Dwain Eckberg - US grants

This is a proposal to study physiologic and pathophysiologic autonomic cardiovascular control mechanisms, and to assess implications of the derangements of autonomic control that occur in patients with cardiovascular diseases. All of this research will be conducted with human volunteers. Subjects will include healthy young and middle-aged adults, patients with orthotopic cardiac transplants, post-myocardial infarction patients, and patients with congestive heart failure. Autonomic inputs will be altered with aerobic exercise and changes of respiratory rate, depth, and resistance, heart rate and rhythm, and arterial pressure. Measured autonomic cardiovascular responses will include estimates of vagal-cardiac nerve activity (standard deviations of R-R interval or respiratory peak-valley R-R interval changes) and sympathetic activity (antecubital vein plasma norepinephrine or directly measured postganglionic muscle sympathetic nerve activity). The proposed studies will address important basic, methodologic, and clinical problems. Basic physiologic issues include how changes of autonomic sensory input are translated into changes of autonomic cardiovascular output; how respiration modulates oscillations of sympathetic activity; and how simultaneous changes of arterial pressure and respiration modify autonomic activity. In the course of the proposed studies, important methodologic issues will be addressed critically; in particular, efforts will be expended to understand better the significance and limitations of venous plasma norepinephrine, muscle sympathetic nerve activity, and low frequency R-R power spectral density as reflections of sympathetic activity. The major thrust of the proposal will be to better understand pathophysiologic mechanisms in patients with cardiovascular diseases. In particular, studies will be directed towards understanding why sympathetic activity is high in these patients, why the immediate post-exercise period presents such extraordinary risk to these patients, and what role, if any, acute or chronic reductions of vagal-cardiac nerve activity or increases of sympathetic nerve activity play in the genesis of sudden cardiac death. These questions are large and have enormous public health significance; the research approaches that will be used have a substantial likelihood of providing scientifically credible, unique, new information.

This proposal focuses on sympathetic mechanisms during rhythm disturbances known to precede ventricular fibrillation. Human studies combine two relatively new methods: clinical electrophysiologic testing and sympathetic microneurography. Dog studies employ similar methods, plus sinoaortic baroreceptor denervation and intrapericardial procaine. In humans, sympathetic traffic to the important muscle vascular bed will be analyzed to obtain direct information on sympathetic responses to dysrhythmias [during atrial or ventricular pacing, or diagnostically- induced ventricular tachycardia (and if it occurs, ventricular fibrillation)]. Some studies will be conducted in patients with normal hearts (but supraventricular rhythm disturbances), on no medications. Other studies will be conducted in patients with substrates for catastrophic rhythm disturbances. Results will be analyzed with time and frequency domain techniques, and with exploratory statistical modeling. In dogs, rhythm disturbances will be provoked before and after acute sinoaortic baroreceptor denervation or cardiac denervation produced by intrapericardial procaine injections. A substantial amount of pilot research has been done for this proposal; virtually all hypotheses are grounded upon such preliminary experimental data. In several instances, pilot data included in this application show aspects of human autonomic physiology and pathophysiology that have not been documented before. A wide range of hypotheses will be tested: That during tachydysrhythmias, sympathetic activity increases in inverse relation to arterial pressure, on the basis of three mechanisms: 1) reduced inhibition of sympathetic motoneurons by arterial baroreceptors, 2) loss of entrainment of sympathetic motoneurons by baroreceptors, and 3) tonic stimulation of sympathetic oscillators by the central nervous system, possibly secondary to medullary ischemia. That the relation between arterial pressure and sympathetic activity is continuously redefined during ventricular tachycardia. That therefore, resetting of baroreceptor-sympathetic relations occurs continuously during rhythm disturbances and modifies second-by-second sympathetic responses to changing arterial pressure. That rapid ventricular pacing replicates hemodynamic and sympathetic responses to ventricular tachycardia; that therefore, ventricular pacing can be used as a surrogate for ventricular tachycardia for prospective, controlled laboratory research. That in patients with heart disease, both slow and rapid heart rates increase sympathetic nerve activity. That changes of sympathetic outflow precede the degeneration of ventricular tachycardia to ventricular fibrillation,. That during moderately fast ventricular rhythms, sympathostimulation occurs because the influence of reduced arterial baroreceptor activity overrides the sympathoinhibitory influence of increased cardiac receptor activity. This research may have substantial public health and theoretical significance. Protocols should clarify pathophysiology of rhythms known to precede and perhaps set the stage for ventricular fibrillation. The approach is to simplify a very complex problem by isolating components and studying them prospectively in a controlled human laboratory environment, and then to follow with animal studies to define mechanisms. The protocols involve state-of-the-art methods used by investigators established in the areas of human and animal autonomic research.

baroreflex; neural plasticity; gravity; extraterrestrial environment; environmental adaptation; respiratory airway pressure; heart innervation; vasoconstriction; blood pressure; hypovolemia; blood volume; vagus nerve; heart rate; sympathetic nervous system; in situ hybridization; electrocardiography; human subject;