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2001; Volume 11(4) from Clinical Autonomic Research                                           
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Is history of limited value in the evaluation of patients with syncope?
            The prognosis of patients with syncope of cardiac origin is substantially worse than those with non-cardiac causes.  It is important, therefore, to determine cardiac causes of syncope as early in the evaluation of patients as possible.  In this study of 341 adult patients with syncope, patients with cardiac syncope were older (72±13 years, n=78) compared to neurally mediated syncope (59±21, n=199) or to patients with unexplained syncope (55±21, n=60).  Neurally mediated syncope was frequently "situational" (e.g., in crowded places, after prolonged standing, post-prandial).  The absence of prodromal symptoms was observed in both cardiac syncope and neurally mediated syncope, and therefore is not useful in differentiating between these disorders.  Similarly, "autonomic" symptoms and signs, such as nausea, vomiting before the loss of consciousness, pallor, lightheadedness and yawning, commonly believed to indicate neurally mediated syncope, were observed also in patients with cardiac syncope.  These observations suggest that activation of the autonomic nervous system occurs in all types of syncope, and their occurrence is not helpful in differentiating between the different causes of syncope.  Multiple episodes (>=3) were more frequent in patients with neurally mediated syncope.  Clinical evidence of heart disease is a strong predictor of cardiac syncope.  Even though this study found that only few historical findings have statistical value in predicting causes of syncope, clinical skills remain crucial in the evaluations of these patients.
Alboni P, Brignole M, Menozzi C, et al. Diagnostic value of history in patients with syncope with or without heart disease.  J Am Coll Cardiol 2001;37:1921-1928..

Utility of long-term heart rate monitoring with implantable loop recorders in the evaluation of syncope
  The cause of syncope remains undiagnosed in a substantial proportion of patients despite exhaustive evaluation.  In this study, the authors randomized 60 patients with unexplained syncope into conventional evaluation (heart rate event monitoring with external loop recorders, tilt and electrophysiological studies) or prolonged heart rate monitoring with an implantable loop recorder. Patients with obvious heart disease or neurogenic syncope were excluded from this study.  In this selected patient population, prolonged monitoring with an implantable loop recorder was more likely to result in a diagnosis than was conventional testing (55% versus 19%).  The most common diagnosis was bradycardia and these patients were frequently treated with a pacemaker.  Heart rate event monitors, however, cannot distinguish bradycardias resulting from intrinsic cardiac conduction abnormalities or from neurocardiogenic syncope.  At least one patient in this series had recurrent syncope after pacemaker implantation, suggesting  unrecognized neurally-mediated syncope.
Krahn AD, Klein GJ, Yee R, Skanes AC. Randomized assessment of syncope trial : conventional diagnostic testing versus a prolonged monitoring strategy.  Circulation 2001;104:46-51.

Cardiac pacing in the treatment of cardioinhibitory neurally mediated syncopes
            This study compares pharmacologic treatment with atenolol (100 mg/d) to pacing using a dual-chamber pacemaker with rate-drop response.  No placebo group was included.  The study was performed in 14 centers throughout a 3 year period.  Patients (n=93) with >3 episodes of syncope in the past 2 years were enrolled if other causes of syncope were excluded and if they had a positive response to tilt table testing in association with relative bradycardia (heart rate <60 bpm).  The primary outcome was recurrence of syncope.  The study was suspended because an interim analysis revealed beneficial effects of pacing.  Recurrence of syncope occurred in 2 patients (4%) in the pacing arm after a median of 390 days, versus 12 patients (26%) in the atenolol arm after a median of 135 days.  In conclusion, cardiac pacing was significantly more effective compared to beta-blockers in patients with the cardioinhibitory type of neurally mediated syncope.  Potential limitations of this study should be noted.  Arguably, pharmacological alternatives to beta-blockers may be preferred in patients with cardioinhibitory syncope.  Despite this, over 60% of patients remained syncope-free in the atenolol group. By its nature, the study could not be blinded.  A placebo effect associated with surgical implantation of a pacemaker could be best excluded in a cross-over design study where the pacemaker is blindly deactivated.  Selection bias could explain why patients included in this study that consented to be randomized to pacemaker implantation were older (61±13 years) and had multiple previous syncopal episodes (median of 8, range 3-80).  This is not necessarily a limitation of the study, but highlights the wisdom of reserving pacing as a treatment option for patients with disabling recurrent syncope.
Ammirati F, Colivicchi F, and Santini M, for the Syncope Diagnosis and Treatment Study Investigators.  Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope : a multicenter, randomized, controlled trial.  Circulation 2001;104:52-57.

