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Background A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism. Objective We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID. Methods DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry–based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed. Results CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls—DBNL, TRMT11, GCHFR, and IGHA2—independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls. Conclusion Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID. Key words CVID RNA sequencing proteomics microbiome gut microbiota microbiota gastrointestinal tract duodenum celiac disease Primary immunodeficiency IgA

The use of immune checkpoint inhibitors has dramatically improved the chance of surviving malignant melanomas; however, the effect comes at the cost of toxicities that are difficult to predict. Immune-mediated hepatitis is the most common form of liver toxicity, but fatal outcome is uncommon. We report the case of a 70-year-old female with metastatic malignant melanoma who developed severe liver toxicity characterized by bile duct injury and cholestasis. The condition progressed despite potent immunosuppressive treatment, plasmapheresis, and intensive supportive care; and the patient died while still having tumor response.

Purpose Children with constipation and suspected Hirschsprung’s disease are referred for rectal biopsy. Since this is an invasive procedure, appropriate indications should be applied to minimize the number of “unnecessary” biopsies. Methods We reviewed all constipated children who underwent a rectal biopsy to diagnose a possible Hirschsprung’s disease at a tertiary referral hospital over a 6-year period (2013–2018). We registered clinical and demographic factors in these children and conducted correlation and multivariate regression analysis to evaluate the relation between these factors and a diagnosis of Hirschsprung’s disease. Results We identified 225 children, aged 0–17 years. In total, Hirschsprung’s disease was diagnosed in only 49/225 (22%). Among the 49 children with Hirschsprung’s disease, 29 (59%) were diagnosed in the neonatal period. Among girls, HD was confirmed in only 10/101 (10%) children, and only 1 of these 10 girls was older than 6 months at the time of the biopsy. The following factors correlated significantly with Hirschsprung’s disease diagnosis in children older than 1 month: “male sex”, “failure to thrive”, “gross abdominal distention plus vomiting” and “fulfils the Rome 4 criteria for functional constipation”. Conclusion In children referred for rectal biopsy, the factors most indicative of Hirschsprung’s disease were “male sex”, “failure to thrive”, “gross abdominal distention plus vomiting” and “fulfils the Rome 4 criteria for functional constipation”. Notably, the prevalence of Hirschsprung’s disease decreased with the increasing age of the children. Girls referred for a biopsy rarely had Hirschsprung’s disease, especially those older than 1 month.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67(+)) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.

Cholangiopathies are progressive disorders with largely unknown pathoetiology and limited treatment options. We aimed to develop a novel surgical technique with direct access to the bile ducts that would complement existing mouse models of cholestasis, biliary inflammation, and fibrosis and present a new route of administration for testing of potential treatment strategies. We developed a surgical technique to access the murine biliary tree by injection of different solvents through catheterization of the gall bladder with simultaneous clamping of the common bile duct. To demonstrate the applicability of the technique, we injected either phosphate-buffered saline or dimethyl sulfoxide in concentrations of 50 or 65% and compared these groups with sham-operated mice. The surgery was optimized to achieve a mortality rate close to 0. There were no significant changes in pain, activity level, or mortality from the day of the surgery until euthanization for any groups. Injection of phosphate-buffered saline or 50% dimethyl sulfoxide was generally well-tolerated, whereas 65% dimethyl sulfoxide led to higher weight loss, an increase of serum alanine transaminase, and histological portal inflammation. There were no signs of inflammation in the gut. We have developed a bile duct injection technique that is well-tolerated, easily reproducible, and that may complement existing models of cholangiopathies. Direct access to the bile ducts without causing harm to the hepatobiliary or intestinal tissue may be valuable in future studies of normal biliary physiology and different pathophysiological mechanisms of disease and to test novel therapeutic strategies.NEW & NOTEWORTHY To evaluate tolerability of the bile duct to injection of both polar and nonpolar compounds, we established a novel biliary injection technique. This technique is well-tolerated, easily reproducible, and with direct access to the bile ducts for studies of the murine biliary tree. The bile duct injection technique may complement existing animal models and be a valuable tool in future studies of normal biliary physiology or pathophysiology and to test novel therapeutic strategies.

ObjectiveInitiation of a gluten-free diet without proper diagnostic work-up of coeliac disease is a frequent and demanding problem. Recent diagnostic guidelines suggest a gluten challenge of at least 14 days followed by duodenal biopsy in such patients. The rate of false-negative outcome of this approach remains unclear. We studied responses to 14-day gluten challenge in subjects with treated coeliac disease.DesignWe challenged 20 subjects with biopsy-verified coeliac disease, all in confirmed mucosal remission, for 14 days with 5.7 grams per oral gluten daily. Duodenal biopsies were collected. Blood was analysed by multiplex assay for cytokine detection, and by flow cytometry using HLA-DQ:gluten tetramers.ResultsNineteen participants completed the challenge. Villous blunting appeared at end of challenge in 5 of 19 subjects. Villous height to crypt depth ratio reduced with at least 0.4 concomitantly with an increase in intraepithelial lymphocyte count of at least 50% in 9 of 19 subjects. Interleukin-8 plasma concentration increased by more than 100% after 4 hours in 7 of 19 subjects. Frequency of blood CD4+ effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells increased by more than 100% on day 6 in 12 of 15 evaluated participants.ConclusionA 14-day gluten challenge was not enough to establish significant mucosal architectural changes in majority of patients with coeliac disease (sensitivity ≈25%–50%). Increase in CD4+ effector-memory gut-homing HLA-DQ:gluten tetramer-binding T cells in blood 6 days after gluten challenge is a more sensitive and less invasive biomarker that should be validated in a larger study.Trial registration numberNCT02464150

Background Abdominal adipose tissue (AAT) consists of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), which can be further divided into superficial and deep SAT. Despite being a key factor in the development of metabolic and cardiovascular diseases, what predicts future amount of AAT is largely unknown. Objective To determine long-term predictors of amount of AAT. Methods This was a mean 18-year follow-up study of a cohort of 94 healthy young Caucasian men, with and without a family history of diabetes (FHD). Cardiovascular risk markers were examined both at baseline and at follow-up. At follow-up, computed tomography (CT) of AAT was conducted to assess amount of superficial and deep SAT, and VAT. Results In multiple regression analyses, baseline body mass index (BMI) remained a positive predictor of future amount of superficial and deep SAT, while high-density lipoprotein (HDL) cholesterol was a negative predictor of all three sub-compartments. Baseline risk markers were generally stronger predictors among men with FHD, than among men without. In addition, FHD had greater impact on amount of deep SAT and VAT, than on amount of superficial SAT. Conclusion Our data suggest that the traditional cardiovascular risk markers BMI, HDL cholesterol and family history of diabetes are long-term predictors of the different abdominal adipose tissue compartments from young towards middle age in healthy men. In men with family history of diabetes, cardiovascular risk markers at a young age seem to be of greater importance to future amount of abdominal adipose tissue, than among men without.

