Dennis W.T. Nilsen

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.

Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.

CONTEXT Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B(12) can lower plasma total homocysteine levels. OBJECTIVE To assess the effect of treatment with folic acid and vitamin B(12) and the effect of treatment with vitamin B(6) as secondary prevention in patients with coronary artery disease or aortic valve stenosis. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes. INTERVENTIONS Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B(12), 0.4 mg, plus vitamin B(6), 40 mg (n = 772); folic acid plus vitamin B(12) (n = 772); vitamin B(6) alone (n = 772); or placebo (n = 780). MAIN OUTCOME MEASURES The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. RESULTS Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B(12). The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B(12) vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B(6) vs 222 (14.3%) not receiving vitamin B(6) (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28). CONCLUSIONS This trial did not find an effect of treatment with folic acid/vitamin B(12) or vitamin B(6) on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00354081.

Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12

CONTEXT Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. OBJECTIVE To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. DESIGN, SETTING, AND PARTICIPANTS Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. INTERVENTIONS Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721). MAIN OUTCOME MEASURES Cancer incidence, cancer mortality, and all-cause mortality. RESULTS During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B(12) vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12). Vitamin B(6) treatment was not associated with any significant effects. CONCLUSION Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00671346.

Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease

BACKGROUND Limited data are available on the long-term effects of contemporary drug-eluting stents versus contemporary bare-metal stents on rates of death, myocardial infarction, repeat revascularization, and stent thrombosis and on quality of life. METHODS We randomly assigned 9013 patients who had stable or unstable coronary artery disease to undergo percutaneous coronary intervention (PCI) with the implantation of either contemporary drug-eluting stents or bare-metal stents. In the group receiving drug-eluting stents, 96% of the patients received either everolimus- or zotarolimus-eluting stents. The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularization, stent thrombosis, and quality of life. RESULTS At 6 years, the rates of the primary outcome were 16.6% in the group receiving drug-eluting stents and 17.1% in the group receiving bare-metal stents (hazard ratio, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.66). There were no significant between-group differences in the components of the primary outcome. The 6-year rates of any repeat revascularization were 16.5% in the group receiving drug-eluting stents and 19.8% in the group receiving bare-metal stents (hazard ratio, 0.76; 95% CI, 0.69 to 0.85; P<0.001); the rates of definite stent thrombosis were 0.8% and 1.2%, respectively (P=0.0498). Quality-of-life measures did not differ significantly between the two groups. CONCLUSIONS In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents. (Funded by the Norwegian Research Council and others; NORSTENT ClinicalTrials.gov number, NCT00811772 .).

Reduction in Homocysteine by n-3 Polyunsaturated Fatty Acids after 1 Year in a Randomised Double-Blind Study following an Acute Myocardial Infarction: No Effect on Endothelial Adhesion Properties

We hypothesized that n–3 polyunsaturated fatty acids (n–3 PUFAs) as compared to corn oil administered for 1 year following an acute myocardial infarction (MI) may reduce plasma total homocysteine (p-tHcy), ultrasensitive C-reactive protein (µCRP), and the adhesive properties of the endothelium, expressed as soluble E-selectin (sE-selectin) and soluble intercellular adhesion molecule-1 (sICAM-1). In a prospective, randomised, double-blind study, 300 acute MI patients were allocated to highly concentrated n–3 PUFAs (n = 150) or corn oil (n = 150). After 1 year on treatment there was an intergroup difference in p-tHcy in favour of the n–3 group (n = 118), p = 0.022. However, sE-selectin, sICAM-1 and µCRP were unaffected by the treatment. In conclusion, reduction of p-tHcy by long-term n–3 PUFAs treatment was not associated with demonstrable effects on markers of endothelial adhesion properties.

