Brain lesions in humans may lead to cardiac damage, cardiac arrhythmias and sudden death, a situation seen in patients with subarachnoid hemorrhage but also in patients with numerous other common neurological diseases including stroke and brain injury. Similar cardiac events may also occur in humans exposed to stress. Cardiac changes have been thought to be due to enhanced activity of the sympathetic nervous system as a result of central lesions but absence of an animal model has hampered studies of mechanisms that might contribute directly to the cardiac abnormalities. We have found that interrupting the baroreflex in rats by selectively eliminating NTS (nucleus tractus solitarii) neurons that express the NK1 receptor leads to cardiac arrhythmias and sudden death. A similar outcome followed loss of catecholaminergic neurons in NTS. At post mortem examination we have identified diffuse microscopic areas of myocardial damage. That damage is similar to findings in humans who have sustained central lesions. Each of the cardiac findings has occurred in chronically instrumented animals housed alone without stressful stimuli;yet each animal that died (approximately 30% died suddenly) did so at night, during their period of maximum daily activity. Therefore, we seek here to test the hypothesis: eliminating NTS neurons that express NK1 receptors or that synthesize catecholamines promotes lability of arterial blood pressure and, through augmented sympathetic nerve activity, leads to myocardial damage and damage to cardiac nodal tissue with a predisposition to cardiac arrhythmias and death in animals exposed to stressful events (air jet stress paradigm). In preliminary studies we found that interrupting the baroreflex led to a marked reduction in neuronal nitric oxide synthase (nNOS), the neuronal enzyme that is critical for synthesis of nitric oxide within the stellate ganglia, the source of sympathetic ganglionic innervation to the heart. In that nitric oxide may modulate sympathetic effects on the heart, we propose that this reduction in nNOS contributes to the cardiac abnormalities seen in our experimental animal model and may do so likewise in humans. The proposed study will define the relationship between sympathetic nerve activity, cardiac damage, and cardiac arrhythmias;how stress may augment the deleterious effects of excess sympathetic nerve activity;how nitric oxide in the sympathetic pathways to the heart may contribute to cardiac damage;and how modulating expression of an enzyme involved in synthesis of nitric oxide may affect the process.
This project will identify mechanisms that contribute to cardiac damage, cardiac arrhythmias and sudden death in an animal model with a lesion in the central nervous system. Further, it will determine if modifying those mechanisms influences the deleterious outcomes, which are also well recognized in humans with CNS disease and in humans exposed to profound stress. Therefore, the studies could lead to translational clinical studies of treatments aimed at those mechanisms and thus at a major source of morbidity and mortality in affected humans.
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