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Research Highlights from the Literature

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2002; Volume 12(1) from Clinical Autonomic Research                                           
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Sympathetic activation contributes to catabolism in patients with severe burns.  Clinical improvement with beta-blockade.
            Severe burns are associated with sympathetically-mediated hypermetabolism, resulting in an increase in resting energy expenditure and in muscle protein catabolism.  Herndon et al., hypothesized that this deleterious effect could be overcome by treatment with beta-blockers.  They randomized 25 children to no treatment or to propranolol at a dose titrated to reduce resting heart rate by 20% from a baseline of about 160 beats/min.  The average dose was about 180 mg/d P.O., a large dose for a group of children with an average age of 7 years.  No side effects directly related to beta-blockade were reported.  -blockade reduced energy expenditure from 1742±244 to 1321±173 kcal/day.  The net muscle-protein balance increased by 82% in the propranolol group, whereas it decreased by 27% in the control group.    Thus, sympathetic activation associated with severe stress can lead to a hypercatabolic state.  Careful treatment with ß-blockers may reverse this deleterious process.
Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:1223-29.

Sympathetic activity and obesity
            It is believed that there is an association between sympathetic overactivity, hypertension and obesity.  This association, however, has not been investigated in African Americans, a group at risk for obesity and hypertension.  Abate et al., studied 92 normotensive young African Americans of either gender with a wide range of body mass index (BMI), and 45 white matched controls.  Sympathetic activity, measured by microneurography of the peroneal nerve, correlated with BMI in black women (r=0.45) but not in men.  The dissociation between sympathetic activity and obesity in black men could be explained by the higher sympathetic nerve activity found in lean black men (28±3 bursts/min) compared to lean white men and lean black and white women (18±2, 21±2 and 17±2 bursts/min, respectively).  Thus, sympathetic activity in this group of lean black men was increased to levels found in obese individuals of either race.  The relevance of this finding to risk of acquiring hypertension or obesity are not known.  
Abate NI, Mansour YH, Tuncel M, Arbique D, Chavoshan B, Kizilbash A et al. Overweight and sympathetic overactivity in black Americans. Hypertension 2001; 38:379-83.

Mechanism of central modulation of sympathetic activity by leptin
            Leptin, a peptide produce by fat cells, acts in the central nervous system to reduce appetite and increase energy expenditure.  Some of these actions are mediated by central activation of the sympathetic nervous system.  Leptin also acts on the hypothalamus to increase corticotrophin-releasing factor (CRF).  Correia et al., tested the hypothesis that CRF mediates the increase in sympathetic activity induced by leptin.  They pretreated rats with intracerebroventrical administration of the CRF receptor antagonist alpha-helical corticotrophin releasing factor (9-41), and measured efferent sympathetic traffic directed to intrascapular brown adipose tissue.  Central administration of CRF increased sympathetic traffic and this effect was attenuated by the CRF antagonist.  Circulating leptin also increased efferent sympathetic traffic to adipose tissue, and this was also attenuated by the CRF antagonist.  Interestingly, leptin also significantly increase arterial blood pressure, but this effect was not attenuated by the CRF antagonist.  These results suggest that CRF contributes to the central sympathoexcitatory effects of leptin on thermogenic tissue, but may not contribute to its cardiovascular effects.
Correia MLG, Morgan DA, Mitchell JL, et al. Role of corticotrophin-releasing factor in effects of leptin on sympathetic nerve activity and arterial pressure. Hypertension 2001;38:384-88.

Ambulatory norepinephrine infusion to treat severe orthostatic hypotension
            Symptomatic orthostatic hypotension is often effectively treated with oral pressor agents, but treatment remains a challenge in patients with severe autonomic failure.  Six patients with orthostatic hypotension due to primary autonomic failure refractory to conventional treatment were treated with intermittent self-administered norepinephrine infusions.  Norepinephrine was administered using an ambulatory infusion pump through an implanted port-a-cath.  Symptomatic improvement was observed in all patients.  Although promising, long-term studies may be needed to determine the reliability and safety of this therapeutic approach.  The rapid termination of action of norepinephrine may have the additional advantage of not worsening supine hypertension, which is present in about half of these patients.  A similar approach was previously reported by Polinsky et al., and incorporated a feedback loop with a pressure transducer (Lancet 1983; 8330:901-904).
Oldenburg O, Mitchell A, Nürnberger J, et al.  Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension.  J Am Coll Cardiol 2001;37:219-223.

