Marta Ebbing

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.

Favourable trends in incidence of AMI in Norway during 2001–2009 do not include younger adults: a CVDNOR project

Aims Acute myocardial infarction (AMI) incidence reflects levels of risk factors in the general population and influences coronary heart disease mortality rates. We examined trends in AMI incidence in Norway during 2001–2009 and potential differences between sex and age groups. Methods All AMI hospitalizations (ICD9 410; ICD10 I21, I22) and coronary out-of-hospital deaths (ICD9 410–414; ICD10 I20–I25) in Norway for individuals ≥25 years were obtained during 1994–2009. Incident AMI was defined as a hospitalization or out-of-hospital death due to AMI with no prior hospitalization for AMI during the previous 7 years. Age-standardized and age-group specific rates were calculated and expressed per 100,000 persons. The annual changes in rates were obtained from Poisson regression analyses. The total change in incidence rates during 2001–2009 were then calculated based on the estimated annual change. Results We identified 148,522 incident AMIs (41% women; 21% out-of-hospital deaths) during 2001–2009. Incidence rates declined by 24% (incidence rate ratio, IRR, 0.76, 95% CI 0.75–0.78). Out-of-hospital death rates declined more than hospitalization rates (IRR 0.54, 95% CI 0.52–0.56 vs. IRR 0.84, 95% CI 0.82–0.85; p < 0.001). The decline in incidence rates was observed among those 45 years or older. Among persons under 45 years, AMI incidence rates did not change significantly, while hospitalization rates increased with 11%. Conclusion AMI incidence rates declined during 2001–2009. The decline was due to reductions in rates of out-of-hospital deaths and hospitalizations in individuals 45 years or older. A worrying increase in hospitalization rates was observed in those younger than 45 years.

Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy.

Total plasma homocysteine (tHcy) is an independent risk factor for coronary artery disease, and tHcy is lowered by B vitamins. To assess the effect of homocysteine-lowering B-vitamin treatment on angiographic progression of coronary artery disease, this substudy of the Western Norway B Vitamin Intervention Trial (WENBIT) included patients who had undergone percutaneous coronary intervention. The patients were randomized to daily oral treatment with folic acid, vitamin B(12), and vitamin B(6) or placebo in a 2 x 2 factorial design. The coronary angiograms obtained at baseline and follow-up were evaluated. The primary angiographic end points were the changes in minimum lumen diameter and diameter stenosis. A total of 348 subjects (288 men) with a mean +/- SD age of 60 +/- 10.2 years were followed up for a median of 10.5 months (twenty-fifth, seventy-fifth percentile 9.2, 11.8). The baseline median plasma tHcy level was 10.0 mumol/L (twenty-fifth, seventy-fifth percentile 8.1, 11.0), and treatment with folic acid/vitamin B(12) lowered the tHcy levels by 22%. At follow-up, we found 309 lesions with a significant decrease from baseline in the minimum lumen diameter of a mean of -0.16 +/- 0.4 mm and an increase in the diameter stenosis of 4.4 +/- 0.7%. Treatment with folic acid/vitamin B(12) or vitamin B(6) was not associated with a change in diameter stenosis or minimum lumen diameter. In a post hoc analysis, folic acid/vitamin B(12) treatment was significantly associated with rapid progression (odds ratio 1.84, 95% confidence interval 1.07 to 3.18). In conclusion, vitamin B treatment showed no beneficial effect on the angiographic progression of coronary artery disease, and the post hoc analyses suggested that folic acid/vitamin B(12) treatment might promote more rapid progression.

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.

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.

Elevated plasma dimethylglycine is a risk marker of mortality in patients with coronary heart disease

Aim To investigate whether plasma dimethylglycine was associated with and improved risk prediction of mortality among patients with coronary heart disease (CHD). Methods By Cox modelling, we explored the association between plasma dimethylglycine and mortality in two independent cohorts of patients with suspected stable angina pectoris (SAP) (n = 4156) and acute myocardial infarction (AMI) (n = 3733). We also assessed any improvement in risk prediction by adding plasma dimethylglycine to established CHD risk factors. Results Median follow-up time was 4.7 and 7.0 years among patients with SAP and AMI, respectively. Across both cohorts, elevated plasma dimethylglycine levels were linearly associated with increased risk of all-cause mortality (age and gender adjusted hazard ratios (95% confidence interval, CI) were 1.72 (1.21–2.46) and 1.76 (1.42–2.18) when comparing the fourth versus the first plasma dimethylglycine quartile in patients with SAP and AMI, respectively). There was a particularly strong risk association between plasma dimethylglycine and cardiovascular, as compared with non-cardiovascular, mortality (age and gender adjusted hazard ratios (95% CI) 1.94 (1.21–3.11) and 1.43 (0.83–2.47) among patients with SAP and 1.97 (1.50–2.59) and 1.44 (1.02–2.04) among patients with AMI, respectively). The relationship between dimethylglycine and all-cause and cardiovascular mortality was only slightly attenuated in analyses adjusted for established CHD risk factors. Plasma dimethylglycine also improved risk prediction for all-cause and cardiovascular mortality, and especially among patients with AMI. Conclusions Elevated plasma dimethylglycine was associated with and improved risk prediction of mortality in patients with suspected or verified CHD. This relationship was stronger for death from cardiovascular, as compared with non-cardiovascular, causes.

