American Heart Association

Monthly Archives: January 2013

High-density lipoprotein subclasses and risk of stroke

Osman Mir, MD

High-density Lipoprotein Subclasses and Risk of Stroke and its Subtypes in Japanese Population:The Circulatory Risk in Communities Study. Stroke. 2013; 44: 327-333

In this issue of Stroke, Chei et al. report a population based study on the correlation of stroke subtypes and HDL subtypes. This was a nested case control study. The authors CIRCS patient’s data and choose, based on CT or MRI, identified 241 patients who had an ischemic or hemorrhagic stroke and as a similar number of controls matched by sex, age, community, serum storage year, and fasting status. They subsequently used HPLC based HDL subtype analysis and did a conditional logistic regression model to find out the relationship between HDL subtypes and different stroke subtypes.

The total HDL level was associated with different HDL level subtypes. BMI was inversely correlated with total HDL levels. Small HDL cholesterol levels were strongly and inversely associated with risk of total stroke, ischemic stroke, particularly lacunar infarction, and hemorrhagic stroke, specifically intraparenchymal hemorrhage even after adjusting for cardiovascular risk factors. There was no such relationship with large HDL cholesterol level. There was moderate relationship with medium HDL molecules.

This is the first study to show that higher levels of small and medium HDL particles were associated with lower risk of ischemic or hemorrhagic stroke after adjustment for known cardiovascular risk factors. The risk of stroke was approximately 90% lower among persons at the highest quartile of small or medium HDL cholesterol levels compared to those who were at the lowest quartile. 

The mechanism by which small or medium HDL particles reduce this risk is unknown and probably complex. One possible mechanism, suggested by authors, is that small and medium HDL cholesterol molecules have more capacity to mobilize cholesterol compared to large HDL molecules. There might be pharmacological or non-pharmacological way either with diet or exercise of boosting your HDL level specifically your small or medium HDL that might lead to lower vascular risk for future vascular events.


This article addresses the discrepancy that just boosting your total HDL level does not necessary lower your vascular event rate. These findings are inline with new evidence coming from cardiology that suggests that simply boosting HDL with statins does not lower the risk of future cardiovascular events.

 

Post-stroke Use of Selective Serotonin Reuptake Inhibitors and Clinical Outcome

Shruti Sonni, MD

SSRIs are indicated for treating post-stroke depression because they decrease symptoms, improve recovery and reduce mortality. Studies show that they also impair platelet aggregation because they decrease platelet serotonin uptake, and they have been associated with vasoconstriction, including the reversible cerebral vasoconstriction syndrome. This large nationwide Danish study aims to investigate whether these effects of SSRIs on platelets and vasospastic activity have a clinical significance in ischemic stroke patients. The authors compared 5833 patients on SSRIs post-stroke with non SSRIs users, using propensity matching while controlling for major confounders, and estimated the hazards ratios for acute myocardial infarction (MI), recurrent stroke, major bleeding and death. At follow-up,  2.9% patients had an MI, 8.1% had recurrent ischemic stroke, 20.2% had major bleeding (1.4% had intracranial bleeding), and 34.4% died during follow-up. SSRI users had a lower risk of MI and recurrent stroke, but a higher risk of major bleeding (including a non-significantly higher risk of intracranial bleeding). Mortality was higher in the SSRI group.

Prior studies found that among new SSRI users, the risk of major hemorrhage is significantly higher with intermediate and high degree of serotonin reuptake inhibition. It is unclear how much higher mortality is in stroke patients compared to all SSRI users. The authors attribute the higher mortality in SSRI users to possible “confounding by indication,” suggesting underlying depression in this group could be the reason.

It is unclear whether including patients who reached the primary endpoint of MI, stroke, hemorrhage or death within 30 days would have altered the results of this study, given high risk of recurrent strokes in the 90 day period post-stroke. Also, dosage of SSRIs was not reported in this study. There may be an ideal dose which has a protective antithrombotic effect and has lesser bleeding propensity, which could be best demonstrated by a prospective study. Since it is difficult to quantify the degree of platelet inhibition by SSRIs, it makes reliable utilization of their anti-platelet property challenging. Though this study stimulates an interesting discussion regarding the various aspects of SSRI effects in post-stroke patients, the clinical implications remain confusing.

