American Heart Association

pathogenesis

Resistant Atherosclerosis

Philip Chang, MD

Spence JD, Solo K. Resistant Atherosclerosis: The Need for Monitoring of Plaque Burden. Stroke. 2017

In this study, Spence and Solo demonstrated that measurement of LDL-C levels is likely inadequate to assess a patient’s response to statin therapy. In their database of 4512 patients with 2 measurements of LDL-C and 2 carotid duplex scans measuring total plaque area, they found that neither LDL-C levels nor change in LDL-C levels predicted carotid artery plaque burden or progression of plaque area. Interestingly, they found that in the 6% of patients with low LDL-C levels (<38mg/dL), almost half experienced progression of their plaque burden. In addition, they found that it was not uncommon for patients with LDL-C levels of over 70mg/dL to experience plaque regression. This suggests that merely relying on an LDL-C level to predict plaque burden is insufficient.

Cortical Neuronal Damage in Atherosclerotic Large Artery Disease

Russell Mitesh Cerejo, MD

Yamauchi H, Kagawa S, Kishibe Y, Takahashi M, Higashi T. Progressive Cortical Neuronal Damage and Chronic Hemodynamic Impairment in Atherosclerotic Major Cerebral Artery Disease. Stroke. 2016

In their paper, the authors set out to determine whether selective cortical neuronal damage manifests as a decrease in BZRs in the normal appearing cerebral cortex of patients with atherosclerotic ICA or MCA occlusive disease, and furthermore whether these changes can be correlated with chronic hemodynamic impairment at baseline or hemodynamic deterioration. They studied 80 patients with atherosclerotic ICA or MCA disease with 17 having TIAs, and 38 having completed stroke.

The authors found that the BZR index in 40 patients was increased during follow-up (mean 26±20 months). In multivariable logistic regression analyses, increases in the BZR index were associated with the decreased cerebral blood flow at baseline and an increased oxygen extraction fraction during follow-up. They hypothesize that misery perfusion at baseline is associated with subsequent development of ischemic cortical neuronal damage. The contribution of the increased BZR index at baseline suggests that patients with misery perfusion have already suffered some ischemic cortical neuronal damage and may be at particular risk for progressive cortical neuronal damage.
They also found that increases in the oxygen extraction fraction during follow-up were associated with a lack of statin use. They suggest that revascularization procedures can improve hemodynamic impairment and thus may be beneficial to patients vulnerable to selective neuronal damage. 


Asian patients with paroxysmal AFib have lower stroke risk than those with sustained AFib

Ilana Spokoyny, MD

Takabayashi K, Hamatani Y, Yamashita Y, Takagi D, Unoki T, Ishii M, et al. Incidence of Stroke or Systemic Embolism in Paroxysmal Versus Sustained Atrial Fibrillation: The Fushimi Atrial Fibrillation Registry. Stroke. 2015 

Afib is a major risk factor for stroke, and oral anticoagulation (OAC) has been shown to be the most effective preventative treatment. Since OAC is associated with increased bleeding risk, efforts have been made to stratify risk by identifying patient characteristics which increase the risk of stroke in AFib patients (CHF, Hypertension, Age, Diabetes, etc.). Until recently, paroxysmal and persistent AFib were reported to have the same associated risk of thromboembolic events, and the guidelines recommend OAC treatment for prevention, regardless of the type of AFib. It does seem intuitive that someone in constant AFib for years would have a higher risk of stroke than a patient who had half an hour of AFib after surgery. Several recent studies have shown a lower stroke rate in paroxysmal AFib compared to sustained AFib. There is also limited data in Asian patients, so some equipoise existed which prompted this study. 

Data was obtained from the Fushimi AF Registry, whose only inclusion criteria was the documentation of AF on a 12-lead EKG or Holter monitoring at any time. Paroxysmal AF was defined as lasting under 7 days; persistent AF lasted longer than 7 days was but able to be terminated by medication or electrical cardioversion; permanent AF was refractory to medical or electrical cardioversion. Persistent and permanent AF were combined in this study as SAF (sustained AF), due to difficulty differentiating these in daily clinical practice. Multivariate analyses were performed for the vascular risk factors in both the CHADS2 and CHA2DS2-VASc scores, and also included the variable of “low body weight” (which was shown to correlate with stroke risk in Japanese AF patients).