Trends in Acute Myocardial Infarction Event Rates and Risk of Recurrences After an Incident Event in Norway 1994 to 2009 (from a Cardiovascular Disease in Norway Project)

We explored trends in acute myocardial infarction (AMI) event rates in Norway during 1994 to 2009 and trends in the 6-month, 1-year, and 3-year risk of recurrences after an incident AMI during 2001 to 2008 in men and women ≥25 years. Trends in AMI event rates (incident and recurrent) were analyzed using joinpoint regression analyses and expressed as annual percentage change (APC) in rates. Trends in AMI recurrences were explored using conditional risk models for ordered events in Cox regression. Analyses were stratified by gender and age group. Overall, AMI rates were stable during 1994 to 2002 but declined during 2002 to 2009 (APC = -2.0; 95% confidence interval [CI] -3.1 to -0.9 in men; APC = -2.1; 95% CI -3.8 to -0.5 in women). In the younger age group, rates declined during the whole study period in men (APC = -0.6; 95% CI -1.0 to -0.3) but not in women. Among older patients, no changes were observed during 1994 to 2002, whereas rates declined during 2002 to 2009 (APC = -2.6; 95% CI -3.8 to -1.4 in men; APC = -2.4; 95% CI -4.0 to -0.7 in women). During 2001 to 2008, in the older age group, the 6-month, 1-year, and 3-year risks of recurrences were reduced annually by 4.7%, 4.3%, and 5.4% in men and 5.2%, 5.0%, and 5.7% in women (all ptrend <0.001), respectively. No changes were observed in the younger age group. In conclusion, favorable trends in AMI event rates and recurrences observed in Norway were mostly seen among patients aged 65+ years, whereas less favorable trends were observed among younger patients, especially among women.

Trends in 28-day and 1-year mortality rates in patients hospitalized for a first acute myocardial infarction in Norway during 2001–2009: a “Cardiovascular disease in Norway” (CVDNOR) project

The aim of this study was to investigate the trends in 28‐day and 1‐year mortality rates in patients hospitalized for a first acute myocardial infarction (AMI) in Norway during the period 2001–2009. Potential age group and gender differences in these trends were also examined.

Educational Inequalities in Acute Myocardial Infarction Incidence in Norway: A Nationwide Cohort Study

Background Increasing differences in cardiovascular disease (CVD) mortality across levels of education have been reported in Norway. The aim of the study was to investigate educational inequalities in acute myocardial infarction (AMI) incidence and whether such inequalities have changed during the past decade using a nationwide longitudinal study design. Methods Data on 141 332 incident (first) AMIs in Norway during 2001–2009 were obtained through the Cardiovascular Disease in Norway (CVDNOR) project. Educational inequalities in AMI incidence were assessed in terms of age-standardised incidence rates stratified on educational level, incidence rate ratios (IRR), relative index of inequality (RII) and slope index of inequality (SII). All calculations were conducted in four gender and age strata: Men and women aged 35–69 and 70–94 years. Results AMI Incidence rates decreased during 2001–2009 for all educational levels except in women aged 35–69 among whom only those with basic education had a significant decrease. In all gender and age groups; those with the highest educational level had the lowest rates. The strongest relative difference was found among women aged 35–69, with IRR (95% CI) for basic versus tertiary education 3.04 (2.85–3.24)) and RII (95% CI) equal to 4.36 (4.03–4.71). The relative differences did not change during 2001–2009 in any of the four gender and age groups, but absolute inequalities measured as SII decreased among the oldest men and women. Conclusions There are substantial educational inequalities in AMI incidence in Norway, especially for women aged 35–69. Relative inequalities did not change from 2001 to 2009.