Genetics of atherothrombotic and lacunar stroke.
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ABSTRACT:
SUBMITTER: Debette S
PROVIDER: S-EPMC2798146 | biostudies-literature | 2009 Apr
REPOSITORIES: biostudies-literature
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Genetics of atherothrombotic and lacunar stroke.
Debette Stéphanie S Seshadri Sudha S
Circulation. Cardiovascular genetics 20090401 2
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Project description:Lacunar strokes are appropriately named for their ability to cavitate and form ponds or "little lakes" (Latin: lacune -ae meaning pond or pit is a diminutive form of lacus meaning lake). They account for a substantial proportion of both symptomatic and asymptomatic ischemic strokes. In recent years, there have been several advances in the management of large vessel occlusions. New therapies such as non-vitamin K antagonist oral anticoagulants and left atrial appendage closure have recently been developed to improve stroke prevention in atrial fibrillation; however, the treatment of small vessel disease-related strokes lags frustratingly behind. Since Fisher characterized the lacunar syndromes and associated infarcts in the late 1960s, there have been no therapies specifically targeting lacunar stroke. Unfortunately, many therapeutic agents used for the treatment of ischemic stroke in general offer only a modest benefit in reducing recurrent stroke while adding to the risk of intracerebral hemorrhage and systemic bleeding. Escalation of antithrombotic treatments beyond standard single antiplatelet agents has not been effective in long-term lacunar stroke prevention efforts, unequivocally increasing intracerebral hemorrhage risk without providing a significant benefit. In this review, we critically review the available treatments for lacunar stroke based on evidence from clinical trials. For several of the major drugs, we summarize the adverse effects in the context of this unique patient population. We also discuss the role of neuroprotective therapies and neural repair strategies as they may relate to recovery from lacunar stroke.
| S-EPMC7456600 | biostudies-literature
Project description:Lacunar strokes are a common type of ischemic stroke. They are associated with long-term disability, but the factors affecting the dynamic of the infarcted lesion and the brain imaging features associated with them, reflective of small vessel disease (SVD) severity, are still largely unknown. We investigated whether the distribution, volume and 1-year evolution of white matter hyperintensities (WMH), one of these SVD features, relate to the extent and location of these infarcts, accounting for vascular risk factors. We used imaging and clinical data from all patients [n = 118, mean age 64.9 (SD 11.75) years old] who presented to a regional hospital with a lacunar stroke syndrome within the years 2010 and 2013 and consented to participate in a study of stroke mechanisms. All patients had a brain MRI scan at presentation, and 88 had another scan 12 months after. Acute lesions (i.e., recent small subcortical infarcts, RSSI) were identified in 79 patients and lacunes in 77. Number of lacunes was associated with baseline WMH volume (B = 0.370, SE = 0.0939, P = 0.000174). RSSI volume was not associated with baseline WMH volume (B = 3.250, SE = 2.117, P = 0.129), but predicted WMH volume change (B = 2.944, SE = 0.913, P = 0.00184). RSSI location was associated with the spatial distribution of WMH and the pattern of 1-year WMH evolution. Patients with the RSSI in the centrum semiovale (n = 33) had significantly higher baseline volumes of WMH, recent and old infarcts, than patients with the RSSI located elsewhere [median 33.69, IQR (14.37 50.87) ml, 0.001 ≤ P ≤ 0.044]. But patients with the RSSI in the internal/external capsule/lentiform nucleus experienced higher increase of WMH volume after a year [n = 21, median (IQR) from 18 (11.70 31.54) ml to 27.41 (15.84 40.45) ml]. Voxel-wise analyses of WMH distribution in patients grouped per RSSI location revealed group differences increased in the presence of vascular risk factors, especially hypertension and recent or current smoking habit. In our sample of patients presenting to the clinic with lacunar strokes, lacunar strokes extent influenced WMH volume fate; and RSSI location and WMH spatial distribution and dynamics were intertwined, with differential patterns emerging in the presence of vascular risk factors. These results, if confirmed in wider samples, open potential avenues in stroke rehabilitation to be explored further.