3304 patients were included, split about evenly between paroxysmal and sustained AF. PAF patients were younger, more often symptomatic (palpitations), and less likely to have a history of stroke, CHF, or CKD. The CHADS2/CHA2DS2-VASc scores were lower in PAF patients, and there was a lower rate of OAC use among PAF patients at any age or CHADS2 score compared to SAF patients. About 10 percent of PAF patients progressed to SAF, and there was a significantly higher rate of stroke/systemic embolism among those who progressed compared to those who did not. PAF patients had lower risk of stroke/systemic embolism overall, and this persisted when the patients were stratified by OAC use and CHADS2 score. On multivariate analysis, PAF was an independent risk factor for a reduced risk of stroke/systemic embolism, while age ≥75 and history of stroke portended increase risk. PAF remained significant even when CHADS2 and CHA2DS2-VASc criteria were added to the model, as well as when age was added as a continuous variable. Low body weight (≤50kg) was indeed an independent risk factor for increased risk of stroke/systemic embolism.

This study did not measure the AFib burden, which may be the key to risk stratification in AFib. The other Asian registry mentioned, J-RHYTHM, did not enroll patients who maintained sinus rhythm for over a year, while this registry did. J-RHYTHM showed more thromboembolism in SAF patients, but this difference disappeared after adjusting for vascular risk factors. Neither registry used long-term monitoring or included AF burden as a variable. In this study, patients with PAF were more likely to receive anti-arrhythmic drugs or catheter ablation, which may have decreased AF burden and stroke risk.

In order for these results to influence the guidelines on treatment of PAF, it would have been important to compare the anticoagulated PAF to non-anticoagulated PAF, as well as to age and risk-matched non-AFib patients. However, since this was a registry, it is difficult to make a comparison between treated and untreated patients as there are other contributing factors which influence the initiation of OAC. This can be seen here, as the incidence rate of stroke/systemic embolism per 100 person-years in OAC-treated patients is higher than in untreated patients (and this difference persists for ischemic stroke).

The discrepancies between PAF and SAF shown in this observational registry study are important and may lend evidence to the idea that AF burden is associated with stroke risk. As monitoring technology advances, we are identifying PAF earlier and more often (and committing patients to OAC sooner), but we also have the capability to quantify the AFib burden. Despite guidelines recommending OAC for PAF, only 39% of patients in this registry were prescribed OAC. So, it would be ethical to perform a study of PAF patients which quantifies AFib burden (via wearable or implanted monitor) and randomizes those with low vascular risk scores and a low AF burden to antiplatelet therapy. This would be very useful in creating safe and evidence-based recommendations on the need for OAC therapy in PAF patients.

Ischemia in Intracerebral Hemorrhage: The Blood Pressure Conundrum

Michelle Christina Johansen, MD

Gioia LC, Kate M, Choi V, Sivakumar L, Jeerakathil T, Kosior J, et al. Ischemia in Intracerebral Hemorrhage Is Associated With Leukoaraiosis and Hematoma Volume, Not Blood Pressure Reduction. Stroke. 2015

What corresponds to DWI lesions in intracerebral hemorrhage (ICH)? Is this reflective of true ischemic injury? The INTERACT trials refocused the neurointensivist on aggressive blood pressure control as this was shown to correlate with decreased hematoma growth and better functional outcomes. But is there a downside to controlling the blood pressure too aggressively? Does this result in ischemic insult or DWI changes on MRI? 




Dr. Gioia et al., sought to identify the frequency of ischemic lesions in primary ICH patients with the hypothesis that larger hematoma volumes and blood pressure reduction are associated with the presence DWI lesions. 

The Canadian based study retrospectively identified 117 ICH patients who underwent DWI within 14 days of symptom onset. Hematoma/perihematoma edema volumes were measured using planimetric techniques. Perihematoma and remote DWI lesion volumes were measured using apparent diffusion coefficient. The investigators established two thresholds to define the amount of ischemic damage; moderate (<730×10-6mm/s) and severe (<550×10-6mm/s). Acute blood pressure changes over the first 24 hours were calculated using the formula admission systolic blood pressure (SBP) minus nadir SBP. Mean age of the population was 65 and 52% were male. Hypertension was the most common cause indicated in the medical record for ICH (45.7%).

