American Heart Association

Monthly Archives: March 2014

Evaluation of CT Angiography Plaque Thickness Measurements in High-Grade Carotid Artery Stenosis

Sebina Bulic, MD

Gupta A, Baradaran H, Kamel H, Pandya A, Mangla A, Dunning A, et al. Evaluation of Computed Tomography Angiography Plaque Thickness Measurements in High-Grade Carotid Artery Stenosis. Stroke. 2014

The degree of carotid artery stenosis was, and remains focus of research in terms of surgical or interventional revascularization, primary or secondary stroke prevention. Also, plaque composition and identification of “vulnerable plaque” has been increasingly studied, for further risk stratification beyond the degree of luminal narrowing. Most of the available data is MRI based.

The authors used previously validated methodology using CTA and simple linear measurement of maximum soft plaque thickness on routinely acquired axial CTA images. Data acquired over 3 years (8/2009-8/2012) was analyzed. 6.2% or 76 patients out of 1224-screened patients had high-grade carotid artery stenosis (>70% stenosis) 45 patients or 59.2% of this cohort had TIA or stroke.

Mean values for the maximum total plaque thickness and maximum soft plaque thickness
were significantly higher in subjects with symptomatic carotid disease, whereas
maximum hard plaque thickness was found to be significantly higher in asymptomatic subjects. The degree of NASCET stenosis was not different between groups. For every 1 mm increase in maximum soft plaque thickness, there was approximately a 2.7 times greater likelihood (OR=2.7) of prior ipsilateral stroke or TIA (p<0.0001). For each 1 mm increase in hard plaque thickness, there was 45% (OR=0.55) decreased likelihood of prior ipsilateral stroke or TIA (p=0.007). It was found that maximum soft plaque thickness had the best ability to discriminate between symptomatic and asymptomatic subjects, with an optimal cutoff of 3.5 mm. This study also demonstrated excellent inter-observer reliability.

This study adds to the growing body of evidence on this topic, it is easy to perform, reproducible with excellent inter-observer reliability, however, given constant and dynamic changes in vulnerable plaque elements, prospective studies are needed for better identification of the population at greatest risk.

AcSDKP shown to provide potent neuroprotection in rats after stroke

Vivek Rai, MD

Zhang L, Micael Chopp M, Teng H, Ding G, Jiang Q, Yang XP, et al. Combination Treatment With N-Acetyl-Seryl-Aspartyl-Lysyl-Proline andTissue Plasminogen Activator Provides Potent Neuroprotection in RatsAfter Stroke. Stroke 2014.

In the setting of acute stroke, neuroprotection aims to restrict neuronal injury and prevent death of salvageable neurons thereby increasing the chances of good recovery. Over eighteen years later, Alteplase (rt-PA) remains the only approved treatment for acute ischemic stroke (AIS). Many promising neuroprotective agents failed to show benefit in clinical trials. The search for an effective neuroprotective agent continues.

Zhang et al studied the effects of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) alone and in combination with thrombolytic therapy in a rat model of embolic focal cerebral ischemia. AcSDKP is an endogenously produced circulating peptide in humans and rodents, exerts anti- inflammatory and cardio-protective activities. The authors report that AcSDKP at 1 hour and in combination with rt-PA at 4hours after stroke onset reduced infarct volume and neurological deficits, without increasing the incidence of brain hemorrhage. Further, they showed that AcSDKP can easily cross blood brain barrier and blocks production of several inflammatory proteins and peptides that are important in regulating thrombosis and inflammatory responses after stroke.

The authors have shown that AcSDKP is a promising neuroprotective agent. Among other things, authors used a study protocol that is applicable to clinical trials and the product itself is naturally occurring with no untoward side effects shown so far. I think a strong case is made here for further development of this product for clinical trials. Whether this particular agent holds its promise of being neuroprotective agent that can be used in humans, only time will tell.

Infection and ischemic stroke- the bidirectional connection

Seby John, MD
Ruhnau J, Schulze K, Gaida B, Langner S, Kessler C, Bröker B, et al. Stroke Alters Respiratory Burst in Neutrophils and Monocytes. Stroke. 2014

Infections can cause stroke, and stroke increases the rate of infections. In fact, infection is the most common complication after stroke and contributes to poor functional outcome. Pneumonia for instance occurs in upto 22% of patients and is the leading cause of death after stroke. This bidirectional relationship is complex. Recall the parts of the immune system, it comprises the innate and adaptive immune systems, each differing with respect to how quickly and for how long it responds, central effector cell types and its specificity for pathogens. The association between the adaptive system and stroke has been well investigated, but the function of the innate system in stroke is unknown.

