Björn Fagerberg

Gut metagenome in European women with normal, impaired and diabetic glucose control

Type 2 diabetes (T2D) is a result of complex gene–environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.

Symptomatic atherosclerosis is associated with an altered gut metagenome

Recent findings have implicated the gut microbiota as a contributor of metabolic diseases through the modulation of host metabolism and inflammation. Atherosclerosis is associated with lipid accumulation and inflammation in the arterial wall, and bacteria have been suggested as a causative agent of this disease. Here we use shotgun sequencing of the gut metagenome to demonstrate that the genus Collinsella was enriched in patients with symptomatic atherosclerosis, defined as stenotic atherosclerotic plaques in the carotid artery leading to cerebrovascular events, whereas Roseburia and Eubacterium were enriched in healthy controls. Further characterization of the functional capacity of the metagenomes revealed that patient gut metagenomes were enriched in genes encoding peptidoglycan synthesis and depleted in phytoene dehydrogenase; patients also had reduced serum levels of β-carotene. Our findings suggest that the gut metagenome is associated with the inflammatory status of the host and patients with symptomatic atherosclerosis harbor characteristic changes in the gut metagenome.

Usefulness of Microalbuminuria in Predicting Cardiovascular Mortality in Treated Hypertensive Men With and Without Diabetes Mellitus

In the present study we report on the predictive power of microalbuminuria for total and cardiovascular mortality in a prospective study (mean follow up 6.3 years) of treated hypertensive men, aged 50 to 72 years, with (n = 94) and without (n = 345) maturity onset diabetes mellitus. Thirty-three (35.1%) of the hypertensive patients with diabetes mellitus died during the follow-up period compared with 57 patients (16.5%) in the hypertensive group without diabetes mellitus (p <0.0002). In those with diabetes mellitus and hypertension, a log-rank test revealed a lower cardiovascular mortality in the normoalbuminuric group compared with both the microalbuminuric (p = 0.035) and the macroalbuminuric group (p = 0.002). The logarithm of urinary albumin excretion was a predictor of both total (p = 0.009) and cardiovascular (p = 0.001) mortality during the follow-up period using Cox regression analysis. This relation remained significant even after adjustment for other risk factors. HbA1c was also an independent predictor of total and cardiovascular mortality. In patients without diabetes mellitus, the small group of patients with macroalbuminuria had a markedly increased cardiovascular mortality compared with both the microalbuminuric (p <0.0001) and the normoalbuminuric groups (p <0.0001). No difference was observed between the normoalbuminuric and the microalbuminuric groups. Smoking at entry and concomitant cardiovascular disease at entry were independent predictors of cardiovascular mortality in these patients. We conclude that microalbuminuria was an independent predictor for cardiovascular mortality in treated hypertensive men with maturity onset diabetes mellitus. Macroalbuminuria, but not microalbuminuria, predicted cardiovascular mortality in nondiabetic treated hypertensive men.

Carotid artery intima-media thickness in patients with Type 2 diabetes mellitus and impaired glucose tolerance: a systematic review.

Aims  To review the difference in carotid artery intima media thickness (IMT) between patients with Type 2 diabetes (DM) or impaired glucose tolerance (IGT), and control subjects.

Low adipocyte-derived plasma protein adiponectin concentrations are associated with the metabolic syndrome and small dense low-density lipoprotein particles: atherosclerosis and insulin resistance study.

Circulating plasma adiponectin, an adipocyte-derived protein, has been shown to be decreased in obese subjects as well as in patients with type 2 diabetes and also in subjects who do not have diabetes, but are insulin resistant. We assessed the relationship between plasma levels of adiponectin, the metabolic syndrome and the occurrence of small dense LDL particles (pattern B) in 101 clinically healthy middle-aged subjects recruited from the general population. Low adiponectin levels were associated with the metabolic syndrome and low-density lipoprotein (LDL) particle size (r =.55, P <.001). The relationship between adiponectin and LDL particle size remained in a multiple regression model, in which adiponectin and total body fat explained 30% of the variability in LDL particle size. Furthermore, subjects in the lowest tertile of adiponectin had an increased risk of having pattern B (risk odds ratio [ROR] = 5.6). Because this was a cross-sectional study, no conclusions can be drawn about causality. This is the first population-based study in man demonstrating a relationship between small dense LDL particles and adiponectin.

Circulating oxidized low‐density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58‐year‐old men (AIR study)

Abstract. Sigurdardottir V, Fagerberg B, Hulthe J (Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden). Circulating oxidized low‐density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58‐year‐old men (AIR study). J Intern Med 2002; 252: 440–447.

Metoprolol controlled release/extended release in patients with severe heart failure: analysis of the experience in the MERIT-HF study.

