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
sympathetic ganglia
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
orthostatic hypotension
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.
Send comments or suggestions about Autonomic News to: italo.biaggioni@mcmail.vanderbilt.edu
Hilz
MJ, Dutsch M, Perrine K, Nelson PK, Rauhut U, Devinsky O. Hemispheric
influence on autonomic modulation and baroreflex sensitivity. Ann Neurol.
2001;49:575-84.
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
Back to reference list
La
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
Back to reference list
Kaufmann
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
Back to reference list
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.
Back to reference list
Halcox JP,
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
Back to reference list
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
Back to reference list
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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Watenpaugh
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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