Ruhnau and colleagues studied functions of the innate immune system in patients with acute ischemic stroke. They found that migration, phagocytic function, and defensin production of the monocytes and granulocytes remained intact. However, key bactericidal mechanisms such as oxidative burst and NETosis were significantly reduced in acute stroke patients compared to healthy controls. Furthermore, admission oxidative burst of monocytes were more impaired in stroke patients who later went on to develop severe systemic infections. Despite the limitations of in vitro testing, the authors hypothesize that decreased bactericidal function is causally related to the increased risk of developing infections after stroke.

Factors such as aspiration, crural weakness, bedridden state, urinary incontinence etc. alone cannot entirely explain the increased risk of infection. Immunodeficiency of the innate and adaptive systems in addition offers a better explanation. This raises the question of short-term prophylactic antibiotics. The ESPIAS and PANTHERIS trials that studied this question found no benefit in outcomes, but may have been related to fluroquinolone neurotoxicity. In contrast, studies where minocycline, and mezlocillin/sulbactam (Mannheim Infection in Stroke Study) prophylaxis was used showed improved clinical outcomes. Lets hope that further knowledge of the immune system in stroke may aid in optimally selecting an antimicrobial regimen for prophylaxis, that can be tested in future trials. 

Functional Imaging Meta-Analysis Reveals Biomarkers for Stroke Recovery

Matthew Edwardson, MD

Favre I, Zeffiro TA, Detante O, Krainik A, Hommel M, and Jaillard A. Upper Limb Recovery After Stroke Is Associated With Ipsilesional PrimaryMotor Cortical Activity: A Meta-Analysis. Stroke. 2014

Interpreting the results of functional imaging studies to explore post-stroke plasticity can be challenging. Invariably these studies include only a small sample of subjects. As a result, many functional imaging studies conflict on the exact location of increased brain activity in the recovery period. In this article, Favre and colleagues bring clarity to post-stroke brain remodeling by combining the results of multiple fMRI and PET studies. In subjects with good functional recovery they found increased activity in the ipsilesional M1 and medial-premotor cortex (PMC). Subjects with poor recovery had increased activity in the cerebellar vermis. 

The authors performed activation likelihood estimation to assess cortical activation patterns in 24 prior fMRI and PET studies. Subjects had motor impairments of the upper limb with either partial or complete recovery. 89% had subcortical strokes. Studies were separated into acute (<35 days post-stroke) and chronic (>3 mo. post-stroke) stages. The authors found an increase in cortical activation in contralesional dorsolateral PMC in the acute stage that faded with time. This acute contralesional shift did not correlate with recovery. In contrast, during the chronic stage there was a ventral shift in ipsilesional M1 activation that occurred in those with good recovery.

This meta-analysis consolidates the evidence from prior functional imaging studies and suggests that functional imaging may be a useful biomarker for stroke recovery. Many prior studies show a contralesional shift in cortical activation in the acute phase post-stroke. Whether this shift is adaptive or maladaptive remains unclear; the present meta-analysis found no association with recovery. What is more clear is that later in the recovery process a shift in activation patterns back to the lesional side and particularly a ventral shift in M1 occurs in those with good recovery. The authors also discovered increased activity in the cerebellar vermis in those with poor recovery – a novel finding that requires further confirmation. Studies like this increase our confidence in using functional imaging as a biomarker for stroke recovery. Time to return of ipsilesional activation and ventral shift in ipsilesional M1 may emerge as important endpoints in future stroke rehabilitation trials.

Outcomes of a Contemporary Cohort Of 536 Consecutive Acute Ischemic Stroke Patients Treated With Endovascular Therapy

Sebina Bulic, MD

Dr. Abilleira and colleagues used data from a mandatory, population-based registry, which assesses reperfusion therapies for consecutive AIS patients for period 2011-12 in Catalonia.  Catalonia stroke network includes 17 hospitals, 7 Comprehensive Stroke Centers, 7 Primary Stroke Centers and 3 community hospitals operating on a telestroke system. IV thrombolysis is offered at all sites and endovascular treatment is offered at Comprehensive Stroke Centers.