| S-EPMC7976454 | biostudies-literature
Project description:ObjectiveDetermining which small deep infarcts (SDIs) are of lacunar, arterial, or cardioembolic etiology is challenging, but important in delivering optimal stroke prevention therapy. We sought to distinguish lacunar from nonlacunar causes of SDIs using a gene expression profile.MethodsA total of 184 ischemic strokes were analyzed. Lacunar stroke was defined as a lacunar syndrome with infarction <15mm in a region supplied by penetrating arteries. RNA from blood was processed on whole genome microarrays. Genes differentially expressed between lacunar (n = 30) and nonlacunar strokes (n = 86) were identified (false discovery rate ≤ 0.05, fold change >|1.5|) and used to develop a prediction model. The model was evaluated by cross-validation and in a second test cohort (n = 36). The etiology of SDIs of unclear cause (SDIs ≥ 15mm or SDIs with potential embolic source) (n = 32) was predicted using the derived model.ResultsA 41-gene profile discriminated lacunar from nonlacunar stroke with >90% sensitivity and specificity. Of the 32 SDIs of unclear cause, 15 were predicted to be lacunar, and 17 were predicted to be nonlacunar. The identified profile represents differences in immune response between lacunar and nonlacunar stroke.InterpretationProfiles of differentially expressed genes can distinguish lacunar from nonlacunar stroke. SDIs of unclear cause were frequently predicted to be of nonlacunar etiology, suggesting that comprehensive workup of SDIs is important to identify potential cardioembolic and arterial causes. Further study is required to evaluate the gene profile in an independent cohort and determine the clinical and treatment implications of SDIs of predicted nonlacunar etiology.
| S-EPMC3201749 | biostudies-literature
Project description:IntroductionStudies of differences in very long-term outcomes between people with lacunar/small vessel disease (SVD) versus other types of ischaemic stroke report mixed findings, with limited data on myocardial infarction (MI). We investigated whether long-term mortality, recurrent stroke and MI risks differ in people with versus without lacunar/SVD ischaemic stroke.Patients and methodsWe included first-ever strokes from a hospital-based stroke cohort study recruited in 2002-2005. We compared risks of death, recurrent stroke and MI during follow-up among lacunar/SVD versus other ischaemic stroke subtypes using Cox regression, adjusting for confounding factors.ResultsWe included 812 participants, 283 with lacunar/SVD ischaemic stroke and 529 with other stroke. During a median of 9.2 years (interquartile range 3.1-11.8), there were 519 deaths, 181 recurrent strokes and 79 MIs. Lacunar/SVD stroke was associated with lower mortality (adjusted HR 0.79, 95% CI 0.65 to 0.95), largely due to markedly lower all-cause mortality in the first year. From one year onwards this difference attenuated, with all-cause mortality only slightly and not statistically significantly lower in the lacunar/SVD group (0.86, 95% CI 0.70 to 1.05). There was no clear difference in risk of recurrent stroke (HR 0.84, 95% CI 0.61-1.15) or MI (HR 0.83, 95% CI 0.52-1.34).ConclusionLong-term risks of all-cause mortality, recurrent stroke and MI are similar, or only slightly lower, in patients with lacunar/SVD as compared to other ischaemic stroke. Patients and physicians should be as vigilant in optimising short- and long-term secondary prevention of vascular events in lacunar/SVD as for other stroke types.
