Jannicke Igland

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 folate, related genetic variants and colorectal cancer risk in EPIC

Background: A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. We investigate the associations between plasma folate, several relevant folate-related polymorphisms, and CRC risk within the large European Prospective Investigation into Cancer and Nutrition cohort. Methods: In this nested case-control study, 1,367 incident CRC cases were matched to 2,325 controls for study center, age, and sex. Risk ratios (RR) were estimated with conditional logistic regression and adjusted for smoking, education, physical activity, and intake of alcohol and fiber. Results: Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% confidence interval; Ptrend) for the fifth versus the first quintile of folate status was 0.94 (0.74-1.20; 0.44). The polymorphisms MTHFR677C→T, MTHFR1298A→C, MTR2756A→G, MTRR66A→G, and MTHFD11958G→A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically nonsignificant increased CRC risk [RR (95% CI; Ptrend) TT versus CC = 1.39 (0.87-2.21); 0.12], whereas those with the highest folate concentrations showed a nonsignificant decreased CRC risk [RR TT versus CC = 0.74 (0.39-1.37); 0.34]. The SLC19A180G→A showed a positive association with CRC risk [RR AA versus GG 1.30 (1.06-1.59); <0.01]. Conclusions: This large European prospective multicenter study did not show an association of CRC risk with plasma folate status nor with MTHFR polymorphisms. Impact: Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions. Cancer Epidemiol Biomarkers Prev; 19(5); 1328–40. ©2010 AACR.

The association of gastric cancer risk with plasma folate, cobalamin, and Methylenetetrahydrofolate reductase polymorphisms in the European prospective investigation into cancer and nutrition

Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n = 247) and controls (n = 631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P = 0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 C→T MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 A→C polymorphism (odds ratio, 1.47 for CC versus AA; P = 0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2416–24)

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.

Seasonality of cardiovascular risk factors: an analysis including over 230 000 participants in 15 countries

Objective To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies. Methods Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed. Results In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m2 for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol. Conclusions CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.

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.

Short-term and long-term case fatality in 11 878 patients hospitalized with a first acute myocardial infarction, 1979-2001: the Western Norway cardiovascular registry

Background Few studies have direct estimates of long-term survival after acute myocardial infarction (AMI). Our objective was to provide such estimates, and trends in these estimates, using data from a single hospital over a 23-year period. Design A retrospective cohort study. Methods We examined 28-day, 1-year and 10-year case fatality among 7635 men and 4243 women admitted to Haukeland University Hospital with a first AMI, during 1979-2001. Information on cardiovascular diagnoses and procedures were registered in the Western Norway Cardiovascular Registry, and data on deaths were obtained from the Cause of Death Registry, Statistics Norway. Results From 1979-1985 to 1994-2001, crude 28-day case fatality declined from 31.1 to 19.8% in men and from 37.3 to 26.8% in women (both, P-trend < 0.0001). Crude 10-year case fatality declined from 69.5-55.5% in men and from 80.8-66.1% in women (both, P-trend < 0.0001). Landmark analysis showed a decline in 1-10-year case fatality, among patients less than 60 years of age from 26.1 to 13.8% in men, and from 33.3 to 6.4% in women. In patients ≥ 60 years, the 28-day, 1-year and 10-year age-adjusted case-fatality rates were significantly lower in women than men. Conclusion Landmark analysis showed substantial improvement in up to 10 years survival after hospitalization for a first AM I. A significantly lower age-adjusted case fatality in women ≥ 60 years already after 28 days compared with men is specifically noticed.

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.