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An MUSC blog
Keyword: stroke

An approach to carotid endarterectomy surgery that uses local instead of general anesthesia can better manage cardiac issues and thus result in fewer future complications.

“MUSC has a long history of managing carotid artery disease and reducing stroke rates,” says Ravi Veeraswamy, M.D., chief of MUSC’s Division of Vascular Surgery.

“We're continuing that tradition now with advancements, one of which is performing carotid surgery under a local anesthetic, so a patient never needs to be put to sleep.”

Awake Carotid Endarterectomy: Basics and Benefits

Carotid endarterectomy surgery can effectively remove plaque buildup due to carotid artery disease, or stenosis, with the ultimate goal of preventing future stroke. However, stroke is a significant complication concern of surgeons when performing this procedure—and it can be tough to identify when patients are under general anesthesia.

In an awake approach, patients receive a regional anesthesia block to numb the neck, so they are awake and comfortable for the entire procedure. Using regional in lieu of general anesthesia offers multiple benefits in managing stroke and other cardiac issues.

“One main benefit to this approach is that we know in real time if there is a problem with the patient having a stroke, and we can do something about it then,” says Dr. Veeraswamy. During a general anesthesia approach, surgeons must wait until the procedure is completed and the patient is awake to ascertain whether any stroke-related complications ensued.

“The local anesthesia approach also makes it easier to manage cardiac issues, because patients never have general anesthesia,” he adds.

Besides the anesthesia approach, little else of the carotid endarterectomy surgery is modified.
“We perform the procedure the exact same way as with general anesthesia,” says Dr. Veeraswamy. “It's just more streamlined, because we avoid general anesthesia.”

Outcomes for general versus local anesthesia approaches are equivalent, though Dr. Veeraswamy believes awake carotid has the potential for lower cardiac complication rates. “The rates of stroke or carotid-related complications are similar whether patients are under general or local anesthesia. However, we believe the rates of cardiac complications might be lower with the awake procedure. It certainly gives the referring physician, the surgeon, and the patient another great alternative to general anesthesia.”

Awake Carotid Endarterectomy: The Right Candidates

According to Dr. Veeraswamy, most patients appreciate the added option of choosing general versus local anesthesia for this surgery. Some are floored by this new capability.

“They're amazed that we can operate on their neck and literally be asking them about their family while we're doing it,” says Dr. Veeraswamy.

Still, he admits it’s not for everyone. Personal preference and certain health indications make some people poor candidates for this awake approach, including patients with:

  • Claustrophobia, or a fear of confined spaces. 
  • Anxiety or unease about the idea of being awake for a specialized operation.
  • Arthritis or other health issues that limit their neck movement.

“For these patients, we strongly consider carotid stent placement or carotid endarterectomy surgery under general anesthesia,” says Dr. Veeraswamy.

Carotid Artery Disease: A Tailored Treatment Approach

Dr. Veeraswamy says that this approach is part of MUSC’s greater focus on customizing patient treatment options to individual circumstances and preferences.

“We have the ability to tailor procedures for each patient,” he says. “We can do what's best for one patient, and that may be different than what we do for another patient, because MUSC offers so many options in how we treat patients.”

For more information, contact Dr. Veeraswamy at veeraswa@musc.edu.
 

Endovascular techniques have revolutionized thoracic aortic surgery over the past decade, according to Ravikumar K. Veeraswamy, M.D., chief of MUSC’s Division of Vascular Surgery. MUSC specialists stand at the forefront of this innovation.

“Thoracic aortic surgery is where endovascular techniques have had likely the biggest impact, in terms of reducing morbidity and mortality and improving patient outcomes,” says Dr. Veeraswamy. More specifically, he says a progressive approach to endovascular thoracic surgery for aortic dissections can benefit more patients in the short and long term.

An Endovascular Approach to Aortic Dissections

Many patients with a thoracic aortic dissection, a tear in the inner layer of the aorta, are managed primarily with blood pressure control medications. The goal of this is mainly to control patients’ symptoms such as chest pain and prevent the condition from progressing to an acute state, which requires emergency medical attention and has a high mortality rate.

