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.
| Diedrich, André; Crossman, Alexandra A; Beightol, Larry A et al. (2013) Baroreflex physiology studied in healthy subjects with very infrequent muscle sympathetic bursts. J Appl Physiol (1985) 114:203-10 |
| Rothlisberger, Brian W; Badra, Leslie J; Hoag, Jeffrey B et al. (2003) Spontaneous 'baroreflex sequences' occur as deterministic functions of breathing phase. Clin Physiol Funct Imaging 23:307-13 |
| Badra, L J; Cooke, W H; Hoag, J B et al. (2001) Respiratory modulation of human autonomic rhythms. Am J Physiol Heart Circ Physiol 280:H2674-88 |
| Gonschorek, A S; Lu, L L; Halliwill, J R et al. (2001) Influence of respiratory motor neurone activity on human autonomic and haemodynamic rhythms. Clin Physiol 21:323-34 |
| Taylor, J A; Myers, C W; Halliwill, J R et al. (2001) Sympathetic restraint of respiratory sinus arrhythmia: implications for vagal-cardiac tone assessment in humans. Am J Physiol Heart Circ Physiol 280:H2804-14 |
| Cooke, W H; Ames JE, I V; Crossman, A A et al. (2000) Nine months in space: effects on human autonomic cardiovascular regulation. J Appl Physiol 89:1039-45 |
| Cooke, W H; Hoag, J B; Crossman, A A et al. (1999) Human responses to upright tilt: a window on central autonomic integration. J Physiol 517 ( Pt 2):617-28 |
| Rudas, L; Crossman, A A; Morillo, C A et al. (1999) Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine. Am J Physiol 276:H1691-8 |
| Henry, R A; Lu, I L; Beightol, L A et al. (1998) Interactions between CO2 chemoreflexes and arterial baroreflexes. Am J Physiol 274:H2177-87 |
| Cooke, W H; Cox, J F; Diedrich, A M et al. (1998) Controlled breathing protocols probe human autonomic cardiovascular rhythms. Am J Physiol 274:H709-18 |
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