Subarachnoid Hemorrhage in a Multimodal Approach

Nandakumar Nagaraja MD, MS


Endovascular interventions for acute ischemic stroke can result in complications such as arterial perforation, dissection, subarachnoid hemorrhage or intraparenchymal hematoma. It is important to know the magnitude of these risks related to the procedure and their clinical implications. It helps in the decision making process when discussing with the family to obtain consent for the procedure and be prepared to manage these complications if it occurs.

Yoon and colleagues performed a retrospective analysis of 74 acute ischemic stroke patients who underwent multimodal endovascular intervention weighted toward mechanical thrombectomy with a Solitaire stent. They evaluated for the incidence, clinical implications and prognosis of SAH after the procedure. All patients had a baseline CT and multimodal MRI prior to the procedure; immediate post procedure and 24hr CT scan; and 24 hr MRI to evaluate for blood on GRE in patients who had hyperdense lesion in the post procedure CT scan.

12 (16.2%) patients had SAH; 4 pure SAH and 8 mixed SAH with contrast extravasation. SAH in 5 patients (3 pure and 2 mixed) disappeared on 24 hr imaging. There was no significant difference between the SAH group and the control group for baseline characteristics including demographics, risk factors and stroke etiology. Baseline NIHSS was 12. Half the patients had received iv t-PA and 30-41% of the patients had mechanical clot disruption with IA urokinase in each group. Patients who had angioplasty had higher rates of SAH (33.3%) compared to control group (9.7%), p=0.05. The authors’ consider this to be due to small vessel rupture from mechanical stretch during stent retrieval. There was no significant difference in the clinical outcome between the two groups for recanalization status, SICH, mortality, discharge NIHSS and 3 months mRS assessment and therefore the SAH post procedure was considered to be clinically benign.

Some patients who develop SAH post procedure may not have grossly evident neurological deficits and the symptoms if present may be masked from the deficits of acute ischemic stroke. A significant proportion of the patients could develop cognitive impairment which may be subtle and not detected with routine assessment. The AHA/ASA guidelines for management of aneurysmal SAH recommend a comprehensive evaluation of cognitive, behavioral and psychosocial function after discharge. Though the SAH is due to the procedure and not aneurysmal in this study it may be useful to obtain detailed neuropsychological assessment in these patients after discharge.

Electrochemical failure of the brain cortex

Jose Gutierrez, MD, MPH

Dreier et al. carried on an interesting experiment on rats to evaluate whether the commitment point of neurons distressed by spreading depression varies depending on the perfusion levels. Rats were assigned to three experimental groups: 1) A group where a K+-rich solution was applied to the brain surface through a small subdural window to induce a series of spreading depressions (SD), 2) A group where ischemia was forced by adding purified hemoglobin (nitric oxide scavenger) to the same K+ solution, and 3) A group where hyperemia was sought by adding nimodipine (a vasodilator) to the same K+/Hb+ solution used in group 2. The depolarizing potentials were measured with superficial and deep cortical electrodes and they lasted a little bit longer than an hour in each case. After the experiment was finished, the rats were sacrificed and the brain tissue was observed under the microscope to evaluate the degrees of inflammation, apoptosis, necrosis and asctrocytic activity in the three groups.

The investigators found that, as initially suspected, the greatest degree of necrosis involved all cortical layers and occurred in the groups where SD was accompanied by forced ischemia. Although the others 2 groups also suffered necrosis, this was limited to the superficial cortical layers. Greater degrees of inflammation were observed in the ischemic groups as well compared to the group where hyperemia was forced by adding nimodipine. The areas where necrosis was found recorded negative electric potential, suggesting that negative potentials might be markers of irreversible damage.   

The results of this animal experiment shed light on important aspects of the physiopathology of neuronal dysfunction in the setting of ischemia and electrochemical membrane failure. While not all effects observed in animals occur in a similar fashion in humans, this study opens potential research opportunities of broad clinical impact. Hyperemia for subarachnoid hemorrhage and permissive hypertension for acute stroke are examples of strategies currently in use where the concept of increased perfusion is applied to ischemic conditions. Understanding the mechanisms that can influence the commitment point at which neurons suffer irreversible damage is key in formulating successful neuroprotective strategies.