The standard clinical method for the assessment of viability in ischemic small intestine is still visual inspection and palpation. This method is non-specific and unreliable, and requires a high level of clinical experience. Consequently, viable tissue might be removed, or irreversibly damaged tissue might be left in the body, which may both slow down patient recovery. Impedance spectroscopy has been used to measure changes in electrical parameters during ischemia in various tissues. The physical changes in the tissue at the cellular and structural levels after the onset of ischemia lead to time-variant changes in the electrical properties. We aimed to investigate the use of bioimpedance measurement to assess if the tissue is ischemic, and to assess the ischemic time duration. Measurements were performed on pigs (n = 7) using a novel two-electrode setup, with a Solartron 1260/1294 impedance gain-phase analyser. After induction of anaesthesia, an ischemic model with warm, full mesenteric arterial and venous occlusion on 30 cm of the jejunum was implemented. Electrodes were placed on the serosal surface of the ischemic jejunum, applying a constant voltage, and measuring the resulting electrical admittance. As a control, measurements were done on a fully perfused part of the jejunum in the same porcine model. The changes in tan δ (dielectric parameter), measured within a 6 h period of warm, full mesenteric occlusion ischemia in seven pigs, correlates with the onset and duration of ischemia. Tan δ measured in the ischemic part of the jejunum differed significantly from the control tissue, allowing us to determine if the tissue was ischemic or not (P < 0.0001, F = (1,75.13) 188.19). We also found that we could use tan δ to predict ischemic duration. This opens up the possibility of real-time monitoring and assessment of the presence and duration of small intestinal ischemia.

Invasive treatment of tumors adjacent to large hepatic vessels is a continuous clinical challenge. The primary aim of this study was to examine the feasibility of ablating liver tissue adjacent to large hepatic and portal veins with magnetic resonance imaging–guided high-intensity focused ultrasound (MRgHIFU). The secondary aim was to compare sonication data for ablations performed adjacent to hepatic veins (HV) versus portal veins (PV). MRgHIFU ablations were performed in six male land swine under general anesthesia. Ablation cells of either 4 or 8 mm diameter were planned in clusters (two/animal) adjacent either to HV (n = 6) or to PV (n = 6), with diameter ≥ 5 mm. Ablations were made using 200 W and 1.2 MHz. Post-procedure evaluation was made on contrast-enhanced MRI (T1w CE-MRI), histopathology, and ablation data from the HIFU system. A total of 153 ablations in 81 cells and 12 clusters were performed. There were visible lesions with non-perfused volumes in all animals on T1w CE-MRI images. Histopathology showed hemorrhage and necrosis in all 12 clusters, with a median shortest distance to vessel wall of 0.4 mm (range 0–2.7 mm). Edema and endothelial swelling were observed without vessel wall rupture. In 8-mm ablations (n = 125), heat sink was detected more often for HV (43%) than for PV (19%; p = 0.04). Ablations yielding coagulative necrosis of liver tissue can be performed adjacent to large hepatic vessels while keeping the vessel walls intact. This indicates that perivascular tumor ablation in the liver is feasible using MRgHIFU. • High-intensity focused ultrasound ablation is a non-invasive treatment modality that can be used for treatment of liver tumors. • This study shows that ablations of liver tissue can be performed adjacent to large hepatic vessels in an experimental setting. • Liver tumors close to large vessels can potentially be treated using this modality.

Aim To investigate viability assessment of segmental small bowel ischemia/reperfusion in a porcine model. Methods In 15 pigs, five or six 30-cm segments of jejunum were simultaneously made ischemic by clamping the mesenteric arteries and veins for 1 to 16 h. Reperfusion was initiated after different intervals of ischemia (1-8 h) and subsequently monitored for 5-15 h. The intestinal segments were regularly photographed and assessed visually and by palpation. Intraluminal lactate and glycerol concentrations were measured by microdialysis, and samples were collected for light microscopy and transmission electron microscopy. The histological changes were described and graded. Results Using light microscopy, the jejunum was considered as viable until 6 h of ischemia, while with transmission electron microscopy the ischemic muscularis propria was considered viable until 5 h of ischemia. However, following ≥ 1 h of reperfusion, only segments that had been ischemic for ≤ 3 h appeared viable, suggesting a possible upper limit for viability in the porcine mesenteric occlusion model. Although intraluminal microdialysis allowed us to closely monitor the onset and duration of ischemia and the onset of reperfusion, we were unable to find sufficient level of association between tissue viability and metabolic markers to conclude that microdialysis is clinically relevant for viability assessment. Evaluation of color and motility appears to be poor indicators of intestinal viability. Conclusion Three hours of total ischemia of the small bowel followed by reperfusion appears to be the upper limit for viability in this porcine mesenteric ischemia model.