According to Dr. Veeraswamy, a growing body of evidence shows that placing endovascular stent grafts is a better treatment option for aortic dissections and can offer many patients both immediate and long-term benefits.

“We are very forward thinking about thoracic stent grafts for aortic dissections,” says Dr. Veeraswamy. “A lot of patients with this condition are just managed by controlling the patient's blood pressure and pain and having them follow up as an outpatient. Here, we use a thoracic stent graft to help improve the natural progression of the disease.”

Endovascular stent graft surgery repairs an aortic dissection from the inside of the vessel to improve patients’ symptoms and prevent potential long-term and life-threatening complications such as stroke.

Endovascular Aortic Dissections: Who is a Candidate?

Dr. Veeraswamy’s team has particular expertise in treating acute aortic dissections that require emergency treatment. His success treating more complicated type B dissections with this endovascular approach was recently published in The Annals of Thoracic Surgery.

“Based on my work with acute, complicated, type B dissections, which have a fairly poor prognosis, we were able to reduce the mortality and stroke rate to just under 4 percent,” he explains. “We had successful treatment in approximately 80 percent of patients — sometimes even more than that.”

Dr. Veeraswamy says he’s happy to see any patient who has a thoracic aortic problem. “We have access to new stent grafts and new techniques that may allow us to treat patients who cannot be treated at other facilities,” he explains. “We have lower profile devices, and we have the ability to treat patients who have a difficult anatomy as it pertains to the great vessels of the aortic arch or the abdominal vessels.”

Endovascular Aortic Dissections: Expertise Required

While Dr. Veeraswamy notes the benefits of treating thoracic aortic dissections with this endovascular approach, he admits it’s a technical procedure that involves many moving parts.

“This procedure is fairly complex and requires advanced imaging systems, specialized technology, and a lot of expertise on the part of the surgeons and the rest of the team,” he says.

MUSC’s vascular surgery program brings together a comprehensive team, advanced technology and expertise. Each of those components is crucial to optimize outcomes and minimize complications, says Dr. Veeraswamy. “These procedures really need to be performed at a tertiary care facility, with experienced practitioners, and a whole team of people looking after patients,” he says.

“I personally have a lot of experience treating this disease process,” he adds. “I'm hopeful that we can help the patients in South Carolina — both in the short term and long term — by utilizing the latest available technology to effectively manage aortic dissection and improve patients’ lives.”

For more information, contact Dr. Veeraswamy at veeraswa@musc.edu
 

A pericytePictured Above: A fluorescent pericyte cell body (red) with processes
extending along adjacent capillaries (green). Courtesy of Dr. Andy Shih and Robert Underly of the Medical University of South Carolina.

 

Pericytes are the primary locus of matrix-mellaproteinase-9-dependent (MMP-9) capillary damage and blood leakage during ischemia, according to preclinical findings reported by Medical University of South Carolina (MUSC) investigators in an article published online on November 14, 2016 by The Journal of Neuroscience. In vivo two-photon microscopy revealed MMP-9 activity and plasma leakage disproportionately occurred at locations where pericyte somata were attached to the endothelium. These results suggest that pericytes, normally essential for blood-brain barrier (BBB) function, contribute to capillary damage during stroke.

The BBB—a highly specialized vascular structure—prevents the entry of blood-borne substances that can harm the brain (e.g., neurotransmitters such as glutamate, clotting factors such as fibrin, and free radical–generating substances such as iron). During ischemic stroke and related cerebrovascular diseases, the BBB is damaged, allowing incursion of blood plasma that injures neurons and other structures essential for normal cerebral function. 

The role of pericytes as builders and custodians of the BBB is well recognized, but how pericytes respond to blood flow loss in the adult brain has largely been a mystery, until now.

