Altered Plasma Fatty Acids Associate with Gut Microbial Composition in Common Variable Immunodeficiency.

PURPOSE: Fatty acid (FA) abnormalities are found in various inflammatory disorders and have been related to disturbed gut microbiota. Patients with common variable immunodeficiency (CVID) have inflammatory complications associated with altered gut microbial composition. We hypothesized that there is an altered FA profile in CVID patients, related to gut microbial dysbiosis. METHODS: Plasma FAs were measured in 39 CVID patients and 30 healthy controls. Gut microbial profile, a food frequency questionnaire, and the effect of the oral antibiotic rifaximin were investigated in CVID patients. RESULTS: The n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) (1.4 [1.0-1.8] vs. 1.9 [1.2-2.5], median (IQR), P < 0.05), and docosahexaenoic acid (DHA) (3.2 [2.4-3.9] vs. 3.5 [2.9-4.3], P < 0.05), all values expressed as weight percent of total plasma FAs, were reduced in CVID compared to controls. Also, n-6 PUFAs (34.3 ± 3.4 vs. 37.1 ± 2.8, mean ± SD, P < 0.001) and linoleic acid (LA) (24.5 ± 3.3 vs. 28.1 ± 2.7, P < 0.0001) and the FA anti-inflammatory index (98.9 [82.1-119.4] vs. 117.0 [88.7-153.1], median (IQR), P < 0.05) were reduced in CVID. The microbial alpha diversity was positively associated with plasma n-6 PUFAs (r = 0.41, P < 0.001) and LA (r = 0.51, P < 0.001), but not n-3 PUFAs (P = 0.78). Moreover, a 2-week course of rifaximin significantly reduced the proportion of n-6 PUFAs (P = 0.04, UNIANOVA). Serum immunoglobulin G (IgG) levels correlated with plasma n-3 PUFAs (rho = 0.36, P = 0.03) and DHA (rho = 0.41, P = 0.009). CONCLUSION: We found a potentially unfavorable FA profile in CVID, related to low IgG levels. High plasma n-6 PUFAs were related to increased gut microbial diversity and altered by rifaximin therapy.

Instability in NAD+ metabolism leads to impaired cardiac mitochondrial function and communication.

Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.

Index of microvascular resistance to assess the effect of rosuvastatin on microvascular function in women with chest pain and no obstructive coronary artery disease: A double-blind randomized study.

INTRODUCTION: Many women undergoing coronary angiography for chest pain have no or only minimal coronary artery disease (CAD). However, despite the lack of obstructive CAD, they still have an increased risk of major adverse cardiovascular events. Pleiotropic effects of statins may influence microvascular function, but if statins improve microvascular function in unselected chest pain patients is not well studied. This study assessed microvascular function by using the thermodilution-derived test "the index of microvascular resistance" (IMR) with the aim of determining the (i) IMR level in women with chest pain and non-obstructive CAD and if (ii) IMR is modified by high-dose statin treatment in these patients. Additional objectives were to identify the influence of statins on the health status as assessed with generic health questionnaires and on biomarkers of endothelial activation. MATERIALS AND METHODS: The study was a randomized, double-blind, single-center trial comparing 6 months of rosuvastatin treatment with placebo. In total, 66 women without obstructive CAD were included. Mean age was 52.7 years and 55.5 years in the placebo and rosuvastatin group, respectively. Microvascular function was assessed using the IMR, health status was assessed using the SF-36 and EQ-5D questionnaires, and biochemical values were assessed at baseline and 6 months later. RESULTS AND CONCLUSIONS: In the placebo group IMR was 14.6 (SD 5.7) at baseline and 14.4 (SD 6.5) at follow-up. In the rosuvastatin group IMR was 16.5 (SD 7.5) at baseline and 14.2 (SD 5.8) at follow-up. IMR did not differ significantly between the two study groups at follow-up controlled for preintervention values. C-reactive protein (CRP) was comparable between the groups at baseline, while at follow-up CRP was significantly lower in the rosuvastatin group compared to placebo [0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L; p = 0.002]. Whereas rosuvastatin treatment for 6 months attenuated CRP levels, it did not improve microvascular function as assessed by IMR (Clinical Trials.gov NCT01582165, EUDRACT 2011-002630-39.3tcAZ).