In a consecutive hospital-based autopsy series, we examined the relationship between apolipoprotein E (apoE) and Alzheimer’s disease (AD) and investigated the clinicopathological relationship in AD. The study population included 99 patients (mean age 81 years) with AD-related neuropathological findings at death, of whom 83 were diagnosed with AD according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) classification, and a control group of patients without neurodegenerative disease (n = 1429). The patients were apoE genotyped and the density of β-amyloid senile plaques, neuritic plaques and neurofibrillary tangles was estimated in the cortex and hippocampus. The utility of immunohistochemical staining using an antibody directed against apoE4 in paraffin-embedded tissue was also evaluated. Among patients with “definite AD” according to CERAD, 65 % were e4 carriers, compared to 32 % among controls (p

Global characterization of tissue proteomes from small amounts of biopsy material has become feasible due to advances in mass spectrometry and bioinformatics tools. In celiac disease (CD), dietary gluten induces an immune response which is accompanied by pronounced remodeling of the small intestine. Removal of gluten from the diet abrogates the immune response and the tissue architecture normalizes. In this study differences in global protein expression of small intestinal biopsies from CD patients were quantified by analyzing formalin-fixed, paraffin-embedded material using liquid-chromatography mass spectrometry and label-free protein quantitation. Protein expression was compared in biopsies collected from the same patients before and after one year treatment with gluten-free diet (n=10) or before and after three-day gluten provocation (n=4). Differential expression of proteins in particular from mature enterocytes, neutrophils, and plasma cells could distinguish untreated from treated CD mucosa, and immunoglobulin variable region IGHV5-51 expression was found to serve as a CD-specific marker of ongoing immune activation. In patients that had undergone gluten challenge coordinated up-regulation of wound response proteins including the CD autoantigen transglutaminase 2 was observed. Our study provides a global and unbiased assessment of antigen-driven changes in protein expression in the celiac intestinal mucosa.

Numerous studies have addressed the association between the apolipoprotein E polymorphism and cardiovascular disease, but only a few reports are based on findings at autopsy. In the present retrospective study, we have used autopsy findings from a general hospital population to further investigate this issue.We collected information from 1522 consecutive autopsy reports (886 men, mean age 65.7 years; 636 women, mean age 69.7 years) conducted at Oslo University Hospital, Norway, in the period from 1996 to 2000. Cause of death and signs related to cardiovascular disease including the degree of atherosclerosis in the aorta and the coronary arteries, signs of myocardial infarction, heart weight, and signs of cerebrovascular disease were recorded. The patients were genotyped, and the apolipoprotein E allele frequencies (ɛ2, 8.0%; ɛ3, 72.6%; and ɛ4, 19.4%) were not statistically different from a group of healthy controls. Approximately 35% of the patients died from a cardiovascular disease. Genotypes differed significantly (P.05), with more ɛ4-carriers (34.3% vs. 29.6%) and fewer ɛ2-carriers (11.8% vs. 13.9%) among patients who died from cardiovascular disease compared to those who died from other causes. A similar distribution of genotypes was seen in patients recorded with myocardial infarction or cerebrovascular disease. There was an association between the presence of ɛ4 and atherosclerosis in the aorta and coronary arteries, but this did not reach statistical significance. Among patients with signs of coronary heart disease, standardized heart weights were significantly higher in ɛ2-carriers compared to ɛ4-carriers.The present autopsy study suggests that the risk of developing and dying from cardiovascular disease, including coronary heart disease and cerebrovascular disease, is influenced by the apolipoprotein E polymorphism.

Background Aims: A strong association between human inflammatory biliary diseases and gut inflammation has led to the hypothesis that gut microbes and lymphocytes activated in the intestine play a role in biliary inflammation. The NOD.c3c4 mouse model develops spontaneous biliary inflammation in extra- and intrahepatic bile ducts. We aimed to clarify the role of the gut microbiota in the biliary disease of NOD.c3c4 mice. Methods: We sampled cecal content and mucosa from conventionally raised (CONV-R) NOD.c3c4 and NOD control mice, extracted DNA and performed 16S rRNA sequencing. NOD.c3c4 mice were rederived into a germ free (GF) facility and compared with CONV-R NOD.c3c4 mice. NOD.c3c4 mice were also co-housed with NOD mice and received antibiotics from weaning. Results: The gut microbial profiles of mice with and without biliary disease were different both before and after rederivation (unweighted UniFrac-distance). GF NOD.c3c4 mice had less distended extra-hepatic bile ducts than CONV-R NOD.c3c4 mice, while antibiotic treated mice showed reduction of biliary infarcts. GF animals also showed a reduction in liver weight compared with CONV-R NOD.c3c4 mice, and this was also observed in antibiotic treated NOD.c3c4 mice. Co-housing of NOD and NOD.c3c4 mice indicated that the biliary phenotype was neither transmissible nor treatable by co-housing with healthy mice. Conclusions: NOD.c3c4 and NOD control mice show marked differences in the gut microbiota. GF NOD.c3c4 mice develop a milder biliary affection compared with conventionally raised NOD.c3c4 mice. Our findings suggest that the intestinal microbiota contributes to disease in this murine model of biliary inflammation. Lay summary: Mice with liver disease have a gut microflora (microbiota) that differs substantially from normal mice. In a normal environment, these mice spontaneously develop disease in their bile ducts. However, when these mice, are raised in an environment devoid of bacteria, the disease in the bile ducts diminishes. Overall this clearly indicates that the bacteria in the gut (the gut microbiota) influences the liver disease in these mice. © 2016 European Association for the Study of the Liver.

Steroid refractory acute graft-versus-host-disease of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation. Treatment options are limited and not predictably effective. We describe the treatment of steroid-refractory acute graft-versus-host-disease with vedolizumab, an antibody directed against integrin α4β7, in 6 patients. All patients responded, and 4 of 6 patients are alive with a median follow-up of 10 months.

The objective of this study was to study the prevalence of gastrointestinal (GI) symptoms and histopathology in patients with common variable immunodeficiency (CVID) as well as linking the findings to GI infections and markers of systemic immune activation.In this cross-sectional study, we addressed GI symptoms in 103 patients and GI histopathological findings in 53 patients who underwent upper and lower endoscopic examination. The most frequent histopathological findings were linked to GI symptoms, B-cell phenotype, and markers of systemic immune activation (soluble (s)CD14, sCD25, and sCD163). Microarray analysis compared "celiac-like disease" in CVID to celiac disease. Screening for selected bacterial and viral infections in fecal samples and gut mucosal biopsies was performed.The main findings of this study were as follows: most common GI symptoms were bloating (34%), pain (30%), and diarrhea (26%). The most frequent histopathological findings were increased intraepithelial lymphocytes in the descending part of the duodenum, i.e., "celiac-like disease" (46% of patients), decreased numbers of plasma cells in GI tract mucosa (62%), and lymphoid hyperplasia (38%), none of which were associated with GI symptoms. Reduced plasma cells in GI mucosa were associated with B-cell phenotypic characteristics of CVID, and increased serum levels of sCD14 (P=0.025), sCD25 (P=0.01), and sCD163 (P=0.04). Microarray analyses distinguished between CVID patients with "celiac-like disease" and celiac disease. Positive tests for bacterial and viral infections were scarce both in fecal samples and gut mucosal biopsies, including PCR test for norovirus in biopsy specimens (0 positive tests).In conclusion, GI pathology is common in CVID, but does not necessarily cause symptoms. However, reduced plasma cells in GI mucosa were linked to systemic immune activation, "celiac-like disease" in CVID and true celiac disease appear to be different disease entities, as assessed by gene expression, and infections (including norovirus) are rarely a cause of the CVID enteropathy.

