Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings

Department of Internal Medicine, University of Iowa Hospitals, Iowa City 52247.

To characterize the neural excitatory state of heart failure, simultaneous measurements of efferent sympathetic nerve activity to muscle (by microneurography) and rest hemodynamics were obtained in 10 normal subjects (age 25 +/- 2 years, mean +/- SEM) and 29 patients with heart failure (age 49 +/- 2 years; New York Heart Association functional class II to IV; left ventricular ejection fraction 21 +/- 1%; cardiac index = 2.16 +/- 0.13 liters/min per m2; pulmonary capillary wedge pressure 23 +/- 2 mm Hg). Sympathetic nerve activity was significantly higher in the patients with heart failure (54.7 +/- 4.5 bursts/min) than in normal subjects (16.7 +/- 2.2 bursts/min, p less than 0.001). Multiple linear regression analyses indicated that sympathetic activity in these human subjects was most strongly and inversely correlated with left ventricular stroke work index (r = -0.86, p less than 0.0001) and stroke volume index (r = -0.85, p less than 0.0001). There was a strong positive correlation between sympathetic nerve activity and pulmonary artery diastolic (r = 0.82, p less than 0.0001) and mean (r = 0.81, p less than 0.0001) pressures. Similar correlations were seen when patients with heart failure were analyzed separately. There was no significant correlation between sympathetic nerve activity and mean arterial pressure, left ventricular ejection fraction (by radionuclide ventriculography), cardiac chamber size (by echocardiography) or arterial oxygen tension in the patients with heart failure. Direct measurements of sympathetic nerve activity correlated closely with plasma norepinephrine (r = 0.72, p less than 0.0001) in patients with heart failure. Thus, sympathetic nerve activity at rest parallels impairment of cardiac performance in patients with heart failure.

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				H. Murakami, J.-L. Liu, and I. H. Zucker Angiotensin II Enhances Baroreflex Control of Sympathetic Outflow in Heart Failure Hypertension, February 1, 1997; 29(2): 564 - 569. [Abstract] [Full Text]

				P. van de Borne, R. Oren, E. A. Anderson, A. L. Mark, and V. K. Somers Tonic Chemoreflex Activation Does Not Contribute to Elevated Muscle Sympathetic Nerve Activity in Heart Failure Circulation, September 15, 1996; 94(6): 1325 - 1328. [Abstract] [Full Text]

				G. Grassi, G. Seravalle, B. M. Cattaneo, A. Lanfranchi, S. Vailati, C. Giannattasio, A. Del Bo, C. Sala, G. B. Bolla, M. Pozzi, et al. Sympathetic Activation and Loss of Reflex Sympathetic Control in Mild Congestive Heart Failure Circulation, December 1, 1995; 92(11): 3206 - 3211. [Abstract] [Full Text]

				F. H. H. Leenen, B. S. Huang, H. Yu, and B. Yuan Brain `Ouabain' Mediates Sympathetic Hyperactivity in Congestive Heart Failure Circ. Res., November 1, 1995; 77(5): 993 - 1000. [Abstract] [Full Text]

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