536 patients underwent EVT. Mechanical thrombectomy was done in 90.5% patients, 7.5% had combined approaches and 2.0% had intra-arterial thrombolysis. Median baseline NIHSS was 17.5 (13, 21) with occlusion level 87.9% in anterior circulation, specifically 6.6% proximal ICA, 16.6% distal ICA and T-ICA, 12.1% tandem occlusions, 52.4% M1 occlusions, 12.1% M2 occlusions and 0.2% A1 occlusion. Posterior circulation strokes occurred in 12.1% patients. 53% of patients received prior IVT.  73.9% achieved TICI IIb and III scores. Symptomatic bleedings were observed in 5.6% patients. At 3months, 22.2% patients were dead and 43.3% of all patients achieved a good functional outcome mRS <=2. Revascularized group showed higher rates of functional independence at 3 months.  (53.5% vs. 14.3%; p< 0.001). Lower mortality rates at 3 months were seen in patients with anterior circulation strokes and among those ≤ 80 years. Stroke severity (NIHSS> 14), hypertension and age > 80 years showed a deleterious, independent effect. Coexistence of atrial fibrillation doubled the chances of being independent at 90 days. Interestingly, this study did not show an association between prior IVT and better outcomes.

Unfortunately, specific details of the endovascular procedure such as the use of antithrombotic medication during the procedure, the brand name of the mechanical device were not recorded. Also, as recognized by authors, a key limitation of this study is the absence of a contemporary control group.

Endovascular therapy is now used routinely foracute ischemic stroke. Having Class I Level A evidence proving its efficacy would be wonderful, but is it possible to conduct prospective randomized trial in which patients that would clearly benefit from endovascular therapy would be denied such treatment if randomized in no treatment group? I would be very reluctant to do so, but without randomization of all patients with ischemic stroke any further attempt for clinical trial is destined to fail. This study just confirms my belief that well run registries collecting data from all patients with endovascular therapy and carefully measuring outcomes would be reasonable alternative.

Sugar-High: Elevated HbA1c levels correlate with WMD

Peter M Hannon, MD

Rozanski M, Richter TB, Grittner U, Endres M, Fiebach JB, and Jungehulsing GJ. Elevated Levels of Hemoglobin A1c Are Associated With Cerebral White Matter Disease in Patients With Stroke. Stroke. 2014

“Patchy, nonspecific T2/FLAIR hyperintense white matter disease that is greater than expected for age.” These words, or something similar grace many an MRI read.  A number of studies have found consistent correlations between white matter disease (WMD),  age and HTN, however there has been inconsistent or even contradictory correlations between WMD and other factors such as DM, HL, smoking and renal function.   In this study, Rozanski et al found that in patients with first acute ischemic stroke (AIS), WMD was significantly associated with age, HTN and higher levels of HbA1c, but not elevated levels of TG, LDL, or total cholesterol.

512 patients with first AIS were enrolled in the study.  Standard screening labs were drawn at admission, and fasting lipids and HbA1c on day 2. The mean age was 68.5, 37% were women, and the median NIHSS was 3.  MRI imaging was performed during workup, and WMD burden was measured utilizing the Wahlund score (WS).  Of all patients, 77% had HTN, 49.5% had HL, 24% had AFib and 23% had DM.

Per the authors, this is the first study that they know of that shows a correlation between elevated HbA1c and WMD burden. Median levels of HbA1c were 5.7 to 5.9% in patients with any sign of WMD, vs. 5.3% in patients without hyperintensities.  Interestingly, DM alone did not correlate as strongly, which the authors felt may be explained by the fact that patients diagnosed with DM may be under better control, thus have lower HbA1c’s.

WMD has gained interest in the potential role it may play in cognitive decline and as a risk factor in stroke, and by all accounts appears related to ongoing microvascular damage. This study reaffirms the role of age and HTN play in the process, but in this case at least, also points to elevated HbA1c as another key causative factor—even independent of a diagnosis of DM.
  All this underscores, yet again, the critical importance of risk factor monitoring and management, hopefully long before a first AIS.