Endothelial Function in Patients with Multiple Sclerosis: The Role of GLP-1 Agonists, Lipoprotein Subfractions, and Redox Balance.

INTRODUCTION: Epidemiological studies have suggested an increased vascular risk in patients with multiple sclerosis (MS). There is increasing evidence of the beneficial effects of GLP-1 agonists (GLP-1a) in preventing vascular complications and slowing the progression of neurodegeneration. Our objective was to explore the changes in the endothelial function of MS patients after 12 months of GLP-1a therapy. We also explored the role of lipoprotein subfractions and the antioxidant capacity of plasma. METHODS: MS patients were enrolled in a prospective, unicentric study. GLP-1a (dulaglutide) was administered to 13 patients. The control population consisted of 12 subjects. Endothelial function was determined by peripheral arterial tonometry and expressed as reperfusion hyperemia index (RHI). Trolox equivalent antioxidant capacity (TEAC) was used to assess the total antioxidant capacity of the plasma. The levels of lipoprotein subfractions were evaluated. RESULTS: The GLP-1a group did not have a significant change in their RHIs after 12 months (2.1 ± 0.6 vs. 2.1 ± 0.7; p = 0.807). However, a significant increase in their TEACs was observed (4.1 ± 1.4 vs. 5.2 ± 0.5 mmol/L, p = 0.010). On the contrary, the subjects in the control group had a significant worsening of their RHIs (2.1 ± 0.5 vs. 1.8 ± 0.6; p = 0.030), without significant changes in their TEACs. Except for a significant decrease in very-low-density lipoprotein (VLDL) (30.8 ± 10.2 vs. 22.6 ± 8.3 mg/dL, p = 0.043), no other significant changes in the variables were observed in the control group. VLDL levels (beta = -0.637, p = 0.001), the use of GLP-1a therapy (beta = 0.560, p = 0.003), and small LDL (beta = 0.339, p = 0.043) were the only significant variables in the model that predicted the follow-up RHI. CONCLUSION: Our results suggest that the application of additional GLP-1a therapy may have atheroprotective and antioxidant effects in MS patients with high MS activity and thus may prospectively mitigate their vascular risk. However, the lipoprotein profile may also play an important role in the atherogenic risk of MS subjects.

Cardiac autonomic function in patients with early multiple sclerosis.

PURPOSE: Cardiac autonomic dysfunction has been reported in patients with long-standing multiple sclerosis (MS); however, data in early disease are limited. The present study was aimed at evaluating cardiac autonomic function in patients with early MS in the context of white matter metabolic status, which could potentially affect functions of the autonomic brain centers. METHODS: Cardiac sympathetic and baroreflex cardiovagal responses to the Valsalva maneuver, orthostatic test, and the Stroop test were evaluated in 16 early, treatment-naïve patients with relapsing-remitting MS, and in 14 healthy participants. Proton magnetic resonance spectroscopic imaging (MRSI) of the brain was performed in eight of these MS patients and in eight controls. RESULTS: Valsalva maneuver outcomes were comparable between patients and controls. At baseline, norepinephrine levels were lower (p = 0.027) in MS patients compared to controls. The patients had higher heart rate (p = 0.034) and lower stroke volume (p = 0.008), but similar blood pressure, cardiac output and norepinephrine increments from baseline to 2 min of the orthostatic test compared to controls. MS patients and controls did not differ in responses to the Stroop test. MRSI showed lower total N-acetylaspartate/total creatine (p = 0.038) and higher myo-inositol/total creatine (p = 0.013) in MS lesions compared to non-lesional white matter. CONCLUSION: Our results show normal cardiac sympathetic and baroreflex cardiovagal function in MS patients with relapsing-remitting MS with lesions at the post-acute/early resolving stage. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov under the Identifier: NCT03052595 and complies with the STROBE checklist for cohort, case-control, and cross-sectional studies.

Neurofilament light chain and MRI volume parameters as markers of neurodegeneration in multiple sclerosis.

BACKGROUND: Neurofilament light chain (NfL) is considered a major marker of neurodegeneration and disease activity. Higher levels of NfL are associated with worse clinical outcomes and increased brain atrophy. In treated patients with Relapsing-Remitting Multiple Sclerosis (RRMS), we aimed to determine the level of NfL, an association between NfL and demographic, clinical and magnetic resonance imaging (MRI) characteristics as well as brain volume parameters. We wanted to confirm that level of NfL is clinically useful as biomarker of neurodegeneration and disease activity. METHODS: 56 treated RRMS patients were enrolled. Plasmatic levels of NfL (pNfL) were measured by SIMOA® technique. Clinical severity of MS was expressed by Expanded Disability Status Scale (EDSS), and volumetric analysis of MRI data was performed using Icobrain software. RESULTS: The mean pNfL level was significantly higher in MS patients than in healthy controls (14.73 ± 6.38 versus 6.67 ± 3.9, p<0.001). In patients, we did not find association between pNfL and MRI activity, number of new T2 lesions, and number of enhancing lesions. Levels of pNfL correlated significantly with atrophy of whole brain volume (Wbv), atrophy of grey matter volume (Gmv), and negatively with Wbv. We found significantly positive correlation between pNfL levels and EDSS. CONCLUSION: Study shows association of pNfL with Wbv, presence of brain atrophy and EDSS, and strong correlation of EDSS with multiple MRI volume parameters. We did not confirm association pNfL with disease activity. Our data suggest that pNfL and MRI volume parameters could be considered as biomarkers of neurodegeneration in MS.

Lipoprotein profiling in early multiple sclerosis patients: effect of chronic inflammation?

BACKGROUND: Inflammatory cytokines contribute to proatherogenic changes in lipid metabolism by reduction of HDL-cholesterol (HDL-C) levels, impairment of its antiinflammatory and antioxidant functions. Therefore, the protective actions of HDL-C can be limited in chronic inflammatory diseases such as multiple sclerosis (MS). The aim of this study was to assess the association between lipoprotein subfractions and inflammatory status in early stages of multiple sclerosis. METHODS: Polyacrylamide gel electrophoresis Lipoprint© System was used for lipoprotein profile analysis in 19 newly diagnosed MS patients, and in matched 19 healthy controls. Serum levels of interleukin (IL) 1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, interferon-γ and TNF-α were measured by multiplex bead assay. RESULTS: Concentrations of the measured cytokines and lipoprotein subclasses were comparable between MS patients and controls. Male, but not female MS patients had significantly higher total HDL-C and small HDL-C subfraction than healthy controls. Large HDL-C negatively correlated with all measured cytokines except IL-17 in MS but not in controls. Intermediate HDL-C subfractions correlated positively with all measured cytokines except G-CSF in MS females but not in MS males or controls. CONCLUSION: Our results of higher HDL-C and mainly its small HDL-C subfraction suggest that male MS patients are at higher risk of atherosclerosis and the subtle dyslipidemia is present in early stages of the disease. The correlations between specific HDL-C subfractions and the inflammatory cytokines demonstrate mutual links between systemic inflammation and lipid metabolism in MS. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03052595 Registered on Feb 14, 2017.

Oxidative stress in patients with newly diagnosed multiple sclerosis: any association with subclinical atherosclerosis?