Bariatric surgery reduces fasting total fatty acids and increases n-3 polyunsaturated fatty acids in morbidly obese individuals.

BACKGROUND: Obesity is a global pandemic leading to increased mortality and increased risk of cardiovascular disease. Bariatric surgery is an established treatment of obesity leading to weight loss and reduction of mortality. To further elucidate how bariatric surgery improves metabolic control, we explored the fatty acid (FA) profiles in morbidly obese subjects treated with lifestyle intervention and subsequent bariatric surgery. METHODS: The intervention group consisted of 34 morbidly obese patients scheduled for bariatric surgery and the control group of 17 non-obese patients scheduled for elective laparoscopic procedures. The intervention group had to undergo lifestyle changes preoperatively. Fasting blood samples were drawn at admission, after lifestyle intervention and 1 year after bariatric surgery. RESULTS: At admission, the morbidly obese patients had significantly higher levels of monounsaturated FAs (MUFAs) and lower levels of n-6 polyunsaturated FAs (PUFAs) and n-3 PUFAs than healthy controls (all p-values <.05). In the intervention group, there was a significantly lower level of total FAs after lifestyle intervention, and from admission to 1 year after surgical intervention (both, p < .05), primarily reflecting a lower proportion of saturated FAs (SFAs). Following bariatric surgery, but not after lifestyle changes, there was an increase in the proportion of n-3 PUFA (p < .05) reaching levels not significantly different from healthy controls. CONCLUSIONS: Our findings suggest that a reduced proportion of the proposed anti-atherogenic n-3 PUFAs characterizes morbidly obese individuals, and that this FA profile is reversed by bariatric surgery, but not by lifestyle intervention.

The Carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis.

BACKGROUND AND PURPOSE: γ-butyrobetaine (γBB) is a metabolite from dietary Carnitine, involved in the gut microbiota-dependent conversion from Carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Orally ingested γBB has a pro-atherogenic effect in experimental studies, but γBB has not been studied in relation to atherosclerosis in humans. The aim of this study was to evaluate associations between serum levels of γBB, TMAO and their common precursors Carnitine and trimethyllysine (TML) and carotid atherosclerosis and adverse outcome. METHODS: Serum γBB, Carnitine, TML and TMAO were quantified by high performance liquid chromatography in patients with carotid artery atherosclerosis (n = 264) and healthy controls (n = 62). RESULTS: Serum γBB (p = 0.024) and Carnitine (p = 0.001), but not TMAO or TML, were increased in patients with carotid atherosclerosis. Higher levels of γBB and TML, but not TMAO or Carnitine were independently associated with cardiovascular death also after adjustment for age and eGFR (adjusted HR [95%] 3.3 [1.9-9.1], p = 0.047 and 6.0 [1.8-20.34], p = 0.026, respectively). CONCLUSIONS: Patients with carotid atherosclerosis had increased serum levels of γBB, and elevated levels of γBB and its precursor TML were associated with cardiovascular mortality. Long-term clinical studies of γBB, as a cardiovascular risk marker, and safety studies regarding dietary supplementation of γBB, are warranted.

Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclerosis.

Observational studies have suggested that vitamin D may reduce inflammation in relapsing-remitting multiple sclerosis (RRMS), but this has not been clearly confirmed in randomized controlled trials. To further explore the possible anti-inflammatory effects of vitamin D in RRMS, we examined the effect of high-dose oral vitamin D3 on eleven markers of systemic inflammation in 68 RRMS patients enrolled in a double-blinded randomized placebo-controlled trial of vitamin D3 supplementation (20,000 IU/week) (NCT00785473). Serum inflammation markers and 25-hydroxyvitamin D (25(OH)D) were measured at baseline and week 96, and no restrictions were set on additional standard immunomodulatory treatment for RRMS. The mean 25(OH)D level rose from 56 ± 29 to 123 ± 34 nmol/L among patients receiving vitamin D3 supplementation, whereas only a minor increase from 57 ± 22 to 63 ± 24 nmol/L was seen in the placebo group. However, no significant differences appeared between the vitamin D group and the placebo group for any of the inflammation markers. Patients on immunomodulatory therapy had significantly higher levels of interleukin-1 receptor antagonist and chemokine (C-X-C motif) ligand 16 than patients without immunomodulatory treatment, but there were no clear synergistic effects between immunomodulatory therapy and vitamin D3 supplementation on any of the inflammation markers. The rise in 25(OH)D levels after vitamin D3 supplementation was unaffected by immunomodulatory treatment. We conclude that in this study of RRMS patients, high-dose oral vitamin D3 supplementation prominently increased serum 25(OH)D levels without affecting markers of systemic inflammation, while a more anti-inflammatory phenotype was found among patients on immunomodulatory treatment.

