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.

Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen. A molecular basis for induction of antibodies to DNA and eukaryotic transcription factors.

We have previously demonstrated that experimental expression of the polyomavirus transcription factor T-antigen has the potential to induce anti-DNA antibodies in mice. Two sets of independent evidences are presented here that demonstrate a biological relevance for this model. First, we describe results demonstrating that mice inoculated with T-antigen-expressing plasmids produced antibodies, not only to T-antigen and DNA, but also to the DNA-binding eukaryotic transcription factors TATA-binding protein (TBP), and to the cAMP-response-element-binding protein (CREB). Secondly, we investigated whether polyomavirus reactivation occurs in SLE patients, and whether antibodies to T-antigen, DNA, and to TBP and CREB are linked to such events. Both within and among these SLE patients, frequent polyomavirus reactivations were observed that could not be explained by certain rearrangements of the noncoding control regions, nor by corticosteroid treatment. Linked to these events, antibodies to T-antigen, DNA, TBP, and CREB were detected, identical to what we observed in mice. Antibodies recognizing double-stranded DNA were confined to patients with frequent polyomavirus reactivations. The results described here indicate that cognate interaction of B cells recognizing DNA or DNA-associated proteins and T cells recognizing T antigen had taken place as a consequence of complex formation between T ag and DNA in vivo in the context of polyomavirus reactivations.

Preinfarction blood pressure and smoking are determinants for a fatal outcome of myocardial infarction: a prospective analysis from the Finnmark Study.

BACKGROUND: Serum cholesterol levels, blood pressure, and smoking are the classic coronary risk factors, but what determines whether a myocardial infarction will be fatal or not? OBJECTIVE: To investigate cardiovascular risk factors that may influence survival in subjects with coronary heart disease (myocardial infarction and sudden death). SUBJECTS AND METHODS: All inhabitants aged 35 to 52 years in Finnmark County, Norway, were invited to a cardiovascular survey in 1974-1975 and/or 1977-1978. Attendance rate was 90.5%. A total of 6995 men and 6320 women were followed up for 14 years with regard to incident myocardial infarction and sudden death. Predictors for 28-day case fatality rate after first myocardial infarction were analyzed. RESULTS: During 186 643 person-years, 635 events among men and 125 events among women were registered. The case fatality rate was 31.6% in men and 28.0% in women (P =.50). Among men (women) with baseline systolic blood pressure lower than 140 mm Hg, the 28-day case fatality rate was 24.5% (22.6%), among those with systolic blood pressure of 140 through 159 mm Hg, the case fatality rate was 35.6% (28.2%), and among those with systolic blood pressure of 160 mm Hg or higher, the case fatality rate was 48.2% (41.7%). Of the 760 subjects with myocardial infarction, 348 died during follow-up. In Cox regression analysis, systolic blood pressure at baseline was strongly related to death (relative risk per 15 mm Hg, 1.22; 95% confidence interval, 1.13-1.31). Daily smoking at baseline (relative risk, 1.40; 95% confidence interval, 1.07-1.85) and age at time of event (relative risk per 5 years, 1.12; 95% confidence interval, 1.01-1.24) were additional significant risk factors, while total serum and high-density lipoprotein cholesterol levels were unrelated to survival. Similar results were obtained with diastolic blood pressure in the model. CONCLUSIONS: Preinfarction blood pressure was an important predictor of case fatality rate in myocardial infarction. Daily smoking and age were additional significant predictors.

Impact of body weight on blood pressure with a focus on sex differences: the Tromso Study, 1986-1995.

BACKGROUND: The prevalence of obesity and hypertension is increasing in Western societies. We examined the effects of initial body mass index ([BMI] weight in kilograms divided by height in meters squared) and change in BMI on change in blood pressure, and we assessed sex differences. METHODS: A general population in the municipality of Tromso, northern Norway, was examined in 1986 and 1987 and again in 1994 and 1995. Altogether, 75% of the individuals, women aged 20 to 56 years and men aged 20 to 61 years, attended the baseline examination. A total of 15,624 individuals (87% of all still living in the municipality) were examined twice. RESULTS: Mean BMI increased between the examinations, more for the younger than the older examinees, and also more among women than men (P<.001). Adjusted for several covariates, BMI change was associated with systolic and diastolic blood pressure change for both sexes (regression coefficients: 1.43 [95% confidence interval (CI), 1.23-1. 64] and 0.90 [95% CI, 0.76-1.04], respectively, for men; and 1.24 [95% CI, 1.09-1.39] and 0.74 [95% CI, 0.63-0.84] for women). Baseline BMI was associated with systolic and diastolic blood pressure change for women only (regression coefficients: 0.38 [95% CI, 0.30-0.47] and 0.17 [95% CI, 0.11-0.23], respectively). CONCLUSIONS: For women, both BMI at baseline and BMI change were independently associated with blood pressure change. For a given increase in BMI, obese women had a greater increase in blood pressure than lean women. This was not the case for men, for whom BMI change was the only significant predictor. Furthermore, a BMI increase for obese women induced a greater systolic blood pressure increase compared with men.

