Showing posts with label etiology. Show all posts
Showing posts with label etiology. Show all posts
Sunday, March 20, 2022
A simple score to predict atherosclerotic or embolic intracranial large-vessel occlusion stroke before endovascular treatment
So you're identifying the cause of the stroke but you didn't take the obvious next step to CREATE EXACT PROTOCOLS THAT PREVENT THE NEXT STROKE.
Thursday, August 13, 2020
Usefulness of stent strut deformity during thrombectomy for predicting the stroke etiology in acute large artery occlusion
I can see almost zero usefulness in stroke etiology(the cause). Survivors want to know: WHAT THE FUCK ARE YOU DOING TO CURE ME?
Usefulness of stent strut deformity during thrombectomy for predicting the stroke etiology in acute large artery occlusion
Monday, October 29, 2018
Minor stroke due to large artery occlusion. When is intravenous thrombolysis not enough? Results from the SITS International Stroke Thrombolysis Register
Thrombolysis is never enough. Because you are fucking ignoring the neuronal cascade of death.
Are you that ignorant of stroke etiology?
First Published November 29, 2017
Research Article
Are you that ignorant of stroke etiology?
Minor stroke due to large artery occlusion. When is intravenous thrombolysis not enough? Results from the SITS International Stroke Thrombolysis Register
Sunday, August 16, 2015
Meeting the Criteria for Intravenous Thrombolysis
There is so much that can be improved here with just a little bit of research. Our doctors still do not understand the whole etiology of stroke damage, without understanding the problem there is no way to even attempt to fix it.
Meeting the Criteria for Intravenous Thrombolysis
Thrombolytic therapy for treating qualified patients presenting with acute ischemic stroke (AIS) has been available for 20 years. Outcomes are critically related to the time from symptom onset until intervention is provided. Although intravenous thrombolysis has assumed an important role in managing patients with AIS, several factors must be considered to use this treatment safely.Time is Brain
The importance of time in
managing patients with AIS is emphasized in guidelines published by
major organizations, including the American Heart Association/American
Stroke Association (AHA/ASA), that define time goals for identifying,
evaluating, and treating stroke patients in the emergency department
(ED) (Table 1).1 Of special importance is the achievement of a
“door-to-needle” time of less than 1 hour(Not good enough - In the ambulance!). Underlying this goal, there
is a graduated diminution in the effect of recombinant tissue
plasminogen activator (rt-PA) on stroke outcome with every minute that
goes by.
 |
| These goals are totally wrong, the BHAG is delivery of tPA in the ambulance - Big Hairy Audacious Goal |
Looking at the major trials that have informed our
knowledge of thrombolysis of stroke in the past 20 years, there appears
to be a correlation between the time-window in which most of the
patients in each trial were treated and the overall outcome of that
trial (Figure 1, page 4). The National Institute of Neurological
Disorders and Stroke (NINDS) trials were first, and reported a positive
effect of rt-PA treatment given within 0 and 3 hours of symptom onset.2
Two parts of the study investigated 2 hypotheses, but otherwise
followed identical protocols. Part 1 explored the 24-hour change in
National Institutes of Health Stroke Scale (NIHSS) score, while Part 2
examined 3-month recovery using 4 outcome measures. The Barthel Index
(BI) measures ability to perform activities of daily living, the
modified Rankin scale (mRS) assesses overall function with a score of 0
indicating absence of symptoms and 5 representing severe disability, the
Glascow outcome scale (GOS) is a global function assessment ranging
from 1 (good recovery) to 5 (death), and the 42-point NIHSS quantifies
neurologic deficit in 11 categories.
