Göran Bergström

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.

Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1

While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types - principal and intercalated cells - has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1(-/-) mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1(-/-) mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.

Very Urgent Carotid Endarterectomy Confers Increased Procedural Risk

Background and Purpose— Current Swedish guidelines recommend that carotid endarterectomy should be performed within 14 days of a qualifying neurological event, but it is not clear if very urgent surgery after an event is associated with increased perioperative risk. The aim of this study was to determine how the time between the event and carotid endarterectomy affects the procedural risk of mortality and stroke. Methods— We prospectively analyzed data on all patients who underwent carotid endarterectomies for symptomatic carotid stenosis between May 12, 2008, and May 31, 2011, with records in the Swedish Vascular Registry (Swedvasc). Patients were divided according to time between the qualifying event and surgery (0–2 days, 3–7 days, 8–14 days, 15–180 days). Stroke rate and mortality at 30 days postsurgery were determined. Results— We analyzed data for 2596 patients and found that the combined mortality and stroke rate for patients treated 0 to 2 days after qualifying event was 11.5% (17 of 148) versus 3.6% (29 of 804), 4.0% (27 of 677), and 5.4% (52 of 967) for the groups treated at 3 to 7 days, 8 to 14 days, and 15 to 180 days, respectively. In a multivariate analysis, time was an independent risk factor for perioperative complications: patients treated at 0 to 2 days had a relative OR of 4.24 (CI, 2.07–8.70; P<0.001) compared with the reference 3- to 7-day group. Conclusions— In this study of patients treated for symptomatic carotid disease, it was safe to perform surgery as early as Day 3 after a qualifying neurological event in contrast to patients treated within 0 to 2 days, which has a significantly increased perioperative risk.

Vascular Function and Blood Pressure in GH Transgenic Mice

Acromegaly is associated with cardiovascular disease. We studied vascular function and mean arterial blood pressure in transgenic mice overexpressing bovine GH. Mean arterial blood pressure was measured in conscious, unrestrained male and female bovine GH and littermate control mice during normal as well as high salt intake using telemetric devices. Structure in artificially perfused maximally dilated hindquarter vascular beds and vascular reactivity and endothelial function in small mesenteric vessels were studied in female bovine GH and control mice. Mean arterial blood pressure was increased in female bovine GH transgenic (126 ± 3 mm Hg) and male bovine GH transgenic (129 ± 4 mm Hg) compared with female (109 ± 3 mm Hg, P < 0.05) and male (111 ± 3 mm Hg, P < 0.05) controls respectively. Increased salt intake had no effect on mean arterial blood pressure. Perfusion studies showed a significant decrease in the average diameter of the female bovine GH transgenic hindquarter vascular bed (P < 0.05). The res...

Ultrasound-assessed plaque occurrence in the carotid and femoral arteries are independent predictors of cardiovascular events in middle-aged men during 10 years of follow-up

OBJECTIVES To examine if plaques in the carotid and femoral arteries were associated with cardiovascular events during a 10-year follow-up independently of usual risk factors for such diseases. METHODS Plaque occurrence in both carotid arteries, and in the right femoral artery were assessed at baseline by B-mode ultrasound in a population-based sample of 58-year-old men (n=391) with no cardiovascular disease, and varying degrees of obesity and insulin sensitivity at entry. Anthropometry and blood pressure were recorded. Fasting venous blood samples were used for measurement of cardiovascular risk factors. Cardiovascular events occurring during follow-up were obtained by access to register data. RESULTS Systolic blood pressure, serum triglycerides and waist-hip ratio as well as baseline occurrence of carotid and femoral plaques were associated with events. Logistic multi-variate analyses showed that carotid plaques (OR 2.09, 95% CI 1.05-4.16, p=0.037), femoral plaques (OR 1.99, 95% CI 1.01-3.91, p=0.047) and concomitant presence of carotid, and femoral plaques (OR 2.53, 95% CI 1.23-5.21, p=0.011) were associated with cardiovascular events independently of other risk factors. Plaques occurred in 0-3 arteries and there was a parallel increase in cardiovascular risk (p=0.004). CONCLUSION Occurrence of carotid or femoral plaques at baseline had similar predictive value for cardiovascular events. Increased plaque burden, with plaques in both carotid and femoral arteries increased the cardiovascular risk further. Hence, the results from this study indicate that ultrasound examination of both the carotid and femoral arteries was the preferred method to predict cardiovascular risk.

Cadmium exposure is accompanied by increased prevalence and future growth of atherosclerotic plaques in 64‐year‐old women

There is currently widespread exposure to the toxic metal cadmium through the diet as well as through smoking, and it has been suggested that cadmium exposure may increase the risk of cardiovascular disease. Here we examined whether cadmium exposure is associated with prevalence and growth of atherosclerotic plaques in the carotid arteries.

