FutureMS cohort profile: a Scottish multicentre inception cohort study of relapsing-remitting multiple sclerosis.

PURPOSE: Multiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate or aggressive disease course is very limited. There is, therefore, a need for integrated predictive tools to inform individualised treatment decision making. PARTICIPANTS: Established with the aim of addressing this need for individualised predictive tools, FutureMS is a nationally representative, prospective observational cohort study of 440 adults with a new diagnosis of relapsing-remitting MS living in Scotland at the time of diagnosis between May 2016 and March 2019. FINDINGS TO DATE: The study aims to explore the pathobiology and determinants of disease heterogeneity in MS and combines detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow-up at year 1 is complete. Here, we describe the cohort design and present a profile of the participants at baseline and 1 year of follow-up. FUTURE PLANS: A third follow-up wave for the cohort has recently begun at 5 years after first visit and a further wave of follow-up is funded for year 10. Longer-term follow-up is anticipated thereafter.

Percutaneous coronary intervention causes a rapid but transient mobilisation of CD34(+)CD45(-) cells.

OBJECTIVE: Circulating CD34(+)CD45(-) cell concentrations are increased in patients with coronary artery disease, however their pathophysiological significance is unknown. We determined CD34(+)CD45(-) cell concentrations following percutaneous coronary intervention (PCI) in order to explore their role in acute vascular injury. METHODS: In a prospective time-course analysis, we quantified using flow cytometry circulating CD34(+)CD45(-) cells, traditional CD34(+)VEGFR-2(+) putative endothelial progenitor cells (EPCs), CD14(+) VEGFR(-) 2(+)Tie-2(+) angiogenic monocytes and intercellular adhesion molecule expression (CXCR-4 and CD18) in patients, before and during the first week following diagnostic angiography (n=13) or PCI (n=23). Vascular endothelial growth factor-A (VEGF-A) and C reactive protein (CRP) were quantified by ELISA. RESULTS: Unlike diagnostic angiography, PCI increased circulating neutrophil and CRP concentrations at 24 and 48 h, respectively (p<0.002 for both). CD34(+)CD45(-) cell concentrations were unaffected by angiography (p>0.4), but were transiently increased 6 h following PCI (median (IQR) 0.93 (0.43-1.49) vs 1.51 (0.96-2.15)×10(6) cells/L; p=0.01), returning to normal by 24 h. This occurred in the absence of any change in serum VEFG-A concentration, adhesion molecule expression on CD34(+) cells, or mobilisation of traditional EPCs or angiogenic monocytes (p>0.1 for all). CONCLUSIONS: PCI transiently increases circulating CD34(+)CD45(-) cells, without increasing CD34(+) adhesion molecule expression or VEGF-A concentrations, suggesting that CD34(+)CD45(-) cells may be mobilised from the vessel wall directly as a result of mechanical injury. Traditional putative EPC and angiogenic monocytes are unaffected by PCI, and are unlikely to be important in the acute response to vascular injury.

Endothelial progenitor cells, atheroma burden and clinical outcome in patients with coronary artery disease.

OBJECTIVE: We wished to determine the effect of an acute coronary syndrome (ACS) on putative endothelial progenitor cell (EPC) populations, and define their relationship to coronary artery disease (CAD) severity and clinical outcome, in order to clarify their clinical relevance. DESIGN AND SETTING: A prospective cohort study conducted in a tertiary referral cardiac centre. PATIENTS: Two-hundred-and-one patients undergoing coronary angiography for suspected angina or ACS. MAIN OUTCOME MEASURES: Putative EPC populations were determined by flow cytometry. CAD was quantified using the Gensini scoring system. Survival free from revascularisation, recurrent myocardial infarction and death were determined at 3 years. RESULTS: Circulating CD34(+)VEGFR-2(+) and CD34(+)VEGFR-2(+)CD133(+) cells were rare (<0.007% of mononuclear cells), were not increased in patients with ACS, and were unrelated CAD severity or clinical outcome (p>0.1 for all). By contrast, CD34(+)CD45(-) cells were increased in patients with CAD compared with those with normal coronary arteries (p=0.008) and correlated with atheroma burden (r=0.44, p<0.001). Increased concentrations of circulating CD34(+)CD45(-) cells were associated with a shorter cumulative event-free survival (p<0.02). Proangiogenic monocytes (CD14(+)VEGFR-2(+)Tie-2(+)) and endothelial cell-colony forming units were increased in patients with ACS (p<0.01 for both), however, concentrations reflected myocardial necrosis, and did not predict the extent of CAD or clinical outcome. CONCLUSIONS: Traditional EPC populations, CD34(+)VEGFR-2(+) and CD34(+)VEGFR-2(+)CD133(+) are not related to the extent of CAD or clinical outcome. However, CD34(+)CD45(-) cells are increased in patients with CAD and predict future cardiovascular events. It is likely that CD34(+)CD45(-) concentrations reflect the extent of vascular injury and atheroma burden.

Circulating endothelial progenitor cells are not affected by acute systemic inflammation.

Vascular injury causes acute systemic inflammation and mobilizes endothelial progenitor cells (EPCs) and endothelial cell (EC) colony-forming units (EC-CFUs). Whether such mobilization occurs as part of a nonspecific acute phase response or is a phenomenon specific to vascular injury remains unclear. We aimed to determine the effect of acute systemic inflammation on EPCs and EC-CFU mobilization in the absence of vascular injury. Salmonella typhus vaccination was used as a model of acute systemic inflammation. In a double-blind randomized crossover study, 12 healthy volunteers received S. typhus vaccination or placebo. Phenotypic EPC populations enumerated by flow cytometry [CD34(+)VEGF receptor (VEGF)R-2(+)CD133(+), CD14(+)VEGFR-2(+)Tie2(+), CD45(-)CD34(+), as a surrogate for late outgrowth EPCs, and CD34(+)CXCR-4(+)], EC-CFUs, and serum cytokine concentrations (high sensitivity C-reactive protein, IL-6, and stromal-derived factor-1) were quantified during the first 7 days. Vaccination increased circulating leukocyte (9.8 + or - 0.6 vs. 5.1 + or - 0.2 x 10(9) cells/l, P < 0.0001), serum IL-6 [0.95 (0-1.7) vs. 0 (0-0) ng/l, P = 0.016], and VEGF-A [60 (45-94) vs. 43 (21-64) pg/l, P = 0.006] concentrations at 6 h and serum high sensitivity C-reactive protein at 24 h [2.7 (1.4-3.6) vs. 0.4 (0.2-0.8) mg/l, P = 0.037]. Vaccination caused a 56.7 + or - 7.6% increase in CD14(+) cells at 6 h (P < 0.001) and a 22.4 + or - 6.9% increase in CD34(+) cells at 7 days (P = 0.04). EC-CFUs, putative vascular progenitors, and the serum stromal-derived factor-1 concentration were unaffected throughout the study period (P > 0.05 for all). In conclusion, acute systemic inflammation causes nonspecific mobilization of hematopoietic progenitor cells, although it does not selectively mobilize putative vascular progenitors. We suggest that systemic inflammation is not the primary stimulus for EPC mobilization after acute vascular injury.