Although the improvement trend in 291 patients in Part
1 failed to meet the primary outcome of improvement by ≥4 points in the
NIHSS score or a complete resolution of the neurologic defect, there
were statistically significant differences in secondary outcomes of BI
(odds ratio [OR] 1.8; 95% confidence interval [CI] 1.1 to 2.8; P=.012), mRS (OR 2.3; 95% CI 1.4 to 3.6; P<.001), GOS (OR 2.0; 95% CI 1.2 to 3.1; P=.005) and total NIHSS score (OR 2.2; 95% CI 1.3 to 3.7; P=.002).
Data from 333 Part 2 patients showed similar benefit in a primary
outcome using BI, mRS, GOS, and NIHSS, with increased odds of a
favorable outcome at 3 months in patients given rt-PA compared with
placebo (OR 1.7; 95% CI 1.2 to 2.6; P=.008). Mortality at 90 days was similar between groups (17% vs. 21%; P=.30).
The whole previous paragraph can be explained by not recognizing the neuronal cascade of death continues the first week because tPA administration does not address that.
Results in 3 subsequent trials that included patients
treated with rt-PA or placebo between 0 and 6 hours of symptom onset
(ECASS 1, ECASS 2, and ATLANTIS Part A) were neutral.3-5
However, in each of these trials, only a minority (not more than
one-fifth) of patients were actually treated within 3 hours of stroke
onset.
The European Cooperative Acute Stroke Study 1 (ECASS
1) enrolled 620 patients, of whom only 14% were <3 hours from symptom
onset.5 The study failed to show a significant difference
between groups for the primary outcome of 90-day BI and mRS, although a
secondary endpoint of combined BI and mRS scores was significantly
different between groups, favoring rt-PA (P<.001). ECASS 2
enrolled 800 patients, stratified between 0 to 3 hours and 3 to 6 hours
after symptom onset, with 20% of patients enrolled in the 0 to 3-hour
window, and the remainder in the 3 to 6-hour window.4
Although nonsignificant trends in favor of rt-PA were observed for all
outcomes, the primary endpoint, dichotomized mRS outcome (with a score
of 0 to 1 considered favorable, and 2 to 6 considered unfavorable) at 90
days, was similar between groups (40.3% vs. 36.6%; P=.277).
The ATLANTIS Part A trial enrolled 142 patients, with a
primary efficacy endpoint of number of patients with a decrease of :;:4
points on the NIHSS at 24 hours and day 30, and total infarct volume at
day 30.3 Forty-six (about a third) of the patients in this
study were enrolled between 5 and 6 hours after onset, and the safety
concerns due to hemorrhaging that emerged in these patients resulted in
early termination of the study by the Data and Safety Monitoring Board
(DSMB). In the study population as a whole, the significantly greater
number of patients with ≥4 point NIHSS improvement in the rt-PA compared
with the placebo group at 24 hours (40% vs. 21%; P=.02) was offset by fewer rt-PA compared with placebo group patients having this outcome at 30 days (60% vs. 75%; P=.05).
None of the efficacy endpoints, including functional recovery, favored
rt-PA at 30 and 90 days, while symptomatic intracerebral hemorrhage
(sICH) within 10 days (11% vs. 0%; P<.01) and 90-day mortality (23% vs. 7%; P<.01)
were significantly increased in rt-PA compared with placebo patients.
In the subgroup of rt-PA (n=22) and placebo (n=24) patients treated in
the 5- to 6-hour window, both 30-day (27.3% vs. 4.2%; P=.03) and 90-day (36.1% vs. 4.2%; P=.01) mortality and rate of sICH at day 10 (18.2% vs. 0%; P=.03) were significantly greater in the rt-PA group. Significantly more rt-PA (23%) compared with placebo (8%; P<.05)
patients in the 5- to 6-hour window had baseline NIHSS scores >20;
which may have confounded the results. However, overall, only 15% of the
patients were enrolled within 3 hours, and the negative results of this
study were therefore attributed to patients treated >3 hours after
stroke onset.
ATLANTIS Part B, which was a reconfiguration of the
ATLANTIS trial based on the safety experience outlined above, and the
interval FDA approval of rt-PA for the treatment of acute ischemic
stroke within 3 hours of onset, had a treatment window restricted to 3
to 5 hours after symptom onset.6 The primary outcome was
proportion of patients with an excellent neurologic recovery at day 90
(NIHSS ≤1). Following an interim analysis, ATLANTIS Part B was
terminated for futility by the DSMB after 547 patients had received
study medication, prior to completing the targeted enrollment of 968
patients. Significant benefits of rt-PA treatment on the 90-day primary
and secondary efficacy endpoints were not observed. Patients in the
rt-PA group, compared with placebo, had significantly increased sICH
(7.0% vs. 1.1%; P<.001), asymptomatic ICH (11.4% vs. 4.7%; P=.004), and fatal ICH (3.0% vs. 0.3%; P<.001) within the first 10 days, although 90-day mortality was similar between groups (11.0% vs. 6.9%; P=.09).
ECASS 3 enrolled 821 patients randomized to alteplase or placebo treatment between 3 and 4.5 hours after stroke onset.7
The primary endpoint was dichotomized mRS (0 to 1 favorable, 2 to 6
unfavorable outcome) at 90 days. Significantly more patients in the
rt-PA group had a favorable outcome compared with placebo (52.4% vs.
45.2%; P=.04). Mortality was similar in rt-PA and placebo groups (7.7% vs. 8.4%; P=.68), while intracranial hemorrhage (27.0% vs. 17.6%; P=.001), including sICH (2.4% vs. 0.2%; P=.008), was significantly greater in the rt-PA group.
A pooled analysis was performed that included
individual patient data from the NINDS, ECASS (1-3), ATLANTIS, and
EPIPHET trials, all of which compared intravenous rt-PA with placebo.8
A pooled analysis is different from a meta-analysis in that a
meta-analysis assesses individual trial outcomes to provide an overall
estimate of the effect size for the variables of interest, with a
weighted contribution from each study; a pooled analysis is not
analyzing individual trial outcomes, but is instead analyzing the
individual patient data from subjects in those trials. A pooled analysis
is predicated on the contributing studies having patient populations,
interventions, and outcome measures that are similar enough that
individual patient data can be pooled and analyzed together, as if
obtained in a single “mega-trial,” which can provide more reliable
results than can a standard meta-analysis.9
When the data for approximately 3,500 patients were
combined for the pooled analysis, the odds of a favorable 3-month
outcome with rt-PA treatment decreased as the time from onset to
treatment increased, with no benefit observed after approximately 4.5
hours (Table 2).8 Adjusted odds of mortality increased with time from onset to start of treatment (P=.0444).
The incidence of parenchymal hemorrhage was also significantly
increased, with an adjusted OR of 5.37 (95% CI: 3.22, 8.95; P<.0001)
for treatment started 0 to 360 minutes from stroke onset. A similar
hemorrhage incidence was observed across the four 90-minute time windows
studied.
Using rt-PA Safely: AHA/ASA 2013 Guidelines
The AHA/ASA guidelines for the
early management of patients with AIS, updated in 2013, emphasize the
importance of early treatment.1 However, the AHA/ASA policy
statement on emergency medical services within stroke systems of care
notes that symptom onset time, essential to determining treatment time
from onset, is a common documentation omission.10
The guidelines define patient inclusion and exclusion
characteristics, and stress the importance of documenting eligibility
assessment. Eligibility characteristics are divided between patients for
whom treatment can be initiated within 3 hours of symptom onset, and
eligibility restrictions when treatment initiation would occur between 3
and 4.5 hours after symptom onset.
Exclusion Criteria Highlights
Leaky Brain or Leaking Body
Exclusion criteria for rt-PA
can be divided into broad categories. The first considerations have to
do with “leaky brain” (recent CNS parenchymal injury from stroke,
trauma, or surgery) and “leaking body” (ie, active bleeding).
Any bleeding, including any that occurs outside the brain, excludes a
patient from rt-PA treatment. This exclusion is further qualified to
include any significant head trauma or prior stroke in the previous 3
months, symptoms suggesting subarachnoid hemorrhage, recent intracranial
or intraspinal surgery, active internal bleeding, or arterial puncture
at a noncompressible site in the previous 7 days.Bad Brain
Conditions associated with
compromised blood vessel integrity in the brain, such as tumors,
arteriovenous malformation, and aneurysm (“bad brain”) are exclusion
criteria for rt-PA treatment. This “bad brain” category also includes a
radiographic correlate, a CT scan that demonstrates multilobar
infarction; frank hypodensity in over one-third of the cerebral
hemisphere on a non-contrast head CT is an exclusion criterion for rt-PA
treatment.
Bleeding Diathesis
Exclusions to rt-PA therapy also include a platelet count <100,000/mm3,
heparin within 48 hours with an elevated aPTT, or current use of an
anticoagulant with an INR >1.7 or PT >15 seconds. If the patient
is taking a direct thrombin or factor Xa inhibitor, laboratory markers
such as a thrombin time and/or ecarin clotting time can be considered if
feasible to obtain within a treatment time-frame, and if elevated,
would qualify as exclusions.
Other Exclusions
Patients with blood glucose
<50 mg/dL (2.7 mmo/L) or elevated blood pressure (systolic >185
mm Hg or diastolic >110 mm Hg) that cannot be readily controlled with
a dose or 2 of a medication, such as labetolol, or a nicardipine drip,
should not be given rt-PA treatment.
Relative rt-PA Exclusion Criteria for Treatment Within 3 Hours of Symptom Onset
There are also relative
exclusion criteria, entities that are not absolute exclusions per se but
war risks and benefits of administering rt-PA for a stroke within 3
hours of symptom onset. These relative contraindications include minor
or rapidly improving symptoms, pregnancy, seizure at onset with
residual neurological impairments, major surgery or serious trauma
within the previous 14 days, recent gastrointestinal or urinary tract
hemorrhage (within the previous 21 days), or recent acute myocardial
infarction (within the previous 3 months).
Exclusions for Using Intravenous rt-PA 3 to 4.5 Hours after Symptom Onset
If a patient can be treated in
the time period from 3 to 4.5 hours after stroke onset, the general
exclusions are supplemented by additional relative exclusion criteria.
These include patients aged >80 years, with a severe stroke (NIHSS >25), with imaging evidence of ischemic injury involving more than
one-third of the middle cerebral artery territory, taking an oral
anticoagulant regardless of INR, or with a history of both diabetes and
prior ischemic stroke.
Safety of rt-PA Treatment in Stroke Mimics
Earlier treatment may
increase the risk of providing rt-PA to a patient who presents with
clinical features of a stroke but ultimately has an alternative
diagnosis. Studies have shown that rt-PA treatment is not associated
with adverse outcomes when given to these patients. In a retrospective
study of approximately 70 stroke mimics treated with rt-PA, there were
no instances of sICH.11 In a large study of 5581 consecutive patients treated with rt-PA, 100 (1.8%) were determined to be stroke mimics.12 An sICH occurred in 1 stroke mimic patient for a rate of 1.0%, compared with 7.9% in patients who had ischemic strokes.
Additional Treatment Decision Considerations
A patient with an acute
ischemic stroke and no exclusion criteria, presenting within a window of
time such that treatment can be initiated within 3 or 4.5 hours of
stroke onset, may be a straightforward candidate for intravenous
thrombolysis. There may, at times, be considerations that require
additional clinical judgment, such as whether or not a patient may have a
stroke that is too mild, or a stroke that is too severe, or if the
patient may be too old.