Attenuation of left ventricular dilatation after acute myocardial infarction by early initiation of Enalapril therapy

This trial investigated the effect of enalapril, administered early, on left ventricular (LV) volumes after myocardial infarction. Four hundred twenty-eight patients included in the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II) were examined with echocardiography within 5 days, at 1 month and at 6 months after myocardial infarction. Enalaprilat (1 mg) or placebo infusion was initiated within 24 hours after infarction, followed by oral treatment to a target dose of 20 mg/day. A significant attenuation of LV dilatation was noted at 1 month in patients treated with enalapril compared with those receiving placebo. Changes in LV end-diastolic volume indexes during the first month were (mean +/- SEM) 5.7 +/- 1.0 ml/m2 for the placebo group and 1.9 +/- 0.8 ml/m2 for the enalapril group (p < 0.02). Changes in LV end-systolic volume indexes were 3.1 +/- 0.8 and 0.5 +/- 0.6 ml/m2, respectively (p < 0.02). The between-group difference was most marked in patients with anterior wall infarction (p < 0.005). Volume changes beyond the first month were similar in both groups but the differences observed at 1 month were maintained. The larger volumes in the placebo versus enalapril group were significant or borderline significant at 1 and 6 months. Thus, enalapril treatment initiated early after myocardial infarction and continued for 6 months can attenuate LV dilatation during the first month resulting in smaller LV volumes after 1 and 6 months.

Improvement of serum lipids and blood pressure during intervention with n‐3 fatty acids was not associated with changes in insulin levels in subjects with combined hyperlipidaemia

Abstract. Objectives. To investigate the effect of an omega‐3 fatty acid concentrate K85 on serum lipids, lipoproteins, insulin metabolism and blood pressure in subjects with combined hyperlipidaemia.

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

Abstract.  Ebbing M., Bønaa K.H., Arnesen E., Ueland P.M., Nordrehaug J.E., Rasmussen K., Njølstad I., Nilsen D.W., Refsum H., Tverdal A., Vollset S.E., Schirmer H., Bleie Ø., Steigen T., Midttun Ø., Fredriksen Å., Pedersen E.R., Nygård O. (From the Departments of 1Heart Disease, Haukeland University Hospital, Bergen; Heart Disease, University Hospital of North Norway; Department of Community Medicine, University of Tromsø, Tromsø; Institute of Medicine, University of Bergen, Bergen; Department of Clinical Medicine, University of Tromsø, Tromsø; Department of Cardiology, Stavanger University Hospital, Stavanger; Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK; Division of Epidemiology, the Norwegian Institute of Public Health, Oslo; Department of Public Health and Primary Health Care, University of Bergen; Bevital AS, Bergen; Norway) Combined Analyses and Extended Follow‐Up of Two Randomized Controlled Homocysteine‐Lowering B‐Vitamin Trials. J Intern Med 2010; 268: 367–382.

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.

Low levels of cellular omega-3 increase the risk of ventricular fibrillation during the acute ischaemic phase of a myocardial infarction

AIM OF THE STUDY Animal studies have demonstrated evidence of an anti-arrhythmic effect of marine n-3 fatty acids (FAs). In humans the same mechanism may explain the observed reduction in sudden cardiac death (SCD) associated with intake of fish. Whether high levels of n-3 FAs could protect against ventricular fibrillation (VF) during the acute ischaemic phase of a myocardial infarction (MI) is, however, not known. MATERIALS AND METHODS We measured red blood cell content of eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA) expressed as a percentage of total FAs (the omega-3 index) at admission in 460 patients hospitalised with an acute coronary syndrome. Out of 265 patients suffering their first MI, 10 (cases) experienced an episode of VF during the initial 6h of symptom onset. The omega-3 index of these patients was compared to that of 185 first-MI patients (controls) free of VF for at least 30 days post-admission. RESULTS The median value of the omega-3 index in the VF cases was 4.88% as compared to 6.08% in the controls (p=0.013). After adjustment for age, sex, ejection fraction, high-sensitivity C-reactive protein, use of beta-blocker, differences of infarct characteristics and previous angina pectoris, a 1% increase of the omega-3 index was associated with a 48% reduction in risk of VF (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.28-0.96; p=0.037). CONCLUSION Our study supports an anti-arrhythmic effect of n-3 FAs through their incorporation into myocardial cell membranes, reducing the risk of VF during ischaemia.