The authors, after controlling for age, baseline NIHSS and perihematoma edema volumes, found that perihematoma DWI lesions were independently associated with larger hematoma volumes. There was no association between changes in blood pressure (maximal systolic blood pressure drop) and the presence of DWI lesions. They did find remote DWI lesions in 17 patients. For the remote lesions, once again no relationship was found with blood pressure, but they did note these patients were more likely to use antiplatelet drugs, have a history of ICH and larger leukoaraiosis (hyperintensity on FLAIR) volumes.

How should the results of this study be applied? The mean time to MRI was 2 days which is a consideration when drawing conclusions between volumes and the presence of DWI lesions. That being said, there was excellent interreliability among the radiologists and they accounted for edema volume which should help mitigate over calculation of hematomal volumes. Blood pressure data was missing in 4 patients with perihematoma DWI lesions in a relatively small cohort of patients (38). Would a larger sample size have led to different results? How does the fact that the majority of patients had lobar ICH affect the data? Thus we are still unable to define the relationship between blood pressure control and patients with cerebral amyloid angiopathy.

Where does the vascular neurologist go from here when faced with perihematoma diffusion restriction after ICH? In ischemic injury, we allow for permissive hypertension to provide critical blood flow to the penumbra yet research supports aggressive blood pressure control for ICH. The authors of this study did not find a relationship between aggressive blood pressure control and ischemia but it cannot be ruled out. In their discussion, they suggest that larger hematomas be treated more conservatively with respect to blood pressure control but appropriately caveat this statement with the need for larger clinical trials. While the answer remains unclear, we must strive to clarify this issue so that our patients can receive the best medical care based on evidence.

Poststroke Angiogenesis: Architect and/or Demolition Crew?

Mark N. Rubin, MD

Greenberg DA. Poststroke Angiogenesis, Pro: Making the Desert Bloom. Stroke. 2015


Adamczak J, and Hoehn M. Poststroke angiogenesis, Con: The Dark Side of Angiogenesis. Stroke. 2015


This installment of the “Controversy” series involves what to make of post-stroke angiogenesis: the hypoxia-triggered generation of new capillaries after a stroke of any subtype. The fact that angiogenesis exists in the post-stroke setting–experimental and clinical–is not the point of debate but to what degree this process influences patient outcome. Experimental, pathological case study and treatment trial data exist in this field, but a fundamental clinical question remains unanswered: does manipulating this pathophysiologic process make patients better?



Dr. Greenberg from the Buck Institute for Research on Aging proposes that post-stroke angiogenesis is a viable therapeutic target, mostly because it is fairly well understood at a biochemical level, broadly applicable across the patient population and there are myriad promising biochemical targets in the process that have not yet been investigated. Furthermore, there is the optimistic view that angiogenesis allows for more rapid clearing of ischemic debris, setting a clean slate for post-stroke neuronal reorganization (e.g., functional recovery). Prof. Doctors Adamczak and Hoehn from the Max Planck Institute argue that angiogenesis is more demolition crew than architect. While not arguing that restoration of cerebral blood flow is beneficial to neuronal tissue, they point out the double-edged sword of pro-angiogenic factors (namely Vascular Endothelial Growth Factor, better known as VEGF), which also promote increased cerebral edema which is injurious to brain. They cite evidence that supporting anti-angiogenic factors actually decreases infarct volume.

Dr. Liu from UCSF ties the debate together with a resounding “you’re probably both right but we don’t know enough in general. Plus, how does this all relate to collateralization, which is so hot right now?” She also suggests a careful marriage of nanotechnology and pharmacotherapy may help deliver the right mix of biochemicals–whichever those may be–to the right place at the right time, thus mitigating the known inefficacy and/or risks of systemic delivery of pro-angiogenic factors.

Read on for details of the Basic Science Controversy In Stroke!

The stress of it all: Examining the hemodynamics of AVMs before and after treatment

Mark L. McAllister, MD

Alaraj A, Shakur SF, Amin-Hanjani S, Mostafa H, Khan S, Aletich VA, et al. Changes in Wall Shear Stress of Cerebral Arteriovenous Malformation Feeder Arteries After Embolization and Surgery. Stroke. 2015

Cerebral AVMs are a concern to the stroke neurologist because of their propensity to present as an intracerebral hemorrhage. The connections of arteries directly to veins without the intervention of a high resistance capillary network alter normal cerebral hemodynamics. How the long term changes in vessel characteristics including vascular remodeling respond to the abnormal physics caused by AVMS is not fully understood.


