Description
e found that traumatic brain injury (TBI) assaults the entire cardiovascular system with acute, marked in-creases in blood pressure, heart rate, toxic reactive oxygen species (ROS), and impaired blood flow regulation in the brain. These profound and often unpredictable consequences of TBI dramatically compromise our ability to effectively treat patients during the critical post-TBI phase of treatment. Equally disturbing is the possibility that these immediate and catastrophic cardiovascular responses to TBI could have long term, detrimental effects on TBI survivors which are not understood. The urgency of this research is particularly acute for our military personnel who frequently sustain both impact- and blast-induced head injuries. Our overarching challenge is two-fold and inextricably linked: (1) To understand the consequences and best treatment of the immediate cardiovascular challenges induced by TBI; and (2) To understand the linkage of immediate cardiovascular impact and its long-term, life-altering effects. This is a collaborative project among experienced investigators from the Wayne State University School of Medicine, the University of Vermont, the University of Texas, and the Uni-formed Services University for the Health Sciences. We propose the unifying hypothesis that increased cardio-vascular reactivity and diminished cerebrovascular responsiveness after TBI results from an immediate, dramatic and pathological activation of the sympathetic nervous system which leads to a surge of catecholamines and the attendant generation of destructive reactive oxygen species (ROS). Furthermore, we contend that this flood of ROS leaves a lasting pathological imprint on cardiac and vascular smooth muscle and endothelial cells to negatively alter normally well controlled, homeostatic responses of the systemic cardiovascular system and cerebral blood flow regulation. A corollary is that alteration in cerebral blood flow regulation, which is exquisitely designed to maintain constant blood flow (autoregulation) and to deliver blood on demand (functional hyperemia), through a process called neurovascular coupling, would impact the entire body and its health. Using validated animal models of both impact- and our unique and innovative open field model of blast-induced TBI, we will elucidate the basis of long-term increased cardiovascular reactivity following TBI. Central to our program is the elucidation of the underlying mechanisms of the cerebrovascular dysfunction following TBl which exhibits many similarities to small vessel disease of brain, a major cause of stroke and dementia. We will quantify cardiac function two days (acutely) and sixty days (chronic, long term) following TBI with assessments of: (1) blood pressure; (2) cardiac diastolic relaxation time assessed by magnetic resonance imaging; (3) left ventricular ejection fraction volumes measured by Doppler echocardiography; (4) stiffness of conduit blood vessels as-sessed with measurements of pulse wave velocity; (5) vascular myogenic tone and endothelial-dependent vasodilation in perfused resistance vessels; and (6) endothelial and vascular smooth muscle cell rigidity measured with atomic force microscopy. Neurovascular coupling will be assessed ex vivo by measuring brain parenchy-mal arteriole vasodilation in response to neuronal stimulation and in vivo as blood flow in response to sensory stimulation. Key in translating our rodent findings to humans, we will explore the basis of elevated sympathetic nervous system activity and its impact on a greater blood pressure responses and diminished endothelial-dependent vasodilation and cerebral autoregulation at rest, and in response to stress, in men and women with a history of TBI when compared to humans without a history of TBI.
Duties
Perform basic science and human studies.Submit abstract, write paper, and present at national meeting.