The Risk of Stroke or Clinical Impairment in AVM Patients

Diogo C. Haussen, MD


Bruce E. Pollock et al. The Risk of Stroke or Clinical Impairment After Stereotactic Radiosurgery for ARUBA-Eligible Patients. Stroke. 2013; 44: 437-441.

The initial experiences of surgical treatment for brain arteriovenous malformations (BAVM) in the early 1900s by Harvey Cushing and contemporaries were extremely challenging. Despite the remarkable advances in the understanding of this disease over the last decades, the most appropriate approach to unruptured BAVM remains unknown.

The ongoing ARUBA trial is a RCT of medical therapy vs. intervention (radiotherapy, neurosurgery and/or endovascular embolization). When completed, it will help us decide the best treatment for our patients with BAVM. Until the results of this trial are published, however, we must rely on other studies to guide our treatments. 

Pollock and colleagues report such a study in Stroke. In their interesting and timely study they analyzed the risks to patients undergoing stereotactic radiosurgery (SRS) for unruptured BAVM. They used the same eligibility criteria as the ARUBA trial to select retrospectively from their database 165 patients with 2 or more years of follow-up, They looked at the same outcomes as  ARUBA: the composite of ‘symptomatic stroke or death’, as well as ‘death or clinical impairment (modified Rankin Scale ≥2)’. 

The BAVM obliteration rate post initial SRS was ~70% and the time to obliteration was ~3.3 years. Fifteen patients (8.6%) had a hemorrhagic stroke during follow up and 4% developed permanent radiation-related focal neurological deficit after SRS. The rate of stroke or death was 10.3% at 5-years and 11.5% at 10-years after SRS. The only independent predictor of stroke or death in multivariate analysis was ‘increasing BAVM volume’. The risk of death or clinical impairment was 8.4% at 5-years and 12% at 10-years.


 The mean age and gender distribution are equivalent. The frequency of Spetzler-Martin subtypes were comparable, with the exception that grade IV patients encompassed 13% and grade V 0% of ARUBAs patients, while the composite of grade IV-V composed 19.5% of BAVMs of the report in question. The larger proportion of higher grade BAVMs (possibly including grade V lesions) in Pollock’s study may overestimate adverse event rates compared to what will be seen in ARUBA.

The authors provide us a solid and insightful analysis, which reflects the difficulties and uncertainties related to the treatment of BAVMs. As detailed, their rates of hemorrhagic stroke post SRS was comparable to the annual bleeding rate noted in the natural history of BAVM for the first five years, then decreasing below the risk for untreated BAVM as more patients achieve nidus obliteration. While we will have to wait for ARUBA to publish their results, this study can help us inform our patients about one current treatment for BAVMs.

Statin Therapy and Outcome After Ischaemic Stroke

Waimei Tai, MD

 

In a recent article published in Stroke, Chróinín et. al. looked at the benefit of statins across all patients with ischemic stroke using a meta-analysis method, looking at both retrospective and prospective cohorts, and randomized controlled trials. The vast majority of patients (99%) were from cohort studies that followed patients with ischemic stroke, with one very large registry of 86 thousand patients (76% of the entire data set) heavily weighted in this data analysis. The results, including this large registry or excluding this large registry, were both in favor of statin use for improving 90 day clinical outcome.

Looking specifically at statin use thrombolysis-treated patients, the story is murkier. Here all the studies were observational, and statin therapy at time of stroke onset was associated with higher odds of all cause death at 90 days.

Caution should be taken as this meta-analysis is predominately from observational studies and there may have patient selection bias where generally sicker patients were less likely to take oral statins soon after stroke.

This study bolsters current practice of initiating or continuing statin therapy when possible for ischemic stroke patients with the hope improve long term outcomes in ischemic stroke patients.

Defining best practices and following guidelines for acute stroke therapy and prevention is important to ensuring all stroke patients get the best care possible.  Protocols based in science can help streamline care and improve workflow while ensuring that patients are getting the appropriate treatments. This study and others similar to it can help provide the scientific support for current best practices.