MUSC researchers recently harnessed cutting-edge technology to image pericytes in the intact brains of live mice and to spatially and temporally track the proteolytic enzyme, MMP-9, as the BBB degraded and blood began leaking into the brain.

Findings from this novel study not only provide critical new information about pericytes as a potent source of MMP-9 during BBB leakage but also open new discovery pathways for future therapies in neurological conditions involving ischemia.

It all began when Robert Underly, a PhD candidate in the MUSC College of Graduate Studies Neuroscience Program and first author on the article, noticed that, when a laser was used to induce ischemic strokes in the laboratory, BBB leakage occurred at very specific sites along the capillaries. "I'd assumed that blood leakage occurred along the entire capillary length,” said Underly. “But it wasn't like that. There were hotspots that leaked first and more than the rest of the capillary bed. That was really unexpected."

Andy Y. Shih, Ph.D., Assistant Professor of Neurosciences and senior author on the article, and his team followed up on Underly's observation.  "We found a very close association between where the round cell bodies of pericytes were located and where the leaks occurred,” said Shih. “So that was our first clue that the pericytes were possibly doing something harmful in the early stages of an ischemic stroke."

It is well known that the BBB becomes dysfunctional when genetic defects disrupt pericyte-endothelial signaling from birth. However, very little is known about how normally developed pericytes in the adult brain respond during acute ischemia, and only one or two studies have investigated this in vivo.

"Pericytes have a lot of potential functions—they seem to be a sort of a jack-of-all-trades,” said Shih. “We've had an idea of what these cells do, but we haven't been able to visualize and track them in vivo until recently."

 

The team was also intrigued by a handful of published studies showing that various inflammatory signaling cascades can induce pericyte MMP-9 expression.

"The problem is that, like pericytes, MMPs are hard to study in vivo—most of what we know about them is from studies on cultured cells or extracted brains,” said Underly. “We wanted to probe this process in live animals so we could see the spatiotemporal relationship between pericytes and MMP activation in vivo—in the acute stroke time frame."

To do this, the team combined several novel tools to create a unique study protocol using transgenic mice, two-photon fluorescent microscopy, and a fluorescent gelatin-based reporter of MMPs that only one other research group had ever used to study the intact brain.

The researchers also used photothrombosis to block blood flow in a small area of the capillary bed and imaged transgenic mouse lines expressing bright fluorescent reporters specifically in the pericytes to clearly identify them.

"The successful combination of technologies is certainly one of the innovations of this project,” said Shih. “It's the first study to combine these tools to look at the relationship among pericytes, MMP activity, and BBB leakage in ischemia."

Their findings revealed that ischemia resulted in extremely rapid (within tens of minutes), localized activation of MMP-9 and plasma leakage. Furthermore, plasma leakage occurred preferentially where the pericyte somata adjoined the capillary wall—not homogenously along the length of the capillaries as previously imagined by the group. These results provide strong evidence that pericytes—normally protectors of the BBB—contribute to early BBB degradation during ischemic stroke.

Using the new technology, the team did not have to extract and cut the brain and so did not lose the structure of the vasculature and blood flow.

“We had an intact system and could see where things were coming from and we were very surprised,” said Shih. “I thought, 'I've been looking at this for years and I never knew that there was this beautiful co-localization.' It told us we were looking at something really interesting. The pericytes seem to nurture or damage the BBB depending on the conditions they're put in."

This discovery opens many directions for further study and could eventually lead to new therapeutic options for patients experiencing an acute stroke.

"The very rapid reaction we saw to ischemia is really important and provides clues to potential mechanisms by which MMPs may be up-regulated,” explained Underly. “This is a future direction for our research—to define upstream regulators of this process that can be therapeutically targeted."

"The findings raise so many new research questions,” said Shih. “For example, why do pericytes have so much MMP? What are they doing with it? What happens to pericytes days to weeks after an ischemic event? There's so much still to be understood about the acute phenomena—we're focused on that for now. In the future, we could look at later, post-injury, events to see what happens next in the life of the pericyte."