The incidence of new-onset atrial fibrillation (AF) is increased by uncontrolled hypertension, and antihypertensive treatment reduces new-onset AF. However, it is unclear whether alcohol intake and smoking influence the risk of new-onset AF during antihypertensive treatment.In the Losartan Intervention For Endpoint reduction in Hypertension (LIFE) study, a double-blinded, randomized, parallel-group study, 9193 hypertensive patients with electrocardiogram (ECG)-documented left ventricular hypertrophy (LVH), randomized to once-daily losartan- or atenolol-based antihypertensive therapy were followed for a mean of 4.8 years. At baseline, 8831 patients (54% women, mean age 67 years, mean blood pressure 174/98 mmHg after placebo run-in) had neither a history of AF nor AF on ECG, and they were thus at risk of developing this condition during the study.New-onset AF occurred in 353 (4%) patients. Univariate Cox analyses showed that intake of alcohol10 units/week compared with less or no alcohol intake predicted new-onset AF (Hazard ratio, HR = 1.60 [95% CI 1.02-2.51], p = 0.043). Multivariate Cox regression analysis showed that intake of alcohol10 units/week predicted new-onset AF (p = 0.010) independently of most other univariate predictors, except when also baseline serum cholesterol, serum potassium and urinary albumin/creatinine ratio were included in the model (HR = 1.60 [95% CI 0.94-2.72], p = 0.081). Impact of smoking was not significant in Cox univariate or multivariate analyses, and there were no significant interactions between high alcohol intake and either smoking or gender on the risk of getting AF.Up to 10 drinks of alcohol per week appears to be safe with respect to the risk for AF in hypertensive patients with LVH. Our data suggest that alcohol intake above this level may be marginally deleterious, while no effect of smoking on risk of AF was detected in hypertensive patients with LVH.

Objective: Evaluation of intestinal viability is essential in surgical decision-making in patients with acute intestinal ischemia. There has been no substantial change in the mortality rate (30-93%) of patients with acute mesenteric ischemia (AMI) since the 1980’s. As the accuracy from the first laparotomy alone is 50%, the gold standard is a second-look laparotomy, increasing the accuracy to 87-89%. This study investigates the use of machine learning to classify intestinal viability and histological grading in pig jejunum, based on multivariate time-series of bioimpedance sensor data. Approach: We have previously used a bioimpedance sensor system to acquire electrical parameters from perfused, ischemic and reperfused pig jejunum (7 + 15 pigs) over 1-16 hours of ischemia and 1-8 hours of reperfusion following selected durations of ischemia. In this study we compare the accuracy of using end-point bioimpedance measurements with a feedforward neural network (FNN), versus the accuracy when using a recurrent neural network with long short-term memory units (LSTM-RNN) with bioimpedance data history over different periods of time. Main results: Accuracies in the range of what has been reported clinically can be achieved using FNN’s on a single bioimpedance measurement, and higher accuracies can be achieved when employing LSTM-RNN on a sequence of data history. Significance: Intraoperative bioimpedance measurements on intestine of suspect viability combined with machine learning can increase the accuracy of intraoperative assessment of intestinal viability. Increased accuracy in intraoperative assessment of intestinal viability has the potential to reduce the high mortality and morbidity rate of the patients.

Allograft Duodenal Cuff Biopsy as Surrogate in Evaluation of Pancreatic Transplant Rejection - A Multicenter Data Effort

Alterations in trans-sarcolemmal and sarcoplasmic reticulum (SR) Ca2+ fluxes may contribute to impaired cardiomyocyte contraction and relaxation in heart failure. We investigated the mechanisms underlying heart failure progression in mice with conditional, cardiomyocyte-specific excision of the SR Ca2+-ATPase (SERCA) gene. At 4 weeks following gene deletion (4-week KO) cardiac function remained near normal values. However, end-stage heart failure developed by 7 weeks (7-week KO) as systolic and diastolic performance declined. Contractions in isolated myocytes were reduced between 4- and 7-week KO, and relaxation was slowed. Ca2+ transients were similarly altered. Reduction in Ca2+ transient magnitude resulted from complete loss of SR Ca2+ release between 4- and 7-week KO, due to loss of a small remaining pool of SERCA2. Declining SR Ca2+ release was partly offset by increased L-type Ca2+ current, which was facilitated by AP prolongation in 7-week KO. Ca2+ entry via reverse-mode Na+–Ca2+ exchange (NCX) was also enhanced. Up-regulation of NCX and plasma membrane Ca2+-ATPase increased Ca2+ extrusion rates in 4-week KO. Diastolic dysfunction in 7-week KO resulted from further SERCA2 loss, but also impaired NCX-mediated Ca2+ extrusion following Na+ accumulation. Reduced Na+-K+-ATPase activity contributed to the Na+ gain. Normalizing [Na+] by dialysis increased the Ca2+ decline rate in 7-week KO beyond 4-week values. Thus, while SERCA2 loss promotes both systolic and diastolic dysfunction, Na+ accumulation additionally impairs relaxation in this model. Our observations indicate that if cytosolic Na+ gain is prevented, up-regulated Ca2+ extrusion mechanisms can maintain near-normal diastolic function in the absence of SERCA2.