Vitamin D status and effect of interferon-ß1a treatment on MRI activity and serum inflammation markers in relapsing-remitting multiple sclerosis.

To explore if vitamin D modulates interferon-ß1a treatment effects in relapsing-remitting multiple sclerosis, we examined relationships between serum vitamin D and magnetic resonance imaging (MRI) activity and ten systemic inflammation markers in 88 patients, before and during treatment. Odds ratios for all MRI parameters were negatively associated with vitamin D levels before therapy, but converged to equally low values irrespective of vitamin D status during treatment. During therapy, similar alterations of MRI activity and inflammation markers were found across patients categorized by mean vitamin D values. This suggests that vitamin D status has no major influence on interferon-ß1a treatment effects.

An immunomodulating fatty acid analogue targeting mitochondria exerts anti-atherosclerotic effect beyond plasma cholesterol-lowering activity in apoe(-/-) mice.

Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs) and proliferation of mitochondria. This study aimed to penetrate the effect of TTA on the development of atherosclerotic lesions in apolipoprotein (apo)-E(-/-) mice fed a high-fat diet containing 0.3% TTA for 12 weeks. These mice displayed a significantly less atherosclerotic development vs control. Plasma cholesterol was increased by TTA administration and triacylglycerol (TAG) levels in plasma and liver were decreased by TTA supplementation, the latter, probably due to increased mitochondrial fatty acid oxidation and reduced lipogenesis. TTA administration also changed the fatty acid composition in the heart, and the amount of arachidonic acid (ARA) and eicosapentaenoic acid (EPA) was reduced and increased, respectively. The heart mRNA expression of inducible nitric oxidase (NOS)-2 was decreased in TTA-treated mice, whereas the mRNA level of catalase was increased. Finally, reduced plasma levels of inflammatory mediators as IL-1α, IL-6, IL-17, TNF-α and IFN-γ were detected in TTA-treated mice. These data show that TTA reduces atherosclerosis in apoE(-/-) mice and modulates risk factors related to atherosclerotic disorders. TTA probably acts at both systemic and vascular levels in a manner independent of changes in plasma cholesterol, and triggers TAG catabolism through improved mitochondrial function.

Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity.

BACKGROUND: Serum markers of inflammation are candidate biomarkers in multiple sclerosis (MS). ω-3 fatty acids are suggested to have anti-inflammatory properties that might be beneficial in MS. We aimed to explore the relationship between serum levels of inflammation markers and MRI activity in patients with relapsing remitting MS, as well as the effect of ω-3 fatty acids on these markers. METHODS: We performed a prospective cohort study in 85 relapsing remitting MS patients who participated in a randomized clinical trial of ω-3 fatty acids versus placebo (the OFAMS study). During a period of 24 months 12 repeated magnetic resonance imaging (MRI) scans and nine serum samples were obtained. We measured 10 inflammation markers, including general down-stream markers of inflammation, specific markers of up-stream inflammatory pathways, endothelial action, and matrix regulation. RESULTS: After Bonferroni correction, increasing serum levels of CXCL16 and osteoprotegerin were associated with low odds ratio for simultaneous MRI activity, whereas a positive association was observed for matrix metalloproteinase (MMP) 9. CXCL16 were also associated with low MRI activity the next month, but this was not significant after Bonferroni correction. In agreement with previously reported MRI and clinical results, ω-3 fatty acid treatment did not induce any change in the inflammation markers. CONCLUSIONS: Serum levels of CXCL16, MMP-9, and osteoprotegerin reflect disease activity in MS, but are not affected by ω-3 fatty acid treatment. CXCL16 could be a novel biomarker and potential predictor of disease activity in MS.