Indeed, in vivo cellular-level imaging research has a bright future.

"There's a renaissance happening with the development of new molecular tools to image and modify cell function in vivo," said Shih. "We're going to see a lot more integration between tool-makers and in vivo imaging groups in the next decade or two. There are going to be many more studies looking at the intact brain."

"It's important to fund projects like this because with in vivo imaging we're able to track exactly what happens when brain function breaks down,” said Underly. “The disease state occurs in front of our eyes."

Predicting speech fluency after stroke. Brain images showign features of damage to grey-matter and white-matter regions of brain, reflecting their importance in predicting speech fluency.

Image Caption: Predicting speech fluency after stroke. These are features of gray-matter cortical regions (left) and white-matter tracts (right), reflecting their importance in predicting speech fluency scores. Regions/connections are marked in red when they strongly influence speech fluency, in blue when their influence is moderate, and are left uncolored when the influence is weak or non-existent. Image used courtesy of Dr. Leonardo Bonilha and Dr. Grigori Yourganov of the Medical University of South Carolina, who own the copyright for the image. Published in the June 22 issue of the Journal of Neuroscience (doi:10.1523/JNEUROSCI.4396-15.2016).

Loss or impairment of the ability to speak is one of the most feared complications of stroke—one faced by about 20% of stroke patients. Language, as one of the most complex functions of the brain, is not seated in a single brain region but involves connections between many regions.

In an article published in the June 22, 2016 issue of the Journal of Neuroscience (doi:10.1523/JNEUROSCI.4396-15.2016), investigators at the Medical University of South Carolina (MUSC) and the University of South Carolina (USC) report that mapping all of the brain’s white matter connections after stroke, in addition to imaging the areas of cortical tissue damage, could better predict which patients will have language deficits and how severe those deficits will be. The totality of the brain’s connections is referred to as the connectome.

“Imaging the connectome of patients after stroke enables the identification of individual signatures of brain organization that can be used to predict the nature and severity of language deficits and one day could be used to guide therapy,” said MUSC Health neurologist Leonardo Bonilha M.D., Ph.D., senior author on the Journal of Neuroscience article, whose laboratory focuses on connectome imaging, particularly as it relates to language loss after stroke. Grigori Yourganov, Ph.D., is the first author on the article. Julius Fridriksson, Ph.D., Chris Rorden, Ph.D., and  Ezequiel Gleichgerrcht, Ph.D, aphasia researchers at USC who recently received NIH funding to establish a Center for the Study of Aphasia Recovery and who are long-time collaborators of the Bonilha laboratory, are also authors on the article.

This study is the one of the first to use whole-brain connectome imaging to examine how disruptions to white matter connectivity after stroke affect language abilities. White matter fiber tracts are the insulated wires that connect one area of the brain to others. White matter is named for the myelin sheaths (insulation) that cover the many axons (wires) that make up the fiber tracts.

“If you have two brain areas and both of them have to work together in order to carry out a function and the stroke lesion takes out axons that connect those brain areas—the two areas are intact but the communication between them is disrupted and so there is dysfunction,” said Yourganov.

Currently, structural magnetic resonance imaging (MRI) is used after stroke to assess lesions in the cortical tissue—the brain’s grey matter. However, the extent of cortical damage often does not correlate with the severity of language deficits.

“Stroke patients sometimes have significant impairments beyond the amount of cortical damage,” said Bonilha. “It is also hard to predict how well a patient will recover based on the cortical lesion alone.”

Could connectome-based imaging be a useful complement for assessing damage to the brain’s connections after stroke and for guiding rehabilitative therapy?