The sympathetic nervous system is implicated in the development and maintenance of hypertension. However, the predictive impact of arterial plasma catecholamines has never been reported. We investigated arterial catecholamines and blood pressures (BPs) prospectively over 20 years in a group of well-characterized middle-aged men.Fifty-six of original 79 men were available for the follow-up. Multiple regression analysis was done with mean BP at follow-up as a dependent variable, and arterial plasma catecholamines and BP at baseline as independent variables.Half of the originally normotensive men developed hypertension during follow-up. There were significant differences in the screening BP values measured at baseline between the new hypertensives and the sustained normotensives. Multiple regression analysis revealed arterial adrenaline at baseline as an independent predictor of mean BP at follow-up in the new hypertensives (beta = 0.646, R2 = 0.42, p = 0.007). Furthermore, arterial noradrenaline at baseline was a negative independent predictor of mean BP at follow-up in the sustained normotensives (beta = -0.578, R2 = 0.334, p = 0.020). Noradrenaline increased with age in the group as a whole (1318+/-373 vs 1534+/-505 pmol/l, p = 0.010) while adrenaline did not change.Our data suggest that arterial adrenaline is involved in the development of hypertension over 20 years in middle-aged men. Men with sustained normotension may have an inherent protection against sympathetic overactivity. Furthermore, screening BP at baseline in normotensive men differentiated between those who developed hypertension and those who remained normotensive at follow-up.

OBJECTIVE Low insulin sensitivity is closely related to both cardiovascular diseases and diabetes development. Still, correlates of insulin sensitivity have mainly been examined in cross-sectional studies. As far as we are aware, the longitudinal stability of insulin sensitivity in young men is largely unknown. We aimed for the first time to examine both the stability (tracking) and longitudinal predictors of future insulin sensitivity in healthy young men with and without a family history of diabetes or hypertension. METHODS We performed a 17-year follow-up study of a cohort of 100 healthy young men. Cardiovascular risk markers, including insulin sensitivity measured by the gold standard method--hyperinsulinaemic isoglycaemic glucose clamp--were examined both at baseline and at follow-up. RESULTS Baseline insulin sensitivity showed no significant correlation with insulin sensitivity at follow-up, whereas all other measured cardiovascular risk markers had significant correlation (tracking coefficients 0.4-0.7). In multiple regression analyses, family history of hypertension and baseline triglycerides remained the negative predictors of future insulin sensitivity. This was driven by the strong correlations in men with family history of diabetes. CONCLUSION Our data suggest that clamp-derived insulin sensitivity is not a stable feature in young men, and that family history of hypertension and baseline triglycerides were associated with future insulin sensitivity, especially in men with a family history of diabetes, and irrespective of blood pressure status 17 years earlier. These findings provide further insight into the development of insulin sensitivity and related diseases.

Approximately 10-20% of the general population have masked hypertension. However, how best to identify affected individuals is uncertain, and what predicts future masked hypertension is largely unknown. This study aimed to identify longitudinal predictors of masked hypertension.A long-term follow-up study of 100 healthy young men who had normal (n = 28) or high (n = 72) screening blood pressure (BP) at the compulsory military draft was carried out. They were examined in a detailed and highly standardized way for cardiovascular risk markers at baseline and at follow-up after a mean of 17.4 years.At follow-up, 40% had masked hypertension. Participants with high screening BP had a 4.8 times higher likelihood of having masked hypertension at follow-up compared to men with low screening BP (odds ratio 4.8, 95% confidence interval 1.7-13.5, p = 0.003). Furthermore, only 25% of the men with masked hypertension had high normal office BP at follow-up, and the remaining 75% would, according to guidelines, not be recommended ambulatory BP measurements, and thus go undiagnosed.Our data suggest that high screening BP at a young age is an important predictor of future masked hypertension in young men, and that BP measurement according to guidelines is insufficient to uncover masked hypertension.

We aimed to compare the effects of two different vasodilating principles, angiotensin II-receptor blockade and calcium channel blockade, on peripheral insulin-mediated glucose uptake in patients with hypertension and other cardiovascular risk factors. Twenty-one hypertensive patients (11 women and 10 men) with mean age 58.6 years (range 46-75 years), body mass index 29.2 +/- 1.0 kg/m(2) and blood pressure 160 +/- 3/96 +/- 2 mm Hg entered a 4-week run-in period with open-label amlodipine 5 mg. Thereafter they were randomized double-blindly to additional treatment with amlodipine 5 mg or losartan 100 mg. After 8 weeks of treatment, all patients underwent clinical examination and laboratory testing, and 17 of them underwent a hyperinsulinaemic isoglycaemic glucose clamp. After a 4-week open-label wash-out phase, the participants crossed over to the opposite treatment regimen and final examinations with hyperinsulinaemic isoglycaemic glucose clamp after another 8 weeks. Blood pressure was lowered to the same level in both treatment periods. The glucose disposal rate was significantly higher after treatment with losartan 100 mg + amlodipine 5 mg compared to amlodipine 10 mg (4.9 +/- 0.4 vs 4.2 +/- 0.5 mg/kg/min, P = 0.039). Thus our data suggest that angiotensin II-receptor blockade with losartan improves glucose metabolism at the cellular level beyond what can be expected by the vasodilatation and blood pressure reduction alone.

In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, there was a 25% risk reduction for stroke with angiotensin receptor blocker-based therapy (losartan) as compared with beta-blocker-based therapy (atenolol) despite comparable blood pressure reductions. This substudy examines treatment effects on the amount and density of atherosclerotic lesions in the common carotid arteries and the carotid bulb in 81 patients during 3 years of treatment. There were no statistically significant changes in the amount of carotid plaque in patients treated with losartan compared with an atenolol-based treatment program. A statistically nonsignificant increase in plaque density and index (average of plaque amount and density) was seen in the atenolol group compared with those treated with losartan. The small number of patients evaluated may have limited the power to detect a difference in outcome. The difference in carotid plaque index increase between the treatment groups during 3 years of treatment could not be statistically linked to specific treatments in the present substudy.

We studied plasma adrenaline (A) in relation to physical fitness, metabolic cardiovascular risk factors and cardiovascular responses. Men (age 21-24 years) with high and normal (both n=19) screening blood pressure (BP) were studied cross-sectionally. We measured peak oxygen uptake (VO2peak) (treadmill exercise), and plasma catecholamines, heart rate (HR), finger systolic (SBP) and diastolic (DBP) BP, and insulin-adjusted glucose disposal rate (GDR/I) during a hyperinsulinaemic glucose clamp (rest) and mental arithmetic stress test (MST). By multiple regression, A at rest (Arest) (beta=0.37, p0.05) and during MST (Amst) (beta=0.40, p0.01) were associated with high screening BP. In the respective models, Arest was negatively related to body mass index (BMI) (beta=-0.56, p0.001) and Amst positively to VO2peak (beta=0.54, p0.001). BP and HR responses correlated positively with VO2peak, but were determined by Amst in multiple regression models. Independently of BMI and VO2peak, serum high-density lipoprotein cholesterol was positively related to A levels, whereas GDR/I was independently related only to VO2peak. Increased adrenaline secretion may be related to high BP, but may at the same time be associated with a beneficial metabolic profile.