OBJECTIVES: Multiple sclerosis (MS) is a chronic inflammatory autoimmune and neurodegenerative disease of the central nervous system (CNS) typically affecting young adults. Although the pathogenesis of MS is not fully understood, there is evidence to suggest that inflammation-induced oxidative stress can play a role in demyelination and axonal damage. Oxidative stress also participates in the pathogenesis of endothelial dysfunction and atherogenesis. Data from large epidemiological studies showed a higher risk of vascular events in MS patients. The aim of our study was to analyse the presence of oxidative stress and its association with the parameters of subclinical atherosclerosis in the early stages of MS. MATERIAL AND METHODS: We compared 13 newly diagnosed MS patients with a group of 13 healthy age- and BMI-matched controls. Blood samples were measured for total antioxidant activity using TEAC assay. Endothelial function, expressed as reperfusion hyperaemia index (RHI) and arterial stiffness, expressed as augmentation index standardized to a pulse of 75/min (AI@75) were assessed using peripheral arterial tonometry. RESULTS: MS patients had significantly lower TEAC compared to controls [0.8 (0.4-2.4) vs. 1.2 (0.6-3.8) mmol/l; p=0.004]. The frequency of increased arterial stiffness (61.6% vs. 30.8%) and endothelial dysfunction (46.2% vs. 38.5%) was comparable in MS patients and in controls. There was no significant association between TEAC, increased arterial stiffness or endothelial dysfunction in patients and controls. CONCLUSION: Our study showed decreased antioxidant capacity in newly diagnosed MS patients compared to controls. We failed to find association of subclinical atherosclerosis with oxidative stress in newly diagnosed MS.

LDL and HDL lipoprotein subfractions in multiple sclerosis patients with decreased insulin sensitivity.

OBJECTIVES: Increased metabolic and cardiovascular morbidity has been reported in multiple sclerosis (MS) patients. Previously, we have found decreased insulin sensitivity and hyperinsulinemia in a group of newly diagnosed MS patients. We hypothesize that these features may be associated with an altered lipid profile and low, intermediate, or high density lipoprotein (LDL, IDL, HDL) subclasses accelerating atherosclerosis and thus contributing to the cardiovascular risk increase in these patients. SUBJECTS AND METHODS: In a group of 19 newly diagnosed untreated MS patients with previously found hyperinsulinemia and insulin resistance and a matched group of 19 healthy controls, the lipoprotein subclasses profile was determined. Polyacrylamide gel electrophoresis was used to separate and measure the LDL (large LDL and small dense LDL), HDL (large, intermediate and small), and IDL (A, B and C) subclasses with the Lipoprint© System (Quantimetrix Corporation, Redondo Beach, CA, USA). RESULTS: No difference was found either in the conventional lipid or lipoprotein subclasses profile between the MS patients and healthy controls. We found an inverse association between the level of IDL-B with fasting insulin (r=-0.504, p=0.032), the insulin resistance estimated by homeo-static model assessment - insulin resistance (HOMA-IR) (r=-0.498, p=0.035), insulin response expressed as area under the curve (AUC; r=-0.519, p=0.027), and area above the baseline (AAB; r=-0.476, p=0.045) and positive association with insulin sensitivity estimated by insulin sensitivity index (ISI) Matsuda (r=0.470, 0.048) in MS patients, but not in healthy controls suggesting the first signs in lipoprotein subclasses profile change. CONCLUSIONS: Our data indicate that changes in lipoprotein profile and subclasses are preceded by insulin resistance and hyperinsulinemia in patients with newly diagnosed MS.

Autonomic Nervous System Response to Stressors in Newly Diagnosed Patients with Multiple Sclerosis.

Autonomic dysfunction is commonly detected in patients with multiple sclerosis (MS). However, data evaluating autonomic nervous system function in early MS are limited. Present study investigates response to two different stressors in newly diagnosed MS patients, looking for the signs of autonomic dysfunction at the beginning of the disease. We examined 19 MS patients and 19 age, sex, and body mass index matched healthy controls. MS patients were newly diagnosed, untreated, and with low expanded disability status scale (EDSS) values [median 1.0 (interquartile range 1.0-1.5)]. Two stressors were used to evaluate the response of autonomic nervous system: Stroop word-color interference mental stress test and orthostasis. Plasma levels of epinephrine and norepinephrine, blood pressure (BP), and heart rate variability (HRV) parameters were evaluated. At the end of Stroop test MS patients had lower systolic BP (121 ± 15 vs. 132 ± 17 mmHg, p = 0.044), lower heart rate (79 ± 9 vs. 88 ± 16 1/min, p = 0.041), and lower epinephrine increment (10 ± 22 vs. 30 ± 38 pg/ml; p = 0.049) compared to healthy controls. Norepinephrine response was unaffected in MS, however, with lower norepinephrine levels during the test (p = 0.036). HRV parameters were similar in both groups. No differences in BP, heart rate, catecholamines, and HRV parameters between groups during orthostatic testing were found. We found slightly diminished sympathetic response to mental stress test, but unchanged response to orthostasis, in newly diagnosed untreated MS patients. The results suggest that autonomic dysfunction in MS is connected with more developed disease.