The study led by Bonilha took an important first step toward answering these questions. The study, which enrolled 90 patients at MUSC and USC with aphasia due to a single stroke occurring no less than six months prior, assessed four areas related to speech/language using the Western Aphasia Battery—speech fluency, auditory comprehension, speech repetition, and oral naming—as well as a summary score of overall aphasia. Within two days of behavior assessment, each of the patients underwent imaging studies—both T1- and T2- weighted MRI, typically used after stroke to map cortical damage, and diffusion imaging, used for connectome mapping. The team then used a type of machine learning algorithm—support vector regression (SVR)—to analyze the imaging results and make predictions about each patient’s language deficits.  In essence, an algorithm was created that could derive the WAB score from either a feature relevant to imaging of the grey matter damage by structural MRI or a feature relevant to connectome imaging of the brain’s white matter fiber tracts. The team used 89 of the 90 patients as training sets for SVR and then used the algorithm to predict language defect/preservation in the 90th patient. This was done for each of the 90 patients and, in each patient, for both features identified via structural MRI and connectome imaging.

The accuracy of the algorithm’s prediction of WAB score for each patient was then assessed by comparing it to the WAB score determined via behavioral testing. Connectome-based analysis was as accurate as cortical lesion mapping for predicting WAB scores. In fact, it was better at predicting auditory comprehension scores than was lesion-based imaging using structural MRI and only slightly less accurate at predicting speech fluency, speech repetition, and naming scores.

The study demonstrates that damage to the white matter fiber tracts that connect the brain’s regions plays a role beyond cortical damage in language impairment after stroke. Furthermore, this study also discloses that connections in the brain’s parietal region are particularly important for language function, especially fluency. This region is less likely to sustain damage after stroke, even in patients who experience aphasia, suggesting that damage or preservation of the brain’s connections in this region could play a key role in determining who will experience aphasia and who will have the best chances for recovery. The integrity of these connections could not be mapped with conventional structural MRI but can now be assessed through connectome-based analysis.

The study findings also suggest that connectome-based analysis could be used to inform a more individualized approach to stroke care. Because the algorithms developed using these study patients as the training set are generalizable to a broader stroke population, connectome-based analysis could one day be used to identify the distinctive features of each patient’s stroke—which connections have been lost and which preserved—and then the algorithm could be used to predict the type and severity of language impairment and the potential for recovery. This information could then be used to direct rehabilitative therapy to improve outcomes. 

“By mapping much more accurately the individual pattern of brain structural connectivity in a stroke survivor, we can determine the integrity of neuronal networks and better understand what was lesioned and how that relates to language abilities that are lost,” said Bonilha. “This is, broadly stated, a measure of post-stroke brain health. It is the individual signature pattern that could also be used to inform about the personalized potential for recovery with therapy and guide treatments to focus on the deficient components of the network.”

 

Summary: Investigators at the Medical University of South Carolina report impressive 90-day outcomes in patients with large-vessel ischemic stroke who underwent thrombectomy using a direct-aspiration, first pass technique.

In an article published online April 16, 2016 by the Journal of Neurointerventional Surgery (doi: 10.1136/neurintsurg-2015-012211), investigators at the Medical University of South Carolina (MUSC) report promising 90-day outcomes for stroke patients with large-vessel clots who underwent thrombectomy or clot removal using the direct-aspiration, first pass technique (ADAPT).  Approximately 58% of stroke patients with a large-vessel clot removed using the technique achieved a good outcome at 90 days, defined as a Modified Rankin Score (mRS) of 0 to 2.

ADAPT aims to remove the clot in its entirety with a large-diameter aspiration catheter in a single pass. In contrast, stent retrievers, currently considered standard of care, frequently fragment the clot for removal and can require several passes.

ADAPT was developed by MUSC Health neuroendovascular surgeons M. Imran Chaudry, M.D., Alejandro M. Spiotta, M.D., Aquilla S. Turk, D.O., and Raymond D. Turner, M.D., all co-authors on the April 2016 Journal of Neurointerventional Surgery article. MUSC Health neurosurgery resident Jan Vargas, M.D., is first author on the article.

“The goal in ADAPT is to take the largest-bore catheter available up to the blood clot and put suction where it’s blocked and pull it out of the head to reestablish flow in that blood vessel,” said Turk. If the first-pass attempt is unsuccessful, stent retrievers can still be used to remove the clot.

