Ronald G. Victor

BACKGROUND: Hypertension is a frequent complication of chronic renal failure, but its causes are not fully understood. There is indirect evidence that increased activity of the sympathetic nervous system might contribute to hypertension in patients with end-stage renal disease, but sympathetic-nerve discharge has not been measured directly in patients or animals with chronic renal failure. METHODS: We recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with hemodialysis (of whom 14 had hypertension), 5 patients receiving hemodialysis who had undergone bilateral nephrectomy (of whom 1 had hypertension), and 11 normal subjects. RESULTS. The mean (+/- SE) rate of sympathetic-nerve discharge was 2.5 times higher in the patients receiving hemodialysis who had not undergone nephrectomy than in the normal subjects (58 +/- 3 vs. 23 +/- 3 bursts per minute, P < 0.01). In contrast, the rate of sympathetic-nerve discharge was similar in the patients receiving hemodialysis who had undergone bilateral nephrectomy (21 +/- 6 bursts per minute) and the normal subjects. The rate of sympathetic-nerve discharge in the patients receiving hemodialysis who had not undergone nephrectomy was also significantly higher (P < 0.01) than that in the patients with bilateral nephrectomy, and it was accompanied in the former group by higher values for vascular resistance in the calf (45 +/- 4 vs. 22 +/- 4 units, P < 0.05) and mean arterial pressure (106 +/- 4 vs. 76 +/- 14 mm Hg, P < 0.05). The rate of sympathetic-nerve discharge was not correlated with either plasma norepinephrine concentrations or plasma renin activity. CONCLUSIONS: Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.

Patients with heart failure have increased vascular resistance and evidence for increased neurohumoral drive. High levels of circulating norepinephrine are found in patients with heart failure, but it is not known whether they reflect increased sympathetic neural activity or result from altered synthesis, release, or metabolism of norepinephrine. We used microneurography (peroneal nerve) to directly record sympathetic nerve activity to muscle (mSNA) and also measured plasma norepinephrine levels in patients with heart failure and in normal control subjects. Our goal was to determine whether sympathetic nerve activity is increased in patients with heart failure and whether plasma norepinephrine levels correlate with levels of mSNA in heart failure. Resting muscle sympathetic nerve activity in 16 patients with moderate to severe heart failure (54 +/- 5 bursts/min, mean +/- SE) was significantly higher (p less than .01) than the levels of activity in either nine age-matched normal control subjects (25 +/- 4 bursts/min) or 19 "young" normal control subjects (24 +/- 2 bursts/min). We found a significant correlation between plasma norepinephrine levels and mSNA (r = .73, p less than .05). Neither mSNA nor plasma norepinephrine levels correlated with total systemic vascular resistance, cardiac index, left ventricular ejection fraction, or heart rate. However, both mSNA and plasma norepinephrine levels showed significant positive correlations (p less than .05) with left ventricular filling pressures (r = .80, mSNA vs filling pressures; r = .82, norepinephrine levels vs filling pressures) and mean right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to determine the contribution of muscle afferents and central command in regulating sympathetic nerve activity during static exercise in humans. In 20 healthy subjects, we recorded heart rate, arterial pressure, and efferent sympathetic nerve activity in the leg during arm exercise. Microelectrodes were inserted percutaneously into a fascicle of the peroneal nerve to measure sympathetic discharge to muscle. Measurements were obtained in nine subjects during sustained handgrip (30% maximal voluntary contraction) followed by relaxation or by arrested circulation of the forearm. Heart rate and arterial pressure increased during the first and second minutes of handgrip. Muscle sympathetic nerve activity increased from 261 +/- 46 to 504 +/- 97 units (mean +/- SE; units = burst frequency X amplitude; P less than 0.05) during the second minute of handgrip. During forearm ischemia following handgrip, heart rate returned promptly to control, whereas arterial pressure and muscle sympathetic nerve activity (631 +/- 115 units) remained elevated. In contrast, muscle sympathetic nerve activity returned toward control during relaxation without arrested circulation. These data indicate that muscle sympathetic nerve activity is increased by stimulation of chemically sensitive muscle afferents. To determine the influence of central command on muscle sympathetic nerve activity, we compared responses during an involuntary and a voluntary biceps contraction, each at 20% maximal voluntary contraction. Both maneuvers raised arterial pressure, but heart rate increased only during voluntary contraction. More importantly, muscle sympathetic nerve activity rose during involuntary contraction, but fell during voluntary effort.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown. METHODS AND RESULTS: To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45+/-12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized (1)H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups. CONCLUSIONS: In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure.