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Research Highlights from the Literature

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2003; Volume 13(1) from Clinical Autonomic Research                                           
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Neural Development.  What makes a sympathetic neuron cholinergic?
    Brain-derived neurotrophic factor (BDNF) is part of the family of neurotrophins involved in neuronal development and function.  Yang et al. used a cell culture model to study the effect of BDRF on the functional connections that exists between sympathetic neurons and cardiac myocytes.  Short exposure (15 minutes) to BDNF lead to a rapid shift from excitatory noradrenergic to inhibitory cholinergic transmission in response to neuronal stimulation.  Neurons lacking the p75 neurotrophin receptor did not release acetylcholine in response to BDNF, and neurons overexpressing p75 showed increased cholinergic transmission.  These findings suggest that BDNF, acting through p75, induces the preferential release of acetylcholine in response to neuronal stimulation.
    During development, sympathetic neurons innervating rodent sweat glands undergo a targeted change in neurotransmitter phenotype from noradrenergic to cholinergic, even though neurons continue to express tyrosine hydroxylase (TH, the enzyme that converts tyrosine into dopa, the rate-limiting step in noradrenaline synthesis).  Habecker et al. found that adult cholinergic sympathetic neurons also express aromatic L-amino acid decarboxylase (the enzyme that converts dopa into dopamine), but the levels of the TH co-factor tetrahydrobiopterin (BH4) dropped significantly as neurons switched from making norepinephrine to acetylcholine.  Immunoreactivity for the rate-limiting BH4 synthetic enzyme GTP cyclohydrolase became undetectable.  Furthermore, extracts from sweat glands suppressed BH4 in cultured mouse sympathetic neurons, and addition of the BH4 precursor sepiapterin rescued catecholamine production.  These results suggest that sweat glands elicit differentiation of noradrenergic neurons into cholinergic transmission by inhibiting the synthesis of BH4.
    Agrin, a nerve-derived factor, participates in acetylcholine neuromuscular synapse formation. Gingras et al examined its role in the formation of autonomic ganglia synapse, between cholinergic preganglionic axons and sympathetic neurons in the superior cervical ganglion (SCG).  Synapse number decreased significantly in dissociated cultures of SCG neurons from agrin-deficient mice.  Synapses were rescued by adding recombinant neural agrin to the cultures.  These results suggest that neural agrin plays an organizational role in the formation and/or differentiation of cholinergic synapses.
    Yang B, Slonimsky JD, and Birren SJ (2002) A rapid switch in sympathetic neurotransmitter release properties mediated by the p75 receptor. Nat Neurosci 5:539-545.
 Habecker BA, Klein MG, Sundgren NC et al (2002) Developmental regulation of neurotransmitter phenotype through tetrahydrobiopterin. J Neurosci 22:9445-9452.
    Gingras J, Rassadi S, Cooper E et al (2002) Agrin plays an organizing role in the formation of sympathetic synapses. J Cell Biol 158:1109-1118.