Using quantitative magnetic resonance angiography (QMRA), Alaraj et al. estimated the wall shear stress (WSS), the force of blood against the cerebrovascular endothelium, in the patients with AVMs before and after treatment. In a cohort of 21 patients undergoing embolization of their AVM, the investigators demonstrated that the WSS was increased in the feeder arteries of the AVM compared to the normal contralateral vessel prior to the procedure. After embolization, the WSS fell to levels comparable to the contralateral vessels.

Additionally, in a subset of 17 patients who underwent resection of the AVM after embolization further reduction of the WSS was demonstrated. The mean WSS forces after surgical receptions demonstrated a trend to be lower than the mean on the contralateral normal vessel, but this did not achieve statistical significance.
Given that WSS has been implicated as a stimulus for vessel remodeling and vessel diameter, noninvasive measurement of WSS using QMRA may represent an intriguing method to monitor the efficacy of treatment for cerebral AVMs. Further, this study is important in that it is contrast to the only other study of WSS in AVMs which found identical WSS in the AVM feeders and normal contralateral vessels. The authors contend that their use of QMRA is more accurate than the TCD used in the 1995 study.

Interleukin 23 levels are increased in carotid atherosclerosis – A possible role for the IL-23/IL-17 axis?

Michelle Christina Johansen, MD

Abbas A, Gregersen I, Holm S, Daissormont I, Bjerkeli V, Krohg-Sørensen K, et al. Interleukin 23 Levels Are Increased in Carotid Atherosclerosis: Possible Role for the Interleukin 23/Interleukin 17 Axis. Stroke. 2015

The world of immunology and elucidation of cytokine pathways is not usually the focus of the vascular neurologist, but perhaps our attention should be redirected. It is well established that atherosclerosis is a state of inflammation and prior studies have shown an increased expression of IL-23 in carotid lesions, with particularly high levels in symptomatic patients. Targeting of IL-23, a member of the IL-12 family of cytokines with pro-inflammatory properties, is already underway in other autoimmune diseases including psoriasis, inflammatory bowel disease and rheumatoid arthritis. How is this interleukin, with its role in producing IL-17 related to cerebrovascular disease?



Abbas et. al in their study reinvestigated the association of IL-23 to atherosclerosis and sought to better establish any relationship between expression and cerebrovascular disease. 177 patients with internal carotid stenosis (≥50%) were recruited and classified according to symptoms: 69 patients had a stroke/TIA/amaurosis fugax ipsilateral to the stenosed carotid artery in the prior 2 months and 108 patients either had symptoms >2 months or had no symptoms. The patients were compared to 24 healthy controls from the same area of Norway. Plasma samples were obtained by venipuncture. Plaque samples were obtained for examination from 68 of the patients with carotid atherosclerosis and compared to non-atherosclerotic control vessels of organ donors.

Those with carotid atherosclerosis (177) were found to have markedly raised plasma IL-23 levels compared to controls (24). Notably, the level of IL-23 increased in a step wise fashion with the highest plasma levels in those with the most recent symptoms (<1month). Even those without symptoms still had higher levels of IL-23 than healthy controls. When the plaque samples were evaluated, IL-23 as well as IL-23 receptors (R) were 18 fold higher in those with atherosclerosis. However, there was no association between levels of IL-23 and presence or absence of symptoms.

In order to better elucidate the role of IL-23, plasma dendritic cells, peripheral blood mononuclear cells and monocytes from patients with carotid atherosclerosis were evaluated. The investigators found those with carotid atherosclerosis had increased levels of IL-23/IL-23R in dendritic cells as well as increase release of IL-17 from mononuclear cells when stimulated with IL-23 in comparison to healthy controls. IL-23 promoted release of tumor necrosis factor (TNF) only in those with carotid atherosclerosis.