In the article, the investigators report the results of a retrospective study of 191 consecutive patients with acute ischemic stroke who underwent ADAPT at MUSC Health. In 94.2% of patients, blood vessels were successfully opened—by direct aspiration alone in 145 cases and by the additional use of stent retrievers in another 43 cases. Good outcomes at 90 days (mRS, 0-2) were achieved in 57.7% of patients who were successfully revascularized with aspiration alone and in 43.2% of those who also required a stent retriever. The average time required to reopen the blocked blood vessels was 37.3 minutes—29.6?minutes for direct aspiration alone and 61.4 minutes for cases that also required stent retrievers. Patients presented for thrombectomy on average 7.8 hours after stroke onset.

These results confirm the promise of ADAPT, which was first described by the MUSC Health team in a seminal 2014 article in the Journal of Neurointerventional Surgery. Since the publication of that article, a number of single-center series studies have reported impressive recanalization times (the time it takes to open the blood vessel) and good neurological outcomes with ADAPT using a large-bore catheter, suggesting that it could offer an alternative approach to stent retrievers for mechanical thrombectomy.

Stent retrievers have been considered standard of care for stroke patients since the publication in the October 2015 issue of Stroke of a scientific statement on thrombectomy by the American Heart Association. That statement recommended rapid clot removal in addition to tissue plasminogen activator (tPA), a clot-busting drug that can minimize stroke complications if administered in a tight time window. The recommendation was based on the promising findings of five large clinical trials comparing treatment with tPA alone versus treatment with tPA plus thrombectomy using stent retrievers in large-vessel clots: MR CLEAN, EXTEND-IA,  ESCAPE, SWIFT PRIME, and REVASCAT.

A definitive answer as to whether ADAPT could likewise become standard of care for stroke patients with large-vessel clots will require clinical trials comparing the efficacy of the direct aspiration technique versus stent retrievers in this population of stroke patients.

The MUSC Health neuroendovascular surgery team is currently running the COMPASS trial (COMParison of ASpiration vs Stent retriever as first-line approach; Clinicaltrials.gov identifier NCT02466893) in conjunction with colleagues Dr. J. Mocco of Mount Sinai and Dr. Adnan Siddiqui of the University of Buffalo. The trial is randomizing patients to either ADAPT or a stent retriever as the initial thrombectomy technique. The trial, scheduled to enroll 270 patients, has enrolled 90 patients in the past year at ten sites in the United States.

Image Caption: Left: Frontal view of the skull showing occlusion of the right internal carotid artery (ICA) beginning at the level of the vertical petrous potion (arrow). Right: Frontal view of the skull after thrombectomy shows the revascularization of the ICA and the distal arteries supplying the right side of the brain.

Watchman deviceMUSC Health is the first hospital in South Carolina to offer a left atrial appendage (LAA) closure device that reduces stroke risk for high-risk patients with non-valvular atrial fibrillation. The WATCHMAN™, (Boston Scientific Corporation, Marlborough, MA) approved by the U.S. Food and Drug Administration in March 2015, is intended for percutaneous transcatheter closure of the LAA. Six of these devices have been implanted at MUSC Health by Frank A. Cuoco, M.D., MBA, Director of the Cardiac Electrophysiology Lab. “In atrial fibrillation, most blood clots that are responsible for stroke form in the LAA,” he says. “Implanting this device has been shown to be equivalent to warfarin for overall stroke prevention and superior to warfarin for reduction of bleeding and overall cardiovascular mortality.” Six weeks after implantation, patients are able to stop warfarin. They remain on clopidogrel and aspirin for 6 months while the device completely seals, and then require only aspirin going forward. This therapy offers a proven alternative to patients who cannot or do not want to use warfarin to reduce their risk of stroke.

fingertips touchingSending imperceptible white-noise vibrations through the wrist could increase the dexterity of those recovering from stroke, according to an article published in Physiological Results July 14.

