The technique of hypothermic circulatory arrest (HCA) is an established neuroprotective strategy allowing complex repairs of the thoracic aorta and congenital cardiac malformations. Despite its utility in clinical medicine, HCA is not without significant neurological sequelae which include intellectual and neuropsychomotor impairment, seizures, choreoathetosis, delayed development and stroke. Under continuous NIH support since 1992 our laboratory has completed an important body of work in which we have investigated the mechanisms of neurologic injury in a clinically relevant model of cardiopulmonary bypass (CPB) and HCA. In our canine model, which replicates clinical experience during cardiac surgical procedures, dogs subjected to two hours of HCA at 180C sustain a consistent neurologic deficit and histological pattern of selective neuronal death. The recent sequencing of the complete canine genome and the development of canine oligonucleotide microarrays has given us a unique opportunity to examine the molecular mechanisms of neurologic injury following HCA (both for prolonged and brief durations) as well as with standard cardiopulmonary bypass (CPB). Our current proposal focuses on the following objectives: 1.) To delineate, using microarray analysis, the underlying genomic regulation responsible for excitotoxic neuronal injury caused by 1 and 2 hours of HCA and standard CBP without HCA 2.) To identify neuroprotective changes in gene expression that result from a novel therapeutic strategy (Valproic acid) and 3.) To investigate gene-products (proteins) present in the cerebral spinal fluid (CSF) and serum for identification of brain and/or neuronal specific protein biomarkers for diagnosis and prognosis in HCA and CPB. To help us accomplish these goals, we have enlisted the help of an outstanding multidisciplinary group of investigators from the Johns Hopkins Medical Institutions (JHMI) Microarray Core Facility, Division of Cardiology, Department of Pathology and the University of Florida/Banyan Biomarkers;in addition to our previous collaboration with neuroscientists at the Kennedy Krieger Institute. We are confident that we have assembled a team with broad expertise to help us as we pursue these exciting new directions in our work. Multidisciplinary translational research is the cornerstone to reducing neurologic injury in patients undergoing hypothermic circulatory arrest. By applying an integrated approach of genomics and proteomics to our canine model of HCA, we hope to uncover new insights in the mechanisms of brain injury, how pharmacologic intervention attenuates that injury, and how we can clearly identify the injury, even when subtle on exam.

Public Health Relevance

Brain injury resulting from various causes is a significant international health concern. In this project, we focus on brain injury that occurs commonly in cardiac surgery (with both short and prolonged application of hypothermic circulatory arrest, HCA, and standard cardiopulmonary bypass, CPB, without HCA) in order to elucidate its mechanisms, develop biomarkers for diagnosis and prognosis, and discover effective therapies. Clearly, the translation of this work to clinical practice can have benefits not only for those patients with neurologic complications from HCA but also for patients undergoing routine cardiac surgical procedures and for those suffering brain injury from a number of factors, such as, stroke, traumatic brain injury or anoxic brain injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091541-19
Application #
8241120
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Miller, Marissa A
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
19
Fiscal Year
2012
Total Cost
$999,087
Indirect Cost
$251,986
Name
Johns Hopkins University
Department
Surgery
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Blue, Mary E; Wilson, Mary Ann; Beaty, Claude A et al. (2014) Brain injury in canine models of cardiac surgery. J Neuropathol Exp Neurol 73:1134-43
Mishra, Manoj K; Beaty, Claude A; Lesniak, Wojciech G et al. (2014) Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest. ACS Nano 8:2134-47
Arnaoutakis, George J; George, Timothy J; Wang, Kevin K et al. (2011) Serum levels of neuron-specific ubiquitin carboxyl-terminal esterase-L1 predict brain injury in a canine model of hypothermic circulatory arrest. J Thorac Cardiovasc Surg 142:902-910.e1