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STAT

An MUSC blog
Keyword: heart disease

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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