Tumor necrosis factor superfamily members CD137 and OX40 ligand in vascular inflammation

Atherosclerosis, an inflammatory disease, is the major cause of cardiovascular disease - the main cause of death worldwide. T cells are central orchestrators of inflammation in atherosclerosis and critically depend on costimulation for adequate function. Hence, costimulation is pivotal for maintaining immunological homeostasis of inflammatory responses, and a dysregulated immune response may aggravate inflammation in atherosclerosis. Costimulators are therefore of central interest in the pathogenesis of cardiovascular disease. CD137 and OX40 ligand are important costimulatory molecules of the tumor necrosis factor superfamily, but their role in vascular inflammation has been unclear. We used human biobanks and clinical cohorts in combination with experimental models of atherosclerosis and atherothrombosis to investigate the involvement of CD137 and OX40 ligand in the pathogenesis of cardiovascular disease. We observed that CD137 was expressed in human and murine atherosclerosis, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. By studying gene expression in cell lines, we found an association between the single nucleotide polymorphism (SNP) rs2453021 and CD137 mRNA expression in human lymphoid cells. The minor allele of this SNP was associated with an increased intima media thickness in human carotid arteries in individuals with risk factors of cardiovascular disease. To study the influence of CD137 activation on atherothrombosis, we turned to an experimental plaque rupture model. We observed that CD137 mRNA expression was higher in ruptured compared to non-ruptured murine carotid lesions. Stimulation of CD137 promoted vascular and systemic inflammation, but did not increase plaque rupture frequency. Others have reported an association between the SNP rs3850641 in OX40 ligand and cardiovascular risk. We did observe expression of OX40 ligand on endothelial cells within human carotid atherosclerotic lesions, and the OX40 ligand expression was induced by tumor necrosis factor (TNF) in cultured vascular endothelial cells. However, we found no association with the risk for stroke in two independent populations. In conclusion, the studies in this thesis demonstrate expression of CD137 and OX40 ligand in human atherosclerotic lesions, and that activation of CD137 promotes inflammation and atherosclerosis development in hypercholesterolemic mice. These new insights on the pathophysiology of atherosclerosis warrant further studies of the therapeutic potential of interventions in costimulation for treatment of cardiovascular disease

Low-cost exercise interventions improve long-term cardiometabolic health independently of a family history of type 2 diabetes : a randomized parallel group trial

Introduction To investigate the effect of an exercise prescription and a 1-year supervised exercise intervention, and the modifying effect of the family history of type 2 diabetes (FH), on long-term cardiometabolic health. Research design and methods For this prospective randomized trial, we recruited non-diabetic participants with poor fitness (n=1072, 30-70 years). Participants were randomly assigned with stratification for FH either in the exercise prescription group (PG, n=144) or the supervised exercise group (EG, n=146) group and compared with a matched control group from the same population study (CON, n=782). The PG and EG received exercise prescriptions. In addition, the EG attended supervised exercise sessions two times a week for 60 min for 12 months. Cardiometabolic risk factors were measured at baseline, 1 year, 5 years, and 6 years. The CON group received no intervention and was measured at baseline and 6 years. Results The EG reduced their body weight, waist circumference, diastolic blood pressure, and low-density lipoprotein-cholesterol (LDL-C) but not physical fitness (p=0.074) or insulin or glucose regulation (p>0.1) compared with the PG at 1 year and 5 years (p Conclusions Low-cost physical activity programs have long-term beneficial effects on cardiometabolic health regardless of the FH of diabetes. Given the feasibility and low cost of these programs, they should be advocated to promote cardiometabolic health.Peer reviewe

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Oral nutritional supplement use is weakly associated with increased subjective health-related quality of life in malnourished older adults : a multicentre randomised controlled trial

Malnutrition is common among older adults in health-care settings and is associated with decreased quality of life (QoL). The present study aimed to investigate the effect on health-related QoL (HRQoL) among older adults after 6 months of treatment with individual dietary advice (DA) and/or oral nutritional supplements (ONS), utilising 409 patients included in a multicentre randomised controlled trial of patients >= 65 years old, stratified according to nutrition status (malnourished/at risk of malnutrition), admitted to hospital in Sweden 2010-2014. Patients were randomised into four arms: DA, ONS, DA + ONS or routine care (control). The intervention started at discharge from hospital, with HRQoL measured using European QoL five-dimension, three-level (EQ-5D-3L) and European QoL-visual analogue scale (EQ-VAS) at baseline and at 6-month, 1-year and 3-year follow-ups. Data were analysed using the Kruskal-Wallis test and multiple linear regression. Overall, HRQoL increased from baseline to follow-ups, although the magnitude of change in EQ-5D-3L did not differ significantly between the four arms in any of the nutrition groups. However, a significant difference was observed for change in EQ-VAS from baseline to 6-month follow-up in the malnourished group, with mean changes of 22 center dot 4 and -3 center dot 4 points for the ONS and control groups, respectively (P = 0 center dot 009). In the multiple linear regression analyses, participants in the ONS arm had 27 center dot 5, 34 center dot 4 and 38 center dot 8 points larger increases in EQ-VAS from baseline to the 6-month (P = 0 center dot 011), 1-year (P = 0 center dot 007) and 3-year (P = 0 center dot 032), respectively, follow-ups than the control group. The use of ONS improved subjectively assessed HRQoL in these malnourished older adults

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Nutritional status predicts preterm death in older people : a prospective cohort study