Recent data indicate that IL-23 is a dominant cytokine controlling inflammation in peripheral tissues and joints, but what role does it have to play in stoke? This study suggests that IL-23 plays a unique role in the patient with atherosclerosis compared to healthy controls. The study has limitations such as a small control sample size, but is it possible that the release of IL-23, the interaction with its receptor or the stimulation of IL-17 represent three potential targets for new therapies? Could we control some of the sequela of stroke by a modulation of this cascade? While other trials targeting the inflammatory response in stroke are underway using Methotrexate and Tysabri, perhaps further research should be directed at the IL-23/IL-17 cascade in hopes that in vivo trials could provide even more exciting results.

Paragonimus Hemorrhagicus

Vikas Pandey, MD

Xia Y, Ju Y, Chen J, You C. Hemorrhagic stroke and cerebral paragonimiasis. Stroke. 2014

Paragonimiasis is a parasitic infection caused by the Paragonimus species (most commonly Paragonimus Westermani) of lung flukes and is particularly common in East Asia however the more than 30 species of the flukes are becoming more prevalent worldwide. Commonly causing a pulmonary syndrome consisting of lung parenchymal hemorrhage and hemoptysis, the species is becoming more and more notorious for causing intracerebral hemorrhage, as those with both acute and chronic cerebral paragonimiasis appear at risk of having cerebral hemorrhages. The group from West China Hospital at Sichuan University set out to characterize cerebral paragonimiasis and its impact on cerebrovascular disease.



The authors retrospectively analyzed the clinical and imaging characteristics, diagnosis and treatment outcomes of 10 patients with hemorrhagic cerebral paragonimiasis. The group had an average age of 15.7 years and ranged from 4 to 46 showing the younger cohort that the disease affects. The diagnosis of paragonimiasis was done by ELISA serologic testing for Paragonimus-specific IgG antibody and blood eosinophil quantification was conducted on blood samples. The manifestations of the paragonimiasis were vascular malformation, tumor apoplexy, subarachnoid hemorrhage, intraventricular hemorrhage, cavernous hemangioma, subdural hemorrhage and spontaneous intracerebral hemorrhage. Four out of the ten cases were confirmed by pathology. The hemorrhages seen were atypical of occult vascular malformations and the hemorrhages themselves had atypical appearances such as dot, strip, sheet or cord-shaped hematomas. Other imaging testing was done to rule out other cerebrovascular disease on an as needed basis. The misdiagnosis rate was approximately 100%.

The importance of early detection of paragonimiasis is exemplified by the fact that paragonimiasis can be cured by therapy upon early diagnosis but delayed treatment can cause death in as high as 5% of patients. The mechanism of hemorrhage is thought to be due to vessel wall changes caused by parasitic inflammation resulting in concentric thickening, lumen stenosis and occlusion, as well as erosion of the vessel wall causing subsequent rupture. The alarmingly high misdiagnosis rate and the known increase in prevalence of paragonimiasis makes this disease one that should not be overlooked, especially in areas where the parasite is endemic or in cases of atypical hemorrhagic stroke symptom presentation and appearance on imaging.

@DrVikasNeuro

Effects of Extracranial Carotid Stenosis on Intracranial Blood Flow

Rajbeer Singh Sangha, MD

Shakur SF, Hrbac T, Alaraj A, Du X, Aletich VA, Charbel FT, and Amin-Hanjani S. Effects of Extracranial Carotid Stenosis on Intracranial Blood Flow. Stroke. 2014

A higher degree of extracranial carotid stenosis is associated with increased stroke risk and has become a key determinant in treatment decision-making. The dominant mechanism via which strokes occur is thought to be thrombo-embolic, however it has been postulated that hemodynamically-consequential narrowing of the vessel lumen can also result in cerebral hypoperfusion and may even potentiate the effects of distal embolization. Shakur et al. looked to characterize impact of degree of stenosis, stenosis length, and residual lumen on intracranial blood flow in patients with extracranial carotid stenosis.



