or no such treatment. We investigated their effects on cardiovascular outcomes in the trial populations combined, during the trials and during an extended follow-up, and performed exploratory analyses to determine the usefulness of homocysteine as a predictor of cardiovascular outcomes. DESIGN: Pooling of data from two randomized controlled trials (1998-2005) with extended post-trial observational follow-up until 1 January 2008. SETTING: Thirty-six hospitals in Norway. SUBJECTS: 6837 patients with ischaemic heart disease. INTERVENTIONS: One capsule per day containing folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg), or folic acid plus vitamin B12, or vitamin B6 alone or placebo. MAIN OUTCOME MEASURES: Major adverse cardiovascular events (MACEs; cardiovascular death, acute myocardial infarction or stroke) during the trials and cardiovascular mortality during the extended follow-up. RESULTS: Folic acid plus vitamin B12 treatment lowered homocysteine levels by 25% but did not influence MACE incidence (hazard ratio, 1.07; 95% CI, 0.95-1.21) during 39 months of follow-up, or cardiovascular mortality (hazard ratio, 1.12; 95% CI, 0.95-1.31) during 78 months of follow-up, when compared to no such treatment. Baseline homocysteine level was not independently associated with study outcomes. However, homocysteine concentration measured after 1-2 months of folic acid plus vitamin B12 treatment was a strong predictor of MACEs. CONCLUSION: We found no short- or long-term benefit of folic acid plus vitamin B12 on cardiovascular outcomes in patients with ischaemic heart disease. Our data suggest that cardiovascular risk prediction by plasma total homocysteine concentration may be confined to the homocysteine fraction that does not respond to B-vitamins.

Activated factor XII type A predicts long-term mortality in patients admitted with chest pain.

BACKGROUND: We assessed the relation between admission levels of activated factor XII type A (XIIaA), and long-term all-cause and cardiac mortality and recurrent troponin T (TnT) positive cardiovascular events in a consecutive cohort of 870 patients admitted with a clinically strongly suspected acute coronary syndrome (ACS). METHODS AND RESULTS: After a 24-month follow-up period, 138 patients (15.8%) had died and 155 (17.8%) had suffered from a recurrent TnT positive (TnT > 0.05 ng mL(-1)) event. XIIaA levels were significantly lower in long-term survivors than in patients who died (22.9 (17.7-32.1) vs. 27.2 (20.0-39.7) pmol L(-1) [median, 25 and 75% percentiles], P < 0.001). The unadjusted hazard ratio for death within 2 years in patients with XIIaA in the highest quartile was 2.49 (95% confidence interval (CI), 1.52-4.06) as compared with patients with XIIaA in the lowest quartile. In a stepwise Cox regression model for death within 2 years, XIIaA added prognostic information for all-cause mortality (HR 2.05; 95% CI, 1.21-3.47) above and beyond age, a history of heart failure, ST-segment elevation, TnT and B-type natriuretic peptide (BNP). In the subgroup of patients with an admission TnT < or = 0.05 ng mL(-1), XIIaA provided independent prognostic information for all-cause mortality (HR 3.88; 95% CI, 1.66-9.08) and for the combined endpoint of death or recurrent TnT positive event (HR 2.46; 95% CI, 1.34-4.50). CONCLUSION: XIIaA, a recently identified in vivo form of activated factor XII is an independent indicator of long-term all-cause mortality in patients admitted with chest pain, providing prognostic information above and beyond conventional risk factors.

Holotranscobalamin and methylmalonic acid as prognostic markers following an acute myocardial infarction.