| S-EPMC8915237 | biostudies-literature
Project description:BackgroundEarly neurological deterioration (END) occurs in many patients with acute ischemic stroke due to a variety of causes. Although pharmacologically induced hypertension (PIH) and anticoagulants have been investigated in several clinical trials for the treatment of END, the efficacy and safety of these treatments remain unclear. Here, we investigated whether PIH or anticoagulation is better as a rescue therapy for the progression of END in patients with lacunar stroke.MethodsThis study included patients with lacunar stroke who received rescue therapy with END within 3 days of symptom onset between April 2014 and August 2021. In the PIH group, phenylephrine was administered intravenously for 24 h and slowly tapered when symptoms improved or after 5 days of PIH. In the anticoagulation group, argatroban was administered continuously intravenously for 2 days and twice daily for next 5 days. We compared END recovery, defined as improvement in NIHSS from baseline, excellent outcomes (0 or 1 mRS at 3 months), and safety profile.ResultsAmong the 4818 patients with the lacunar stroke, END occurred in 147 patients. Seventy-nine patients with END received PIH (46.9%) and 68 patients (46.3%) received anticoagulation therapy. There was no significant difference in age (P = 0.82) and sex (P = 0.87) between the two groups. Compared to the anticoagulation group, the PIH group had a higher incidence of END recovery (77.2% vs. 51.5%, P < 0.01) and excellent outcomes (34.2% vs. 16.2%, P = 0.04). PIH was associated with END (HR 2.49; 95% CI 1.06-5.81, P = 0.04). PIH remained associated with END recovery (adjusted HR 3.91; 95% CI 1.19-12.90, P = 0.02). Safety outcomes, like hemorrhagic conversion and mortality, were not significantly different between the two groups.ConclusionsAs a rescue therapy for the progression of END in lacunar stroke patients, PIH with phenylephrine was more effective with similar safety compared to anticoagulation with argatroban.
| S-EPMC11380375 | biostudies-literature
Project description:Neuroinflammation is believed to be involved in the pathophysiological mechanisms of silent brain infarcts (SBI). However, the immunological profile of SBI has been scarcely investigated. In the context of a national research project named SILENCE, aimed at investigating clinical, biochemical and pathogenic features of SBI, we have measured the plasma profile of some inflammatory-related molecules in SBI patients (n?=?21), patients with recent lacunar infarcts (LI, n?=?28) and healthy controls (n?=?31), consecutively enrolled in four Italian centres. A panel of chemokines (MIG, CTACK, IL16, SDF1a, MCP1), growth factors (SCF, SCGFb, HGF, IL3), immunoglobulin-type adhesion molecules (ICAM1, VCAM1), proinflammatory cytokines (IL18, INFa2, MIF, IL12p40), cell surface receptors on T-cells (IL2Ra), and inductors of apoptosis (TRAIL) was assessed in plasma samples by Luminex xMAP™ technology. Immunological parameters were compared using non-parametric statistics and performance to distinguish SBI and LI was evaluated by receiver operating characteristic (ROC) analysis. Plasma levels of ICAM1 were significantly higher in both SBI and LI patients as compared to controls (SBI?LI>Ctrl). A different trend was observed for IL16 (SBI<LI>Ctrl), SCF (LI<SBI>Ctrl) and SCGFb (SBI>LI<Ctrl). SBI subjects had significantly increased levels of MIG when compared to controls (LI?SBI>Ctrl) and IL18 when compared to LI patients (Ctrl?SBI>LI). All the other immunological markers did not significantly differ among groups. According to ROC analysis, the best predictor for SBI condition was the chemokine MIG (AUC?=?0.84, sensitivity 86%, specificity 77%), while SCF had the best performance in distinguishing LI patients (AUC?=?0.84, sensitivity 86%, specificity 68%). These results confirm the involvement of inflammatory processes in cerebrovascular disorders, particularly in SBI, a very common age-related condition. The differences in plasma profile of inflammatory molecules may underlie different pathological mechanisms in SBI and LI patients.
| S-EPMC3706426 | biostudies-literature
Project description:Twenty-five percent of ischemic strokes are lacunar in type, but the cause remains unclear. Pathological descriptions of lacunar lesions are available but have not been systematically assessed. We therefore systematically summarized studies describing lacunar lesions by extracting data on the number of patients and lesions, clinical details, pathological methods, brain regions and/or vessels examined, and both parenchymal and vascular findings. Among 39 papers describing >4000 lesions (>50% from one study), 15 papers examined patients with a clinical lacunar syndrome. Terminology varied, many studies only reported macroscopic pathology and many lesions were cavitated (ie, old). Aside from symptomatic lesions occurring more often in the internal capsule or caudate nucleus, we found no other differences between symptomatic and asymptomatic patients. Perivascular edema and thickening, inflammation and disintegration of the arteriolar wall were common, whereas vessel occlusion was rare. The causal mechanisms of lacunar stroke remain poorly defined because of methodological inconsistencies and challenges. Standardised pathological definitions based on well-characterized post-mortem derived material supported by detailed clinical and imaging data are needed.