OBJECTIVES We hypothesized that insulin sensitivity and vagal cardiac control are independently related in young men after adjustment for fitness and other confounding variables. DESIGN Male volunteers aged 21-24 years with high (borderline hypertensive; n = 20) and low-normal (normotensive; n = 21) screening blood pressure (BP) were studied cross-sectionally. METHODS Mean R-R interval (RR) and heart rate variability (HRV) were computed from 30-min ECGs, and baroreflex sensitivity (BRS) and latency (phase shift) from 15-min beat-to-beat finger blood pressure (BP) and heart rate recordings. Insulin-adjusted glucose disposal rate (GDR/I) was measured with a 90-min hyperinsulinaemic glucose clamp and fitness by peak oxygen uptake (VO2peak) during a treadmill test. RESULTS HRV, baroreflex function, GDR/I, and VO2peak did not differ between the groups. GDR/I correlated positively with time and frequency domain HRV, including high-frequency power (HF) (r = 0.40, P = 0.01) and root-mean squared successive differences (RMSSD) (r = 0.43, P = 0.005), but not BRS or phase shift. GDR/I correlated with VO2peak (r = 0.70, P < 0.0001) and was explained (R = 0.56) by VO2peak (beta = 0.57, P < 0.0001) and RR (beta = 0.29, P = 0.03), independently of HRV and measures of obesity. Conversely, RR (beta = 0.55, P = 0.0004) and HRV, including HF (beta = 0.44, P = 0.006) and RMSSD (beta = 0.46, P = 0.004) were explained by GDR/I, independently of VO2peak. CONCLUSIONS Insulin sensitivity and autonomic cardiac control are related independently of physical fitness in young men.

Background There may be a link among stress, adrenal medullary activation, and the development of hypertension. Obesity is characterized by sympathetic activation and predisposes to hypertension, but may be associated with low or normal adrenal medullary activity. We hypothesized that plasma epinephrine (E) levels and adrenal medullary responsiveness to mental stress are lower in overweight than in lean borderline hypertensive subjects. Methods We compared groups of lean ( n = 62) and overweight ( n = 29) borderline hypertensive young men as well as lean ( n = 36) and overweight ( n = 7) normotensive young men from the same population. Plasma catecholamines and heart rate (HR) were measured at rest during a hyperinsulinemic glucose clamp and during mental arithmetic–induced stress. Results Plasma norepinephrine (NE) and E, HR, and responses to stress were increased in borderline hypertensive subjects. Our results showed that NE was increased only in lean borderline hypertensive subjects at rest, but in overweight subjects as well during stress, with ΔNE being similar in lean and overweight subjects. We found that E was higher in lean than in overweight borderline hypertensive subjects at rest and during stress (both P P P P P = .02). Conclusions Sympathetic neural activity and responsiveness are increased in borderline hypertensive young men, but measures of overweight are independently related to lower plasma E and HR responses. We suggest that adrenal medullary activation in borderline hypertension mainly characterizes lean subjects.

The cardiovascular metabolic syndrome is characterized by the presence of several cardiovascular risk factors, including blood pressure (BP) elevation. We aimed to study the relation between mental stress, plasma catecholamines, BP and BP responses to mental stress in healthy young Caucasian men selected from different levels of screening BP. We included 98 men with high and 22 men with normal screening BP. They were examined at baseline in the laboratory, during a hyperinsulinemic, isoglycemic glucose clamp and during mental stress. At baseline in the laboratory, the men with high screening BP were characterized by elevated BP (p0.005) and plasma catecholamines (p0.05), but unaltered serum lipid levels compared to men with normal screening BP. After 2 h rest the differences almost disappeared, but could be reproduced during a mental arithmetic stress test. The men with elevated screening BP had significantly higher fasting glucose (p = 0.01) and lower insulin sensitivity (p0.005). In a multiple regression model, norepinephrine during mental stress (R2 = 0.10, p0.05) was the main variable to retrospectively explain allocation to the normal or high screening BP group. In conclusion, young healthy men with elevated screening BP are characterized by increased sympathetic activity and insulin resistance. Norepinephrine during mental stress is the main variable to explain allocation to the normal or elevated screening BP group. We have shown that one single screening BP measurement predicts insulin resistance and elevated fasting glucose in this cohort.

We assessed plasma noradrenaline (NA) and adrenaline (A) at rest during a hyperinsulinaemic glucose clamp and responses to a mental arithmetic stress test (MST) in relation to blood pressure (BP) responses (Finapres) and distress in 20 men with high (or =140/90 mmHg) and 21 men with normal (or =115/75 mmHg) screening BP, 21-24 years of age. Perceived stress, effort and overall discomfort were scored 1-10. Catecholamines and BP increased in both groups, change in diastolic BP (DeltaDBP; 9.9 vs. 3.8 mmHg, p0.05) and DeltaDBP carryover (recovery period minus baseline) (7.2 vs. 2.2 mmHg, p0.01) being greater in men with high screening BP. Independently of BP status, change in systolic BP (DeltaSBP) and DeltaSBP carryover were related to A (both p0.001), and DeltaDBP and DeltaDBP carryover to DeltaNA (both p0.001). The subjective score sum correlated with maximal NA (rs = 0.40) and A (rs = 0.37) (both p0.05). Maximal NA was independently related to stress (p0.05) and the subjective score sum (p0.01). DeltaA% was greater in the high- (scoreor =6) than in the low-stress category, independently of BP status (p0.05). High screening BP is associated with impaired BP recovery after mental stress. Plasma catecholamine responses are related to BP responses and carryover effects, and reflect perceived stress in young men.