OBJECTIVE: To evaluate whether low levels of holotranscobalamin (holoTC) or elevated levels of methylmalonic acid (MMA), both indicators of vitamin B(12) deficiency, might predispose to new cardiovascular events following an acute myocardial infarction (MI). DESIGN: A prospective prognostic study. SETTING: One hospital center in Stavanger, Norway. SUBJECTS: A total of 300 patients admitted with an acute MI. METHODS: Registration of new TnT positive coronary events (defined as TnT>0.05 microg/l and a typical MI pattern) and/or cardiac death during a median follow-up time of 45 months. RESULTS: We compared the recurrence of events in the lowest quartile of holoTC (Q1<73.9 pmol/l) to the event rate above the 25% percentile (Q2-4). For methylmalonic acid (MMA) the same comparison was carried out for the upper quartile (Q4 > or =0.24 micromol/l) as compared with the event rate below the 75% percentile (Q1-3). After 18 and 45 months of follow-up, the odds ratio (OR) for Q1 vs Q2-4 for holoTC was 1.15 (95% confidence interval (CI) 0.91-1.46, P=0.25) and 1.05 (95% CI 0.86-1.29, P=0.64), respectively. For MMA the OR for Q4 vs Q1-3 was 0.95 (95% CI 0.76-1.19, P=0.67) after 18 months and 1.01 (95% CI 0.83-1.23, P=0.90) after 45 months. CONCLUSION: This study showed no increased risk of future cardiovascular events associated with low levels of holoTC or high levels of MMA following an acute MI.

Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease.

OBJECTIVES: A high level of total homocysteine (tHcy) is a risk marker for cardiovascular disease (CVD), and is related to inflammation. We wanted to test the effect of homocysteine-lowering B-vitamin therapy, as used in the Western Norway B-vitamin Intervention Trial (WENBIT), on inflammatory markers associated with atherosclerosis. DESIGN: Single centre, prospective double-blind clinical interventional study, randomised in a 2 x 2 factorial design. SUBJECTS AND METHODS: Ninety patients (21 female) with suspected coronary artery disease (CAD), aged 38-80 years, were blindly randomised into one of four groups of daily oral treatment with (A) folic acid (0.8 mg)/vitamin B12 (0.4 mg)/vitamin B6 (40 mg), (B) folic acid/vitamin B12, (C) vitamin B6 alone or (D) placebo. Blood samples were collected before and after 6 months of treatment. RESULTS: Before intervention, median levels of the analytes were: tHcy 11.0 micromol L(-1), neopterin 8.1 nmol L(-1), soluble CD40 ligand (sCD40L) 3.9 ng mL(-1), interleukin (IL)-6 1.9 pg mL(-1), C-reactive protein (CRP) 1.9 mg L(-1) and low-density lipoprotein (LDL) cholesterol 3.3 mmol L(-1). tHcy was significantly associated with neopterin (r = 0.49, P < 0.001) and with IL-6 (r = 0.29, P = 0.01), but not with CRP or sCD40L. Neither treatment with folic acid/B12 nor with B6 induced significant changes in any of these inflammatory biomarkers (P >or= 0.14). In patients receiving folic acid/B12 (groups A and B), tHcy was reduced with 33% (P < 0.001). CONCLUSIONS: In patients with stable CAD, homocysteine-lowering therapy with B-vitamins does not affect levels of inflammatory markers associated with atherogenesis. Failure to reverse inflammatory processes, may partly explain the negative results in clinical secondary B-vitamin intervention trials.

Increased lipid peroxidation during long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial infarction.