Endothelin-1 (ET-1) contributes to sympathetic activation in an animal model of heart failure
ET-1 is a 26-amino acid peptide with potent vasoactive properties.  It is produced by vascular endothelial cells and other tissues including neural tissue.  ET-1 is elevated in patients with chronic heart failure (CHF), plasma concentrations correlate with the severity of the disease, and ET-1 antagonists are beneficial in the treatment of experimental CHF.  Previous studies have suggested that treatment with ET-1 antagonists is associated with a decrease in plasma norepinephrine levels.  To determine if this effect is mediated centrally, the effects of ET-1 antagonists on sympathetic outflow was determined in chronically instrumented, awake rabbits with pacing-induced heart failure and compared to those observed in control animals.  CHF animals had similar heart rate and blood pressure compared to control animals, but had increased renal sympathetic nerve activity.  Infusion by minipump of the combined ETA and ETB receptor antagonist L-754,142, or of the specific ETA antagonist BQ-123 resulted in a decrease in blood pressure and in renal sympathetic nerve activity, and an increase in baroreflex sensitivity in CHF animals.  In contrast, no effect was observed in control animals.  Therefore, blockade of ET-1 receptors may be beneficial in CHF in part by decreasing central nervous system outflow of sympathetic activity.
Liu JL, Pliquett RU, Brewer E,  et. al., Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure.  Am J Physiol 2001;280:R1906-R-1913.

Central mechanisms of glucocorticoid-induced hypertension mediated by the renin-angiotensin system
        It is believed that glucocorticoids participates in the pathogenesis of essential hypertension.  Several mechanisms have been proposed, including the potentiation of the peripheral actions of adrenergic agonists and angiotensin II.  It is also possible that glucocorticoids interact centrally with angiotensin mechanisms.  To test this hypothesis these investigators implanted a corticosterone pellet subcutaneously in chronically-instrumented awake rats and increased plasma corticosterone concentrations approximately two-fold.  Glucocorticoids increased mean arterial blood pressure slightly (119±2 vs. 107±1 mm Hg in control rats).  Intravenous phenylephrine or angiotensin II produced the same increase in blood pressure in corticosterone-treated rats compared to control rats.  In contrast, the increase in blood pressure produced by central (intracerebroventrical) administration of angiotensin II was greater in corticosterone-treated rats.  Similarly, central administration of AT1 angiotensin receptor antagonists lowered blood pressure in corticosterone-treated rats but not in control rats.  These results indicate that corticosteroids act centrally to enhance angiotensin-mediated hypertension.
Scheuer DA, Bechtold AG.  Glucocorticoids potentiate central actions of angiotensin to increase arterial pressure.  Am J Physiol 2001;280:R1717-R-1726.

Exercise increases the risk of subsequent hypoglycemia by producing transient “autonomic failure”, a phenomenon mediated by cortisol
Hypoglycemia is normally restrained by counterregulatory systems that include sympathetic adrenergic activation.  This sympathetic activation, however, is impaired during subsequent hypoglycemic episodes (see Autonomic News, Clinical Autonomic Research 2001;11:1).  This transient autonomic impairment is thought to be mediated by the increase in plasma cortisol produced during the antecedent hypoglycemia (see Davis SN, et al. J Clin Invest 1997;100:429-438).   Exercise increases epinephrine and cortisol to concentrations similar to those seen in hypoglycemia.  Therefore, the authors tested the hypothesis that exercise also impairs counterregulatory responses to subsequent hypoglycemia.  Two 90-minute periods of cycle exercise (50% maximal O2 uptake, one in the morning one in the afternoon) were performed on day one, and controlled hypoglycemia was performed the next day.  Antecedent exercise significantly blunted the increase in plasma epinephrine (-37±6%), muscle sympathetic nerve activity (-90±8%), pancreatic polypeptide (-47±4%), glucagon (-60±4%) and growth hormone (-61±5%) produced during subsequent hypoglycemia.
Galassetti,P.; Mann,S.; Tate,D., et. al. Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia.  Am J Physiol 2001;280:E908-E917.