Gender, body weight, and cardiovascular disease (CVD) are all variables known to influence human heart weight. The impact of cancer is less studied, and the influence of age is not unequivocal. We aimed to describe the relationship between body size and heart weight in a large autopsy cohort and to compare heart weight in patients with cancer, CVD, and other diseases.Registered information, including cause of death, evidence of cancer and/or CVD, heart weight, body weight, and height, was extracted from the autopsy reports of 1410 persons (805 men, mean age 66.5 years and 605 women, mean age 70.6 years). The study population was divided in four groups according to cause of death; cancer (n=349), CVD (n=470), mixed group who died from cancer and CVD and/or lung disease (n=263), and a reference group with patients who did not die from any of these conditions (n=328). In this last group, heart weight correlated only slightly better with body surface area than body weight, and nomograms based on body weight are presented. Compared to the reference group (mean heart weight: 426 g and 351 g in men and women, respectively), heart weight was significantly lower (men: P.05, women: P.001) in cancer patients (men: 392 g, women: 309 g) and higher (P.001) in patients who died from CVD (men: 550 g, women: 430 g). Similar results were obtained in linear regression models adjusted for body weight and age. Among CVD, heart valve disease had the greatest impact on heart weight, followed by old myocardial infarction, coronary atherosclerosis, and hypertension. Absolute heart weight decreased with age, but we demonstrated an increase relative to body weight.The weight of the human heart is influenced by various disease processes, in addition to body weight, gender, and age. While the most prevalent types of CVD are associated with increased heart weight, patients who die from cancer have lower average heart weight than other patient groups. The latter finding, however, is diminished when adjusting for body weight.The present study demonstrates that the weight of the human heart is influenced by various disease processes like cancer and CVD, in addition to body weight, gender and, possibly, age.

Introduction Grade III-IV GvHD is associated with poor outcome. Severe steroid refractory (SR) intestinal manifestations are difficult to treat, and current treatment modalities augment the immunodeficiency and often lead to opportunistic infections, multiorgan failure (MOF) and death. 2nd and 3rd line treatments are less than optimally documented and often with erratic responses. Vedolizumab (Vedo), a monoclonal antibody targeting the homing of T-cells to the intestinal endothelium through inhibition of the binding of integrin a4b7 to MadCAM, is effective in inflammatory bowel disease (IBD) refractory to TNF-a inhibitors. Encouraged by the responses reported in IBD, we used Vedo in six patients with intestinal SR GvHD. Methods Patient characteristics are provided in table 1. Patients 1 and 2 had been through 2nd and 3rd line therapy without response or resolution of the GvHD. Patients 3 to 6 were given Vedo as second line therapy after steroid failure. Patient 4 already had MOF with gastrointestinal GvHD before receiveing Vedo, and died of MOF. Vedo was delivered as prescribed in IBD; 300 mg iv without premedication week 0, 2 and 6, followed by infusions every 8 weeks on clinical indication. Results All patients exhibited clinical responses within 7 - 10 days after start of treatment with decrease in abdominal pain and watery diarrhoea. Serial endoscopies were performed in patients 1,2,3,5 and 6. These revealed gradual macroscopic and histologic improvement; the upper GI-tract showing a more rapid improvement than the colon. Figure 1 shows colon histology before (a, b, c) and after 3 doses of Vedo (d, e, f) in patient 1, 2 and 3. After 3 doses of Vedo, most patients could taper systemic corticosteroid therapy. All patients, except patient 4, were on oral medication including immunosuppressants. Concomitant immunosuppressive therapy was administered as oral cyclosporine or MMF. There were no or sparse clinical symptoms of acute intestinal GvHD Patient 1 is in continued clinical remission of GvHD 8 months after start of therapy. Patient 2 was asymptomatic for 5 months, then a molecular relapse of acute promyelocytic leukemia was diagnosed and intestinal GvHD recurred when all immunosuppression was stopped. In patient 3, the intestinal GvHD resolved after three doses of Vedo, but he developed skin GvHD after cessation of IS and died of an opportunistic infection following treatment with high dose methyl-prednisolone. Patient 4 had MOF prior to start of treatment with Vedo and died in MOF. Patient 5 and 6 have no clinical signs of intestinal GvHD after 2 and 3 doses of Vedo. Five out of six patients could be discharged from hospital after treatment with Vedo. Immunophenotyping of peripheral blood revealed high levels of CD25+ Treg cells in 4 out of 5 evaluable patients prior to treatment and the numbers decreased to normal levels after start of therapy and with signs of clinical effect. Patient 2 stopped IS after a molecular relapse of APL and had a recurrence of GvHD. This recurrence coincided with an increase in Treg percentage. Discussion This case series provides the first proof of concept that targeting integrin a4b7 T-cells is feasible, safe and may provide clinical improvement in intestinal SR GvHD. The mechanism of action is not known, but may be due to the inhibition of the homing of a4b7 expressing allo-reactive T-cells to recipient MadCAM expressing intestinal endothelial cells. The mechanism behind the Treg patterns is unclear. One might speculate that the initial high levels of Tregs are part of the physiologic reaction to the alloreactive inflammation in the intestinal epithelium and that the subsequent normalization occurs as the inflammation subsides. Table 1. Patient 1 2 3 4 5 6 Diagnosis AML AML NHL AML NHL AML Sex male male male female male male Age at transplant 46 58 42 44 50 62 Lines of therapy after steroid refractoriness 2 1 0 0 0 0 Other manifestations 1 2,3,4 1 Steroid dose (mg) at last FU N/A N/A 2 mg/kg 1,7 mg/kg 10 0 Number of Vedolizumab doses at last FU 5 5 3 1 2 3 Immunosuppression at last FU No CyA CyA + steroids MMF + steroids CyA + steroids No watery stools at last FU No Yes No No No No Treg % before start of Vedo (reference: 2,5 - 5,8) 10,2 29,6 4 1,7 33 6,5 Treg % follow up 1 5,7 15 2,1 13,3 13 Treg % follow up 2 6,2 6 Treg % follow up 3 4,6 6,6 Treg % follow up 4 4,9 Treg % follow up 5 8,5* *IS cessation due to molecular relapse followed by relapse of GvHD 1 CMV 2 renal failure 3 hepatic failure 4 multi-organ GvHD Figure 1. Figure 1. Disclosures Off Label Use: Vedolizumab is approved for the treatment of inflammatory bowel disease. The present study describes its effect on steroid-refractory acute intestinal GvHD. Lundin:Takeda: Consultancy, Honoraria.

