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Research Highlights from the Literature

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2003; Volume 13(3) from Clinical Autonomic Research                                           
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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.