| S-EPMC8057646 | biostudies-literature
Project description:Currently, only the general control of the risk factors is known to prevent lacunar cerebral infarction, but it is unknown which type of medication for controlling the risk factors has a causal relationship with reducing the risk of lacunar infarction. To unlock this medical mystery, drug-target Mendelian randomization analysis was applied to estimate the effect of common antihypertensive agents, hypolipidemic agents, and hypoglycemic agents on lacunar stroke. Lacunar stroke data for the transethnic analysis were derived from meta-analyses comprising 7338 cases and 254,798 controls. We have confirmed that genetic variants mimicking calcium channel blockers were found to most stably prevent lacunar stroke. The genetic variants at or near HMGCR, NPC1L1, and APOC3 were predicted to decrease lacunar stroke incidence in drug-target MR analysis. These variants mimic the effects of statins, ezetimibe, and antisense anti-apoC3 agents, respectively. Genetically proxied GLP1R agonism had a marginal effect on lacunar stroke, while a genetically proxied improvement in overall glycemic control was associated with reduced lacunar stroke risk. Here, we show that certain categories of drugs currently used in clinical practice can more effectively reduce the risk of stroke. Repurposing several drugs with well-established safety and low costs for lacunar stroke prevention should be given high priority when doctors are making decisions in clinical practice. This may contribute to healthier brain aging.
| S-EPMC10813761 | biostudies-literature
Project description:ImportanceStroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although smaller in size, they create large problems, leaving many patients with intellectual and physical disabilities. Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow.ObservationsWhen the term lacune was described in the 1800s, its underlying pathophysiological basis was obscure. In the 1960s, C. Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition. For these pathologic changes, he coined the term lipohyalinosis. Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebral small vessel disease (CSVD). During the past 6 years, progress has been made in understanding the clinical mechanisms, imaging characteristics, and genetic basis of LS.Conclusions and relevanceQuestions persist regarding the order of events related to the initiation and progression of CSVD, how LS is related to other sequelae of CSVD, and whether LS is part of a systemic disease process. The relative roles of aging, oxidative stress, mechanical stress, genetic predisposition, and other vascular risk factors should be further studied, especially in the era of widespread antihypertensive use. Although understanding of endothelial dysfunction has increased, future work on the role of media and adventitial dysfunction should be explored. Recent advances in mapping the brain vasculome may generate new hypotheses. The investigation of new therapeutic targets, aimed at reversing CSVD processes and promoting neural repair after LS, depends upon further understanding these basic mechanisms.
| S-EPMC7426021 | biostudies-literature
Project description:Semaphorin 7A (Sema7A), a neural guidance cue, was recently identified to regulate atherosclerosis in mice. However, the clinical relevance of Sema7A with atherosclerotic diseases remains unknown. The aim of this study was to investigate the association between serum Sema7A and the risk of acute atherothrombotic stroke (AAS). We measured serum concentrations of Sema7A in 105 newly onset AAS cases and 105 age- and sex-matched controls, showing that median Sema7A level in AAS cases was over three times of that in controls (5.86 vs 1.66 ng/mL). Adjusted for hypertension, body mass index, fasting blood glucose, total cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, current smoking and alcohol consumption, multivariate logistic regression showed that higher Sema7A was independently associated with the odds of AAS (OR = 6.40, 95% CI: 2.88-14.25). Each 1-standard deviation increase in Sema7A was associated with a threefold higher odds of AAS (OR = 3.42, 95% CI: 1.84-6.35). Importantly, adding Sema7A to a multivariate logistic model containing conventional cardiovascular risk factors improved the area under receiver operating characteristic curves from 0.831 to 0.891 for the association with AAS. In conclusion, elevated serum Sema7A is independently associated with the risk of AAS, suggesting that it may play a potential role in AAS.
| S-EPMC6433662 | biostudies-literature