Association of health behaviour and clinical manifestation in early multiple sclerosis in Germany - Baseline characteristics of the POWER@MS1 randomised controlled trial.

BACKGROUND: Receiving a multiple sclerosis (MS) diagnosis is a significant stressor. Therefore, highly individualised counselling is needed, especially in early MS. Modifiable risk factors (e.g. smoking and obesity) are gaining relevance in MS. Despite evidence for worse MS-related health outcomes, prevalence of adverse health behaviours, such as smoking and physical inactivity, is high across all MS stages. However, knowledge regarding health behaviours as well as their association with MS-related health outcomes among newly diagnosed PwMS in Germany is scarce. Currently, the efficacy of an interactive digital lifestyle management application intended to be used as an add-on to standard care among newly diagnosed PwMS in Germany is evaluated in an ongoing multicentre randomised controlled trial (RCT) ('POWER@MS1'). OBJECTIVES: To describe baseline disease characteristics and health behaviours of the POWER@MS1 cohort and investigate associations between MS characteristics, quality of life (QOL), health behaviours and intention to optimise health behaviour habits. METHODS: This study included 234 persons with early MS from 20 study centres located across Germany who participate in the POWER@MS1 RCT. Participants were recruited by treating neurologists from different regions and health-care settings in Germany. Baseline data was obtained using paper-based questionnaires and a web-based healthy diet screener between July 2019 and end of March 2022 and analysed descriptively. RESULTS: In this early MS cohort (mean disease duration 4 months), a screening tool showed severe symptoms of anxiety in 15 % of the participants. Better means for stress management appeared to be particularly relevant for the whole cohort. Moreover, 19 % were current smokers, 15 % were obese and 36 % were insufficiently physically active. On average, participants only moderately adhered to dietary guidelines for recommended intake of key food groups (e.g. vegetables, fruits and fatty marine fish). Higher EDSS scores were associated with approximately 20 % higher T2-lesion burden (rate ratio RR=1.2, p<0.001) and 13 % higher relapse rate (RR=1.13,p=0.02) per EDSS disability level. Moreover, a higher T2-lesion burden was associated with current smoking (RR=0.76, p=0.033), resulting in approximately 24 % less T2-lesions at disease onset among non-smokers. In addition, smoking was associated with unhealthier dietary habits according to lower diet scores (linear regression coefficient ß=-1.27, p<0.001). Higher EDSS scores (ß=0.19,p<0.001) and higher BMI (ß=0.013,p=0.03) were associated with higher HAQUAMS (lower QOL). Further, lower diet scores (ß=-0.044,p=0.039) were associated with lower QOL. Moreover, higher HAQUAMS (lower QOL) indicated a higher intention to optimise stress management (ß=0.98,p<0.001), physical activity (ß=0.74,p=0.046) and sleep behaviour (ß=1.82,p<0.001). Further, higher intention to optimise stress management was accounted for by higher EDSS scores (ß=0.39,p=0.004) and a higher number of T2-lesions (ß=0.029,p=0.015) in this newly diagnosed MS cohort. CONCLUSION: Results indicate a clear need for modifications of health behaviours among newly diagnosed PwMS participating in POWER@MS1. Individualised psychological and health behaviour counselling appears to be an important factor in treatment, also for similar early MS cohorts and particularly in those who demonstrate a more severe disease in clinical and MRI metrics.

Health behaviors of people with multiple sclerosis and its associations with MS related outcomes: a German clinical cohort.