OBJECTIVE: To assess the oxidative burden of a highly concentrated compound of n-3 PUFAs as compared to corn oil by measuring thiobarbituric acid-malondialdehyde complex (TBA-MDA) by HPLC. We also studied the influence on TBA-MDA of statins combined with n-3 PUFAs or corn oil. DESIGN: A prospective, randomised, double-blind, controlled study. SETTING: One hospital centre in Stavanger, Norway. SUBJECTS: A total of 300 subjects with an acute myocardial infarction (MI). INTERVENTIONS: Gelatine capsules, containing 850-882 mg EPA and DHA as concentrated ethylesters, or 1 g of corn oil, were ingested in a dose of two capsules twice a day for at least 1 y. Alpha-tocopherol (4 mg) was added to all capsules to protect the PUFAs against oxidation. RESULTS: After 1 y TBA-MDA increased modestly in the n-3 PUFA group (n=125), as compared to the corn oil group (n=130), P=0.027. Multiple linear regression analyses of fatty acids in serum total phospholipids (n=56) on TBA-MDA measured after 12 months intervention, showed no dependency. Performing best subsets regression, serum phospholipid concentration of arachidonic acid (20:4 n-6 PUFA) was identified as a predictor of TBA-MDA at 12 months follow-up, P=0.004. We found no impact of statins on TBA-MDA. CONCLUSION: TBA-MDA increased modestly after long-term intervention with n-3 PUFAs compared to corn oil post-MI, suggesting biological changes induced by n-3 PUFAs, rather than simply reflecting their concentration differences. The peroxidative potential of n-3 PUFAs was not modified by statin treatment. SPONSORSHIP: : Pharmacia A/S and Pronova A/S, Norway.

Characteristics and prognostic impact of plasma fibrin monomer (soluble fibrin) in patients with coronary artery disease.

We measured fibrin monomer (FM), soluble fibrin, as a marker of thrombin activity in plasma samples obtained in parallel with the first two routine samples for cardiac markers in 165 patients with acute chest pain admitted consecutively to our hospital. A reference limit of FM in a healthy population was set at 3.0 mg/l. Elevated plasma FM was observed in 48.8% of patients with acute coronary syndromes, in 42.3% of patients with specific non-coronary disease, in 31.5% of those with stable angina pectoris and in 18.2% of patients with non-specific chest pain. No significant difference was observed between sample 1 and sample 2 in patients not receiving thrombolytic treatment during the sampling period (P = 0.46). In patients with coronary artery disease, FM was significantly related to the level of cardiac troponin T (P = 0.001), but no correlation was observed between the individual plasma FM and cardiac troponin T values. Outcome analysis during the following 30 months after the index event in patients with acute coronary syndromes revealed higher FM levels in those with coronary re-events or death than in patients without new events (P = 0.001). This observation indicates a prognostic potential of FM in risk evaluation of patients with coronary artery disease.

Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol.

BACKGROUND: Results of epidemiologic studies and clinical trials indicate that moderate doses of n-3 fatty acids reduce the risk of cardiovascular disease and may improve prognosis. OBJECTIVE: The objective was to evaluate the effect of a high-dose ethylester concentrate of n-3 fatty acids administered early after an acute myocardial infarction (MI) on subsequent cardiac events and serum lipids. DESIGN: Three hundred patients with acute MI were randomly assigned to a daily dose of either 4 g highly concentrated n-3 fatty acids or corn oil, administered in a double-blind manner over 12-24 mo. Median follow-up time was 1.5 y. Clinical follow-up, including the drawing of blood samples, was performed after 6 wk of treatment and later at 0.5-year intervals. RESULTS: Forty-two (28%) patients in the n-3 group and 36 (24%) in the corn oil group experienced at least one cardiac event (cardiac death, resuscitation, recurrent MI, or unstable angina). No significant difference in prognosis was observed between groups for single or combined cardiac events. Total cholesterol concentrations decreased in both groups, with no significant intergroup differences. On average, the monthly increase in HDL cholesterol was 1.11% in the n-3 group and 0.55% in the corn oil group (P = 0.0016). Triacylglycerol concentrations decreased by 1.30%/mo in the n-3 group, whereas they increased by 0.35%/mo in the corn oil group (P < 0.0001). CONCLUSION: No clinical benefit of a high-dose concentrate of n-3 fatty acids compared with corn oil was found despite a favorable effect on serum lipids.

Atherothrombogenic risk modulation by n-3 fatty acids was not associated with changes in homocysteine in subjects with combined hyperlipidaemia.