Patients who have experienced a stroke can have lasting side effects, such as a diminished tactile response in their fingers and hands. A decrease in sensory feedback from the fingers can cause insufficient grip force control, decreased dexterity, decreased fine object manipulation, and an unstable grip, often causing patients to drop objects.

Na Jin Seo, Ph.D., Assistant Professor in the Division of Occupational Therapy at MUSC Health, was the senior investigator for this study, which applied perceptible and imperceptible white-noise vibrations at various intensities and in separate locations on patients’ extremities to determine the optimal level of white-noise vibration needed to improve signal detection. V. Ramesh Ramakrishnan, Ph.D., and Abigail W. Lauer, M.S., in the Department of Public Health Sciences at MUSC Health performed the statistical analyses for the study. The patients’ non-dominant hands were used for the test because it was postulated to be more sensitive to somatosensory feedback. The vibration was then applied to areas of the palm, back of the hand, and inner wrists an attempt to increase sensitivity in the finger pads. The intensities of the vibration varied from 0% to 120% of the threshold.

At 60% of the threshold, the imperceptible white-noise vibrations significantly improved finger tactile sensation in the thumb and index finger when compared to 0%. At 80% of the threshold, no significant changes were seen, and at 120% of the threshold degraded sensory feedback was observed in the fingers, conforming to stochastic resonance behavior.

While the vibration stimuli would quickly decrease as it moved away from the application site, not reaching the fingertips, each site reacted similarly to the same intensities. According to the study, these results indicate that neuronal activity in the fingers is influenced by the vibration.

“This finding suggests a potential for a sensory orthotic that can be worn at the wrist,” says Seo. “It would provide minute vibration and enhance patients’ touch sensation and dexterity, improving their ability for activities of daily living.” 

This study suggests that patients who have experienced an injury or a stroke could gain access to the neuronal network in their hands through imperceptible white-noise vibrations. Wearing a vibrating device on their wrists could help these patients gain back some of the control they may have lost.

MUSC Awarded Four Million Dollar Grant to Study Health Disparities in Stroke Recovery

Stroke disparities blog post imageAfrican Americans are more likely to both experience a stroke and be more adversely affected by it than their white counterparts. In South Carolina, the buckle of the stroke belt, African Americans are twice as likely to die from stroke when compared to whites. Less well known is that recovery after stroke is poorer for African Americans than whites, and that access to rehabilitation (or lack thereof) does not completely account for this discrepancy.

With the support of a four million dollar grant from the American Heart Association (AHA), the largest AHA grant ever given to an institution in South Carolina, MUSC is endeavoring to improve stroke recovery in African Americans through a multidisciplinary project that brings together basic and translational researchers in regenerative medicine, neuroscience, and nursing. The four-year project, entitled Wide spectrum Investigation of Stroke Outcome Disparities on Multiple Levels (WISSDOM), includes research projects with the potential to not only improve our understanding of why African Americans don’t fare well in recovery but to use those insights to make a difference in the lives of stroke patients through community interventions.

Leonardo Bonilha, M.D., Ph.D. (photo, left), and Mark Kindy, Ph.D. (photo, center) of the College of Medicine and Gayenelle Magwood, Ph.D., R.N. (photo, right) of the  College of Nursing are all principal investigators of the subprojects being conducted through WISSDOM. Kindy is exploring whether known stroke risk factors such as hypertension and diabetes that disproportionately affect African Americans also play a role in their recovery from stroke. To do this, he will study the effect of such metabolic factors on vascular stiffness in animal models. Bonilha is using innovative neuroimaging techniques to assess the integrity of brain tissue and neuroplasticity (i.e., the ability of the brain to repair itself) in black and white patients so that questions about why African Americans have poorer stroke recovery than whites can be answered. Magwood is exploring whether a community-based intervention—a 12-week home-based intervention coordinated by a nurse and delivered by a community health worker— can improve stroke recovery after patients finish with rehabilitation.