Donor-specific cellular and humoral immunity after clinical kidney transplantation.

The cellular and humoral immune response against donor lymphocytes was studied in 10 patients transplanted with kidneys from living related donors. Nine of the grafts were functioning well at the time of the study. No direct (T) cell-mediated cytotoxicity against donor cells was demonstrated. Specific anti-donor antibodies were found in two recipients with well accepted grafts. Their antisera were active in antibody-induced cell-mediated cytotoxicity (AICC) and inhibited the mixed lymphocyte culture (MLC), but were negative in complement-dependent cytoxicity (CDC). Thus, no single immunological factor responsible for a favorable clinical course could be demonstrated. Neither complete T nor complete B cell tolerance against donor cells had developed, and a well tolerated graft could co-exist with antibodies directed against donor cells.

Cell-mediated lymphocytotoxicity directed against HLA-D gene products.

Cytotoxic effector cells were generated in human mixed lymphocyte cultures (MLCs) between cell donors differing at the HLA-D/DR region but not at HLA-A,B(C). These cells killed Epstein-Barr virus-infected lymphoblasts (EBV blasts) from donors sharing the HLA-D/DR determinants with the normal MLC-stimulating cells, but not phytohaemagglutinin (PHA) lymphoblasts from the same donors. Because EBV blasts are derived from B cells and express HLA-D/DR antigens, the most likely interpretation of these findings is that the HLA-D/DR antigens may, by themselves, act as targets for cell-mediated cytotoxicity.

Serum total homocysteine and coronary heart disease.

BACKGROUND: Several studies have observed high plasma levels of homocysteine among patients with coronary heart disease (CHD). The only prospective study was based on US physicians, and concluded that homocysteine was associated with subsequent myocardial infarction (MI). However, the association was limited to those above a threshold level of homocysteine. METHODS: We conducted a nested case-control study among the 21,826 subjects, aged 12-61 years, who were surveyed in the municipality of Tromsø, Norway. Among those free from MI at the screening, 123 later developed CHD. Four controls were selected for each case. RESULTS: Level of homocysteine was higher in cases than in controls (12.7 +/- 4.7 versus 11.3 +/- 3.7 mumol/l (mean +/- SD); P = 0.002). The relative risk for a 4 mumol/l increase in serum homocysteine was 1.41 (95% confidence interval (CI): 1.16-1.71). Adjusting for possible confounders reduced the relative risk to 1.32 (95% CI: 1.05-1.65). There was no threshold level above which serum homocysteine is associated with CHD events. CONCLUSIONS: In the general population serum total homocysteine is an independent risk factor for CHD with no threshold level.

The Tromsø heart study: coronary risk factors and their association with living conditions during childhood.

We examined the relation between questionnaire answers concerning living conditions during childhood and coronary risk factors in 7405 men and 7247 women. Poverty during childhood was positively associated with age-adjusted levels (p less than 0.05) of total cholesterol and percentage of current smokers (men only) and negatively associated with body height. When cholesterol was adjusted for age, body mass index, leisure time physical activity, coffee and alcohol consumption, and cigarette smoking there was a significant linear trend in women (p less than or equal to 0.0001) but not in men (p = 0.224). Analysing only subjects born in Troms county, giving a more homogeneous population, the linear trend became significant (p = 0.011) for men also. We conclude that childhood poverty followed by a high standard of living operates, at least partly, as a risk factor for coronary heart disease through conventional risk factors.

Distribution of high-density lipoprotein cholesterol according to age, sex, and ethnic origin: cardiovascular disease study in Finnmark 1977.

As a part of a survey for cardiovascular risk factors high-density lipoprotein cholesterol (HDL-C) was determined in 15 942 men and women aged 20-53. Women had on average 0.24 mmol/l higher HDL-C concentration than men. The difference was of the same magnitude at all ages. For both sexes HDL-C increased with age. The increase was partly influenced by other variables affecting the HDL-C concentration. After adjusting for the effect of height, weight, cigarette-smoking, physical activity in leisure time, and ethnic origin the age-related change was more pronounced, 0.13 mmol/l and 0.16 mmol/l difference between the youngest and the oldest age group for men and women respectively. The population comprised three ethnic groups. HDL-C did not differ among the women of different ethnic origin, but among men those of Lappish origin had higher HDL-C concentrations than the other groups. This difference was reduced after adjusting for other variables and was probably due more to external factors influencing the HDL-C concentration than specific ethnic-genetic traits.

Pattern of childbearing and mortality in married women--a national prospective study from Norway.

