Neurocardiogenic Syncope >>
Leptin and the Sympathetic Nervous System >>
Autoimmune Pandysautonomia, Animal Model >>
Central Hypoventilation Syndrome >>
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Neurocardiogenic syncope. “I only know that I
know nothing”
If Socrates were alive, he would be an accomplished investigator of
neurocardiogenic syncope. The pathogenesis, diagnosis and treatment of this
condition remain unclear. It was initially thought that sympathetic
overactivity induced by upright posture was the triggering event leading to
neurogenic syncope. This concept, however, derived from observations of
vasovagal events induced in normal volunteers without a history of spontaneous
neurogenic syncope. In contrast, sympathetic activation in response to tilt has
been reported to be decreased, rather than increased in syncopal patients, and
this was associated with a decrease gain of baroreflex responses to heart rate
and muscle sympathetic nerve activity (MSNA) (Mosqueda-Garcia et al, J
Clin Invest 1997; 99:2736). Some studies have confirmed this decrease in heart
rate baroreflex gain, but others have reported normal or even increased hear
rate baroreflex gain. Pitzalis et al. found greater heart rate increases
in response to blood pressure falls at rest (obtained from spontaneous sequences
of blood pressure and RR intervals) in 94 tilt-positive patients referred for
evaluation of unexplained syncope, compared to 100 normal controls.
Furthermore, patients with the greatest heart rate baroreflex gain developed
syncope with the shortest tilt time. It is not certain if this alteration in
resting baroreflex gain is a primary mechanism of syncope or an epiphenomenon.
In a study involving a
smaller number of patients Bechir et al. found a blunted increase in MSNA
in response to orthostatic stress (lower body negative pressure), in agreement
with the study of Mosqueda-Garcia et al. Thus, the hypothesis that an
exaggerated tilt-induced increase in sympathetic activity triggers neurogenic
syncope, which is based on observations in normal subjects during incidental
vasovagal reactions (“false positives”), does not seem to hold true in patients
evaluated for spontaneous neurogenic syncope. The relevance of this blunted
increase during tilt of MSNA innervating the lower limbs is unclear because
Stewart and Weldon found that neurogenic syncope patients had the same decrease
in calf blood flow during upright tilt as normal subjects, suggesting that lower
limbs were appropriately vasoconstricted. In contrast, calf blood flow failed
to decrease during tilt in patients with chronic orthostatic intolerance
(postural tachycardia) despite an exaggerated increase in calf volume suggesting
inappropriate venous pooling, which should have triggered greater compensatory
vasoconstriction.
The diagnosis and treatment of neurogenic syncope are also
contentious topics. Head-up tilt has become the standard diagnostic test for
this condition, but is far from being a golden standard because of the uncertain
significance of false positives and false negatives. Drugs like isoproterenol,
nitroglycerine and adenosine have been used to increase the percentage of
positive tilt test results. It has been argued that they can also provide
insight about pathophysiological mechanisms (e.g., involvement of adenosine or
beta-adrenoreceptors), but it may be that they lower the threshold for
triggering syncope just because they increase heart rate. Theodorakis et al.
showed that intravenous clomipramine increased the positive rate of the tilt
test from 41 to 83% in 126 patients referred for unexplained syncope, at the
expense of an increase in the rate of false positives from 4 to 11% of 54
control subjects. Clomipramine increased the predictive accuracy of the tilt
table test (accounting for false positives) from 58 to 86%. This finding is
counterintuitive with the widespread use of serotonin reuptake inhibitors in the
treatment of neurogenic syncope, which is based on a small double blind placebo
controlled trial with paroxetine (Di Girolamo, J Am Coll Cardiol 1999;
33:1227). However, Takata et al. did not find paroxetine of use in
reducing vasovagal reactions induced during lower body negative pressure in
normal subjects. It in not known if these apparent discrepancies can be
explained by differences in the acute vs. chronic effects of serotonin reuptake
inhibitors, or the known differences between normal subjects who develop
vasovagal reactions during postural stress and patients suffering from
spontaneous neurogenic syncope. Theodorakis et al. suggested that
central serotinergic pathways may contribute to the pathogenesis of syncope.
Clomipramine, however, may also block reuptake of norepinephrine in addition to
serotonin. Of interest, Schroeder et al. found that selective blockade
of norepinephrine reuptake appears to prevent tilt-induced vasovagal reactions
in normal subjects. It is conceivable, therefore, that enhanced synaptic
serotonin help trigger neurogenic syncope whereas synaptic norepinephrine has
the opposite effect, but this hypothesis remains to be tested.