Rationale Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. Objective We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. Methods and Results Mice harboring a systemic knockout of the CXCR5 (CXCR5−/−) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5−/− developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5−/− compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5−/− mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. Conclusions Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly.

Endothelial dysfunction is reflected by an impaired nitric oxide (NO)-mediated vasodilatation. Insulin resistance may be linked to endothelial dysfunction by several mechanisms, including disturbances in signaling pathways common to both insulin action and NO production. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may contribute to endothelial dysfunction, and elevated ADMA levels have been associated with both insulin levels and the degree of insulin resistance. The direct link between insulin and ADMA, however, has not yet been established. In the present study, we aimed to investigate the effects of acute hyperinsulinemia on circulating ADMA and L-arginine levels and on forearm blood flow (FBF). Male volunteers, aged 21 to 24 years, with borderline hypertension were included in the study. The participants underwent a 90-minute hyperinsulinemic isoglycemic glucose clamp with insulin levels at the postprandial levels (n=20) or a saline infusion (control) (n=9). Fasting blood samples were drawn at baseline and after 90 minutes. Insulin infusion was accompanied by a reduction in ADMA (0.78 to 0.68 micromol/L, P

The various antihypertensive regimens have varying effects on glucose metabolism and the development of diabetes mellitus. Recent large hypertension trials have shown great differences in the development of new-onset diabetes among antihypertensive drug therapies. The incidence of diabetes is unchanged or increased by thiazide diuretics and b-adrenergic blockers, and unchanged or decreased by angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin-receptor blockers. The differences in new-onset diabetes mellitus have not influenced the outcome of cardiovascular mortality and morbidity in all of the large clinical trials, but drug-induced diabetes among hypertensive patients is known to carry the same cardiovascular risk as that seen in patients with previously known diabetes; however, it might take years for the increased risk to become apparent.

We studied effects of mental stress on whole-blood viscosity (WBV) and blood pressure (BP), and relations between WBV and autonomic nervous system activity and insulin sensitivity. We measured WBV (rotational rheometer), plasma noradrenaline (NA), finger BP, heart rate variability (HRV) and baroreflex sensitivity (BRS; transfer technique) during hyperinsulinaemic glucose clamp and mental arithmetic stress test (MST) in 20 men with high ( > or =140/90 mmHg) and 21 men with normal (< or =115/75 mmHg) screening BP, and 10 women regardless of screening BP (all normotensive). WBV and NA increased during the MST, while HRV and BRS decreased. During the MST, WBV (all shear rates) and the response ((delta)WBV) (low shear) were higher in men with high compared to normal screening BP (p

The Losartan Intervention For End point reduction in hypertension (LIFE) study showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke, and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios (HR) in 4287 and 685 participants who reported intakes of 1-7 and8 drinks/week at baseline, respectively, with those in 4216 abstainers, adjusting for gender, age, smoking, exercise, and race. Within categories, clinical baseline characteristics, numbers randomized to losartan and atenolol, and blood pressure (BP) lowering were similar on the drug regimens. Overall BP control (140/90 mmHg) at end of follow-up was similar in the categories. Composite end point rate was lower with 1-7 (24/1000 years; HR 0.87, P0.05) and8 drinks/week (26/1000 years; HR 0.80, NS) than in abstainers (27/1000 years). Myocardial infarction risk was reduced in both drinking categories (HR 0.76, P0.05 and HR 0.29, P0.001, respectively), while stroke risk tended to increase with8 drinks/week (HR 1.21, NS). Composite risk was significantly reduced with losartan compared to atenolol only in abstainers (HR 0.81 95% confidence interval, CI (0.68, 0.96), P0.05), while benefits for stroke risk reduction were similar among participants consuming 1-7 drinks/week (HR 0.73, P0.05) and abstainers (HR 0.72, P0.01). Despite different treatment benefits, alcohol-treatment interactions were nonsignificant. In conclusion, moderate alcohol consumption does not change the marked stroke risk reduction with losartan compared to atenolol in high-risk hypertensives. Alcohol reduces the risk of myocardial infarction, while the risk of stroke tends to increase with high intake.

Hypertension is a major risk factor for morbidity and mortality. Plasma catecholamines are linked to the pathogenesis of hypertension. Pharmacological intervention, including treatment with beta-blockers, reduces cardiovascular mortality and morbidity. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, the angiotensin receptor blocker losartan significantly reduced cardiovascular end points compared to the beta-blocker atenolol. Thus, for the first time, one drug was shown to be superior to another in hypertension. The present substudy examined the effects of atenolol vs losartan treatment on plasma catecholamines at rest and during hyperinsulinaemia in a cohort of 86 LIFE patients. Plasma adrenaline increased significantly from placebo treatment at baseline to year 1 of treatment (P

(2003). Hypertension treatment and stroke prevention. Blood Pressure: Vol. 12, No. 5-6, pp. 264-268.

There may be a link among stress, adrenal medullary activation, and the development of hypertension. Obesity is characterized by sympathetic activation and predisposes to hypertension, but may be associated with low or normal adrenal medullary activity. We hypothesized that plasma epinephrine (E) levels and adrenal medullary responsiveness to mental stress are lower in overweight than in lean borderline hypertensive subjects.We compared groups of lean (n = 62) and overweight (n = 29) borderline hypertensive young men as well as lean (n = 36) and overweight (n = 7) normotensive young men from the same population. Plasma catecholamines and heart rate (HR) were measured at rest during a hyperinsulinemic glucose clamp and during mental arithmetic-induced stress.Plasma norepinephrine (NE) and E, HR, and responses to stress were increased in borderline hypertensive subjects. Our results showed that NE was increased only in lean borderline hypertensive subjects at rest, but in overweight subjects as well during stress, with DeltaNE being similar in lean and overweight subjects. We found that E was higher in lean than in overweight borderline hypertensive subjects at rest and during stress (both P.001), as were DeltaE and DeltaHR (both P.05). Independent of BP status, body mass index was negatively related to E during stress (P.01) and waist circumference negatively related to resting E (P.001) and DeltaHR (P =.02).Sympathetic neural activity and responsiveness are increased in borderline hypertensive young men, but measures of overweight are independently related to lower plasma E and HR responses. We suggest that adrenal medullary activation in borderline hypertension mainly characterizes lean subjects.