Background: Health behaviors in persons with multiple sclerosis (pwMS) have been associated with MS-related disease outcomes. Objective: The aim of the study was to gain knowledge about current patient health behaviors in a convenience sample representative for pwMS presenting to a large university-based outpatient clinic and to investigate associations between modifiable risk factors with physical impairment, quality of life (QoL) and cardiovascular comorbidities. Methods: A questionnaire was administered at the MS Outpatient Clinic of the University Medical Center Hamburg Eppendorf asking for health behaviors regarding dietary habits assessed with the German adaptation of the validated Spanish short Diet Quality Screener (sDQS), level of physical activity assessed with the Godin Leisure Time Questionnaire (GLTEQ) and tobacco smoking. Participants were asked to report cardiovascular comorbidities using items from the Self-Report Comorbidity Questionnaire for Multiple Sclerosis. Additionally, cardiovascular risk factors like blood pressure, height and weight (to calculate BMI) and waist circumference were measured. MS specific clinical data, e.g., disease course, duration, disability and MS-specific QoL were collected from the clinical database. Descriptive analyses were performed and multivariate regression analyses for complete cases were carried out for each of the three outcome variables including all mentioned modifiable risk factors (dietary behavior, smoking, physical activity and BMI) as independent variables. Results: In this sample of 399 pwMS the mean age was 42 years (SD 12.8) with a mean disease duration since diagnosis of 7.4 years (SD 8.4) and a mean EDSS of 2.8 (SD 1.9). 24% were current smokers, 44% were insufficiently physically active and 54% did not follow a healthy dietary pattern. 49% of this relatively young clinical population was overweight and 27% reported one or more cardiovascular comorbidities. Most modifiable risk factors showed no convincing associations with MS-related disease outcomes in the multiple regression analyses. Conclusion: This clinical cohort of pwMS shows a high prevalence of critical health behaviors and comorbidities and emphasizes the need for monitoring, education and assistance for behavior change in this population.

'That would have been the perfect thing after diagnosis': development of a digital lifestyle management application in multiple sclerosis.

Background: A multiple sclerosis (MS) diagnosis urges decision-making on immunotherapies, while persons with MS (PwMS) need to develop a coping concept in parallel. At this stage, PwMS ask how they themselves may contribute to controlling the disease. Evidence suggests that maintaining a healthy lifestyle (e.g. physical activity and stress management) is a key factor for healthy aging and preserving activity, while data on MS are complex. Objectives: Following the Medical Research Council framework, this study aimed to develop and investigate the feasibility of a new digital health application that conveys evidence-based patient information about lifestyle factors in MS and engages PwMS in relevant behaviour change techniques. Methods: Based on a digital health application promoting lifestyle management in breast cancer survivors, an MS-specific adaptation ('levidex') was developed. Feasibility was tested with 15 PwMS and eight MS experts. Subsequently, a six-week pilot study with eight PwMS was conducted. All participants provided feedback on practicability and acceptability via a questionnaire and took part in a semi-structured telephone interview. Levidex was revised after each test phase. Results: The final levidex tool includes 16 modules, 177 references and several other functions. Feasibility results showed that PwMS and MS experts perceived levidex as understandable (14 out of 15; 6 out of 8), trustworthy (15 out of 15; 8 out of 8), and relevant (10 out of 15; 8 out of 8). Interviews revealed potential for improvement regarding the length and complexity of some content. Piloting of the revised version confirmed good feasibility and high acceptance. Most participants felt inspired to initiate (7 out of 8) or had already implemented (5 out of 8) lifestyle changes after working with levidex. Conclusion: Results suggest that levidex is feasible and well-accepted by PwMS and MS experts. It might be a useful tool to support PwMS in adapting to their diagnosis and initiating health-promoting lifestyle changes.

Cytochrome P450 epoxygenase-derived 5,6-epoxyeicosatrienoic acid relaxes pulmonary arteries in normoxia but promotes sustained pulmonary vasoconstriction in hypoxia.

AIMS: The aim of the study was to investigate the role of cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) in sustained hypoxic pulmonary vasoconstriction (HPV). METHODS: Vasomotor responses of isolated mouse intrapulmonary arteries (IPAs) were assessed using wire myography. Key findings were verified by haemodynamic measurements in isolated perfused and ventilated mouse lungs. RESULTS: Pharmacological inhibition of EET synthesis with MS-PPOH, application of the EET antagonist 14,15-EEZE or deficiency of CYP2J isoforms suppressed sustained HPV. In contrast, knockdown of EET-degrading soluble epoxide hydrolase or its inhibition with TPPU augmented sustained HPV almost twofold. All EET regioisomers elicited relaxation in IPAs pre-contracted with thromboxane mimetic U46619. However, in the presence of KCl-induced depolarization, 5,6-EET caused biphasic contraction in IPAs and elevation of pulmonary vascular tone in isolated lungs, whereas other regioisomers had no effect. In patch-clamp experiments, hypoxia elicited depolarization in pulmonary artery smooth muscle cells (PASMCs), and 5,6-EET evoked inward whole cell currents in PASMCs depolarized to the hypoxic level, but not at their resting membrane potential. CONCLUSIONS: The EET pathway substantially contributes to sustained HPV in mouse pulmonary arteries. 5,6-EET specifically appears to be involved in HPV, as it is the only EET regioisomer able to elicit not only relaxation, but also sustained contraction in these vessels. 5,6-EET-induced pulmonary vasoconstriction is enabled by PASMC depolarization, which occurs in hypoxia. The discovery of the dual role of 5,6-EET in the regulation of pulmonary vascular tone may provide a basis for the development of novel therapeutic strategies for treatment of HPV-related diseases.