Carotid intima-media thickness is not associated with homocysteine and vitamin D levels in obstructive sleep apnea.

Obstructive sleep apnea syndrome (OSA) is associated with increased vascular morbidity. Accelerated atherosclerosis might be one of the most important mechanisms linking OSA with the development of vascular disorders. Homocysteine (HCY) and vitamin D has been associated with atherogenesis. The aim of this study was to assess a possible association between the levels of HCY and vitamin D and the carotid intima-media thickness (cIMT), which is a known marker for subclinical atherosclerosis in patients with OSA. We prospectively enrolled 110 patients with the history of snoring, who underwent standard overnight polysomnography. Clinical characteristics of the population were recorded on admission and blood samples were obtained in the fasting condition following morning. Extracranial cIMT measurements were performed according to the standardized scanning protocol. A significant correlation was found between cIMT and apnea-hypopnea index (r = .276, p = .006), age (r = .486, p < .001), diabetes mellitus (r = .377, p < .001), coronary artery disease (r = .274, p = .006) and history of stroke (r = .251, p = .012). We failed to find any significant correlation between cIMT and the levels of HCY (r = .036, p = .724) or vitamin D (r = .027, p = .800). In conclusion, our data suggest that the association of cIMT with the severity of OSA can be influenced by multiple metabolic consequences of OSA including traditional and non-traditional risk factors. HCY and vitamin D do not seem to play a superior role in this process.

Sleep-disordered breathing and excessive daytime sleepiness in patients with epilepsy - a polysomnographic study.

OBJECTIVES: Epilepsy and sleep-disordered breathing (SDB) are relatively common disorders. SDB induces repetitive arousals and sleep fragmentation and may cause symptomatic epileptic seizures or hypoxic encephalopathy. Epileptic seizures change sleep architecture with increase of light sleep and reduction of REM sleep, which may lead to central apneas. The aim of this study was to evaluate the relationship between SDB and daytime sleepiness in patients with epilepsy, who underwent polysomnography (PSG) due to problems with breathing during sleep or due to excessive daytime sleepiness. METHODS: We enrolled 40 patients with epilepsy. Type, etiology of epilepsy and actual antiepileptic therapy was recorded. All of them underwent overnight PSG. Excessive daytime sleepiness (EDS) was assessed by Epworth Sleepiness Scale (ESS). RESULTS: SDB (apnea-hypopnea index [AHI]<5) was present in 25 patients, 15 patients had no SDB (AHI≥5). EDS was present in 16 patients (40%). ESS significantly correlated with presence of symptomatic epilepsy (r=0.385, p=0.014), presence of SDB (r=0.524, p=0.001), AHI (r=0.416, p=0.003) and duration of REM sleep (r=-0.476, p=0.002). The presence of SDB (beta=0.447, p=0.002) and duration of REM sleep (beta=-0.308, p=0.029) were the only independent variables significantly associated with ESS in regression analysis. CONCLUSION: SDB has negative influence on quality of sleep and daytime vigility in patients with epilepsy. Sleep fragmentation with the reduction of the REM sleep seems to be the most important mechanism leading to EDS. We suppose that PSG could be beneficial in all patients with epilepsy and EDS.