Eva Ringdal Pedersen

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.

Systemic Markers of Interferon-γ–Mediated Immune Activation and Long-Term Prognosis in Patients With Stable Coronary Artery Disease

Objective—Interferon &ggr; (IFN-&ggr;) is centrally involved in atherosclerosis-related inflammation, but its activity cannot be reliably assessed by systemic measurements. In activated macrophages, IFN-&ggr; stimulates production of neopterin and conversion of tryptophan to kynurenine. We evaluated the relationships of plasma neopterin and plasma kyunernine:tryptophan ratio (KTR) to long-term prognosis in patients with stable angina pectoris and angiographically verified significant coronary artery disease. Methods and Results—Samples were obtained from 2380 patients with a mean age of 63.7 years; 77.3% were men. During a median follow-up of 56 months, 10.8% of patients experienced a major coronary event (MCE), and 9.5% died. For MCE, each SD increment of neopterin and KTR (logarithmically transformed) was associated with multivariable adjusted hazard ratios and 95% CIs of 1.28 (1.10 to 1.48) and 1.28 (1.12 to 1.48), respectively. The corresponding hazard ratios (95% CIs) for all-cause mortality were 1.40 (1.21 to 1.62) (neopterin) and 1.23 (1.06 to 1.43) (KTR). Conclusion—In patients with stable angina pectoris, systemic markers of IFN-&ggr; activity, plasma neopterin, and plasma KTR provide similar risk estimates for MCE and mortality. Our results support experimental data linking IFN-&ggr; to acute atherosclerotic complications.

Plasma Dimethylglycine and Risk of Incident Acute Myocardial Infarction in Patients With Stable Angina Pectoris

Objective—Dimethylglycine is linked to lipid metabolism, and increased plasma levels may be associated with adverse prognosis in patients with coronary artery disease. We evaluated the relationship between plasma dimethylglycine and risk of incident acute myocardial infarction in a large prospective cohort of patients with stable angina pectoris, of whom approximately two thirds were participants in a B-vitamin intervention trial. Model discrimination and reclassification when adding plasma dimethylglycine to established risk factors were obtained. We also explored temporal changes and the test–retest reliability of plasma dimethylglycine. Approach and Results—Four thousand one hundred fifty patients (72% men; median age 62 years) were included. Plasma dimethylglycine was associated with several traditional coronary artery disease risk factors. During a median follow-up of 4.6 years, 343 (8.3%) patients experienced an acute myocardial infarction. The hazard ratio (95% confidence interval) for acute myocardial infarction was 1.95 (1.42–2.68; P<0.001) when comparing plasma dimethylglycine quartile 4 to 1 in a Cox regression model adjusted for age, sex, and fasting status. Adjusting for traditional coronary artery disease risk factors only slightly modified the estimates, which were particularly strong among nonsmokers and among patients with serum triglyceride or apolipoprotein B100 levels ⩽median (P for interaction=0.004, 0.004, and 0.03, respectively). Plasma dimethylglycine improved discrimination and reclassification and had high test–retest reliability. Conclusions—Plasma dimethylglycine is independently related to incident acute myocardial infarction and enhances risk prediction in patients with stable angina pectoris. Our results motivate further studies on the relationship between 1-carbon metabolism and atherothrombosis. A potential interplay with lipid and energy metabolism merits particular attention.

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.

Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol.

Abstract Aims The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts. Methods and results Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine—Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24–8.98), 1.64 (1.29–2.08), and 1.77 (1.41–2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02). Conclusions Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions.

Neopterin and kynurenine-tryptophan ratio as predictors of coronary events in older adults, the Hordaland Health Study.