Mild Patient
Deciding to use rt-PA in a
patient with a mild stroke requires careful balancing of the potential
benefits with the risk of sICH with rt-PA treatment. While the risk of
sICH is approximately 6% overall, this risk is affected by stroke
severity; a patient with a mild stroke, that is, with a baseline NIHSS
of 0 to 5, has an approximate 2% risk of sICH, with a slight increase to
approximately 3% in a patient with a mild-to-moderate stroke (NIHSS
6-10) (Figure 2).13-15 Contrasting this with the approximate
20% risk of having a poor outcome without treatment can help put things
in perspective when considering if the potential outcome benefit is
worth the risk of giving rt-PA to a patient who has had a mild stroke.
“Mild” strokes come in 2 varieties. The first is a
stroke that is truly mild. The overall assessment of benefit versus risk
in this first type needs to incorporate the possibility that a patient
who appears to be minimally affected in the ED may not consider his
condition to be mild after 6 weeks or 6 months as he is confronted with
restrictions in his daily activities. Although the stroke may be
associated with an isolated deficit, its focal impact may have a
profound negative effect on the patient’s livelihood and quality of
life, and in such circumstances the benefits of treating with rt-PA may
outweigh the risk. Other “downstream” factors that often are not
considered in the ED include depression,16,17 impaired executive function,18
and unmeasured motor dysfunction.19 These aspects of potential
long-term disability should be considered when contemplating rt-PA
treatment for a mild stroke.
Alternatively, a patient may appear to be having a
“mild” stroke that looks mild, but in actuality is not a mild stroke at
all. The patient may have mild symptoms that may represent a proverbial
“calm before the storm” in an ongoing major vessel occlusion. Collateral
vessels supplying the compromised brain tissue may be sustaining a
patient like this, obscuring the full extent of the neurological deficit
due. The literature suggests that up to 17% of ED stroke patients who
are considered “too mild to treat” will acutely and significantly
deteriorate after several hours, as these collaterals begin to fail.20-22
Approximately two-thirds of these deteriorating patients show rapid
improvement from a significant deficit initially. The profile of the
“too mild to treat” ED patient, who will progressively deteriorate
appears to be of rapid improvement from a significant deficit to a mild
one, accompanied by either (1) imaging that reveals a large-vessel
occlusion or stenosis (especially if present while the deficit is mild)
or (2) symptoms consistent with a large vessel occlusion or cortical
stroke (such weakness combined with numbness, or weakness combined with
aphasia). The exclusion of patients with this profile from thrombolytic
therapy based on a classification as “too mid to treat” or “rapidly
improving” should be done judiciously.
Patient with a Severe Stroke
Determining if a patient is too
severe to treat with rt-PA includes consideration of NIHSS score and
neuroimaging results, in a context of time from symptom onset. The
alteplase prescribing information warns that patients with severe
neurological deficit (eg, NIHSS >22) at presentation are in
particular need of a diligent assessment of risks versus benefits.23 The
hemorrhage risk increases from 5% at NIHSS 11 to 20 to reach 17% at
NIHSS >20.14
Risks should be carefully weighed against benefits if
CT imaging shows major early infarct signs (eg, substantial edema, mass
effect, or midline shift).23 Data from the ECASS trial showed
that patients with frank hypodensity covering greater than one-third of
the territory of the MCA had an 8-fold increased rate of hemorrhage
with rt-PA compared with those who were not rt-PA-treated.24 Accordingly, numerous major guidelines worldwide include this as a treatment exclusion criterion.25-30
Time since stroke onset has a major role in the
treatment decision for these patients and clinical judgement has to be
applied to the interplay of time, stroke severity, and imaging findings.
For example, a patient who presents within a half hour of onset with an
NIHSS of 25 and a normal CT scan may be a candidate for rt-PA despite
the severity of the stroke. Alternatively, for a patient presenting 2.5
to 3.5 hours after onset, with a midrange NIHSS and a CT scan already
showing hypodensities, the risks of giving rt-PA treatment may outweigh
the benefits.