OBJECTIVES This study analyzed the effect of the beta(1)-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure. BACKGROUND There continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure. METHOD SA subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction < 0.25 were identified (n = 795). The analysis was by intention-to-treat. RESULTS The mean ejection fraction at baseline was 0.19, and the yearly placebo mortality during follow-up was 19.1%. Treatment with metoprolol CR/XL compared to placebo resulted in significant reductions in all predefined mortality end points including: total mortality, 45 versus 72 deaths (risk reduction 39%; 95% confidence interval 11% to 58%; p = 0.0086); sudden death, 22 vs. 39 deaths (45% [7% to 67%]; p = 0.024); and death due to worsening heart failure, 13 vs. 28 deaths (55% [13% to 77%]; p = 0.015). Metoprolol CR/XL also reduced the number of hospitalizations for worsening heart failure by 45% compared with placebo (p < 0.0001). The NYHA functional class improved in the metoprolol CR/XL group compared with placebo (p = 0.0031). Metoprolol CR/XL was well tolerated, with 31% fewer patients withdrawn from study medicine (all causes) compared with placebo (p = 0.027). CONCLUSIONS This subgroup analysis of the MERIT-HF study shows that patients with severe heart failure receive a similar mortality benefit and a similar reduction in hospitalizations for worsening heart failure with metoprolol CR/XL treatment as those patients included in the total study.

Cognitive impairment and dementia 20 months after stroke

Background and Purpose: Dementia is common after stroke, but the dementia syndrome does not cover the whole spectrum of cognitive impairment. Our aim was to quantify and compare dementia and cognitive impairments in elderly patients 1.5 years after stroke and a matched normal population. Subjects and Methods: We examined dementia and cognitive impairments in 149 out of an initial total of 243 acute stroke patients after a mean 20 months. Inclusion criteria were age ≧70 years, not living in an institution and no previous cerebral lesion. The patients’ mean age was 81 years. Five controls matched by age and gender and fulfilling the same exclusion criteria were selected for each patient (n = 745) from a population-based survey in the same area. Dementia was diagnosed according to the DSM-III-R criteria, and impairments in different dimensions of cognitive function were assessed. Results: The prevalence of dementia was 28% in the stroke patients and 7.4% in the controls (OR 4.7; 95% CI 3.0–7.5). Seventy-two percent of the patients had cognitive impairments compared to 36% in the controls. Cognitive impairments were more common in nondemented stroke patients than in nondemented controls: 61 vs. 31% (OR 3.5; 95% CI 2.3–5.3). The risk increase attributable to stroke was highest for patients below 80 years of age. Conclusions: Stroke confers an increased risk of dementia and cognitive impairments in the elderly, especially in the younger ones. Apraxia is the most frequent neuropsychiatric impairment after stroke. The concept of dementia does not describe cognitive impairments well, since it underestimates their extent not only after stroke but also in normal ageing.

Effect of acute stroke unit care integrated with care continuum versus conventional treatment : A randomized 1-year study of elderly patients. The Göteborg 70+ stroke study

Background and Purpose The aim of the study was to compare the effect of conventional treatment with the effect of acute stroke unit care integrated with geriatric stroke unit care continuum. Methods A 1-year study was undertaken with 2:1 randomization to stroke unit care or conventional care, with assessment by an independent team. The study was composed of 249 elderly patients (aged ≥70 years) hospitalized for acute stroke, without previous cerebral lesion and without recognized need of care. Main outcome measures were patients at home after 1 year, ability in daily living activities, health-related quality of life score according to questionnaire, death or institutional care, and death or dependence. Results One hundred two patients (61%) in the stroke unit and 49 patients (59%) in the general ward group were alive and at home after 1 year (95% CI −10% to 16%). There were no significant differences in daily life activities or quality of life. In patients with concomitant cardiac disease, there was a reduction in death or institutional care after 3 months in the stroke unit group compared with the group receiving conventional care (28% versus 49%, respectively; 95% CI −40% to −3%). This effect did not remain after 1 year. Patients seeking care after 24 hours often had mild stroke and lived alone. Conclusions There was no effect on the number of patients living at home after 1 year, but after 3 months of stroke unit care, a beneficial effect was found on mortality and the need for institutional care among those with concomitant heart disease. This study involved patients who were considerably older than those investigated in previous randomized studies of acute stroke unit care; thus, these findings will contribute to the specialized register of controlled trials in stroke.

Ultrasound evaluation of atherosclerotic manifestations in the carotid artery in high-risk hypertensive patients. Risk Intervention Study (RIS) Group.

The aim of this study was to evaluate whether high-risk hypertensive patients (n = 137) had larger far-wall common carotid artery intima-media thickness than a control group (n = 37) and to study whether intima-media thickness was related to other signs of atherosclerotic disease. The results showed that intima-media thickness was significantly larger in the hypertension group than in the control group. Lumen diameter and mean cross-sectional area of the intima-media complex were larger both for hypertensive patients with a positive history of manifest clinical cardiovascular disease and for hypertensive patients with no such history than in the control group. There was a significant relationship between far-wall common carotid artery intima-media thickness and plaque status (visual scoring, no, small, moderate/large) in the carotid artery region. In univariate analyses, low diastolic blood pressure and high pulse pressure were both significantly related to plaque status. In multivariate analyses, pulse pressure was significantly and independently related both to common carotid artery intima-media thickness and to plaque status in the carotid artery region. In multivariate analyses, there was also an independent relationship between age and common carotid artery intima-media thickness, between smoking status and plaque status, and between a positive history of manifest clinical cardiovascular disease and plaque status. In conclusion, common carotid artery intima-media thickness and lumen diameter were increased in elderly high-risk hypertensive patients, in whom more than one third of the patients also had a moderate to large plaque in the carotid artery region.(ABSTRACT TRUNCATED AT 250 WORDS)