| 51. |
- Engelter, S. T., et al.
(author)
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Cervical Artery Dissection and Sports
- 2021
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In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12
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Journal article (peer-reviewed)abstract
- Cervical artery dissection (CeAD) occurring in the context of sports is a matter of concern for CeAD patients. They seek advice on the role of sports in CeAD and on the safety of resuming sports after CeAD. The scarcity of studies and guidelines addressing these issues poses a challenge. We aimed at summarizing the current knowledge about CeAD and sports in order to provide an informed, comprehensive opinion for counseling CeAD patients. We took into account pathophysiological considerations, observations of cases reports, series, and registries, and conclusions by analogy from aortic dissection or inherited connective tissue syndromes. In summary, practicing active sports as the cause of CeAD seems uncommon. It seems recommendable to refrain from any kind of sports activities for at least 1 month, which can be extended in case of an unfavorable clinical or neurovascular course. We recommend starting with sport activities at low intensity-preferably with types of endurance sports-and to gradually increase the pace in an individually tailored manner, taking into circumstances of the occurrences of the CeAD in the individual patient (particularly in relation to sports), the meaning of sports activities for the individual well-being, the presence or absence of comorbidities and of neurological sequela, neurovascular findings, and whether there are signs of an underlying connective tissue alteration. Major limitations and several forms of bias are acknowledged. Still, in the absence of any better data, the summarized observations and considerations might help clinicians in advising and counseling patients with CeAD in clinical practice.
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| 52. |
- Guglielmi, V., et al.
(author)
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Triple and quadruple cervical artery dissections: a systematic review of individual patient data
- 2019
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 266:6, s. 1383-1388
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Journal article (peer-reviewed)abstract
- Background and purposeSimultaneous dissection of three or four cervical arteries rarely occurs. As a result, limited information is available on clinical characteristics, underlying causes, treatment, and outcome of these patients.MethodsWe performed a systematic review of individual patient data on triple and quadruple cervical artery dissection (CeAD). We included all cases for whom, at minimum, data on age, sex and affected cervical arteries were available.ResultsOut of 1396 publications identified in the initial search, 52 were included, with data available on 96 patients. Mean age was 42years and 66% were women. 63% had triple CeAD. The most common manifestations were headache (69%), neck pain (44%), motor deficit (36%), and Horner syndrome (34%). 57% had an ischemic stroke, in the majority of these patients the stroke was confined to the vascular territory of a single artery. 83% were managed medically (antiplatelets or anticoagulants) and 11% underwent endovascular treatment. An underlying disease or triggering event was identified in 71%, most commonly trauma (35%, cervical manipulative therapy in 13%), infection (18%), fibromuscular dysplasia (16%), and hereditary connective tissue disorder (8%). In-hospital mortality was 1%. 80% of patients had a good functional outcome (mRS 0-1) at follow-up. Two recurrences (3%) were reported.ConclusionsTriple or quadruple CeAD mostly affected young women, and underlying disease or triggering event could be identified in more than two-thirds of patients. Less than two-thirds of triple or quadruple CeAD patients suffered ischemic stroke. Most patients were managed medically and the majority had a favorable outcome.
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| 53. |
- Kellert, L., et al.
(author)
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Prognostic significance of pulsatile tinnitus in cervical artery dissection
- 2016
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In: European Journal of Neurology. - : Wiley. - 1351-5101. ; 23:7, s. 1183-1187
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Journal article (peer-reviewed)abstract
- Background and purposeOur aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. MethodsAll CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0-1. ResultsSixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22-12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79-0.86), Horner syndrome (OR 1.95, 95% CI 1.16-3.29) and vessel occlusion (OR 0.62, 95% CI 0.40-0.94) and to non-significant predictors age, sex, pain and location of CeAD. ConclusionThe presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome.
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| 54. |
- Kellert, L., et al.
(author)
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University education and cervical artery dissection
- 2018
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 265:5, s. 1065-1070
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Journal article (peer-reviewed)abstract
- We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients). Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non-CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1. University education was more frequent in CeAD-patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57). We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear.
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| 55. |
- Malhotra, Rajeev, et al.
(author)
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HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype
- 2019
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:11, s. 1580-
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Journal article (peer-reviewed)abstract
- Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10−8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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| 56. |
- Olin, JW, et al.
(author)
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A plasma proteogenomic signature for fibromuscular dysplasia
- 2020
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 116:1, s. 63-77
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Journal article (peer-reviewed)abstract
- AimsFibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.Methods and resultsFemales with ‘multifocal’ FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases = 90, Ncontrols = 100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases = 23, Ncontrols = 28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases = 506, Ncontrols = 876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios = 1.36; P = 0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.ConclusionFMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.
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| 57. |
- Rannikmaee, Kristiina, et al.
(author)
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Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease
- 2015
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In: Neurology. - 1526-632X. ; 84:9, s. 918-926
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Journal article (peer-reviewed)abstract
- Objectives:We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.Methods:We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).Results:Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.Conclusions:Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
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| 58. |
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| 59. |
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| 60. |
- Chauhan, Ganesh, et al.
(author)
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Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies
- 2016
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In: The Lancet Neurology. - 1474-4465 .- 1474-4422. ; 15:7, s. 695-707
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Journal article (peer-reviewed)abstract
- Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq. © 2016 Elsevier Ltd
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