Voluntary physical exercise-induced vascular effects in spontaneously hypertensive rats

Forced training has been shown to have beneficial vascular effects in various animal exercise models. In the present study, we explored possible physiological and molecular effects of voluntary physical exercise on various vascular beds. SHR (spontaneously hypertensive rats) performed voluntary exercise for 5 weeks in a computerized wheel cage facility. Ex vivo myograph studies revealed an increased sensitivity of the ACh (acetylcholine)-mediated vasodilation in resistance arteries of the exercised animals (ED50=15.0+/-3.5 nmol/l) compared with the controls (ED50=37.0+/-8.8 nmol/l; P=0.05). The exercise/control difference was abolished after scavenging reactive oxygen radicals. In conduit arteries, ACh induced a similar vasodilatory response in both groups. The in vivo aortic wall stiffness, assessed by means of Doppler tissue echography, was significantly lower in the exercising animals than in controls. This was demonstrated by significantly increased peak systolic aortic wall velocity (P=0.03) and the velocity time integral (P=0.01) in exercising animals compared with controls. The relative gene expression of eNOS (endothelial nitric oxide synthase) was similar in both groups of animals, whereas Cu/ZnSOD (copper/zinc superoxide dismutase) gene expression was significantly increased (+111%; P=0.0007) in the exercising animal compared with controls. In conclusion, voluntary physical exercise differentially improves vascular function in various vascular beds. Increased vascular compliance and antioxidative capacity may contribute to the atheroprotective effects associated with physical exercise in conduit vessels.

Differences in Lesion Severity and Cellular Composition between in vivo Assessed Upstream and Downstream Sides of Human Symptomatic Carotid Atherosclerotic Plaques

Background: The heterogeneous structure of carotid atherosclerotic plaques may be better understood if it is related to blood flow variations, influencing gene expression and cellular functions. Upstream of the maximum stenosis there is laminar blood flow and high shear stress, downstream there is turbulence and low shear stress. We studied if these variations were associated with differences in plaque morphology and composition between sites located up- and downstream of the maximum stenosis in symptomatic carotid plaques. Methods: Patients with symptomatic carotid stenosis were examined with magnetic resonance angiography to localize the maximum stenosis in-vivo, prior to endarterectomy. In 41 endarterectomized specimens, transverse tissue sections prepared up- and downstream of the maximum stenosis were compared using histopathology and immunohistochemistry. Results: The location of maximum stenosis relative the carotid bifurcation varied considerably between plaques. Compared with the downstream side, the upstream side of the stenosis had higher incidence of severe lesions with cap rupture and intraplaque hemorrhage, more macrophages, less smooth muscle cells and more collagen. Conclusions: The up- and downstream sides of symptomatic carotid plaques differed in plaque morphology and composition. This implies that the intraplaque location of sampling sites may be a confounding factor in studies of atherosclerotic plaques.

The Swedish CArdioPulmonary BioImage Study: objectives and design.

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large‐scale ‘omics’ and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Renal hemodynamic responses to intrarenal infusion of ligands for the putative angiotensin IV receptor in anesthetized rats.

Angiotensin IV, a hexapeptide fragment (3-8) of angiotensin II metabolism, has been reported to produce vasodilatation within the renal vasculature by activation of the putative AT4 receptor. However, there are conflicting findings, with previous in vivo studies providing evidence for and against a renal vasodilator action of angiotensin IV. In this study, the renal hemodynamic responses to activation of the putative AT4 receptor were studied in anesthetized rats by left renal arterial infusion of two endogenous ligands, angiotensin IV and LVV-hemorphin-7. Angiotensin IV (10, 100, and 1,000 pmol/min) infusion caused dose-dependent reductions in blood flow to the infused kidney, which were abolished by pretreatment with losartan. In respect to this effect, angiotensin IV was approximately 300-fold less potent than angiotensin II. There were no significant effects of angiotensin IV on mean arterial pressure, heart rate, or blood flow to the noninfused kidney. Intrarenal infusion of LVV-hemorphin-7 (10, 100, and 1,000 pmol/min) had no significant effect on renal blood flow in the infused and noninfused kidneys, or on mean arterial pressure or heart rate. These results provide no evidence for a renal vasodilatory action of angiotensin IV or LVV-hemorphin-7. On the contrary, intrarenal angiotensin IV infusion produced vasoconstriction of the renal vasculature, mediated by activation of AT1 receptors. These observations provide evidence against a vasodilatory role of putative AT4 receptors in the rat kidney.