Given the uncertainties about the mechanisms that trigger
neurogenic syncope, it is not surprising that pharmacological approaches to its
treatment remain unsatisfactory. This has led many to promote the use of
pacemakers, even though pacemakers may prevent the bradycardia but not the
vasodepressor component of neurogenic syncope. There are a few randomized
open-label controlled studies showing significant reductions in syncope
recurrence after implantation of dual-chamber pacemakers, but they were not
double blinded. This major limitation was addressed by Connolly et al.,
by implanting pacemakers in 100 patients with recurrent syncope and randomizing
them to either rate-drop pacing, or no pacing at all. After a 6 month follow-up
period the pacing group had a 30% reduction risk of syncope recurrence, but this
was non-significant. The authors conclude that pacemaker should not be
recommended as first line treatment for neurocardiogenic syncope. It seems,
therefore, that results of previous randomized controlled studies showing
pacemaker benefit were due mostly to the placebo effect of pacemaker placement.
It is unclear if pacemakers will be useful in the relatively
small percentage of patients who develop severe bradycardia during syncope.
Even in those patients, it would be reassuring if severe bradycardia or asystole
are documented during spontaneous syncopal episodes (e.g., during heart rhythm
monitoring) instead of tilt table testing, because there is not always
concordance between these two diagnostic tests. Raj et al. explored the
possibility that patients with severe bradycardia would benefit the most from
pacemaker implantation by following 40 such patients for 46 to 75 months. By 60
months only 32% of patients were syncope-free and most of the failures occurred
in the first 6 months. About half of patients had at least a 75% reduction in
syncopal episodes during long-term follow-up, whereas the other half were
“non-responders”. The authors could not find any characteristic at baseline or
during tilt table testing that would predict future response. In particular,
the initial classification of syncope (cardioinhibitory vs. vasodepressor) was
not a useful predictor of pacemaker benefit. It is difficult to recommend,
therefore, pacemaker implantation in patients with neurocardiogenic syncope, and
it is uncertain that they would be of benefit even in patients with predominant
cardioinhibitory syncope because the vasodepressor component is not resolved
with this approach.
Pitzalis M, Parati G, Massari F et
al.
(2003) Enhanced reflex response to
baroreceptor deactivation in subjects with tilt-induced syncope. Journal
of the American College of Cardiology 41:1167-1173.
Bechir
M, Binggeli C, Corti R et al. (2003)
Dysfunctional baroreflex regulation of sympathetic nerve activity in patients
with vasovagal syncope. Circulation 107:1620-1625.
Stewart JM and Weldon A (2003) Contrasting neurovascular findings in chronic
orthostatic intolerance and neurocardiogenic syncope. Clin Sci (Lond)
104:329-340.
Theodorakis GN, Livanis EG, Leftheriotis D et al.
(2003)
Head-up tilt test with clomipramine challenge in vasovagal syndrome - a new
tilt testing protocol. European Heart Journal 24:658-663.
Takata TS, Wasmund SL, Smith ML et al.
(2002)
Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction
associated with carotid sinus massage and/or lower body negative pressure in
healthy volunteers. Circulation 106:1500-1504.
Schroeder C, Tank J, Boschmann M et al.
(2002)
Selective norepinephrine reuptake inhibition as a human model of orthostatic
intolerance. Circulation 105:347-353.
Connolly SJ, Sheldon R, Thorpe KE et al.
(2003)
Pacemaker therapy for prevention of syncope in patients with recurrent severe
vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial.
JAMA 289:2224-2229.
See also editorial by Kapoor on page 2272 of the same issue.
Raj SR, Koshman ML, and Sheldon RS
(2003) Outcome of
patients with dual-chamber pacemakers implanted for the prevention of neurally
mediated syncope. American Journal of Cardiology 91:565-569.
Leptin,
obesity and the
sympathetic nervous system
Leptin is a hormone produced by fat cells that acts on the hypothalamus
to decrease appetite and, through sympathetic activation, increase energy
expenditure. Abnormally increased leptin levels are observed in most cases of
obesity, implying leptin resistance due to receptor or post-receptor
abnormalities. Activation of leptin receptors leads to stimulation of
phosphoinositol-3 kinase (PI3K), and inhibition of PI3K is known to block the
leptin- induced suppression of feeding. Rahmouni et al. now report that the
increase in renal sympathetic nerve activity (RSNA) produced by
intracerebroventricular (ICV) administration of leptin is attenuated in mice
treated with selective inhibitors of PI3K (LY294002 or wortmannin). The
increase in RSNA induced by a melanocortin receptor agonist was not affected
(negative control). Thus, PI3K appears to mediate both the appetite suppression
and sympathetic activation induced by the central actions of leptin.