Genetic transmission of autonomic dysfunction in idiopathic congenital central hypoventilation syndrome uncovered by autonomic symptom questionnaire
        Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by depressed ventilatory drive during sleep.  It is also known as Hadda syndrome or “Ondine’s curse”.  About 16% of CCHS are associated with Hirshprung disease.  Autonomic abnormalities (decreased heart rate variability, pupillary abnormalities, GI symptoms) are often observed in CCHS patients.  The mechanism of genetic transmission of CCHS is not completely understood, in part because it is often difficult to identify family members who are not clinically affected by the hypoventilation syndrome, but who are carriers of the relevant genes. The authors of this study hypothesized that such family members may be identified by the study of an associated phenotype (i.e., the presence of autonomic symptoms).  They studied over 2,300 subjects, including 56 CCHS cases, 56 age-, gender- and race-matched controls, and their families.  Subjects were given a questionnaire that included 35 possible autonomic symptoms (e.g., loss of consciousness, dizziness, orthostatic hypotension, constipation, diarrhea, altered lacrimation, etc) as well as “mock” symptoms unrelated to autonomic function.  Two or more positive autonomic symptoms were arbitrarily used as “diagnostic” of a dysautonomia phenotype.  The questionnaire identified a significantly higher incidence of autonomic dysfunction in relatives of CCHS cases than controls (Weese-Mayer DE, et al. Am J Med Genet 2001;100:237-245).  The authors conclude that autonomic dysfunction is part of CCHS, and its presence in family members may lead to the definition of the mechanism of genetic transmission of this disorder.
 Marazita MS, Maher, BS, Cooper ME, et al Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypovolemia syndrome.  Am J Med Gen 2001;100:229-236. 

Spaceflight induces leg vasoconstriction in astronauts, resembling the upright posture on Earth
            Spaceflight is associated with a central redistribution of blood as the downward gravitational pull is lost.  This would be expected to result in an increase in central venous pressure with sympathetic inhibition and reduced peripheral resistance.  However, direct experimental data indicated that central venous pressure is actually decreased rather than increased during spaceflight.  Even though central venous pressure is decreased, left ventricular end-diastolic dimension measured by echocardiography is increased, consistent with increased cardiac filling (Buckey JC, et al. J Appl Physiol 1996;96:19-25).  In this study, the same group of investigators measured calf compliance and blood flow with venous occlusion plethysmography in seven astronauts before, during and after spaceflight.  Arterial blood pressure was slightly higher in space, and calf blood flow decreased relative to supine position on earth.  Calf compliance remained unchanged in space.  Calf vasoconstriction in spaceflight supports the concept that cardiovascular modulation in space approximates that observed during upright posture on Earth.  Preliminary findings showing increase sympathetic nerve activity during spaceflight (Ertl AC, et al. Circulation 1998;98:I-471), are in agreement with these findings.
Watenpaugh DE, Buckey JC, Lane LD, et al. Effects of spaceflight on human calf hemodynamics.  J Appl Physiol 2001;90:1552-1558.


Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR (2001). Reversal of catabolism by beta-blockade after severe burns. New England Journal of Medicine.345:1223-1229.

Abstract: BACKGROUND: The catecholamine-mediated hypermetabolic response to severe burns causes increased energy expenditure and muscle-protein catabolism. We hypothesized that blockade of beta-adrenergic stimulation with propranolol would decrease resting energy expenditure and muscle catabolism in patients with severe burns. METHODS: Twenty-five children with acute and severe burns (more than 40 percent of total body-surface area) were studied in a randomized trial. Thirteen received oral propranolol for at least two weeks, and 12 served as untreated controls. The dose of propranolol was adjusted to decrease the resting heart rate by 20 percent from each patient's base-line value. Resting energy expenditure and skeletal-muscle protein kinetics were measured before and after two weeks of beta-blockade (or no therapy, in controls). Body composition was measured serially throughout hospitalization. RESULTS: Patients in the control group and the propranolol group were similar with respect to age, weight, percentage of total body-surface area burned, percentage of body-surface area with third-degree burns, and length of time from injury to metabolic study. Beta-blockade decreased the heart rates and resting energy expenditure in the propranolol group, both as compared with the base-line values (P<0.001 and P=0.01, respectively) and as compared with the values in the control group (P=0.03 and P=0.001, respectively). The net muscle-protein balance increased by 82 percent over base-line values in the propranolol group (P=0.002), whereas it decreased by 27 percent in the control group (P not significant). The fat-free mass, as measured by whole-body potassium scanning, did not change substantially in the propranolol group, whereas it decreased by a mean (+/-SE) of 9+/-2 percent in the control group (P=0.003). CONCLUSIONS: In children with burns, treatment with propranolol during hospitalization attenuates hypermetabolism and reverses muscle-protein catabolism

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Abate NI, Mansour YH, Tuncel M et al (2001). Overweight and sympathetic overactivity in black Americans. Hypertension.38:379-383.

