Histological and Molecular Adipose Tissue Changes Are Related to Metabolic Syndrome Rather Than Lipodystrophy in Human Immunodeficiency Virus-Infected Patients: A Cross-Sectional Study.

Background: In human immunodeficiency virus (HIV)-infected patients on combination antiretroviral therapy (cART), lipodystrophy shares many similarities with metabolic syndrome, but only metabolic syndrome has objective classification criteria. We examined adipose tissue changes related to lipodystrophy and metabolic syndrome to clarify whether it may be acceptable to focus diagnosis on metabolic syndrome rather than lipodystrophy. Methods: This is a cross-sectional study of 60 HIV-infected men on cART and 15 healthy men. We evaluated lipodystrophy (clinical assessment) and metabolic syndrome (JIS-2009). We compared adipocyte size, leukocyte infiltration, and gene expression in abdominal subcutaneous adipose tissue biopsies of patients with and without lipodystrophy and with and without metabolic syndrome. Results: Lipodystrophy was only associated with increased macrophage infiltration (P = .04) and adiponectin messenger ribonucleic acid ([mRNA] P = .008), whereas metabolic syndrome was associated with larger adipocytes (P < .0001), decreased expression of genes related to adipogenesis and adipocyte function (P values between <.0001 and .08), increased leptin mRNA (P = .04), and a trend towards increased expression of inflammatory genes (P values between .08 and .6). Conclusions: Metabolic syndrome rather than lipodystrophy was associated with major unfavorable abdominal subcutaneous adipose tissue changes. In a clinical setting, it may be more relevant to focus on metabolic syndrome diagnosis in HIV-infected patients on cART with regards to adipose tissue dysfunction and risk of cardiometabolic complications.

Immunosenescence of the CD8(+) T cell compartment is associated with HIV-infection, but only weakly reflects age-related processes of adipose tissue, metabolism, and muscle in antiretroviral therapy-treated HIV-infected patients and controls.

BACKGROUND: Despite effective antiretroviral therapy (ART), HIV-infected patients exhibit systemic inflammation, early onset of age-related diseases, and features of immunosenescence. The role of inflammation in the development of age-related diseases is widely recognized. However, the role of immunosenescence is not well established. Studying immunosenescence in HIV-infection could give insight into its role in ageing processes. In this cross-sectional study, we aimed to investigate whether ART-treated HIV-infected patients exhibit immunosenescence; and whether immunosenescence is associated with age-related processes of inflammation, metabolism, adipose tissue, and muscle. T cell immunosenescence and exhaustion were assessed by flow cytometry analysis of CD8 (+) cells from 43 ART-treated HIV-infected patients (HIV(+)) and ten Controls using markers of differentiation: CD27/CD28; maturation: CD27/CD45RA; senescence: killer cell lectin-like receptor G1 (KLRG1); and exhaustion: programmed death-1 (PD-1). Relationships between CD8 (+) T cell immunosenescence, exhaustion, and age-related processes were assessed using linear regressions. RESULTS: HIV-infection was strongly associated with more highly differentiated and mature CD8 (+) T cell phenotypes. PD-1 and KLRG1 expression did not differ between HIV(+) and Controls, but depended on differentiation and maturation stages of the cells. CD8 (+) T cell maturation was associated with age. KLRG1 expression was associated with age, metabolic syndrome, visceral adipose tissue, and high muscle mass. PD-1 expression was not associated with age-related parameters. CONCLUSIONS: HIV-infection strongly affected CD8 (+) T cell differentiation and maturation, whereas age-related processes were only weakly associated with immune parameters. Our findings suggest that, in contrast to inflammation, immunosenescence appears to be highly dependent on HIV-infection and is only to a small extent associated with age-related parameters in well-treated HIV-infection.

Leptin, IL-6, and suPAR reflect distinct inflammatory changes associated with adiposity, lipodystrophy and low muscle mass in HIV-infected patients and controls.

