Differential modulation of
autonomic function by brain hemispheres
Clinical observations in patients with lesions of suprabulbar brain structures due to stroke, brain tumors or epilepsy have suggested that brain hemispheres modulate autonomic function, and that this modulation differs between the right and left sides. Similar observations have been made in normal subjects using neuroimaging techniques. In this study, cardiovascular function was monitored in fifteen patients with intractable seizures during sequential hemispheric inactivation achieved by intracarotid infusion of amobarbital. Inactivation of the left hemisphere reduced baroreflex sensitivity, and increased heart rate, blood pressure and low frequency blood pressure variability, suggesting increased sympathetic tone. In contrast, inactivation of the right hemisphere decreased blood pressure and increased high frequency heart rate variability, suggesting increased parasympathetic tone. Respiration was unchanged during the segments being analyzed, eliminating this factor as the cause of the autonomic changes. These results add to growing evidence supporting differential modulation of autonomic function by brain hemispheres.
Hilz MJ, Dutsch M, Perrine K, et al. Hemispheric influence on autonomic modulation and baroreflex sensitivity. Ann Neurol 2001;49:575-584.
Impaired autonomic function is an independent mortality
risk factor in heart failure
Patients post myocardial infarction are at greater risk of death due to cardiac arrhythmias. Because the population at risk is large, whereas the incidence of death is low, it is important to identify the relatively small subset of patients with increased risk that would benefit from an implantable cardiac defibrillator. The presence of nonsustained ventricular tachycardia or depressed left ventricular function are classical risk factors used in stratifying patients in clinical trials. On the other hand, the presence of cardiac autonomic impairment is rarely taken into account. In this study, the data from over 1,000 patients participating in the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) trial was analyzed. Depressed baroreflex sensitivity and impaired heart rate variability were found to be independent markers of increased mortality. Mortality increased 22 fold in patients who had these two markers and nonsustained ventricular tachycardia. Depressed baroreflex sensitivity predicted higher mortality in patients with impaired left ventricular function, even in the absence of nonsustained ventricular tachycardia. Thus, analysis of autonomic function aids in the identification of patients at risk of cardiac and arrhythmic mortality who might benefit from implantable cardioverter defibrillation therapy.
La Rovere MT, Pinna GD, Hohnloser SH, et al. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias. Circulation 2001;103:2072-2077.
Autoimmune autonomic neuropathies
Autoimmune processes have long been suspected as causes of autonomic impairment, but it is only recently that autoantibodies targeted at specific autonomic antigens have been identified. Previously, this group reported the presence of antibodies specific for ganglionic acetylcholine receptors in a majority of patients with acute pandysautonomia (Vernino et al. New Engl J Med 2000;343:847-855). In this study, they report seven patients with myasthenia gravis and subacute autonomic impairment ranging from gastroparesis to severe panautonomic failure. Gastrointestinal dysmotility was a common feature. All had antibodies against muscle acetylcholine receptors, and three (all of whom had thymoma) had antibodies against neuronal ganglionic acetylcholine receptors (titers were 125, 255 and 17,200 pmol/L, normal <50). Autonomic antibodies were not identified in the other four patients. Lambert-Eaton antibodies were not found in these patients. These observations confirm the presence of autonomic impairment in a subset of patients with myasthenia gravis, and provide further evidence of the importance of autoimmune processes in subacute autonomic failure.
Vernino S, Cheshire WP, Lennon VA. Myasthenia gravis with autoimmune neuropathy. Auton Neurosci 2001;88:187-192.