As Director of WISSDOM, Robert Adams, M.D. will oversee the four-year project in its entirety and serve as its key contact. Daniel T. Lackland, Ph.D., a long-time collaborator of Adams who has devoted his 30-year career to addressing disparities in South Carolina and beyond, will serve as WISSDOM’s Training Director, and Bruce Ovbiagele, M.D., Chair of Neurology, as the head of its advisory committee.

This grant builds upon the 10.8 million dollar COBRE (Center Of Biomedical Research Excellence) grant awarded last year to MUSC to found the South Carolina Stroke Recovery Research Center. The COBRE grant is led by Steve Kautz, Ph.D., Chair of the Department of Health Sciences Research and Co-Director of the Center for Rehabilitation Research. (Read more about the COBRE grant here).

Photograph courtesy of Sarah Pack. 

Statins can lower low-density lipoprotein cholesterol (LDL-C) levels by 25%-50%, but for many patients that is not enough to reach target levels, leaving them at residual risk for cardiovascular events. Some patients experience muscle aches when taking statins and must discontinue therapy or take a suboptimal dose. The search has been on for agents that can provide additional benefit in patients already taking statins or that can provide an alternative therapeutic option for those who do not tolerate them, but with largely disappointing results.

That is why the dramatic reduction in LDL-C levels achieved by proprotein convertase subtilisin–kexin type 9 (PC3K9) inhibitors are being met with such excitement. The interim results of the Osler-1 and -2 trials (NCT01439880 and NCT01854918) and the Odyssey Long Term trial (NCT01507831) were published online on March 15 in the New England Journal of Medicine (Osler: http://dx.doi.org/10.1056/NEJMoa1500858; Odyssey: http://dx.doi.org/10.1056/NEJMoa1501031). The results showed a more than 60% decrease in LDL-C levels (from a median of 119-120 mg/dL to 48 mg/dL; P<.001) and a significant decrease in cardiovascular events in patients taking the PC3K9 inhibitor evolocumab (Amgen; Osler) or alirocumab (Sanofi/Regeneron; Odyssey) in addition to standard therapy vs those receiving standard therapy alone. Those decreases were maintained over time.  The FDA has scheduled a target action date for evolocumab and alirocumab for August and July, respectively, and could approve both for certain indications as early as September of this year.

“PCSK9 inhibitors are the most exciting thing going on right now in the field of lipids. They are rocking the lipid world,” says MUSC Health cardiologist Pamela B. Morris, M.D., who is the principal investigator for the MUSC site of two trials of these inhibitors: GAUSS III, which is testing the efficacy of evolocumab in patients who have been verified as being statin intolerant, and FOURIER (NCT01764633), which is seeking to definitively establish whether the dramatic decreases in LDL-C seen with evolocumab indeed reduce the risk for cardiovascular events long term in patients already receiving statin therapy.

Side effects of PCSK9 inhibitors include  minor injection-site reactions and a few cases of memory deficit that were at first thought to due to excessively low LDL-C levels; the Osler interim results showed that this was not the case.

PCSK9 inhibitors are monoclonal antibodies that must be subcutaneously injected, and it is still being assessed whether better efficacy and patient adherence can be achieved with a smaller dose every two weeks or a larger dose once a month.

If approved, PCSK9 inhibitors will offer a promising new treatment option for patients who could not take statins or who did not reach target LDL-C levels despite taking the highest dose of statins they could tolerate.

How They Work: The body clears LDL-C via LDL receptors on the surface of liver cells, which bind to LDL-C and target it for degradation. Depending of the body’s needs, the LDL receptor is then itself degraded or is recycled (as many as 200 times) to clear more LDL-C. PCSK9 binds to the LDL-C/LDL receptor complex and targets the receptors for degradation rather than recycling. When PCSK9 levels are decreased, more LDL-C receptors are recycled to the cell surface to clear LDL-C. Indeed, patients with a loss-of-function PCSK9 mutation tend to have very low levels of LDL-C and very low rates of cardiovascular disease, an observation that helped spark interest in PCSK9 inhibitors. 

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