Abstract: A large body of clinical investigation implicates an important role for the sympathetic nervous system in linking obesity with hypertension. However, the experimental support for this hypothesis is derived from strictly white cohorts. The goal of this study was to determine whether being overweight begets sympathetic overactivity in black Americans, the ethnic minority at highest risk for hypertension. We recorded postganglionic sympathetic nerve discharge with microelectrodes in muscle nerve fascicles of the peroneal nerve in 92 normotensive young adult black men and women within a wide range of body mass index. The same experiments were performed in a control group of 45 normotensive white men and women of similar ages and body mass indices. The major new findings are 2-fold. First, in young, normotensive, overtly healthy black women, being overweight begets sympathetic overactivity (r=0.45, P=0.0009), a putative intermediate phenotype for incident hypertension. Second, in black men, sympathetic nerve discharge is dissociated from body mass index (r=0.03, P=NS). This dissociation is explained in part by a 20% to 40% higher rate of sympathetic nerve discharge in lean black men compared with lean white men and lean black and white women (28+/-3 versus 18+/-2, 21+/-2, and 17+/-2 bursts/min, respectively; P<0.05). Sympathetic nerve discharge in lean black men is comparable to that of overweight black men and women as well as white men and women. These data provide the first microneurographic evidence for tonic central sympathetic overactivity in blacks, both adiposity-related sympathetic overactivity in black women and adiposity-independent sympathetic overactivity in black men

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Correia MLG, Morgan DA, Mitchell JL, Sivitz WL, Mark AL, Haynes WG (2001). Role of corticotrophin-releasing factor in effects of leptin on sympathetic nerve activity and arterial pressure. Hypertension.38:384-388.

Abstract: Leptin and corticotrophin-releasing factor increase sympathetic nervous activity to interscapular brown adipose tissue, kidneys, and adrenal glands. Leptin is known to increase hypothalamic corticotrophin-releasing factor. In this study, we tested the hypothesis that leptin-dependent increases in sympathetic nervous activity are mediated through increases in central nervous system corticotrophin-releasing factor activity. We examined the effects of intracerebroventricular administration of corticotrophin-releasing factor and intravenous leptin on sympathetic nervous activity to interscapular brown adipose tissue through multifiber neurography in anesthetized Sprague-Dawley rats pretreated with intracerebroventricular alpha-helical corticotrophin-releasing factor(9-41) (corticotrophin-releasing factor receptor antagonist) or vehicle. Centrally administered corticotrophin- releasing factor substantially increased interscapular brown adipose tissue sympathetic nervous activity. The responses to corticotrophin-releasing factor were substantially attenuated in animals pretreated with alpha-helical corticotrophin- releasing factor(9-41). Leptin-dependent increases in interscapular brown adipose tissue sympathetic nervous activity were significantly inhibited by pretreatment with alpha-helical corticotrophin-releasing factor(9-41). Interestingly, leptin also significantly increased arterial pressure over 6 hours, but this pressor action was not attenuated by the corticotrophin-releasing factor receptor antagonist. These results suggest that corticotrophin-releasing factor may mediate the sympathoexcitatory effect of leptin on thermogenic tissue without altering its cardiovascular actions

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Oldenburg O, Mitchell A, Nurnberger J et al (2001). Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension. Journal of the American College of Cardiology.37:219-223.