Autonomic nervous system, Argentinean soccer, and cardiovascular risk
    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but malignant ventricular tachycardia characterized by syncope and sudden death at a young age triggered by exercise or emotion, in the absence of structural heart disease. Sumitomo et al. report on 29 patients 10±6 (SD) years of age with CPVT.  Autosomal dominant inheritance was seen in 8%.  Syncope was the initial presentation in 80% of patients, and CPVT could be induced by exercise in all.  During a follow-up of 6.8±4.9 years, sudden death was seen in 25% of patients, and $-blockers were effective in only 30%.  An autosomal dominant form of the disease can be caused by mutations in the cardiac ryanodine receptor gene RYR2.  Postma et al. reported three families with a resecive form of CPVT, each with a different mutation, but all causing stop codons with loss of the expression of the cardiac calsequestrin gene CASQ2.  Only 2 of 16 heterozygous carriers of these mutations had ventricular arrhythmias triggered by exercise.  Both RYR2 and CASQ2 play a role in the release of calcium from the myocardial sarcoplasmatic reticulum.  It is not clear why sympathetic activation triggers arrhythmia in patients with these genetic effects, but these patients, although rare, demonstrate that emotion and stress can induce sympathetic activation leading to fatal arrhythmias and sudden death.  There is indirect evidence that this may also occur in the general population.  Carroll et al. reported that hospital admissions for acute myocardial infarction (AMI) increased by 25% in the UK on June 30, 1998, the day that England lost to Argentina in the World Soccer Cup, and the following two days.  No excess admissions occurred for other diagnosis or on the days of the other England matches. 
    Not only can sympathetic activation contribute to AMI, but increase sympathetic activity can be the result of AMI, and is thought to worsen prognosis.  Graham et al. found that sympathetic activation is seen not only transiently during AMI, but remained elevated for 3-6 months after AMI, as determined by sequential measurements of muscle sympathetic nerve activity (MSNA) in 13 patients compared to normal controls, patients with coronary artery disease without AMI, and patients hospitalized for other acute illnesses.  This sympathetic hyperactivity was inversely correlated to left ventricular ejection fraction. It is possible, therefore, that increased sympathetic activation is secondary to mild systolic dysfunction in uncomplicated AMI.  Regardless of its origin, protracted sympathetic activation may contribute to increased cardiovascular risk in patients following AMI, and may explain the benefit of anti-adrenergic strategies in the treatment of such patients.
    Whereas sympathetic hyperactivity is a risk factor in patients with coronary artery disease and heart failure, it is also believed that AMI induces local autonomic denervation resulting in prolonged QT interval.  This is also observed in patients with diabetic autonomic neuropathy and is associated with poor prognosis.  Therefore, it is thought that the autonomic nervous system modulates QT interval, but traditional autonomic blockade combining propranolol and atropine has produced conflicting results. Diedrich et al. used the alternative approach of interrupting neurotransmission at the level of autonomic ganglia with trimethaphan to determine its effect on the QT interval.  Patients with pure autonomic failure (PAF, known to have severe sympathetic tone to the heart) had very low heart rate variability and a prolonged QTc at baseline compared with patients with multiple system atrophy (MSA, known to have relatively preserved sympathetic cardiac sympathetic tone), and normal subjects. In MSA and in normal subjects, trimethaphan dose-dependently prolonged QTc to a similar duration as in PAF patients, supporting a role of autonomic tone in modulation of QT interval.
    Sumitomo N, Harada K, Nagashima M et al (2003) Catecholaminergic polymorphic ventricular tachycardia: Electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart 89:66-70.
    Postma AV, Denjoy I, Hoorntje TM et al (2002) Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia. Circulation Research 91:E21-E26.
    Carroll D, Ebrahim S, Tilling K et al (2002) Admissions for myocardial infarction and World Cup football: database survey. Br Med J 325:1439-1442.
    Graham LN, Smith PA, Stoker JB et al (2002) Time course of sympathetic neural hyperactivity after uncomplicated acute myocardial infarction. Circulation 106:793-797.
    Diedrich A, Jordan J, Shannon JR et al (2002) Modulation of QT Interval During Autonomic Nervous System Blockade in Humans. 106:2238-2243.

Treating syncope by crossing legs and drinking water
    Pharmacological treatment to prevent neurogenic syncope remains unsatisfactory.  Krediet et al. found that asking the patient to cross their legs and tense their muscles aborted tilt-induced syncope, and had an apparent beneficial effect in those patients that routinely evoked this maneuver during daily life.  Even though a placebo-controlled trial is not feasible, it seems reasonable to instruct patients to use this maneuver.  Similarly, Schroeder et al. found that acute ingestion of 500  ml of water 15 minutes before tilt, significantly improved orthostatic tolerance, with increased peripheral vascular resistance, and blunting of the increase in heart rate and the decrease in stroke volume associated with head-up tilt.  Cerebral blood flow regulation also improved after water drinking.  This approach could be used in situations known to increase susceptibility to neurogenic syncope.
    Krediet CT, van Dijk N, Linzer Met al (2002) Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation 106:1684-1689.
    Schroeder C, Bush VE, Norcliffe LJ et al (2002) Water drinking acutely improves orthostatic tolerance in healthy subjects. Circulation 106:2806-2811.

 Measuring baroreflex function in mice
    Genetically modified mice can provide a powerful tool to investigate autonomic function, but autonomic measurements in small rodents are challenging.  Ma et al. characterized baroreflex and baroreceptors afferent functions in mice, and showed the expected sigmoidal relationship between changes in blood pressure baroreflex afferent activity measured at the aortic depressor nerve, and between blood pressure changes and renal sympathetic efferent nerve activity.  Nerve activity was measured directly using miniaturized bipolar electrodes.  These techniques can be used to evaluate baroreceptor afferent and baroreflex efferent function in mice models of cardiovascular disease.
    Ma X, Abboud FM, and Chapleau MW (2002) Analysis of afferent, central, and efferent components of the baroreceptor reflex in mice. Am J Physiol Regul Integr Comp Physiol 283:R1033-R1040.