Influence of Patient Age on Treatment Choice
Older patients have worse outcomes after stroke than their younger counterparts.31-34
Their strokes are more severe, they deteriorate more readily, and they
do not respond to therapies as well. These characteristics may be
confounded by the tendency towards less aggressive management of elderly
patients, as fewer investigative and invasive procedures are done with
these patients.35 Primary randomized clinical trial
literature showed that age >80 years was associated with an increased
risk of ICH with rt-PA.36,37 That being said, although some studies showed rt-PA treatment is more effective in younger patients,38-40 older patients have been shown to benefit from rt-PA treatment.35,40 This is particularly evident in the more recent literature.41-44
In addition, more recent clinical reporting suggests that an age of 80
is not associated with an increased risk of sICH in selected patients
treated with rt-PA.40,45-51 The caveat to these latter
reports is that the data they are based on was largely obtained outside
of randomized controlled trials and may be affected by selection bias;
even if so, they still demonstrate that, from a real-world perspective,
the medical community at large is selecting older patients to treat with
rt-PA in a manner that leads to favorable outcomes and has a comparable
safety profile to that in younger patients.
Summary
Time is brain. There is a
minute-by-minute reduction of good outcome achievement with rt-PA, until
it reaches a nadir by 4.5 hours from onset. Considerations for using
rt-PA in patients with a mild stroke include that small strokes can have
big consequences for the patient, and rapid improvement of
cortical/large artery strokes may reverse within hours. In patients with
a severe stroke, caution should be taken when choosing rt-PA for
patients with NIHSS >22 who can be treated within 3 hours. Patients
with NIHSS >25 who present >3 hours after onset of symptoms should
not be given rt-PA (without careful consideration of the risks and
benefits). Regardless of interval from onset to presentation, rt-PA
should be avoided in patients with a CT hypodensity >1/3 of the
hemisphere.
Patients of any age who present within 3 hours may be
given rt-PA; however, caution is important when treating patients >80
years of age. If 3 to 4.5 hours have elapsed since symptom onset,
extreme care is warranted when giving rt-PA treatment in patients aged >>80 years.
Saturday, February 15, 2014
A study of epigenetics in ischaemic stroke
Once again a thesis does more for clarifying stroke than all the stroke associations put together. Read the riot act to your doctor until a stroke protocol is created from this.
A study of epigenetics in ischaemic stroke
Author:
Pogoryelova, Oksana
Awarding Body:
University of Aberdeen
Current Institution:
University of Aberdeen
Date of Award:
2013
Availability of Full Text:
EThOS Persistent ID:
uk.bl.ethos.582717
Supervisor:
Not available
Sponsor:
Not available
Qualification Name:
Thesis (Ph.D.)
Qualification Level:
Doctoral
Abstract:
Author: Pogoryelova, Oksana| Access through EThOS: | |
| Access through Institution: |
Ischaemic stroke rates are expected to rise significantly in the
next decades due to an aging population. This increases the demand for
new stroke biomarkers for early detection of patients at risk and new
targets for treatment. It has been hypothesized that epigenetics may be
important in the aetiology of stroke. The study consisted of three types
of investigation: analysis of candidate gene polymorphism, candidate
gene methylation analysis and epigenome-wide methylation analysis (EWAS)
of pooled stroke and control samples. The stroke types studied were
large vessel disease (LVD), small vessel disease (SVD) and cardioembolic
stroke (CE). DNA from peripheral blood samples was used for EWAS and
methylation analysis. Significant increases in rare allele frequency
were observed in the EHMT2 and DNMT3B genes for all stroke cases; MBD2,
DNMT3B and DNMT3L polymorphisms were associated with LVD. IL10, SOD3,
LINE1 and PITX2 were significantly hypomethylated in LVD. IL10 and
ALOX15 were hypomethylated in CE compared to controls. Methylation
levels of following genes were associated with age (LINE1, IL10, MTHFR,
TNFα, and PITX2), gender (SOD3 and LINE1), total cholesterol level
(SOD3) and systolic blood pressure (IL10). HDAC9 genetic polymorphism
was associated with the MTHFR methylation level. A distinctive
methylation pattern for each stroke subtype was found by EWAS. The CE
pool was hypomethylated at genome, chromosome and gene level, while LVD
and SVD pools had regions with higher and lower methylation levels
compared to the controls. GNAS was identified as new candidate gene by
EWAS. The results suggested that genetic polymorphism and DNA
methylation levels of candidate genes were associated with ischaemic
stroke. Stroke subtypes had distinct methylation profiles suggesting
differences in underlying aetiology. Variations in methylation levels
detected in this study could lead to identification of specific
biomarkers. Replication on a large number of subjects is required before
final conclusions can be drawn.