BACKGROUND Immune system activation is involved in atherosclerosis. Neopterin production and tryptophan catabolism through the kynurenine pathway, measured by the kynurenine-tryptophan ratio (KTR), are induced by interferon gamma, thus both are considered markers of cell mediated immune activation. This study prospectively investigated their predictive value on acute coronary events among Norwegian community-dwelling older adults without previous coronary heart disease. METHODS 1112 men and 1631 women, 71-74 years old were examined during 1997-99 as part of the Hordaland Health Study. They were followed until an acute coronary event (defined as unstable angina, non-fatal or fatal acute myocardial infarction or sudden death) or December 31, 2006. Kaplan-Meier hazard curves were constructed for quartiles of plasma neopterin and KTR. Cox proportional hazards models adjusted for sex, body mass index, smoking, hypertension, renal function and cholesterol were used to examine the relation between neopterin and KTR quartiles and the study endpoint. RESULTS Median (interquartile range) values were 8.6 (7.2-10.4) nmol/L for neopterin and 25.8 (25.3-31.1) nmol/μmol for KTR. During the follow up, 265 participants had at least one acute coronary event. Increased baseline levels of plasma neopterin and KTR were associated with continuous increased risk of developing the study endpoint (P-values for trend <0.001 and 0.019, respectively). Adjusted hazard ratios comparing the fourth quartile to the first were 1.65 (95% CI; 1.11-2.47; P=0.013) for neopterin and 1.57 (95% CI 1.03-2.39; P=0.036) for KTR. CONCLUSION Plasma neopterin and KTR levels predict acute coronary events in older adults without previous coronary heart disease.

Associations of Plasma Kynurenines With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris

Objective—Enhanced tryptophan degradation, induced by the proinflammatory cytokine interferon-&ggr;, has been related to cardiovascular disease progression and insulin resistance. We assessed downstream tryptophan metabolites of the kynurenine pathway as predictors of acute myocardial infarction in patients with suspected stable angina pectoris. Furthermore, we evaluated potential effect modifications according to diagnoses of pre-diabetes mellitus or diabetes mellitus. Approach and Results—Blood samples were obtained from 4122 patients (median age, 62 years; 72% men) who underwent elective coronary angiography. During median follow-up of 56 months, 8.3% had acute myocardial infarction. Comparing the highest quartile to the lowest, for the total cohort, multivariable adjusted hazard ratios (95% confidence intervals) were 1.68 (1.21–2.34), 1.81 (1.33–2.48), 1.68 (1.21–2.32), and 1.48 (1.10–1.99) for kynurenic acid, hydroxykynurenine, anthranilic acid, and hydroxyanthranilic acid, respectively. The kynurenines correlated with phenotypes of the metabolic syndrome, and risk associations were generally stronger in subgroups classified with pre-diabetes mellitus or diabetes mellitus at inclusion (Pint⩽0.05). Evaluated in the total population, hydroxykynurenine and anthranilic acid provided statistically significant net reclassification improvements (0.21 [0.08–0.35] and 0.21 [0.07–0.35], respectively). Conclusions—In patients with suspected stable angina pectoris, elevated levels of plasma kynurenines predicted increased risk of acute myocardial infarction, and risk estimates were generally stronger in subgroups with evidence of impaired glucose homeostasis. Future studies should aim to clarify roles of the kynurenine pathway in atherosclerosis and glucose metabolism.

Urinary excretion of kynurenine and tryptophan, cardiovascular events, and mortality after elective coronary angiography

AIMS Kynurenine is a potent endothelium-derived vasodilator. Its synthesis from tryptophan is stimulated by interferon γ and may represent an important compensatory pathway for the regulation of vascular function in inflammatory conditions. We assessed associations of urine kynurenine to tryptophan ratio (KTR) levels to incident major coronary events (MCEs), acute myocardial infarction (AMI), and ischaemic stroke and mortality in patients with suspected stable coronary artery disease (CAD). METHODS AND RESULTS A total of 3224 patients (mean age 62 years, 69% men) underwent urine and blood sampling prior to elective coronary angiography and were subsequently followed up for median 55 months. A total of 8.4% experienced an MCE, 7.8% suffered an AMI, and 7.6% died. In age- and gender-adjusted analyses, the hazard ratios [HRs; 95% confidence intervals (CI)] of MCE, AMI, and all-cause mortality were 1.43 (1.29-1.59), 1.44 (1.29-1.59), and 1.38 (1.23-1.54) per standard deviation increment of the (log-transformed) urinary KTR, respectively. These estimates were only minimally attenuated after adjustment for potential confounders. The addition of the urine KTR to a model of conventional risk factors significantly improved goodness of fit, discrimination, and risk classification for these clinical endpoints. No association was seen between the urine KTR and the risk of incident ischaemic stroke. CONCLUSION A novel urinary inflammation marker, KTR, is strongly associated with adverse prognosis in patients with suspected stable CAD. Underlying pathomechanisms should be further elucidated.

