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Research Highlights from the Literature

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2001; Volume 11(1) from Clinical Autonomic Research 
(Click on the reference to view the abstract)

The Streeten Syndrome revisited: A possible locus on chromosome 18q influencing postural systolic blood pressure changes is linked to a familial form of orthostatic intolerance originally described by David Streeten. 
    In a study of 498 hypertensive white sibling-pairs, using a genome-wide scan which included 387 autosomal short-tandem-repeat polymorphisms, linkage was found on chromosome 18q for the postural systolic blood pressure response.The marker that demonstrated the strongest linkage for the systolic blood pressure response (D18S858) lies within 20 centiMorgans of a marker previously linked to the rare familial orthostatic hypotensive syndrome (Am J Hum Gen 1998; 63:1425) originally reported by Streeten as familial hyperbradikininism (Lancet 1972; 2:1048). The eventual identification of the gene located in this region could improve our understanding of cardiovascular regulation in general, and orthostatic intolerance in particular.
(Pankow JS, et al. Hypertension 2000;36:471-476)

alpha-synuclein deposits and oxidative damage in Lewy body diseases.
    Alpha-synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. Antibodies to specific nitrated tyrosine residues revealed the selective and specific nitration of µ-synuclein in these disorders. These observations suggest that oxidative and nitrative damage of µ-synuclein plays a role in these neurodegenerative synucleinopathies 
(Giasson BI, et al. Science 2000; 290:985-9)

Overexpression of the alpha1B-adrenergic receptor results in a phenotype resembling multiple system atrophy
   
Transgenic mice overexpressing either the wild-type or constitutively active µ1B-adrenergic receptors showed granulovascular neurodegeneration in multiple brain regions and a parkinsonian-like, age-progressing hindlimb disorder.The authors speculate that this apoptotic neurodegeneration corresponds to the Shy-Drager syndrome.However, mice also had a grand mal seizure disorder, not characteristic of MSA.
(Zuscik MJ, et al. Nat.Med 2000; 6:1388-94)

Acute hypoglycemia induces transient autonomic failure.
    Five minutes of hypoglycemia in normal volunteers was enough to induce a blunting of the counterregulatory and sympathetic response to a second period of hypoglycemia induced 24 hours later.This transient autonomic impairment may explain the observation that diabetics with hypoglycemia are less protected to subsequent hypoglycemia (“hypoglycemia begets hypoglycemia”).
(Davis SN, et al. Diabetes 2000; 49:1897-903)

Overexpression of beta2-adrenergic receptors results in cardiomyopathy and heart failure phenotype
   
Transgenic (TG) mice overexpressing b2-adrenergic receptors had normal cardiac function, assessed by echocardiogram, until 6 months of age.Starting at 9 months, however, TG mice showed progressive reduction in fractional shortening and systolic wall thickening, and increase in left ventricular dimensions and left ventricular mass, indicating onset of heart failure, left ventricular hypertrophy and remodeling. Mortality due to heart failure was 81% by 15 months in TG mice vs. 4% in wild-type mice. The onset of heart failure was slower and the expression levels of receptors required are much higher than previously described for the b1-adrenergic receptor. Chronic and sustained overstimulation of b1- and µ2-adrenergic receptors may contribute to the development of cardiomyopathy.
(Du XJ, et al. Cardiovasc Res 2000;48:448-454).

Sympathetic abnormalities in obesity-related hypertension. 
    There is increasing interest about the role of the autonomic nervous system in the development of obesity-related hypertension. Direct measurements of sympathetic activity, using muscle sympathetic nerve activity (MSNA), were greater in a group of obese hypertensives (62±3 bursts/ 100 heart beats), compared to obese normotensive subjects (49±3 bursts/100 heart beats), lean hypertensive subjects (44±3 bursts/100 heart beats) and lean normotensive control subjects (32±2 bursts/100 heart beats). Furthermore, whereas in lean hypertensive subjects only baroreflex control of HR was impaired, in obese hypertensive subjects both HR and MSNA baroreflex changes were attenuated. These results suggest that increased sympathetic activity plays a role in the pathophysiology of obesity-related hypertension.
(Grassi G, et al. Hypertension 2000;36:538-542).

Positive isoproterenol tilt table testing does not co-segregate with the chronic fatigue syndrome in monozygotic twins.
   
It has been proposed that orthostatic intolerance and neuraly-mediated syncope contribute to the symptoms of chronic fatigue.This hypothesis was tesed in a cotwin control study of 21 monozygotic twins who were discordant for chronic fatigue syndrome.The goal was to determine if neurally-mediated syncope would co-segregate with CFS. A positive tilt table test result was observed in 4 twins with CFS (19%) and in 4 healthy twins (19%). This difference was not statistically significant (matched-pair odds ratio, 1.0; 95% confidence interval, 0.2- 5.4, P>.90). These results do not support a major role for neurally-mediated syncope in CFS.It should be noted, however, the relatively large incidence of neurally-mediated syncope in the healthy individuals in this study.
(Poole J, et al. Arch Intern Med 2000;160:3461-3468)