Importance of endothelium-derived hyperpolarizing factor
(EDHF) in vascular tone
Endothelial cells provide tonic vasodilation at rest and in response to endothelial-dependent vasodilators like acetylcholine and bradikinin. This is an important factor in the regulation of vascular tone and blood pressure, and is impaired in conditions that induce endothelial cell dysfunction, such as hypercholesterolemia. Nitric oxide is recognized as crucial component of endothelium-derived vasodilation, but other factors may also play a role. One putative candidate is EDHF, a soluble transferal factor proposed to hyperpolarize underlying vascular smooth muscle cells by activating ATP-dependent K+ channels. The biochemical identity of EDHF remains controversial, but metabolites of cytochrome P-450 epoxygenase have been proposed to have EDHF activity. In this study, the role of EDHF was examined in the isolated human forearm model of healthy volunteers. Studies were done after inhibition of cyclooxygenases with oral aspirin (1 gm), and NO production with the NO synthase inhibitor L-NMMA (4 :mol/min intrabrachial infusion). To study the role of putative EDHF mechanisms, miconazole (0.125 mg/min intrabrachial infusion) was used as an inhibitor of all cytochrome P-450 enzymes, and KCl (0.33 mmol/min intrabrachial infusion) was used to hyperpolarize the forearm vasculature and prevent further action of released EDHF. Miconazole had no effect on resting forearm blood flow, suggesting that cytochrome P-450 products do not influence basal tone, but produced a mild inhibition of bradikinin-induces vasodilation. The later effect appeared to be selective because it was not observed with nitroprusside-induced vasodilation. Similarly, bradikinin-induced vasodilation was less during KCl infusion. There are limitations, acknowledged by the investigators, inherent to these human experiments. KCl increases, and L-NMMA decreases resting vascular tone, making comparisons difficult. Also, the inhibitors used are competitive antagonists but cannot be given at high enough doses that produce maximal blockade. Nonetheless, these results suggest that cytochrome P-450 products, inducing hyperpolarization, contribute to bradikinin-induced vasodilation.
Halcox JP, Narayanan S, Cramer-Joyce L, et al. Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation. Am J Physiol 2001;280:H2470-H2477.
Role of Neurotrophin-4 (NT-4) in the development of
Neurotrophins are a family of growth factors that modulate neuron survival and differentiation. The prototypic member of the Neurotrophins is nerve growth factor, whereas the least understood is NT-4. Mice deficient for NT-4 showed a significant reduction (20-30%) of preganglionic sympathetic neurons in the intermediolateral column of the thoracic spinal cord. In contrast, neuron numbers in the superior cervical ganglion, stellate ganglion and the celiac/superior mesenteric ganglion were unchanged. Number of axons in the thoracic sympathetic trunk connecting the stellate ganglion with lower paravertebral ganglia were also reduced, whereas axon numbers in the cervical sympathetic trunk were unaltered. The loss of intermediolateral column neurons were not apparent in the immediate postnatal period, suggesting that NT-4 is important later in development. Levels of catecholamines and tyrosine hydroxylase immunoreactivity were reduced in the stellate ganglion and the celiac ganglion but not in the superior cervical ganglion. Surprisingly, NT-4 KO mice had slightly higher mean blood pressure compared to wild-type controls (111±2 vs 105±1), and had higher blood pressure variability (SD, 6.1±0.2 vs 4.4±0.4). Thus, NT-4 is important for the establishment and/or maintenance of synapses of intermediolateral neurons on postganglionic cells. The precise impact of NT-4 deficiency on autonomic cardiovascular control deserves further study.
Roosen A, Schober A, Strelau J, et al. Lack of Neurotrophin-4 causes selective structural and chemical deficits in sympathetic ganglia and their preganglionic innervation. J Neurosci 2001;21:3073-3084.
Ambulatory norepinephrine infusion to treat severe
Symptomatic orthostatic hypotension is often effectively treated with oral pressor agents, but can be 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. A similar approach incorporating a feedback loop with a pressure transducer, was previously reported by Polinsky et al (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 (CCHS) uncovered by
autonomic symptom questionnaire
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 arbritarily 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 Gen 2001;100:237-245). autonomic dysfunction is part of CCHS, and that the presence of autonomic symptoms 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. Preliminary findings showing increase sympathetic nerve activity in space (Ertl AC, et al. Circulation 1998;98:I-471), are in agreement with these findings. Calf vasoconstriction in spaceflight supports the concept that cardiovascular modulation in space approximates that observed during upright posture on Earth.
Watenpaugh DE, Buckey JC, Lane LD, et al. Effects of spaceflight on human calf hemodynamics. J Appl Physiol 2001;90:1552-1558.
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MJ, Dutsch M, Perrine K, Nelson PK, Rauhut U, Devinsky O. Hemispheric
influence on autonomic modulation and baroreflex sensitivity. Ann Neurol.
Abstract: Several studies suggest hemispheric lateralization of autonomic cardiovascular control. There is controversy regarding which hemisphere dominates sympathetic or parasympathetic activity. Hemispheric influences on baroreflex sensitivity (BRS) have not yet been evaluated. To determine hemispheric autonomic control in epilepsy patients, we assessed cardiovascular and baroreflex modulation before and during hemispheric inactivation. For 15 patients with drug-refractory epilepsy, we analyzed autonomic heart rate (HR) and blood pressure (BP) modulation and BRS before and during left and right intracarotid amobarbital procedure (IAP). After Blackman-Tukey spectral analysis, we calculated the low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.5 Hz) power of HR and BP as well as BRS as the LF transfer function gain between BP and HR. Right hemispheric inactivation induced a significant decrease of BP and an increase of HF power of HR and BP (p < 0.05). Left inactivation increased HR, BP, and LF power of both signals and decreased BRS by nearly 30% (p < 0.05). The results confirm previous IAP studies showing sympathetic lateralization in the right hemisphere and, moreover, demonstrate parasympathetic predominance and up-regulation of BRS in the left hemisphere. In epilepsy patients, unilateral electrical activity might derange autonomic balance between both hemispheres and contribute to cardiovascular dysregulation and sudden fatalities
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Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R et al.
Baroreflex sensitivity and heart rate variability in the identification of
patients at risk for life-threatening arrhythmias - Implications for clinical
trials. Circulation. 2001;103:2072-77.
Abstract: Background-The need for accurate risk stratification is heightened by the expanding indications for the implantable cardioverter defibrillator, The Multicenter Automatic Defibrillator Implantation Trial (MADIT) focused interest on patients with both depressed left ventricular ejection fraction (LVEF) and the presence of nonsustained ventricular tachycardia (NSVT), Meanwhile, the prospective study Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) demonstrated that markers of reduced vagal activity, such as depressed baroreflex sensitivity (BRS) and heart rate variability (HRV), are strong predictors of cardiac mortality after myocardial infarction. Methods and Results We analyzed 1071 ATRAMI patients after myocardial infarction who had data on LVEF, 24-hour ECG recording, and BRS, During follow-up (21+/-8 months), 43 patients experienced cardiac death, 5 patients had episodes of sustained VT, and 30 patients experienced sudden death and/or sustained VT. NSVT, depressed BRS, or HRV were all significantly and independently associated with increased mortality. The combination of all 3 risk factors increased the risk of death by 22x, Among patients with LVEF<35%, despite the absence of NSVT, depressed BRS predicted higher mortality (18% versus 4.6%, P=0.01). This is a clinically important finding because this group constitutes 25% of all patients with depressed LVEF. For both cardiac and arrhythmic mortality, the sensitivity of low BRS was higher than that of NSVT and HRV. Conclusions-BRS and HRV contribute importantly and additionally to risk stratification. Particularly when LVEF is depressed, the analysis of BRS identifies a large number of patients at high risk for cardiac and arrhythmic mortality who might benefit from implantable cardioverter defibrillator therapy without disproportionately increasing the number of false- positives
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H, Hague K, Perl D. Accumulation of alpha-synuclein in autonomic nerves in
pure autonomic failure. Neurology. 2001;56:980-981.
No abstract is available for this reference
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Vernino S, Cheshire WP,
Lennon VA. Myasthenia gravis with autoimmune autonomic neuropathy.
Autonomic Neuroscience-Basic & Clinical. 2001;88:187-92.
Abstract: The autoantibodies that impair neuromuscular junction transmission in myasthenia gravis are specific for the nicotinic acetylcholine receptor (AChR) of muscle. Antibodies specific for AChRs in ganglionic neurons are found in a majority of patients with subacute autonomic neuropathy. Dysautonomia is not a recognized feature of myasthenia gravis, but there have been rare reports of myasthenia gravis coexisting with autonomic failure, usually in association with thymoma. Here we report seven patients who had myasthenia gravis with subacute autonomic failure. Their autonomic dysfunction ranged from isolated gastroparesis to severe panautonomic failure. Gastrointestinal dysmotility was a common feature. All had antibodies against muscle AChR, and three (all of whom had thymoma) had antibodies against neuronal ganglionic AChRs. In several patients, gastrointestinal function improved clinically after administration of an acetylcholinesterase inhibitor. These observations support a rare but definite clinical association between myasthenia gravis and autonomic failure and strengthen the concept that subacute autonomic neuropathy is an autoimmune disorder.
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Narayanan S, Cramer-Joyce L, Mincemoyer R, Quyyumi AA. Characterization of
endothelium-derived hyperpolarizing factor in the human forearm
microcirculation. Am J Physiol Heart Circ Physiol. 2001;280:H2470-H2477.
Abstract: The identity of endothelium-dependent hyperpolarizing factor (EDHF) in the human circulation remains controversial. We investigated whether EDHF contributes to endothelium-dependent vasomotion in the forearm microvasculature by studying the effect of K+ and miconazole, an inhibitor of cytochrome P-450, on the response to bradykinin in healthy human subjects. Study drugs were infused intra-arterially, and forearm blood flow was measured using strain-gauge plethysmography. Infusion of KCl (0.33 mmol/min) into the brachial artery caused baseline vasodilation and inhibited the vasodilator response to bradykinin, but not to sodium nitroprusside. Thus the incremental vasodilation induced by bradykinin was reduced from 14.3 +/- 2 to 7.1 +/- 2 ml x min(-1) x 100 g(-1) (P < 0.001) after KCl infusion. A similar inhibition of the bradykinin (P = 0.014), but not the sodium nitroprusside (not significant), response was observed with KCl after the study was repeated during preconstriction with phenylephrine to restore resting blood flow to basal values after KCl. Miconazole (0.125 mg/min) did not inhibit endothelium-dependent or -independent responses to ACh and sodium nitroprusside, respectively. However, after inhibition of cyclooxygenase and nitric oxide synthase with aspirin and NG-monomethyl-L-arginine, the forearm blood flow response to bradykinin (P = 0.003), but not to sodium nitroprusside (not significant), was significantly suppressed by miconazole. Thus nitric oxide- and prostaglandin-independent, bradykinin-mediated forearm vasodilation is suppressed by high intravascular K+ concentrations, indicating a contribution of EDHF. In the human forearm microvasculature, EDHF appears to be a cytochrome P-450 derivative, possibly an epoxyeicosatrienoic acid
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Roosen A, Schober A, Strelau
J, Bottner M, Faulhaber J, Bendner G et al. Lack of neurotrophin-4 causes
selective structural and chemical deficits in sympathetic ganglia and their
preganglionic innervation. J Neurosci. 2001;21:3073-84.
Abstract: Neurotrophin-4 (NT-4) is perhaps the still most enigmatic member of the neurotrophin family. We show here that NT-4 is expressed in neurons of paravertebral and prevertebral sympathetic ganglia, i.e., the superior cervical (SCG), stellate (SG), and celiac (CG) ganglion. Mice deficient for NT-4 showed a significant reduction (20-30%) of preganglionic sympathetic neurons in the intermediolateral column (IML) of the thoracic spinal cord. In contrast, neuron numbers in the SCG, SG, and CG were unchanged. Numbers of axons in the thoracic sympathetic trunk (TST) connecting the SG with lower paravertebral ganglia were also reduced, whereas axon numbers in the cervical sympathetic trunk (CST) were unaltered. Axon losses in the TST were paralleled by losses of synaptic terminals on SG neurons visualized by electron microscopy. Furthermore, immunoreactivity for the synaptic vesicle antigen SV2 was clearly reduced in the SG and CG. Levels of catecholamines and tyrosine hydroxylase immunoreactivity were dramatically reduced in the SG and the CG but not in the SCG. Despite this severe phenotype in the sympathetic system, blood pressure levels were not reduced and displayed a pattern more typical of deficits in baroreceptor afferents. Numbers of IML neurons were unaltered at postnatal day 4, suggesting a postnatal requirement for their maintenance. In light of these and previous data, we hypothesize that NT-4 provided by postganglionic sympathetic neurons is required for establishing and/or maintaining synapses of IML neurons on postganglionic cells. Impairment of synaptic connectivity may consequently reduce impulse flow, causing a reduction in transmitter synthesis in postganglionic neurons
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Marazita ML, Maher BS,
Cooper ME, Silvestri JM, Huffman AD, Smok-Pearsall SM et al. Genetic
segregation analysis of autonomic nervous system dysfunction in families of
probands with idiopathic congenital central hypoventilation syndrome. Am J
Med Genet. 2001;100:229-36.
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.
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DE, Buckey JC, Lane LD, Gaffney FA, Levine BD, Moore WE et al. Effects of
spaceflight on human calf hemodynamics.
J Appl Physiol. 2001;90:1552-58.
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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