Progression of dysarthria and dysphagia: clinical signs of multiple system atrophy
            Parkinson syndromes are commonly associated with dysarthria and dysphagia.  The progression of these symptoms was evaluated in patients with autopsy-proven cases of Parkinson disease (PD, n=17), or "atypical parkinson disorders” such as dementia with Lewy bodies (14), corticobasal degeneration (13), multiple system atrophy (MSA, 15), and progressive supranuclear palsy (24). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (specificity, 100%) but failed to distinguish between them.  Once its presence was established, it was a poor prognostic sign, regardless of the diagnosis.  Survival time after onset of dysphagia was similar in Parkinson disease, MSA, and progressive supranuclear palsy (15-24 months).
Muller,J.; Wenning,G.K.; Verny,M., et al. Progression of Dysarthria and Dysphagia in Postmortem-Confirmed Parkinsonian Disorders.  Arch Neurol 2001; 58:259-64

Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M et al. Diagnostic value of history in patients with syncope with or without heart disease. Journal of the American College of Cardiology, 37(7):1921-8. 2001.
Abstract: OBJECTIVES: We sought to establish what historical findings are predictive of the cause of syncope. BACKGROUND: The clinical features of the various types of syncope have not been systematically investigated. METHODS: Three hundred forty-one patients with syncope were prospectively evaluated. Each patient was interviewed using a standard questionnaire. A cause of syncope was assigned using standardized diagnostic criteria. RESULTS: A cardiac cause of syncope was established in 23% of the patients, a neurally mediated cause in 58% and a neurologic or psychiatric cause in 1%, and in the remaining 18%, the cause of syncope remained unexplained. In a preliminary analysis including age, gender and the presence of suspected or certain heart disease after the initial evaluation, only heart disease was an independent predictor of a cardiac cause of syncope (odds ratio 16, p = 0.00001), with a sensitivity of 95% and a specificity of 45%. In contrast, the absence of heart disease allowed us to exclude a cardiac cause of syncope in 97% of the patients. In patients with certain or suspected heart disease, the most specific predictors of a cardiac cause were syncope in the supine position or during effort, blurred vision and convulsive syncope. Significant and specific predictors of a neurally mediated cause were time between the first and last syncopal episode >4 years, abdominal discomfort before the loss of consciousness and nausea and diaphoresis during the recovery phase. In the patients without heart disease, palpitation was the only significant predictor of a cardiac cause. CONCLUSIONS: The presence of suspected or certain heart disease after the initial evaluation is a strong predictor of a cardiac cause of syncope. A few historical findings are useful to predict cardiac and neurally mediated syncope in patients with and without heart disease.

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Krahn AD, Klein GJ, Yee R, Skanes AC. Randomized assessment of syncope trial : conventional diagnostic testing versus a prolonged monitoring strategy. Circulation, 104(1):46-51. 2001.
Abstract: BACKGROUND: Establishing a diagnosis in patients with unexplained syncope is complicated by infrequent and unpredictable events. Prolonged monitoring may be an alternative strategy to conventional testing with short-term monitoring and provocative tilt and electrophysiological testing. Methods and Results-Sixty patients (aged 66+/-14 years, 33 male) with unexplained syncope were randomized to "conventional" testing with an external loop recorder and tilt and electrophysiological testing or to prolonged monitoring with an implantable loop recorder with 1 year of monitoring. If patients remained undiagnosed after their assigned strategy, they were offered crossover to the alternate strategy. A diagnosis was obtained in 14 of 27 patients randomized to prolonged monitoring compared with 6 of 30 patients undergoing conventional testing (52% versus 20%, P=0.012). Crossover was associated with a diagnosis in 1 of 6 patients undergoing conventional testing compared with 8 of 13 patients who completed monitoring (17% versus 62%, P=0.069). Overall, prolonged monitoring was more likely to result in a diagnosis than was conventional testing (55% versus 19%, P=0.0014). Bradycardia was detected in 14 patients undergoing monitoring compared with 3 patients undergoing conventional testing (40% versus 8%, P=0.005). CONCLUSIONS: A prolonged monitoring strategy is more likely to provide a diagnosis than conventional testing in patients with unexplained syncope. Consideration should be given to earlier implementation of a monitoring strategy