Favourable effects of n-3 fatty acids on the atherogenic risk profile were recently demonstrated in subjects with combined (type IIb) hyperlipidaemia, not responding to a therapeutic diet. Re-examination of a previous patient material was performed to assess the influence of n-3 fatty acids on homocysteine and several coagulation factors. Subjects were randomly allocated to receive either a concentrated compound of 85% eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (n = 28), or corn oil (n = 29), in a daily dose of 4g for 12 weeks. The intervention was double-blind. Homocysteine remained unchanged in both groups after 12-week treatment. N-3 fatty acids supplementation did not affect the levels of fibrinogen, coagulation factor VII or tissue factor pathway inhibitor (TFPI), while plasminogen activator inhibitor (PAI) increased significantly (Student's t-test; p <0.05). Total blood platelets were significantly reduced in subjects receiving n-3 fatty acids (Student's t-test; p <0.05), whereas bleeding times increased non-significantly.

Long-term effects on cardiac output and peripheral resistance in patients treated with enalapril after acute myocardial infarction. CONSENSUS II Multi-Echo Study Group. Cooperative New Scandinavian Enalapril Survival Study.

In the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II), in which enalapril treatment was initiated intravenously within 24 h after acute myocardial infarction, there was a neutral effect on 6-month mortality, whereas a beneficial effect on the progression of congestive heart failure was noted. We studied the effect of enalapril on left ventricular systolic function in terms of cardiac output and mean acceleration time measured by pulsed-wave Doppler in the left ventricular outflow tract and peripheral resistance. Early angiotensin-converting enzyme inhibition after acute myocardial infarction did not result in a general improvement of cardiac output. However, a small increase in cardiac output was observed in a subgroup of enalapril-treated patients with ejection fraction > or = 45%, probably due to a reduction in peripheral resistance in these patients.

Systemic thrombin generation and activity resistant to low molecular weight heparin administered prior to streptokinase in patients with acute myocardial infarction.

One hundred patients were included in a randomized open trial to assess the systemic factor Xa (FXa) and thrombin inhibitory effect as well as the safety profile of low molecular weight heparin (LMWH) given subcutaneously in conjunction with streptokinase (SK) in patients with acute myocardial infarction (MI). The treatment was initiated prior to SK, followed by repeated injections every 12 h for 7 days, using a dose of 150 anti-Xa units per kg body weight. The control group received unfractionated heparin (UFH) 12,500 i.u. subcutaneously every 12 h for 7 days, initiated 4 h after start of SK infusion. All patients received acetylsalicylic acid (ASA) initiated prior to SK. Serial blood samples were collected prior to and during the first 24 h after initiation of SK infusion for determination of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III (TAT) complexes, fibrinopeptide A (FPA) and cardiac enzymes. Bleeding complications and adverse events were carefully accounted for. Infarct characteristics, as judged by creatine kinase MB isoenzyme (CK-MB) and cardiac troponin T (cTnT), were similar in both groups of patients. A comparable transient increase in F1 + 2, TAT and FPA was noted irrespective of heparin regimen. Increased anti-Xa activity in patients given LMWH prior to thrombolytic treatment had no impact on indices of systemic thrombin activation. The incidence of major bleedings was significantly higher in patients receiving LMWH as compared to patients receiving UFH. However, the occurrence of bleedings was modified after reduction of the initial LMWH dose to 100 anti-Xa units per kg body weight. In conclusion, systemic FXa- and thrombin activity following SK-infusion in patients with acute MI was uninfluenced by conjunctive LMWH treatment.

Effect of enalapril initiated early after acute myocardial infarction on heart failure parameters, with reference to clinical class and echocardiographic determinants. CONSENSUS II Multi-Echo Study Group.

BACKGROUND AND HYPOTHESIS: Although the angiotensin-converting enzyme inhibitor enalapril has recently been shown to reduce mortality and the need for hospitalization in patients with left ventricular dysfunction and congestive heart failure, this drug was found to have no significant impact on short-term mortality after acute myocardial infarction (AMI) in the CONSENSUS II trial. The effect of enalapril initiated early after AMI on clinical and echocardiographic determinants of left ventricular (LV) function was studied in a subset of patients from CONSENSUS II. METHODS: Symptoms and signs of heart failure were classified as NYHA and dyspnea classes. Echocardiography included LV end-systolic volumes (ESV) and end-diastolic volumes (EDV), as well as ejection fraction (EF), wall motion index (WMI), and mitral flow indices. In all, 428 patients were included and followed for an average of 5.1 months by serial examinations, starting 2-5 days after myocardial infarction (MI) and repeated after 1 month and at the completion of the study. RESULTS: There was no beneficial effect of enalapril on clinically determined function. Changes (i.e., changes in NYHA class) in the functional status remained correlated with changes in echocardiographic determinants throughout the study in patients belonging to the placebo group: EDV index (r = 0.36, p = 0.002, ESV index (r = 0.49, p < 0.001), EF (r = -0.41, p < 0.001), and WMI (r = 0.29, p = 0.008). In a stepwise logistic regression model, the best baseline parameters to predict NYHA class at final visit in all patients were age (p = 0.014) and ESV index (p = 0.001). CONCLUSION: Enalapril treatment for an average period of 5.1 months following MI resulted in no clinically significant beneficial effects on NYHA and dyspnea class. Changes in clinical function class were correlated with changes in echocardiographic determinants in placebo-treated patients, but not in patients given enalapril.

Benefit of converting enzyme inhibition on left ventricular volumes and ejection fraction in patients receiving beta-blockade after myocardial infarction. CONSENSUS II multiecho study group.

Beta-blockers reduce infarct size and improve survival after acute myocardial infarction (MI). Post-MI angiotensin-converting enzyme inhibition also improves survival and may attenuate left ventricular (LV) dilatation. We evaluated the effect of early enalapril treatment on LV volumes and ejection fraction (EF) in patients on concomitant beta-blockade after MI. Intravenous enalaprilat or placebo was administered <24 hours after MI and was continued orally for 6 months. LV volumes were assessed by echocardiography 3 +/- 2 days, 1 and 6 months after MI. Change in LV diastolic volume during the first month was attenuated with enalapril (2.7 vs placebo 6.5 ml/m2 change; p < 0.05), and significantly lower LV diastolic and systolic volumes were observed with enalapril treatment compared with placebo at 1 month (enalapril 47.21 23.9 vs placebo 53.1/29.2 ml/m2; p < 0.05) and at 6 months (enalapril 47.9/24.8 vs placebo 53.8/29.6 ml/m2; p < 0.05). EF was also significantly higher 1 month after MI in these patients (enalapril 50.4% vs placebo 46.4%; p < 0.05). Our date demonstrate that early enalapril treatment attenuates LV volume expansion and maintains lower LV volumes and higher EF in patients receiving concurrent beta-blockade after MI. A possible additive effect of combined therapy should be evaluated prospectively.

Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.

BACKGROUND: Elevated plasma levels of atrial natriuretic peptide (ANP) and the N-terminal fragment of the ANP prohormone (N-ANP) are associated with decreased left ventricular function and decreased long-term survival after acute myocardial infarction (AMI). Previous data suggest that plasma brain natriuretic peptide (BNP) may increase proportionally more than plasma ANP after AMI and in chronic heart failure. The diagnostic and prognostic value of plasma BNP as an indicator of left ventricular dysfunction and long-term survival after AMI, relative to that of ANP and N-ANP, remain to be established. METHODS AND RESULTS: Venous blood samples for analysis of ANP, N-ANP, and BNP were obtained on day 3 after symptom onset from 131 patients with documented AMI. Left ventricular ejection fraction was determined by echocardiography in a subsample of 79 patients. Twenty-eight cardiovascular and 3 noncardiovascular deaths occurred during the follow-up period (median, 1293 days). All three peptides proved to be powerful predictors of cardiovascular mortality by univariate Cox proportional hazards regression analyses (ANP: P < .0001; N-ANP: P = .0002; BNP: P < .0001). In a multivariate model, plasma BNP (P = .021) but not ANP (P = .638) or N-ANP (P = .782) provided additional prognostic information beyond left ventricular ejection fraction. Logistic regression analysis showed that ANP (P = .003) and N-ANP (P = .027) but not BNP (P = .14) were significantly associated with a left ventricular ejection fraction < or = 45%. CONCLUSIONS: These results suggest that plasma BNP determination provides important, independent prognostic information after AMI. Although plasma ANP appears to be a better predictor of left ventricular dysfunction, plasma BNP may have greater potential to complement standard prognostic indicators used in risk stratification after AMI because of its strong, independent association with long-term survival, enhanced in vitro stability, and simplicity of analysis.