STUDY OBJECTIVE: The aim of the study was to investigate the effect of different pattern of childbearing on total mortality. DESIGN: A cohort study with all currently married women aged 25 years or more at the Norwegian census in 1970 with follow up to the end of 1985. Information on childbearing was obtained by questionnaires collected by enumerators. Follow up on death was found by a linkage based on the unique Norwegian identification number, between census information and the death register in the Central Bureau of Statistics. SETTING: The study was a national population survey. PARTICIPANTS: A total of 822,593 women with 11.5 million years of follow up and 112,023 deaths. MAIN RESULTS: Nulliparous women had higher mortality than parous women in all age groups. Parity showed a weak association with increasing mortality among high parous women. Lowest mortality was found for parous women with 2-4 children and a late first and last birth, adjusted for socioeconomic group by level of women's education. CONCLUSION: The findings indicate that postponed childbearing may benefit the health of women.

Serum lipids and glucose concentrations in subjects using antihypertensive drugs: Finnmark 1977.

As a side project to a study of coronary risk factors 4878 men and women aged 20-53 were interviewed about present and previous use of antihypertensive drugs. Serum lipid and glucose concentrations were compared in 124 present users, 73 previous users, and 124 controls matched for age, sex, and systolic and diastolic blood pressure. Users of betablockers, thiazides, and other antihypertensive drugs had higher total cholesterol, triglycerides, and glucose and lower HDL-cholesterol than the other groups, but only the difference in HDL-cholesterol was statistically significant. Smokers had statistically significant lower HDL-cholesterol than non-smokers in drug users, whereas there were only minor differences between them in previous and never users. This indicates an interaction between smoking and current antihypertensive medication. The unfavourable serum lipid pattern may, if caused by drug use, explain the lack of influence that antihypertensive treatment has had on the incidence of coronary heart disease in intervention studies.

Total mortality is increased in rheumatoid arthritis. A 17-year prospective study.

The purpose of this study was to determine the total and cause-specific mortality in rheumatoid arthritis (RA) patients compared to a control population in northern Norway. One hundred and eighty-seven patients with RA and 930 population controls matched for age, gender and municipality were followed until death or for a maximum of 17 years. The total mortality in RA patients was twice that of their controls (MRR = 2.0, 95% CI = 1.6-2.5). Patients possessing serum rheumatoid factors did not have a higher relative mortality than the seronegative patients. There was no statistically significant increased mortality from cancer or cardiovascular diseases. Indications for a higher death rate in RA patients than in controls were found for infection and sudden death.

Influence of blood transfusions on kidney transplant and uremic patient survival.

The influence of blood transfusions on kidney graft survival in 167 first cadaveric transplants and 85 first living related transplants is presented. Blood transfusions had no effect upon kidney graft survival in the patients transplanted with kidneys from living related donors. A significantly better graft survival was observed in the transfused group of patients transplanted with cadaveric kidneys. This beneficial effect was most pronounced in men. When patient survival was analyzed, however, a possible beneficial effect of blood transfusions was almost nulled out when patients dying while waiting for a transplant were included. The majority of these latter patients had been transfused and many had formed HLA antibodies.

Haemoglobin predicts total mortality in a general young and middle-aged male population. The Tromsø Study.

OBJECTIVE: The prognostic value of haemoglobin within normal references is seldom emphasized. The relationship between haemoglobin and mortality has been questioned because of the possible confounding of other risk factors. We investigated whether there was a curve linear relationship between haemoglobin and total mortality, and evaluated the possible modifying effects of smoking, body mass index, total cholesterol and systolic blood pressure. MATERIALS AND METHODS: In all, 6541 men aged between 20 and 49 years were examined in 1974 in a prospective, population-based study from the municipality of Tromsø, Northern Norway. During 20 years of follow-up (127 120 person-years), 495 deaths were identified. RESULTS: We found a U-shaped relationship between quintiles of haemoglobin and total mortality. Among the 35-49 years group, the multiple adjusted hazard ratios (95% CI) were 1.83 (1.31-2.57) in quintile 1 and 1.72 (1.23-2.41) in quintile 5, compared to quintile 3 of haemoglobin. Compared to the age-adjusted hazard ratios, the multiple adjustments tended to non-significantly enhance the association in the lowest quintiles and non-significantly attenuate the association in the highest quintiles. The relationship was most pronounced in smokers in a dose-response manner, but also present in non-smokers. CONCLUSIONS: High and low haemoglobin levels have an independent prognostic effect on mortality, although a possible effect of residual confounding cannot be ruled out. Smokers in quintile 1 and quintile 5 of haemoglobin were at increased risk of dying.

Further characterization of human suppressor cells generated in mixed lymphocyte cultures.

Suppressor cells can be generated in mixed lymphocyte cultures (MLC). The studies reported here show that the cells responsible for suppression belong to relatively radioresistant T cells. Furthermore, to generate suppressor cells in MLC, the cells must be able to proliferate, while this is not necessary for expression of the suppressive capacity.

Influence of pretransplant transfusions on kidney graft survival.

A study was made to elucidate the influence of transfusions on graft survival in 42 transplanted patients. In this series of multitransfused patients the number of units given was without significance, whereas transfusions given before onset of renal disease deteriorated graft prognosis. Possible explanations are discussed and a restrictive transfusion policy is advocated for patients, for instance with malformation of the urinary tract, who may be future candidates for transplantation.