Tetradecylthioacetic acid increases fat metabolism and improves cardiac function in experimental heart failure.

Changes in myocardial metabolism, including a shift from fatty acid to glucose utilization and changes in fatty acid availability and composition are characteristics of heart failure development. Tetradecylthioacetic acid (TTA) is a fatty acid analogue lacking the ability to undergo mitochondrial ß-oxidation. TTA promotes hepatic proliferation of mitochondria and peroxisomes and also decreases serum triglycerides and cholesterol in animals. We investigated the effect of TTA, in combination with a high-fat or regular diet, in a rat model of post-myocardial infarction heart failure. TTA had a beneficial effect on cardiac function in post-myocardial infarction heart failure without affecting myocardial remodeling. These effects of TTA on myocardial function were accompanied by decreased free fatty acids in plasma, increased myocardial proportion of n-3 polyunsaturated fatty acids (PUFA) and a decreased proportion of n-6 PUFA. Myocardial enzyme gene expression during TTA treatment suggested that the increase in n-3 PUFA could reflect increased n-3 PUFA synthesis and inadequately increased n-3 PUFA ß-oxidation. Based on our data, it is unlikely that the changes are secondary to alterations in other tissues as plasma and liver showed an opposite pattern with decreased n-3 PUFA during TTA treatment. The present study suggests that TTA may improve myocardial function in heart failure, potentially involving its ability to decrease the availability of FFA and increase the myocardial proportion of n-3 PUFA.

Krill oil attenuates left ventricular dilatation after myocardial infarction in rats.

BACKGROUND: In the western world, heart failure (HF) is one of the most important causes of cardiovascular mortality. Supplement with n-3 polyunsaturated fatty acids (PUFA) has been shown to improve cardiac function in HF and to decrease mortality after myocardial infarction (MI). The molecular structure and composition of n-3 PUFA varies between different marine sources and this may be of importance for their biological effects. Krill oil, unlike fish oil supplements, contains the major part of the n-3 PUFA in the form of phospholipids. This study investigated effects of krill oil on cardiac remodeling after experimental MI. Rats were randomised to pre-treatment with krill oil or control feed 14 days before induction of MI. Seven days post-MI, the rats were examined with echocardiography and rats in the control group were further randomised to continued control feed or krill oil feed for 7 weeks before re-examination with echocardiography and euthanization. RESULTS: The echocardiographic evaluation showed significant attenuation of LV dilatation in the group pretreated with krill oil compared to controls. Attenuated heart weight, lung weight, and levels of mRNA encoding classical markers of LV stress, matrix remodeling and inflammation reflected these findings. The total composition of fatty acids were examined in the left ventricular (LV) tissue and all rats treated with krill oil showed a significantly higher proportion of n-3 PUFA in the LV tissue, although no difference was seen between the two krill oil groups. CONCLUSIONS: Supplement with krill oil leads to a proportional increase of n-3 PUFA in myocardial tissue and supplement given before induction of MI attenuates LV remodeling.

Cystatin C levels in plasma and peripheral blood mononuclear cells among hyperhomocysteinaemic subjects: effect of treatment with B-vitamins.

Homocysteine has been related to increased risk of CVD. Matrix degradation and inflammation may be involved in this link between hyperhomocysteinaemia and CVD. Recent studies suggest that cystatin C can modulate matrix degradation and inflammation. The present study measured cystatin C at protein (plasma) and mRNA levels (peripheral blood mononuclear cells (PBMC)) in hyperhomocysteinaemic individuals (n 37, female seven and male thirty, aged 20-70 years) before and after B-vitamin supplementation for 3 months in a randomised, placebo-controlled double-blind trial. In a cross-sectional study, seventeen of the hyperhomocysteinaemic subjects were age- and sex-matched to healthy controls (n 17). Our main findings were: (i) as compared with controls, hyperhomocysteinaemic subjects tended to have higher plasma concentrations of cystatin C and lower mRNA levels of cystatin C in PBMC; (ii) compared with placebo, treatment of hyperhomocysteinaemic individuals with B-vitamins significantly increased plasma levels of cystatin C and mRNA levels of cystatin C in PBMC; (iii) while plasma levels of cystatin C were positively correlated with plasma levels of TNF receptor-1, mRNA levels of cystatin C in PBMC were inversely correlated with this TNF parameter. Taken together, our findings suggest that disturbed cystatin C levels may be a characteristic of hyperhomocysteinaemic individuals, potentially related to low-grade systemic inflammation in hyperhomocysteinaemic subjects, and that B-vitamins may modulate cystatin C levels in these individuals.