Hypoxic pulmonary vasoconstriction in isolated mouse pulmonary arterial vessels.

NEW FINDINGS: What is the central question of this study? Hypoxic pulmonary vasoconstriction has never been characterized in isolated mouse pulmonary arteries of different generations in detail. What is the main finding and its importance? We found that only small intrapulmonary arteries (80-200 µm in diameter) exhibit hypoxic pulmonary vasoconstriction. The observed response was sustained, significantly potentiated by depolarization-induced preconstriction and not dependent on the endothelium or TRPC6 channels. ABSTRACT: Hypoxic pulmonary vasoconstriction (HPV) is a physiological response of pulmonary arteries, which adapts lung perfusion to regional ventilation. The properties of HPV vary significantly between animal species. Despite extensive use of mouse models in studies of HPV, this physiological response has never been characterized in isolated mouse pulmonary arteries in detail. Using wire myography, we investigated the effect of 80 min exposure to hypoxia on the tone in mouse pulmonary arteries of different generations in the presence and absence of preconstriction. Hypoxia induced a sustained relaxation in non-preconstricted extrapulmonary arteries (500-700 µm in diameter), but not in the presence of KCl-induced preconstriction. Large intrapulmonary arteries (450-650 µm in diameter) did not exhibit a significant response to the hypoxic challenge. In contrast, in small intrapulmonary arteries (80-200 µm in diameter), hypoxia elicited a slowly developing sustained constriction, which was independent of the endothelium. The response was significantly potentiated in arteries preconstricted with KCl, but not with U46619. Hypoxic pulmonary vasoconstriction was not altered in pulmonary arteries of TRPC6-deficient mice, which suggests that this response corresponds to the sustained phase of biphasic HPV observed earlier in isolated, buffer-perfused and ventilated mouse lungs. In conclusion, we have established a protocol that allows the study of sustained HPV in isolated mouse pulmonary arteries. The data obtained might be useful for future studies of the mechanisms of HPV in mice.

Hydrogen sulfide contributes to hypoxic inhibition of airway transepithelial sodium absorption.

In lung epithelial cells, hypoxia decreases the expression and activity of sodium-transporting molecules, thereby reducing the rate of transepithelial sodium absorption. The mechanisms underlying the sensing of hypoxia and subsequent coupling to sodium-transporting molecules remain unclear. Hydrogen sulfide (H2S) has recently been recognized as a cellular signaling molecule whose intracellular concentrations critically depend on oxygen levels. Therefore, it was questioned whether endogenously produced H2S contributes to hypoxic inhibition of sodium transport. In electrophysiological Ussing chamber experiments, hypoxia was established by decreasing oxygen concentrations in the chambers. Hypoxia concentration dependently and reversibly decreased amiloride-sensitive sodium absorption by cultured H441 monolayers and freshly dissected porcine tracheal epithelia due to inhibition of basolateral Na(+)/K(+)-ATPase. Exogenous application of H2S by the sulfur salt Na2S mimicked the effect of hypoxia and inhibited amiloride-sensitive sodium absorption by both tissues in an oxygen-dependent manner. Hypoxia increased intracellular concentrations of H2S and decreased the concentration of polysulfides. Pretreatment with the cystathionine-γ-lyase inhibitor d/l-propargylglycine (PAG) decreased hypoxic inhibition of sodium transport by H441 monolayers, whereas inhibition of cystathionine-ß-synthase (with aminooxy-acetic acid; AOAA) or 3-mercaptopyruvate sulfurtransferase (with aspartate) had no effect. Inhibition of all of these H2S-generating enzymes with a combination of AOAA, PAG, and aspartate decreased the hypoxic inhibition of sodium transport by H441 cells and pig tracheae and decreased H2S production by tracheae. These data suggest that airway epithelial cells endogenously produce H2S during hypoxia, and this contributes to hypoxic inhibition of transepithelial sodium absorption.