- See more at: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.582717#sthash.rU4z1697.dpufAwarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2013 Availability of Full Text:
Access through EThOS:
Thesis available to order.
Please login/register to view download & delivery options.
Access through Institution:
http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=201969
EThOS Persistent ID: uk.bl.ethos.582717 Supervisor: Not available Sponsor: Not available Qualification Name: Thesis (Ph.D.) Qualification Level:
Doctoral Abstract:
Ischaemic stroke rates are expected to rise significantly in the next decades due to an aging population. This increases the demand for new stroke biomarkers for early detection of patients at risk and new targets for treatment. It has been hypothesized that epigenetics may be important in the aetiology of stroke.
Author:
Pogoryelova, Oksana
Awarding Body:
University of Aberdeen
Current Institution:
University of Aberdeen
Date of Award:
2013
Availability of Full Text:
EThOS Persistent ID:
uk.bl.ethos.582717
Supervisor:
Not available
Sponsor:
Not available
Qualification Name:
Thesis (Ph.D.)
Qualification Level:
Doctoral
Abstract:
| Access through EThOS: | |
| Access through Institution: |
Ischaemic stroke rates are expected to rise significantly in the
next decades due to an aging population. This increases the demand for
new stroke biomarkers for early detection of patients at risk and new
targets for treatment. It has been hypothesized that epigenetics may be
important in the aetiology of stroke. The study consisted of three types
of investigation: analysis of candidate gene polymorphism, candidate
gene methylation analysis and epigenome-wide methylation analysis (EWAS)
of pooled stroke and control samples. The stroke types studied were
large vessel disease (LVD), small vessel disease (SVD) and cardioembolic
stroke (CE). DNA from peripheral blood samples was used for EWAS and
methylation analysis. Significant increases in rare allele frequency
were observed in the EHMT2 and DNMT3B genes for all stroke cases; MBD2,
DNMT3B and DNMT3L polymorphisms were associated with LVD. IL10, SOD3,
LINE1 and PITX2 were significantly hypomethylated in LVD. IL10 and
ALOX15 were hypomethylated in CE compared to controls. Methylation
levels of following genes were associated with age (LINE1, IL10, MTHFR,
TNFα, and PITX2), gender (SOD3 and LINE1), total cholesterol level
(SOD3) and systolic blood pressure (IL10). HDAC9 genetic polymorphism
was associated with the MTHFR methylation level. A distinctive
methylation pattern for each stroke subtype was found by EWAS. The CE
pool was hypomethylated at genome, chromosome and gene level, while LVD
and SVD pools had regions with higher and lower methylation levels
compared to the controls. GNAS was identified as new candidate gene by
EWAS. The results suggested that genetic polymorphism and DNA
methylation levels of candidate genes were associated with ischaemic
stroke. Stroke subtypes had distinct methylation profiles suggesting
differences in underlying aetiology. Variations in methylation levels
detected in this study could lead to identification of specific
biomarkers. Replication on a large number of subjects is required before
final conclusions can be drawn.
- See more at: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.582717#sthash.rU4z1697.dpuf
Subscribe to:
Posts (Atom)