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Ammirati F, Colivicchi F, Santini M. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope : a multicenter, randomized, controlled trial. Circulation, 104(1):52-7. 2001.
Abstract: BACKGROUND:This clinical investigation was performed to compare the effects of permanent dual-chamber cardiac pacing with pharmacological therapy in patients with recurrent vasovagal syncope. Methods and Results-Patients from 14 centers were randomized to receive either a DDD pacemaker provided with rate-drop response function or the beta-blocker atenolol at the dosage of 100 mg once a day. Inclusion criteria were age >35 years, >/=3 syncopal spells in the preceding 2 years, and positive response to tilt table testing with syncope occurring in association with relative bradycardia. The primary outcome was the first recurrence of syncope after randomization. Enrollment was started in December 1997, and the first formal interim analysis was performed on July 30, 2000. By that time, 93 patients (38 men and 55 women; mean age, 58.1+/-14.3 years) had been enrolled and randomized, although follow-up data were available for all patients (46 patients in the pacemaker arm, 47 patients in the pharmacological arm). The interim analysis showed a significant effect in favor of permanent cardiac pacing (recurrence of syncope in 2 patients [4.3%] after a median of 390 days) compared with medical treatment (recurrence of syncope in 12 patients [25.5%] after a median of 135 days; OR, 0.133; 95% CI, 0.028 to 0.632; P=0.004). Consequently, enrollment and follow-up were terminated. CONCLUSIONS:DDD pacing with rate-drop response function is more effective than beta-blockade for the prevention of syncopal recurrences in highly symptomatic vasovagal fainters with relative bradycardia during tilt-induced syncope.
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Liu JL, Pliquett RU, Brewer E, Cornish KG, Shen YT, Zucker IH. Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure. American Journal of Physiology-Regulatory Integrative and Comparative Physiology. 2001;280:R1906-R1913.
Abstract: Endothelin-1 (ET-1) is elevated in chronic heart failure (CHF). In this study, we determined the effects of chronic ET-1 blockade on renal sympathetic nerve activity (RSNA) in conscious rabbits with pacing-induced CHF. Rabbits were chronically paced at 320-340 beats/min for 3-4 wk until clinical and hemodynamic signs of CHF were present. Resting RSNA and arterial baroreflex control of RSNA were determined. Responses were determined before and after the ET-1 antagonist L-754,142 (a combined ETA and ETB receptor antagonist, n = 5) was administered by osmotic minipump infusion (0.5 1).h(-1) for 48 h). In addition, five rabbits with CHF were treated with the specific ETA receptor antagonist BQ-123. Baseline RSNA (expressed as a percentage of the maximum nerve activity during sodium nitroprusside infusion) was significantly higher (58.3 +/- 4.9 vs. 27.0 +/- 1.0, P < 0.001), whereas baroreflex sensitivity was significantly lower in rabbits with CHF compared with control (3.09 +/- 0.19 vs. 6.04 +/- 0.73, P < 0.001). L-754,142 caused a time-dependent reduction in arterial pressure and RSNA in rabbits with CHF. In addition, BQ-123 caused a reduction in resting RSNA. For both compounds, RSNA returned to near control levels 24 h after removal of the minipump. These data suggest that ET-1 contributes to sympathoexcitation in the CHF state. Enhancement of arterial baroreflex sensitivity may further contribute to sympathoinhibition after ET-1 blockade in heart failure.