Serum osteoprotegerin levels and long-term prognosis in patients with stable angina pectoris

OBJECTIVES Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily with pleiotropic effects on bone metabolism, endocrine function and the immune system. Circulating OPG levels are elevated in cardiovascular disease (CVD). We assessed serum OPG as predictor of long-term prognosis in patients with suspected stable angina pectoris (SAP) undergoing elective coronary angiography. METHODS Samples were obtained from 1025 patients (median [25th, 75th percentile] age 62 [54, 70] years, 71.9% men). At inclusion, 43.2% of patients had single or double vessel disease, whereas 34.3% had triple vessel disease. RESULTS During a median follow-up of 73 months, 11.0% of patients died, 5.9% died from CVD and 10.0% experienced an acute myocardial infarction (MI). In univariable analyses, strong associations were observed between OPG concentrations and all-cause mortality, CVD mortality and the incidence of MI (fatal or nonfatal). However, adjustment for conventional risk factors attenuated the risk estimates which were no longer significant, except for the subgroup with levels above the 90th percentile. For decile 10 versus deciles 1-9 of serum OPG, the following multivariable hazard ratios (95% confidence intervals) were observed: All-cause mortality: 1.94 (1.18, 3.18), p=0.01; CVD mortality: 2.29 (1.16, 4.49), p=0.02; and MI: 1.76 (1.02, 3.06), p=0.04. CONCLUSION In patients with SAP, elevated serum OPG is associated with increased risk of all-cause mortality, CVD mortality and MI, but independent effects are mainly confined to levels above the 90th percentile.

Dietary intake of n–3 long-chain polyunsaturated fatty acids and coronary events in Norwegian patients with coronary artery disease

BACKGROUND Consumption of fish and n-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) has been associated with reduced risk of coronary artery disease (CAD) mortality. OBJECTIVE The aim was to examine the relation between dietary intake of n-3 LCPUFAs or fish and risk of future coronary events or mortality in patients with well-characterized CAD. DESIGN This was a substudy of 2412 participants in the Western Norway B Vitamin Intervention Trial with a median follow-up time of 57 mo. Patients aged >18 y diagnosed with CAD (81% men) completed a food-frequency questionnaire at baseline, from which daily intakes of eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids as well as fish were estimated on the basis of diet and intakes of supplements including fish and cod liver oils. The main endpoint was a composite of coronary events, including coronary death, nonfatal acute myocardial infarction, and unstable angina pectoris. RESULTS The mean (+/-SD) intakes of n-3 LCPUFAs in quartiles 1-4 were 0.58 +/- 0.29, 0.83 +/- 0.30, 1.36 +/- 0.44, and 2.64 +/- 1.18 g/d, respectively. We found no dose-response relation between quartiles of n-3 LCPUFAs (based on intake as percentage of total energy) or fish and coronary events or separate endpoints. A post hoc additive proportional hazards model showed a slightly increased risk of coronary events at an intake of n-3 LCPUFAs < approximately 0.30 g/d. CONCLUSION Among Norwegian patients with CAD consuming relatively high amounts of n-3 LCPUFAs and fish, there were no significant trends toward a reduced risk of coronary events or mortality with increasing intakes. This trial was registered at clinicaltrials.gov as NCT00354081.