The study was a retrospective analysis of 105 patients that were identified having ≥ 50% carotid stenosis who underwent revascularization. Patients in this study had undergone quantitative flow measurements of the extracranial and intracranial arteries using quantitative magnetic resonance angiography (QMRA). On multivariate analysis, MCA flow ratio was not significantly associated with percentage stenosis, stenosis length, or residual lumen. However, mean MCA flow ratio was significantly lower in symptomatic compared to asymptomatic patients (0.92 vs. 1.22, P=0.001). In contrast, mean ICA flow ratio was similar among these two groups (0.55 vs. 0.55, P=0.99).
The study findings suggest that in symptomatic extracranial carotid disease, the reduction in MCA flow may play an important role, thus implicating intracranial hemodynamics in the pathophysiology of this disease. It would be interesting to be able to classify the level of collaterals in these patients as this may be a determinant in whether patients remain asymptomatic. Furthermore, more studies should be conducted to better quantify the characteristics present in patients who suffer from symptomatic extracranial carotid disease vs asymptomatic extracranial carotid disease. Elucidating the pathophysiological mechanisms will better allow us to stratify ischemic stroke risk in the asymptomatic population.  

Lefties are Never Right: Is Atherosclerotic plaque in the Left carotid artery more vulnerable than on the Right?

Michelle Christina Johansen, MD

Selwaness M, van den Bouwhuijsen Q, van Onkelen RS, Hofman A, Franco OH, van der Lugt A, et al. Atherosclerotic Plaque in the Left Carotid Artery Is More Vulnerable Than in the Right. Stroke. 2014

Left hemispheric strokes can be devastating, impacting the patient’s language center and leading to hemiparesis and hemiplegia. Large vessel atherosclerosis is an established stroke subtype and plaque located at the carotid bifurcation has been implicated in as high as 18% of all strokes. Selwaness et al open their paper by noting that a significantly higher proportion of ischemic events are diagnosed in the left hemisphere compared to the right.  The team hypothesize that the higher incidence of events occurring in the lefthemisphere is related to either a higher prevalence, severity or vulnerability of atherosclerotic disease in the left carotid artery. 




Carotid MRI’s were performed on 1414 stroke free participants to assess not only the location but also degree of stenosis and components of the carotid plaque. The authors invited participants from The Rotterdam Study, a prospective population based cohort study who were routinely undergoing carotid ultrasound to also undergo MRI imaging of the bilateral carotids. The mean age of the final cohort was 72 and 53% were male.  Image quality was considered sufficient in 95% of scans. Luminal stenosis was calculated using the NASCET criteria.  The investigators classified the composition of plaques as either lipid-rich, containing intraplaque hemorrhage or calcification based on imaging characteristics. 

Overall, 1196 subjects or 85% had plaque in both carotid arteries meaning only 218 subjects had unilateral plaques. Within these patients, the investigators found that left sided plaques were twice as prevalent as right sided with no sex predominance but those with unilateral left sided plaques tended to be younger (68 vs 71). The degree of luminal stenosis did not differ between right and left and clinically relevant stenosis defined by NASCET also did not differ. When the components were analyzed individually, lipid-rich plaques was slightly more prevalent on the left (27.6% vs 23.4% p 0.006) and intraplaque hemorrhage (IPH) was also more frequent in left carotid artery plaques (23.1% vs 19.7% p 0.01).  Calcification was equal on both sides. When a single or predominant component was assigned, IPH and lipid were most prevalent in left-sided plaques but this time right sided plaques were predominantly composed of calcification.

The conclusion of the investigators is that carotid atherosclerotic plaque size and composition are not symmetrically distributed and that plaques on the left are more vulnerable than on the right due to the presence of IPH versus calcification. 

This inference should give the practicing vascular neurologist pause. In treatment of asymptomatic carotid stenosis, the mantra has been best medical management. Many are familiar with the CREST data which showed that among asymptomatic patients, the primary outcome (periprocedural stroke, death and myocardial infarction rates) did not differ significantly between stenting and surgery (4.9% vs. 5.6%) but the study was not powered to obtain significance (p=0.07). There are ongoing trails (CREST-2) to evaluate if optimal medical management is in fact sufficient in these patients. If in fact left sided plaques are more vulnerable to rupture, while we wait for the outcome of clinical trials should a practicing Neurologist change practice? For example, would one lower the blood pressure of a patient with left sided stenosis more aggressively than their right sided counterpart? Is dual antiplatelet therapy warranted even in the absence of intracranial stenosis? The authors appropriately discuss many limitations in evaluation of their data to include the fact that significance was only obtained when the plaques were assigned a predominant component, a small n and potential observer bias. This limits the broad application of their study results but the questions raised demand further research and consideration. 

“Let not the right side of your brain know what the left side doeth.”
~ George Bernard Shaw