BACKGROUND: HIV-infected patients could exhibit accelerated ageing, since age-associated complications like sarcopenia; increased inflammation; lipodystrophy with loss of subcutaneous adipose tissue and/or gain of visceral adipose tissue (VAT); and cardiovascular disease occur at an earlier age. Inflammation is involved in age-associated complications. However, it is not understood whether it is the same inflammatory changes that are involved in the various ageing-associated complications. Our objective was to study whether leptin, interleukin 6 (IL-6), and soluble urokinase plasminogen activator receptor (suPAR) were associated distinctively with adiposity, lipodystrophy and sarcopenia, in HIV-infected patients and healthy Controls. RESULTS: Systemic leptin levels were significantly higher in patients with lipodystrophy than without, whereas there was no difference in IL-6 or suPAR levels. Leptin was significantly positively associated with fat mass index (FMI) and abdominal VAT, but not with lean mass index (LMI). IL-6 was significantly associated with both FMI and VAT, and low LMI. High suPAR was associated with low LMI, and weakly with high FMI and VAT. CONCLUSIONS: Leptin reflected adiposity- and lipodystrophy-related inflammation, but not sarcopenia. IL-6 reflected both adiposity-, but also sarcopenia-related inflammation; and suPAR was a marker of sarcopenia-related inflammation. Our results indicate that different inflammatory processes can be active simultaneously contributing to the systemic low grade inflammatory state. Identifying major contributors to circulating leptin, IL-6, and suPAR levels could levels could therefore improve our understanding of which inflammatory processes are involved in the various age-related complications.

A randomized study of the effects of exercise training on patients with atrial fibrillation.

BACKGROUND: Exercise training is beneficial in ischemic and congestive heart disease. However, the effect on atrial fibrillation (AF) is unknown. METHODS: Forty-nine patients with permanent AF (age [mean ± SD], 70.2 ± 7.8 years; male-to-female ratio, 0.75; body mass index [mean ± SD], 29.7 ± 4.3 kg/m(2)) were randomized to 12-week aerobic exercise training or a control group. Exercise capacity, 6-minute walk test (6MWT), cardiac output, quality of life, and natriuretic peptides were measured. Cardiac output was measured at rest and during ergometer testing, and atrial natriuretic peptide and N-terminal pro-B-type natriuretic peptide were measured before and after the training period. Quality of life was evaluated using the Short-Form 36 and Minnesota Living With Heart Failure (MLHF-Q) questionnaires. RESULTS: Improved exercise capacity and 6MWT were observed in the active patients (P < .001), and at study end, there was a significant difference between the active patients and the controls (P = .002). Resting pulse decreased in the active patients (94.8 ± 22.4 to 86.3 ± 22.5 beats/min, P = .049) but remained unchanged in the controls. Cardiac output was unchanged from baseline to end-of-study period. The MLHF-Q score improved in the active group (21.1 ± 18.0 vs 15.4 ± 17.5, P = .03). Active patients showed progress in 3 of the 8 Short-Form 36 subscales: physical functioning (P = .02), general health perceptions (P = .001), and vitality (P = .02). Natriuretic peptides were unchanged. CONCLUSION: Twelve weeks of exercise training increased exercise capacity and 6MWT and decreased resting pulse rate significantly in patients with AF. Overall quality of life increased significantly as measured by the cardiology-related MLHF-Q. Cardiac output and natriuretic peptides were unchanged in both groups.

Chronic intestinal ischemia and splanchnic blood-flow: reference values and correlation with body-composition.