Cardiac troponin T immunoassay on biotin--streptavidin-coated microplates: preliminary performance in acute myocardial infarction.

We have adapted the cardiac troponin T (TnT) immunoassay system (ELISA troponin T, Boehringer Mannheim, Germany), which is based upon streptavidin-biotin immunoassay technology, to a sensitive microplate system. A coating of microplates with biotinylated bovine serum albumin (biotin-LC-BSA) remained stable for months. A secondary streptavidin coating was prepared as the first step of the assay. By using o-phenylenediamine (o-PD) as a substrate for the peroxidase-anti-TnT conjugate, the system allowed rapid kinetic measurement of TnT levels. The upper limit of a reference population (97.5th percentile) was found to be 0.04 mu g l-1. Intra-assay imprecision at 0.08 mu g l-1 was 8%, and 3-4% between 0.28 and 4 mu g l-1. Between-assay imprecision was 6.2% at 0.28 mu g l-1. Studies of TnT and CK-MB mass concentration in acute myocardial infarction patients, treated with streptokinase, demonstrated a clinical sensitivity of the TnT microplate system similar to that of the CK-MB mass concentration test, during the first 8 h after initiation of thrombolytic therapy, at discriminator levels of 0.1 mu g l-1 (TnT) and 8 mu g l-1 (CK-MB mass concentration). The early CK-MB/TnT ratio was lower in patients with signs of successful reperfusion (early peak CK-MB) than in the remaining patients (p<0.001). Serum samples from two patients with renal failure and one patient with rhabdomyolysis demonstrated strong non-linear behaviour with dilution, indicating the presence of an interfering factor. Kinetic measurement compared favourably with end-point analysis with respect to sensitivity and total analysis time. The system described greatly reduces the costs of TnT measurements compared to the ES systems. The total assay time is 70-90 min.

Left ventricular volumes, ejection fraction, and plasma proatrial natriuretic factor (1-98) after withdrawal of enalapril treatment initiated early after myocardial infarction. CONSENSUS II Multi-Echo Study Group.

OBJECTIVES: To assess whether the reduction in left ventricular dilatation after acute myocardial infarction obtained by early administration of angiotensin converting enzyme inhibitors depends on continuous treatment. DESIGN: Prospective observational and cross sectional study of withdrawal of randomised treatment with enalapril or placebo. PATIENTS: 106 patients on 6 months trial treatment after an acute myocardial infarction. MAIN OUTCOME MEASURES: Left ventricular volumes and ejection fraction as assessed by echocardiography and circulating proatrial natriuretic factor (1-98) before and 4-6 weeks after withdrawal of treatment. RESULTS: There were no significant changes (mean (SD)) in left ventricular systolic (0.7 (4.7) ml/m2) and diastolic (0.4 (6.6) ml/m2) volume indices, ejection fraction (-0.9 (6)%), and proatrial natriuretic factor (172 (992) pmol/l) after withdrawal of enalapril. The significantly lower left ventricular volumes observed with 6 months of enalapril therapy after acute myocardial infarction, as compared with placebo, were maintained 6 weeks after drug withdrawal. CONCLUSION: The results show that the benefit of 6 months of enalapril treatment initiated early after myocardial infarction is maintained for at least 6 weeks after drug withdrawal, suggesting that the treatment effect on left ventricular structure is not reversed by changes in loading conditions caused by subsequent drug withdrawal.