Diabetic foot ulcer burden may be modified by high-dose atorvastatin: A 6-month randomized controlled pilot trial.

BACKGROUND: Diabetic foot ulcers (DFUs) are common complications of diabetes mellitus (DM), with a complex pathogenesis. Treatment is difficult and no single treatment with measurable clinical impact is available. In the present clinical pilot trial, we investigated whether statins could be of use against some of the pathogenic factors in DFUs. METHODS: Thirteen diabetic patients (10 men; 11 with Type 2 DM; mean age 64 years; mean duration of DM 18 years) with neuropathic DFUs <4 months were randomized to treatment with either 10 mg (six patients; six ulcers) or 80 mg (seven patients; nine ulcers) atorvastatin for 6 months in addition to conventional DFU care (i.e. prompt debridement, DFU pressure relief, and management of any underlying infection). RESULTS: There were no significant differences in background factors (i.e. HbA1c 8.9%, micro- and macrovascular complications, concomitant medications) or DFU characteristics (duration, surface area, grading) between the two groups. All ulcers in the group receiving 10 mg atorvastatin healed, compared with six of nine ulcers in the group receiving 80 mg atorvastatin (NS). However, two previously healed DFUs recurred and six new DFUs developed in the low-dose group compared with none and one, respectively, in the high-dose group (P = 0.048). There was a significant decrease in C-reactive protein (-1.5 mg/L; P = 0.044) and a non-significant trend towards beneficial effects on lipids and the ankle-arm blood pressure index in the high-dose compared with the low-dose group. CONCLUSIONS: We observed a possible beneficial effect of 6-months high-dose atorvastatin on DFUs, which should be tested in appropriately sized prospective studies.

Dysregulated RANK ligand/RANK axis in hyperhomocysteinemic subjects: effect of treatment with B-vitamins.

BACKGROUND AND PURPOSE: Homocysteine has been linked to increased risk of ischemic stroke and other cardiovascular events. Matrix degradation and inflammation play an important role in these disorders, and we have demonstrated increased levels of matrix-degrading enzymes and inflammatory cytokines in hyperhomocysteinemic individuals. Recent studies suggest that RANK ligand (RANKL) through interaction with its receptor RANK can modulate matrix degradation and inflammation. The present study aimed to examine the role of the RANKL/RANK axis in hyperhomocystinemia. METHODS: RANKL/RANK was measured on protein or mRNA level before and after B-vitamin supplementation in hyperhomocysteinemic individuals. We also examined the in vitro effects of soluble RANKL in peripheral blood mononuclear cells from hyperhomocysteinemic individuals. RESULTS: Our main findings were: (1) compared to peripheral blood mononuclear cells from controls, cells from hyperhomocysteinemic individuals had significantly higher gene expression of RANKL and RANK; (2) folic acid treatment for 6 weeks in an open, uncontrolled study significantly reduced gene expression of RANKL/RANK in peripheral blood mononuclear cells from these individuals; (3) compared to placebo, treatment with folic acid, vitamin B(12), and vitamin B(6) for 3 months in a randomized, double-blind trial significantly lowered serum levels of soluble RANKL in hyperhomocysteinemic individuals; and (4) in vitro, soluble RANKL markedly increased the release of matrix metalloproteinase-9 and inflammatory cytokines from peripheral blood mononuclear cells in hyperhomocysteinemic subjects. CONCLUSIONS: Our findings suggest a dysregulated RANKL/RANK axis in hyperhomocysteinemic subjects. Based on their role in atherogenesis, this enhanced expression of RANKL and RANK could contribute to the increased risk of cardiovascular disease in hyperhomocystinemia. Moreover, treatment with B-vitamins may have beneficial implications for plaque stability in these individuals.