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Scheuer DA, Bechtold AG. Glucocorticoids potentiate central actions of angiotensin to increase arterial pressure. American Journal of Physiology-Regulatory Integrative and Comparative Physiology. 2001;280:R1719-R1726.
Abstract: Experiments were performed to determine if glucocorticoids potentiate central hypertensive actions of ANG II. Male Sprague-Dawley rats were treated for 3 days to 3 wk with corticosterone (Cort). Experiments were performed in conscious rats that had previously been instrumented with arterial and venous catheters and an intracerebroventricular guide cannula in a lateral ventricle. Baseline arterial pressure (AP) was greater in Cort-treated rats than in control rats (119 +/- 2 vs. 107 +/- 1 mmHg, P< 0.01). Microinjection of ANG II intracerebroventricularly produced a significantly larger increase in AP in Cort-treated rats than in control rats. For example, at 30 ng ANG II, AP increased by 23 +/- 1 and 16 +/- 2 mmHg in Cort-treated and control rats, respectively (P< 0.01). Microinjection of an angiotensin type 1 receptor antagonist significantly decreased AP (-6 +/- 2 mmHg) and heart rate (-26 +/- 7 beats/min) in Cort-treated but not control rats. Increases in AP produced by intravenous administration of ANG II were not different between control and Cort-treated rats. Intravenous injections of ANG II antagonist had no significant effects on mean AP or heart rate in control or Cort-treated rats. Therefore, a sustained increase in plasma Cort augments the central pressor effects of ANG II without altering the pressor response to peripheral administration of the hormone.
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Galassetti P, Mann S, Tate D, Neill RA, Costa F, Wasserman DH et al. Effects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia. Am J Physiol Endocrinol Metab. 2001;280:E908-E917.
Abstract: In the present study the hypothesis tested was that prior exercise may blunt counterregulatory responses to subsequent hypoglycemia. Healthy subjects [15 females (f)/15 males (m), age 27 +/- 1 yr, body mass index 22 +/- 1 kg/m(2), hemoglobin A(Ic) 5.6 +/- 0.5%] were studied during 2-day experiments. Day 1 involved either 90-min morning and afternoon cycle exercise at 50% maximal O2 uptake (VO2(max)) (priorEXE, n = 16, 8 m/8 f) or equivalent rest periods (priorREST, n = 14, 7 m/7 f). Day 2 consisted of a 2-h hypoglycemic clamp in all subjects. Endogenous glucose production (EGP) was measured using [3-3H]glucose. Muscle sympathetic nerve activity (MSNA) was measured using microneurography. Day 2 insulin (87 +/- 6 microU/ml) and plasma glucose levels (54 +/- 2 mg/dl) were equivalent after priorEXE and priorREST. Significant blunting (P < 0.01) of day 2 norepinephrine (-30 +/- 4%), epinephrine (-37 +/- 6%), glucagon (-60 +/- 4%), growth hormone (-61 +/- 5%), pancreatic polypeptide (-47 +/- 4%), and MSNA (-90 +/- 8%) responses to hypoglycemia occurred after priorEXE vs. priorREST. EGP during day 2 hypoglycemia was also suppressed significantly (P < 0.01) after priorEXE compared with priorREST. In summary, two bouts of exercise (90 min at 50% VO2(max)) significantly reduced glucagon, catecholamines, growth hormone, pancreatic polypeptide, and EGP responses to subsequent hypoglycemia. We conclude that, in normal humans, antecedent prolonged moderate exercise blunts neuroendocrine and metabolic counterregulatory responses to subsequent hypoglycemia

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Muller J, Wenning GK, Verny M, McKee A, Chaudhuri KR, Jellinger K et al. Progression of Dysarthria and Dysphagia in Postmortem-Confirmed Parkinsonian Disorders. Arch Neurol. 2001;58:259-64.
Abstract: BACKGROUND: Dysarthria and dysphagia are known to occur in parkinsonian syndromes such as Parkinson disease (PD), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Differences in the evolution of these symptoms have not been studied systematically in postmortem-confirmed cases. OBJECTIVE: To study differences in the evolution of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders. PATIENTS AND METHODS: Eighty-three pathologically confirmed cases (PD, n = 17; MSA, n = 15; DLB, n = 14; PSP, n = 24; and CBD, n = 13) formed the basis for a multicenter clinicopathological study organized by the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Cases with enough clinicopathological documentation for the purpose of the study were selected from research and neuropathological files of 7 medical centers in 4 countries (Austria, France, England, and the United States). RESULTS: Median dysarthria latencies were short in PSP and MSA (24 months each), intermediate in CBD and DLB (40 and 42 months), and long in PD (84 months). Median dysphagia latencies were intermediate in PSP (42 months), DLB (43 months), CBD (64 months), and MSA (67 months), and long in PD (130 months). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (APDs) (specificity, 100%) but failed to further distinguish among the APDs. Survival time after onset of a complaint of dysphagia was similar in PD, MSA, and PSP (15 to 24 months, P =.7) and latency to a complaint of dysphagia was highly correlated with total survival time (rho = 0.88; P<.001) in all disorders. CONCLUSIONS: Latency to onset of dysarthria and dysphagia clearly differentiated PD from the APDs, but did not help distinguish different APDs. Survival after onset of dysphagia was similarly poor among all parkinsonian disorders. Evaluation and adequate treatment of patients with PD who complain of dysphagia might prevent or delay complications such as aspiration pneumonia, which in turn may improve quality of life and increase survival time.
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