Phyllis M Gootman - US grants

The time course of postnatal development of cardiovascular (CV) regulatory mechanisms is being studied from the viewpoint of efferent outflow of the regulatory system. Three specific aims are being pursued: 1) age-related differences in sympathetic (SYMP) activity (both efferent discharge and plasma catecholamine levels), 2) anatomical and physiological characteristics of postnatal development of autonomic regulation of the heart (recordings from cardiac efferent nerves and cardiac vagal motoneurons and use of fluorescent tracers for anatomical localizations of preganglionic parasympathetic and postganglionic SYMP neurons projecting to the heart), 3) determination of the CV responses to chemical stimulation at previously identified CNS sites. Recordings will be obtained from efferent SYMP activity (splanchnic, cervical SYMP, renal), efferent phrenic discharge (monitor of respiratory rhythm generator:RRG), cardiac vagal and SYMP fibers, montoneurons in ventrolateral nucleus ambiguous, aortic pressure, EKG, regional blood flows (particularly renal, superior mesenteric) and appropriate marking pulses. The age- related effects of alterations in afferent discharge from various receptors, e.g., baroceptor, cardiopulmonary, lung stretch, chemoceptors on the CV regulatory system will be evaluated. Common periodicities in SYMP discharge and periodicities related to the cardiac cycle (indicated by EKG) or RRG are being revealed by cross correlation and power spectral analyses, particularly tests for power spectral equivalence and coherence. Evoked responses of autonomic nerves to stimulation of CNS vasoactive and cardiac sites in the brain stem, especially the sequence of activation of different SYMP motoneuron pools, will be obtained. Age-dependency of results will be determined statistically in 6 age groups. The results will contribute to our understanding of both circulatory adjustements to extrauterine environment and to the degree of regulation of neonatal CV function. Evidence of age-related differences in the development of the SYMP rhythm generating systems and interactions with the RRG is clinically significant because studies of infnat diseases, e.g., SIDs, apnea and accompanying bradycardia, indicate their close temporal and functional relationship. Information will be obtained to further elucidate the reflex adjustments to stresses, e.g., hypoxia, hypercapnia, relevant especially to the most vulnerable period in the life of the child.

The long-term objective of the proposed research is to evaluate the role of cardiac mechanisms in the etiology of sudden death in the Sudden Infant Death Syndrome (SIDS). Thus this project is directly related to a problem in infant survival and health. The specific aims of the proposed research are designed to test the hypothesis that a developmental anomaly in cardiac innervation could reduce ventricular electrical stability and favor the onset of sudden cardiac death. The research design and surgical methods have been worked out in the previous grant period; newborn swine with surgically induced imbalance in cardiac autonomic innervation will be continuously monitored (24 hrs.) throughout eight postnatal weeks. Those surviving and similarly surgically prepared littermates will be tested (at ages 2,4,6,8 wks) for cardiovascular responses to: (i) hypoxia, (ii) hypercapnia, (iii) stimulation of cardiopulmonary receptors, and (iv) alterations in baroreceptor afferent inputs. Results obtained from study of these possible precipitating factors should reveal the increased susceptibility of the neonate at risk for sudden death. Sleep is the predominant behavioral state of the neonate and ontogeny of EEG sleep in neonates can be monitored by serial EEG recordings. We plan to examine ECG recordings as a function of state determined by VCR tapes of behavior, diaphragmatic EMG and EEG, and correlate these variables against both age and type of denervation. Nonlinear analysis of heart rate variability in infants has revealed an increase in complexity with maturation and our own results included similar findings in piglets. This grant proposal would pursue these findings and the effects of selected cardiac denervation on this complexity, correlating results with sudden death in denervated piglets. Such studies should confirm our working hypothesis regarding the importance of cardiac innervation in the etiology of sudden death in infants. We are, therefore, postulating an abnormality at the effector level, i.e., at the cardiac level, specifically: maturation of the normal innervation of the heart and its reflex control.