High levels and inflammatory effects of soluble CXC ligand 16 (CXCL16) in coronary artery disease: down-regulatory effects of statins.

AIMS: CXC ligand 16 (CXCL16) may be involved in inflammation and lipid metabolism, and we hypothesized a role for this chemokine in coronary artery disease (CAD). METHODS AND RESULTS: We performed clinical studies in CAD patients as well as experimental studies in cells with relevance to atherogenesis [i.e. endothelial cells, vascular smooth muscle cells (SMC), and peripheral blood mononuclear cells (PBMC)]. We also examined the ability of HMG-CoA reductase inhibitors (statins) to modulate CXCL16 levels both in vivo and in vitro. Our main findings were: (i) patients with stable (n = 40) and unstable (n = 40) angina had elevated plasma levels of CXCL16 compared with controls (n = 20); (ii) low-dose simvastatin (20 mg qd, n = 15) and high-dose atorvastatin (80 mg qd, n = 9) down-regulated plasma levels of CXCL16 during 6 months of therapy; (iii) in vitro, atorvastatin significantly decreased the interleukin (IL)-1beta-mediated release of CXCL16 from PBMC and endothelial cells; (iv) attenuating effect of atorvastatin on the IL-1beta-mediated release of CXCL16 in PBMC seems to involve post-transcriptional modulation as well as down-regulation of CXCL16 release through inhibition of the protease a disintegrin and metalloproteinase 10 (ADAM10); (v) soluble CXCL16 increased the release of IL-8, monocyte chemoattractant peptide 1, and matrix metalloproteinases in vascular SMC and increased the release of IL-8 and monocyte chemoattractant peptide 1 in PBMC, with particularly enhancing effects in cells from CAD patients. CONCLUSION: Our findings suggest that soluble CXCL16 could be linked to atherogenesis not only as a marker of inflammation, but also as a potential inflammatory mediator.

Potential role for immunomodulatory therapy in atherosclerotic plaque stabilisation.

Our understanding of the mechanisms underlying acute coronary syndromes has evolved beyond the view that this syndrome reflects a progressive collection of lipids and cellular debris in the vascular wall. Current evidence has implicated a role for inflammation in the pathogenesis of this process. Thus, inflammatory cytokines may attenuate interstitial collagen synthesis, increase matrix degradation and promote apoptosis in several atheroma-associated cell types, and all these cellular events may enhance plaque vulnerability. Recently, a series of experimental studies have reported the plaque-stabilising effects of immunomodulatory therapy such as chemokine blockade, anti-CD40 ligand and IL-10. It is conceivable that some of these approaches will be tested clinically and, if successful, they could provide novel treatment strategies for atherosclerotic plaque stabilisation.

Effects of conventional and aggressive statin treatment on markers of endothelial function and inflammation.

BACKGROUND: Atherosclerosis is considered to be a chronic inflammatory disorder. Several large-scale clinical studies demonstrate that markers of inflammation, such as high-sensitivity C-reactive protein (hsCRP), fibrinogen, and soluble CD40 ligand, are potent and independent predictors of vascular risk. HYPOTHESIS: The study was undertaken to investigate the effect of increasing the statin dose from conventional to aggressive treatment on lipids levels, inflammation, and endothelial function in patients with coronary artery disease (CAD). METHODS: We randomized 97 patients to either 20 mg simvastatin or 80 mg atorvastatin. Plasma levels of lipids, hsCRP, fibrinogen, soluble adhesion molecules, and nitric oxide-total were analyzed at baseline and after 6 months of treatment. RESULTS: Lipid values were significantly reduced in both treatment groups, but with significantly greater reduction in the aggressively treated group. Furthermore, aggressive statin treatment significantly decreased hsCRP and fibrinogen, while only small reductions were seen in the conventionally treated group, resulting in significant differences between the two treatment groups (p < 0.001). Nitric oxide-total increased significantly in both treatment groups, although the increase was more pronounced in the aggressively treated group (22.6 vs. 15.6%). CONCLUSION: Aggressive statin treatment significantly improved lipid status and reduced markers of inflammation and improved endothelial function compared with conventional treatment in patients with CAD. No interaction was observed, and high-dose treatment did not offer additional benefit compared with standard-dose treatment with respect to soluble adhesion molecules.

