Karen Furie - US grants

DESCRIPTION (provided by applicant): Stroke is an enormous international public health concern, particularly in the developing world where there are limited resources available to provide for an aging population. One of the main contributors to stroke incidence is the highly prevalent Chagas disease, a parasitic infection affecting an estimated 18 million individuals and a major cause of heart failure in Latin America. Chagas disease conveys stroke risk through two established mechanisms: structural cardiac disease and chronic inflammation. Although inflammation is associated with an increased risk of ischemic stroke and poorer outcome, its role has been largely linked to atherogenesis. Chronic inflammation can result in endothelial dysfunction and stimulate the hemostatic system, increasing systemic fibrin production and platelet activation. Brain atrophy has also been associated with chronic inflammation. Adults, young and old, who develop a secondary cardiomyopathy from Chagas are therefore at higher risk of cardioembolism and neurodegeneration. Stroke patients usually survive, but can be left with significant disability affecting their health status, productivity, and quality of life. These factors impact caregivers as well. Thus, the social and economic consequences of stroke are vast. During our R21 planning grant period, we were able to establish a collaborative infrastructure between the research groups in Brazil and the United States and collect preliminary data. We found an association between Chagas disease and stroke that was independent of cardiomyopathy. Cognitive impairment and brain atrophy were also associated with Chagas disease independently of cardiomyopathy. Biomarkers orosomucoid, neprilysin, interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) were identified as diagnostic and therapeutic targets in Chagas disease. As part of this phase, we will address three specific aims: (1) to establish brain magnetic resonance imaging markers of stroke risk in patients with Chagasic congestive heart failure (CM); (2) to determine whether biomarkers can predict stroke risk in patients with Chagasic CM; and (3) to evaluate the efficacy of antiplatelet treatment in decreasing microembolization rate in patients with Chagasic CM. The long-term goal of this project is to establish non-invasive methods of stroke risk stratification and prediction of stroke outcome in patients with Chagas disease. This work will also facilitate the development of novel anti-trypanosomal, anti- inflammatory, and antithrombotic strategies for stroke prevention and management in Brazil.

We propose the Southern New England Partnership In Stroke Research, Innovation and Treatment (SPIRIT), a StrokeNet Regional Coordinating Center (RCC) anchored by 3 leading institutions: Yale School of Medicine, the Warren Alpert School of Medicine at Brown University, and Hartford Hospital. Each Hub is a Comprehensive Stroke Center with 14 total Primary Stroke Centers. Yale is the 7th largest hospital in the United States, and in collaboration with Brown and Hartford Hospital, and their respective networks, SPIRIT captures a diverse geographic area that provides access to 5.7 million people, including most adult and pediatric stroke patients in Connecticut and Rhode Island. This robust patient volume (over 3500 total stroke patients in 2016), combined with an exceptionally strong collaborative and organizational framework, gives SPIRIT great potential for clinical trial implementation. Principal Investigators Dr. Kevin N. Sheth (Yale), Dr. Karen Furie (Brown), and Dr. Mark Alberts (Hartford Hospital) bring a complementary set of leadership and high-level clinical trials experience in stroke. Each leader brings well recognized expertise in international multicenter studies and implementation of stroke systems of care, as well as a track record of high quality stroke trial recruitment and retention. In various capacities, they have worked together for over 12 years, and each PI leads an enthusiastic cadre of faculty across disciplines, to create a highly collaborative environment focused on stroke research, multicenter trials, membership on Institutional Review Boards, clinical trial committees, and extensive mentoring in patient-oriented research. SPIRIT maintains strong connections to NIH funded CTSA networks and is further strengthened by the following characteristics: 1) A pool of talented investigators with nationally recognized clinical and translational research expertise in stroke; 2) Rich diversity (both ethnic/racial as well as urban/rural) of patients in Southern New England currently not captured by the existing StrokeNet network; 3) Active leadership and participation in stroke communities and stroke systems of care in the areas of statewide policy, continuity of care, American Heart Association collaborations and regional education; 4) Deep investigator and patient pools for all three areas of StrokeNet initiatives ? prevention, acute treatment, and recovery; 5) Access to a range of specialized tools already harmonized across centers including a common electronic medical record system (EPIC) and RAPID software for acute stroke imaging, enhancing data sharing and collaboration; 6) Continuous commitment from all three institutions to the central IRB model and use of a Master Trial Agreement; 7) Rich science core with ongoing NIH funded stroke studies and multiple, active StrokeNet proposals currently under review; and 8) An education core designed to identify, support and accelerate the development of tomorrow's stroke investigators. The Yale, Brown, and Hartford stroke teams together ? where the sum of the collaboration is even more exciting than each part ? is poised to make significant contributions to enhance and further the mission of NINDS and StrokeNet to reduce the burden of neurological disease.