To assess the
importance of the sympathetic nervous system in the actions of leptin, Dobbins
et al. compared the effect of ICV infusion of leptin in sympathectomized (SYM)
and control (CON) adult animals. SYM animals lost only half the weight of CON
animals after normalizing for food intake and physical activity, indicating an
important role of the sympathetic nervous system in stimulating energy
expenditure during ICV leptin infusion, presumably by increasing resting
metabolic rate.
Results from animal experimentation suggest not only that
leptin causes sympathetic activation but, conversely, sympathetic activation may
inhibit leptin release, providing negative feedback regulation. To examine the
relationship between leptin and the sympathetic nervous system in humans,
Eikelis et al. studied subjects over a wide range of plasma leptin and
sympathetic activity levels. They found that renal norepinephrine spillover
correlated with plasma leptin (r=0.628, P<0.01) in men of widely differing
adiposity and leptin levels, but other measures of sympathoadrenal function did
not. In contrast, no correlation was found between sympathetic activity (raging
from high in heart failure and hypertension, to low in pure autonomic failure)
and plasma leptin. Thus, these results provide indirect support for the view
that leptin stimulates the sympathetic nervous system in humans, at least for
renal sympathetic outflow, but not for the concept that sympathetic activation
inhibits leptin release.
Rahmouni K, Haynes WG, Morgan DA et al.
(2003) Intracellular mechanisms
involved in leptin regulation of sympathetic outflow. Hypertension
41:763-767.
Dobbins RL, Szczepaniak LS, Zhang W et al. (2003)
Chemical sympathectomy alters regulation of body weight during prolonged ICV
leptin infusion. Am J Physiol Endocrinol Metab 284:E778-E787.
Eikelis N, Schlaich M, Aggarwal A et al. (2003)
Interactions Between Leptin and the Human Sympathetic Nervous System.
Hypertension 41:1072-1079.
An animal model
of autoimmune
pandysautonomia
It was long suspected that subacute pandysautonomia is an autoimmune
process. This was further suggested when high titers of antibodies against the
nicotinic acethylcholine receptor (nAChR) were identified in a significant
proportion of patients with subacute pandysautonomia (Vernino et al. New
Engl J Med 2000;343:847, and Autonomic News. Clin Auton Res 2001; 11:142).
Direct evidence of autonomic neuropathy induced by nicotinic antibodies is now
provided by Lennon et al. Nicotinic acetylcholine receptors are a family
of ligand-gated pentameric ion channels. In humans, 16 different subunits have
been identified (α1-7, α9-10, β1-4, δ, ε, and γ), and pentameric receptors are
formed by various combinations of these subunits. Rabbits immunized once with
recombinant α3
subunit developed circulating nAChR antibodies and features of severe autonomic
neuropathy, with profound gastrointestinal hypomotility, dilated pupils with
impaired light response, and grossly distended bladders. Inferior mesenteric
ganglion neurons were present, but neurotransmission was impaired, confirming a
postsynaptic channelopathy. In addition, ganglionic nAChR protein was found in
small-cell carcinoma lines, identifying this cancer as a potential initiator of
ganglionic nAChR autoimmunity. The data provides direct evidence that immune
responses driven by distinct neuronal nAChR subtypes induce an autoimmune
autonomic neuropathy, as seen in paraneoplastic syndromes.
Lennon
VA, Ermilov LG, Szurszewski JH et al.
(2003) Immunization with
neuronal nicotinic acetylcholine receptor induces neurological autoimmune
disease. J Clin Invest 111:907-913.
Genetic cause
of
autonomic dysfunction in congenital central hypoventilation syndrome
Congenital central hypoventilation syndrome (CCHS, a.k.a. “Ondine’s
curse”) is a rare condition characterized by depressed ventilatory drive during
sleep. About 16% of CCHS are associated with Hirshprung disease, and other
autonomic abnormalities (decreased heart rate variability, pupillary
abnormalities, GI symptoms) are often observed in CCHS patients (Autonomic News.
Clin Auton Res 2002; 12:3). PHOX2B is a homeobox gene expressed in autonomic
neurons thought to be important in their differentiation into their autonomic
phenotype, and is required for neuronal expression of dopamine-β-hydroxylase.
Amiel et al. proposed PHOX2B as a candidate gene to explain the autonomic
abnormalities present in CCHS, and found heterozygous de novo mutations
of this gene in 18 of 29 CCHS patients. It is not yet known how these different
mutations affect autonomic development.
Amiel J,
Laudier B, Attie-Bitach T et al.
(2003)
Polyalanine expansion and frameshift mutations of the paired-like homeobox
gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet
33:459-461.