Hyperhomocysteinemic subjects have enhanced expression of lectin-like oxidized LDL receptor-1 in mononuclear cells.

An elevated plasma concentration of homocysteine is an independent risk factor for cardiovascular disease. However, the mechanisms are still unclear. Lectin-like oxidized LDL receptor-1 (LOX-1) has ligand specificity for oxidized LDL (oxLDL). We hypothesized that homocysteine's atherogenic effects may involve LOX-1-mediated mechanisms. We examined the effect of folic acid supplementation for 6 wk and 12 mo (5 mg/d for 1 wk, 1 mg/d for 37 wk and 0.4 mg/d for the remaining 14 wk) on LOX-1 mRNA levels and on oxLDL-induced release of tumor necrosis factor alpha from peripheral blood mononuclear cells in hyperhomocysteinemic individuals. Compared with healthy controls, hyperhomocysteinemic subjects had elevated mRNA levels of LOX-1 in mononuclear cells (P < 0.001), and their mononuclear cells released more tumor necrosis factor alpha (TNFalpha) upon oxLDL stimulation (P = 0.01). This oxLDL-stimulated release of TNFalpha correlated with LOX-1 expression (r = 0.57, P = 0.026). Folic acid treatment led to a normalization of homocysteine levels accompanied by a reduction in LOX-1 gene expression (P < 0.02) and in oxLDL-stimulated release of TNFalpha (P < 0.05). These novel findings suggest both that homocysteine exerts its atherogenic effect in part by elevating levels of LOX-1, thereby enhancing oxLDL-induced inflammatory responses, and most important, that folic acid supplementation may downregulate these responses.

Disturbed glutathione metabolism and decreased antioxidant levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy--potential immunomodulatory effects of antioxidants.

Oxidative stress has been implicated in the pathogenesis of human immunodeficiency virus (HIV) infection. We examined the effect of highly active antiretroviral therapy (HAART) on plasma levels of several antioxidants and intracellular glutathione-redox status in CD4+ T cells, in 20 HIV-infected patients. HAART was accompanied by both an improvement of glutathione-redox status and an increase in levels of antioxidant vitamins, without full normalization. Glutathione supplementation in vitro increases T cell proliferation and suppresses the spontaneous release of tumor necrosis factor-alpha from peripheral blood mononuclear cells, in HIV-infected patients receiving HAART. Our findings suggest that therapeutic intervention aimed at normalization of oxidative disturbances in HIV infection could be of interest, in addition to HAART.

Circulating antioxidants and lipid peroxidation products in untreated tuberculosis patients in Ethiopia.

BACKGROUND: Knowledge of the antioxidant profile and its relation to lipid peroxidation in tuberculosis patients with or without accompanying HIV infection is scarce, particularly in developing countries. OBJECTIVE: The objective was to further investigate the interaction between HIV, tuberculosis, and antioxidants and their relations with markers of oxidative stress in a large population of Ethiopians. DESIGN: In a cross-sectional study, we evaluated antioxidants and markers of oxidative stress in Ethiopian tuberculosis patients with (n = 25) and without (n = 100) HIV infection and in Ethiopian (n = 45) and Norwegian (n = 25) healthy control subjects. RESULTS: Concentrations of the antioxidant vitamins C and E and of vitamin A were significantly lower in tuberculosis patients than in healthy Ethiopians. Tuberculosis patients also had significantly lower thiol concentrations, particularly of the reduced forms. Tuberculosis patients, particularly those who were co-infected with HIV, had higher malondialdehyde concentrations than did control subjects. High malondialdehyde concentrations were associated with clinical severity as measured by the Karnofsky Performance Status Index and anthropometric scores. Ethiopian control subjects had lower concentrations of vitamin E and higher concentrations of malondialdehyde than did Norwegian control subjects. CONCLUSIONS: Our findings further support a link between oxidative stress, tuberculosis, and HIV infection. However, whether antioxidant supplementation will improve tuberculosis outcome or is of importance for its prevention should be further examined in future prospective studies.