Background &amp; aims: There is an association between malnutrition and mortality. However, it is uncertain whether this association is independent of confounders. The aim of the present study was to examine whether nutritional status, defined according to the three categories in the full Mini Nutritional Assessment (MNA) instrument, is an independent predictor of preterm death in people 65 years and older. Methods: This prospective cohort study included individuals aged &gt;= 65 years who were admitted to hospital between March 2008 and May 2009 and followed-up after 50 months (n = 1767). Nutritional status was assessed with the MNA, and possible risk factors associated with malnutrition were recorded during participants hospital stay. Main outcome measure was overall survival. Results: Based on the MNA definitions, 628 (35.5%) were well-nourished, 973 (55.1%) were at risk of malnutrition, and 166 (9.4%) of the participants were malnourished at baseline. During the follow-up period 655 (37.1%) participants died. At follow-up, the survival rates were 75.2% for well-nourished participants, 60.0% for those at risk of malnutrition, and 33.7% for malnourished participants (p &lt; 0.001). After adjusting for confounders the hazard ratios (95% CI) for all-cause mortality were 1.56 (1.18-2.07) in the group at risk of malnutrition and 3.71 (2.28-6.04) in the malnourished group. Conclusions: Nutritional status defined according to the three categories in the full MNA independently predicts preterm death in people aged 65 years and older. These findings are clinically important and emphasise the usefulness of the MNA for screening of nutritional status.Correction in: Clinical Nutrition, vol. 37, issue 5, pages 1781-1782.DOI: 10.1016/j.clnu.2018.07.002</p

Nutritional status predicts preterm death in older people : a prospective cohort study

Background &amp; aims: There is an association between malnutrition and mortality. However, it is uncertain whether this association is independent of confounders. The aim of the present study was to examine whether nutritional status, defined according to the three categories in the full Mini Nutritional Assessment (MNA) instrument, is an independent predictor of preterm death in people 65 years and older. Methods: This prospective cohort study included individuals aged &gt;= 65 years who were admitted to hospital between March 2008 and May 2009 and followed-up after 50 months (n = 1767). Nutritional status was assessed with the MNA, and possible risk factors associated with malnutrition were recorded during participants hospital stay. Main outcome measure was overall survival. Results: Based on the MNA definitions, 628 (35.5%) were well-nourished, 973 (55.1%) were at risk of malnutrition, and 166 (9.4%) of the participants were malnourished at baseline. During the follow-up period 655 (37.1%) participants died. At follow-up, the survival rates were 75.2% for well-nourished participants, 60.0% for those at risk of malnutrition, and 33.7% for malnourished participants (p &lt; 0.001). After adjusting for confounders the hazard ratios (95% CI) for all-cause mortality were 1.56 (1.18-2.07) in the group at risk of malnutrition and 3.71 (2.28-6.04) in the malnourished group. Conclusions: Nutritional status defined according to the three categories in the full MNA independently predicts preterm death in people aged 65 years and older. These findings are clinically important and emphasise the usefulness of the MNA for screening of nutritional status.Correction in: Clinical Nutrition, vol. 37, issue 5, pages 1781-1782.DOI: 10.1016/j.clnu.2018.07.002</p

Dietary advice and oral nutritional supplements do not increase survival in older malnourished adults : a multicentre randomised controlled trial

Objectives: The study aimed to investigate the effect on survival after 6 months of treatment involving individual dietary advice and oral nutritional supplements in older malnourished adults after discharge from hospital. Methods: This multicentre randomised controlled trial included 671 patients aged 65 years who were malnourished or at risk of malnutrition when admitted to hospital between 2010 and 2014, and followed up after 8.2 years (median 4.1 years). Patients were randomised to receive dietary advice or oral nutritional supplements, separate or in combination, or routine care. The intervention started at discharge from the hospital and continued for 6 months, with survival being the main outcome measure. Results: During the follow-up period 398 (59.3%) participants died. At follow-up, the survival rates were 36.9% for dietary advice, 42.4% for oral nutritional supplements, 40.2% for dietary advice combined with oral nutritional supplements, and 43.3% for the control group (log-rank test p = 0.762). After stratifying the participants according to nutritional status, survival still did not differ significantly between the treatment arms (log-rank test p = 0.480 and p = 0.298 for the 506 participants at risk of malnutrition and the 165 malnourished participants, respectively). Conclusions: Oral nutritional supplements with or without dietary advice, or dietary advice alone, do not improve the survival of malnourished older adults. These results do not support the routine use of supplements in older malnourished adults, provided that survival is the aim of the treatment

Mealtime habits and meal provision are associated with malnutrition among elderly patients admitted to hospital

Background &amp; aims: Large-scale studies performed in hospitals with the validated Mini Nutritional Assessment tool (MNA) are scarce. However, factors associated with malnutrition are important for identifying individuals at risk. The aims of the present study were to estimate the prevalence of malnutrition and to examine the association between mealtime habits, meal provision, and malnutrition among elderly patients admitted to hospital. Methods: This cross-sectional study included patients aged ≥ 65 years admitted to internal medicine, surgical or orthopaedic wards. The MNA was used for their nutritional assessment, and factors potentially associated with malnutrition were recorded. Results: Of 1771 patients (mean age 78 years), 35.5% were well-nourished, 55.1% were at risk of malnutrition and 9.4% were malnourished. Overnight fasts exceeding 11 hours, fewer than four eating episodes a day, and not cooking independently were associated with both malnutrition and risk of malnutrition. Conclusions: The risk of malnutrition was high among elderly patients admitted to hospital, whereas the proportion with fully developed malnutrition was lower than expected. A long overnight fast, few eating episodes, and not cooking independently were associated with an increased risk of malnutrition. Knowledge of these factors when providing care to the elderly may assist health-care professionals to prevent malnutrition.Correction in: Clinical Nutrition, vol. 37, issue 5, pages 1783-1785DOI: 10.1016/j.clnu.2018.05.030</p