AIM: To determine the splanchnic blood flow and oxygen uptake in healthy-subjects and patients and to relate the findings to body-composition. METHODS: The total splanchnic blood flow (SBF) and oxygen uptake (SO2U) were measured in 20 healthy volunteers (10 women) and 29 patients with suspected chronic intestinal ischemia (15 women), age 40-85 years, prior to and after a standard meal. The method is based on the Fick principle using the continuous infusion of an indicator (99mTechnetium-labelled mebrofenin) and catheterization of an artery and the hepatic vein. An angiography of the intestinal arteries was performed during the same investigation. A whole-body dual-energy x-ray absorptiometry scan was performed in healthy volunteers to determine body composition. RESULTS: Angiography revealed no atherosclerotic lesions in the intestinal arteries. The mean baseline SBF was 1087 mL/min (731-1390), and this value increased significantly to 1787 mL/min after the meal in healthy volunteers (P < 0.001). The baseline SBF in patients was 1080 mL/min, which increased to 1718 mL/min postprandially (P < 0.001). The baseline SBF was independent of age, sex, lean body mass and percentage of body fat. The mean meal-induced increase in SBF was equal to 282 mL/min + 5.4 mL/min × bodyweight, (P = 0.025). The SO2U in healthy volunteers and patients was 50.7 mL/min and 48.0 mL/min, respectively, and these values increased to 77.5 mL/min and 75 mL/min postprandially, respectively. Both baseline and postprandial SO2U were directly related to lean body mass. Age and sex exerted no impact on SO2U. CONCLUSION: A direct correlation between body weight and the postprandial increase in SBF was observed. The effect of body weight should be considered in the diagnosis of chronic intestinal ischemia.

Effect of physical exercise training on muscle strength and body composition, and their association with functional capacity and quality of life in patients with atrial fibrillation: a randomized controlled trial.

OBJECTIVE: Atrial fibrillation diminishes cardiac function, exercise tolerance and quality of life. The objective of this study was to determine whether exercise training in atrial fibrillation affects muscle strength, body composition, maximal exercise capacity and walking capacity positively, thus improving quality of life. DESIGN: Randomized clinical trial. Twelve weeks of physical exercise training or control. PATIENTS: Forty-nine patients in permanent atrial fibrillation were randomized to training or control. METHODS: Intervention consisted of aerobic training for 1 h 3 times per week at 70% of maximal exercise capacity vs control. Muscle strength, exercise capacity, 6-minute walk test, lean body mass, fat percentage, and quality of life were assessed. RESULTS: Muscle strength increased in the training group (p = 0.01), but no change was observed in controls. Lean body mass was unchanged in both groups. Fat percentage decreased in both groups, but there was no significant difference between the groups. Exercise capacity improved in the training group (p < 0.001), with no change in the control group. There was a significant difference after the training period between the training and control groups in terms of exercise capacity. (p = 0.001). Six-min walk test improved in the training group compared with controls (p < 0.01). Overall quality of life score, as measured by the Minnesota Living with Heart Failure Questionnaire, improved in the training group (p = 0.03). Quality of life, measured by Short Form-36, improved in the training group in 3 out of 8 subscales: physical functioning (p = 0.02), general health perceptions (p = 0.001) and vitality (p = 0.02). CONCLUSION: Muscle strength, exercise capacity and quality of life increased with exercise training in subjects with atrial fibrillation. Lean body mass was unchanged.

Validation of 99mTechnetium-labeled mebrofenin hepatic extraction method to quantify meal-induced splanchnic blood flow responses using a porcine model.

The aim of this study was to evaluate the measurement of the total splanchnic blood flow (SBF) using a clinical diagnostic method based on Fick's principle and hepatic extraction of 99mTc-mebrofenin (99mTc-MBF) compared with a paraaminohippuric acid (pAH) dilution method in a porcine model. Another aim was to investigate whether enterohepatic cycling of 99mTc-MBF affected the SBF measurement. Five indwelling catheters were placed in each pig (n = 15) in the portal, mesenteric, and hepatic veins, as well as in the aorta and the vena cava. The SBF was measured using both methods. The portal blood flow; the intestinal and hepatic oxygen uptake; the net fluxes of oxygen, lactate, and glucose; and the extraction fraction (EF) of 99mTc-MBF were measured before and for 70 min after feeding. The mean baseline SBF was 2,961 ml/min vs. 2,762 ml/min measured by pAH and 99mTc-MBF, respectively, and increased significantly to 3,977 ml/min and 3,981 ml/min postprandially. The hepatic EF of 99mTc-MBF decreased from 40% at the start of the investigation to 16% 70 min after feeding. The arterial-portal difference in 99mTc-MBF concentration was 0.21% (P = 0.48), indicating no intestinal extraction or metabolism. The clinical method for measuring the SBF based on hepatic 99mTc-MBF extraction is robust compared with the indicator dilution method, despite the decrease seen in hepatic extraction of 99mTc-MBF. Because there was no difference in the content of 99mTc-MBF between the arterial and portal vein plasma, the SBF can be calculated from an arterial and a hepatic vein sample.

Inflammation in HIV-infected patients: impact of HIV, lifestyle, body composition, and demography - a cross sectional cohort study.

OBJECTIVES: To examine mechanisms underlying the increased inflammatory state of HIV-infected patients, by investigating the association of HIV-related factors, demography, lifestyle, and body composition with the inflammatory marker soluble urokinase plasminogen activator receptor (suPAR). METHODS: suPAR was measured in EDTA-plasma and associated with HIV-related factors (HIV-duration, combination antiretroviral treatment (cART), nadir CD4+ cell count, CD4+ cell count, and HIV RNA); demography; lifestyle; and body composition determined by Dual energy X-ray Absorptiometry (DXA) scan, in multiple linear regression analyses adjusted for biological relevant covariates, in a cross-sectional study of 1142 HIV-infected patients. RESULTS: Increased suPAR levels were significantly associated with age, female sex, daily smoking, metabolic syndrome and waist circumference. cART was associated with 17% lower suPAR levels. In cART-treated patients 10-fold higher HIV RNA was associated with 15% higher suPAR, whereas there was no association in untreated patients. Patients with CD4+ cell count <350 cells/µL had higher suPAR levels than patients with CD4+ cell count ≥350 cells/µL , though not significantly. We found no association with nadir CD4+ cell count or with duration of HIV-infection [corrected]. Finally, suPAR was not associated with adipose tissue distribution, but strongly associated with low leg muscle mass [corrected].In patients infected through intravenous drug use (IDU), CD4+ cell counts ≥350 cells/µL were associated with 27% lower suPAR (p = 0.03), andsuPAR was 4% lower pr. year during treatment (p = 0.05); however, there was no association with HIV RNA, duration of HIV-infection, nor cART [corrected]. CONCLUSION: We found elevated suPAR levels in untreated patients compared to patients on cART. Moreover, we observed a significant positive association between suPAR and HIV RNA levels in cART-treated patients. Age, HIV-transmission through IDU, metabolic syndrome, smoking, and low leg muscle mass were also significantly associated with suPAR levels. Our study therefore indicates, that also other aspects of living with HIV than virologic and immunologic markers add to the increased inflammation in HIV-infected patients.

Prognosis in patients with cirrhosis and mild portal hypertension.

OBJECTIVE: Sixty to 70% of upper gastrointestinal bleeding episodes in patients with cirrhosis are caused by oesophageal varices. Prophylaxis is indicated in patients with varices and a hepatic venous pressure gradient (HVPG) above 12 mmHg. The study of the natural history of patients with lower HVPG has been sparse. In this study, long-term survival and the risk of complications in mild portal hypertension were analysed. MATERIAL AND METHODS: Sixty-one patients with cirrhosis and HVPG below 10 mmHg were included in the study. Data were collected from medical files and National Patient Registries. Variceal bleeding, hepatic encephalopathy and death related to cirrhosis were registered. Thirty-nine patients were graded as Child class A, 19 as class B and 3 as class C. Median survival time was 11 years. RESULTS: Twenty-eight patients (46%) developed one or more complications: variceal bleeding in 10 (16%) and hepatic encephalopathy in 18 patients (30%). Twenty-three patients (38%) died from complications of cirrhosis. Two patients (3%) died from variceal bleeding, another two (3%) from gastrointestinal bleeding of unidentified source. Survival rate was significantly decreased compared with that in the background population. CONCLUSIONS: The frequency of complications in patients with mild portal hypertension is considerable, and guidelines for follow-up or medical prophylaxis are warranted. The risk of bleeding from oesophageal varices is low and bleeding-related deaths rare.