Abstract: OBJECTIVES: This study was designed to establish a patient-controlled, ambulatory norepinephrine treatment of refractory orthostatic hypotension due to primary autonomic failure. BACKGROUND: Autonomic dysfunction leads to disabling postural hypotension. Particularly in primary autonomic dysfunction, repeated syncope and immobilization can be the result. Medical treatment of orthostatic hypotension often fails in advanced cases. METHODS: Ambulatory, patient-controlled norepinephrine therapy was initiated in six patients with orthostatic hypotension due to primary autonomic failure that had been refractory to conventional treatment. Before this therapy, three patients were bedridden; one was immobilized in a wheelchair. All had recurrent syncope and tolerated upright tilt-table testing for less than 15 min despite extensive medical treatment. For ambulatory treatment, a port-a-cath system was implanted and, using a CADD ambulatory infusion pump, norepinephrine was infused in individually adjusted dosages. RESULTS: Norepinephrine infusion therapy enabled all patients to sit, stay and walk around for more than 45 min. One patient died after a five-year treatment period, another after nine months because of nonhemorrhagic brain stem infarctions, both in the absence of norepinephrine treatment. The remaining four patients are still mobile after a period of 19, 10, 9 and 7 months, respectively. None of them has suffered complications due to arterial hypo- or hypertension, and there has been no infection of the infusion system. CONCLUSIONS: In these selected patients with refractory orthostatic hypotension due to primary autonomic dysfunction, ambulatory norepinephrine infusion therapy has proved to be a promising new therapeutic option. Further long-term studies including more patients are necessary to assess additional indications, reliability and safety of this new method

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Marazita ML, Maher BS, Cooper ME et al (2001). Genetic segregation analysis of autonomic nervous system dysfunction in families of probands with idiopathic congenital central hypoventilation syndrome. Am J Med Genet.100:229-236.

Abstract: Idiopathic congenital central hypoventilation syndrome (CCHS) is a very rare syndrome with major respiratory complications. Hypothesizing that CCHS is the most severe manifestation of general autonomic nervous system dysfunction (ANSD), we applied a case-control family study design to investigate the genetics of ANSD. Fifty-two probands with CCHS were identified, as well as 52 age-, race-, and gender-matched controls. ANSD phenotypic features were characterized in the cases, controls, and their family members. Our earlier studies found that most ANSD symptoms were more likely in CCHS cases and their relatives than in controls and their relatives (P < 0.05). The goal of the current study was to determine if the familiality of ANSD was consistent with a genetic pattern. We performed major locus segregation analysis of ANSD utilizing regressive models. CCHS probands were assumed to be affected; controls and relatives were designated as affected if they had two or more relevant symptoms. The hypothesis of "no transmission and no familial effects" was rejected in both case and control families. Case families were consistent with transmission of a major effect; control families were not (the difference in the pattern of results was significant, P < 0.0001). In the total data set, the best-fitting model was codominant Mendelian inheritance of a major gene for ANSD. These case-control family studies support our hypothesis that CCHS is the most severe manifestation of a general ANSD, with a family pattern consistent with Mendelian transmission, and demonstrate the potential utility of the approach to studies of other, similarly intractable disorders. Copyright 2001 Wiley-Liss, Inc

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Watenpaugh DE, Buckey JC, Lane LD et al (2001). Effects of spaceflight on human calf hemodynamics. J Appl Physiol.90:1552-1558.

Abstract: Chronic microgravity may modify adaptations of the leg circulation to gravitational pressures. We measured resting calf compliance and blood flow with venous occlusion plethysmography, and arterial blood pressure with sphygmomanometry, in seven subjects before, during, and after spaceflight. Calf vascular resistance equaled mean arterial pressure divided by calf flow. Compliance equaled the slope of the calf volume change and venous occlusion pressure relationship for thigh cuff pressures of 20, 40, 60, and 80 mmHg held for 1, 2, 3, and 4 min, respectively, with 1-min breaks between occlusions. Calf blood flow decreased 41% in microgravity (to 1.15 +/- 0.16 ml x 100 ml(-1) x min(-1)) relative to 1-G supine conditions (1.94 +/- 0.19 ml x 100 ml(-1) x min(-1), P = 0.01), and arterial pressure tended to increase (P = 0.05), such that calf vascular resistance doubled in microgravity (preflight: 43 +/- 4 units; in-flight: 83 +/- 13 units; P < 0.001) yet returned to preflight levels after flight. Calf compliance remained unchanged in microgravity but tended to increase during the first week postflight (P > 0.2). Calf vasoconstriction in microgravity qualitatively agrees with the "upright set-point" hypothesis: the circulation seeks conditions approximating upright posture on Earth. No calf hemodynamic result exhibited obvious mechanistic implications for postflight orthostatic intolerance

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