A case of Orthostatic Intolerance associated by an endogenous circulating sympatholytic factor.
A patient with orthostatic intolerance, tachycardia, hypotension and elevated plasma norepinephrine was found to be unresponsive to the pressor effects of a1-adrenergic receptor agonists.Her plasma contained a factor that acted as a selective and irreversible antagonists of a 1B-adrenergic receptors in vitro.The nature of this antagonist has not been defined, but this finding represents a novel pathophysiological mechanism of orthostatic intolerance.
(Shapiro RE, et al.Hypertension2000;36:553-560)

Is pacing useful in the management of syncope?
    The usefullness of cardiac pacing in the treatment of neurogenic syncope remains controversial.A recent study suggest that the effectiveness of syncope depends on the cardiovascular characteristics of the patients.A-V sequential pacing was successful in 13 of 17 patients with a predominant cardioinhibitory response to tilt, versus 5 of 14 patients with a mixed cardioinhibitory/vasodepressor response (P = 0.024). However, a successful response to A-V pacing was defined as a greater than or equal to 30-second increase between onset of symptoms and syncope, or mitigation of symptoms compared with the baseline tilt test. Future studies should consider the hemodynamic pattern of neurogenic syncope when assessing the usefulness of pacing in the tryeatment of this condition.Long-term follow-up and sham pacing would also be useful.
(Kurbaan AS, et al.Pace 2000; 23:1792-4)

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Davis SN, Mann S, Galassetti P et al. Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans. Diabetes 2000; 49: 1897-903.
Abstract: The aim of this study was to determine whether the duration of antecedent hypoglycemia regulates the magnitude of subsequent counterregulatory failure. A total of 31 lean healthy overnight-fasted individuals (16 men/15 women) were studied. There were 15 subjects (8 men/7 women) who underwent two separate 2-day randomized experiments separated by at least 2 months. On day 1, 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic (5.2 +/- 0.1 mmol/l) or hypoglycemic (2.9 +/- 0.1 mmol/l) glucose clamps (prolonged hypoglycemia) were carried out in the morning and afternoon. Of the other subjects, 16 participated in a 2-day study in which day 1 consisted of morning and afternoon short-duration hypoglycemia experiments (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 5 min), and 10 of these individuals underwent an additional 2-day study in which day 1 consisted of morning and afternoon intermediate-duration hypoglycemia (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 30 min). The next morning (day 2) all subjects underwent an additional 2-h hyperinsulinemic-hypoglycemic clamp (2.9 +/- 0.1 mmol/l). 
The rate of fall of glucose (0.07 mmol/min) was carefully controlled during all hypoglycemic studies so that the glucose nadir was reached at 30 min. Despite equivalent day 2 plasma glucose and insulin levels, there were significant differences in counterregulatory physiological responses. Steady-state epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels were similarly significantly blunted (P < 0.01) by the differing duration day 1 hypoglycemia compared with day 1 euglycemia. Muscle sympathetic nerve activity and endogenous glucose production were also similarly blunted (P < 0.01) by day 1 hypoglycemia (relative to day 1 euglycemia). Day 2 hypoglycemic symptoms were significantly reduced (P < 0.01) after day 1 prolonged intermediate- but not 
short-duration hypoglycemia. In summary, two episodes of short-duration moderate hypoglycemia can produce significant blunting of key neuroendocrine and metabolic counterregulatory responses. Hypoglycemic symptom scores are reduced by prolonged but not short-duration prior hypoglycemia. We conclude that in healthy overnight fasted humans, 1) neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses are sensitive to the blunting effects of even short-duration prior hypoglycemia, and 2) the duration of antecedent hypoglycemia results in a hierarchy of blunted physiological responses with hypoglycemic symptom awareness less vulnerable than neuroendocrine responses
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Du XJ, Gao XM, Wang BH, Jennings GL, Woodcock EA, Dart AM. Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing beta(2)-adrenergic receptors in the heart. Cardiovascular Research 2000; 48: 448-54.
Abstract: Objective: To explore long-term cardiac phenotype in transgenic (TG) mice with 300-fold overexpression of beta (2)-adrenergic receptors (AR). Methods: Echocardiography was performed serially on a cohort of wild-type and TG mice (n=26 each) between 4 and 15 months of age. Survival was monitored and autopsy and histological examinations were performed. Results: Heart rate was higher in TG than in wild-type mice throughout the study period. The left ventricular dimensions and fractional shortening were similar between TG and wild-type groups during 4-6 months. Starting at 9 months, however, TG mice showed progressive reduction in fractional shortening and systolic wall thickening, and increase in left ventricular dimensions and left ventricular mass, indicating onset of heart failure, left ventricular hypertrophy and remodeling. Abnormal waveforms in the electrocardigram and episodes of ventricular ectopic beats were also observed in TG mice. Death of TG mice started at 8.5 months, and the cumulative mortality was 81% by 15 months (P<0.0001 vs. 4% in wild-type mice). The majority of deaths were due to severe heart failure, indicated by cardiac dilatation, lung congestion, pleural effusion and atrial thrombus. Left ventricular sections showed widespread interstitial fibrosis, loss of myocytes and myocyte hypertrophy in TG mice. Conclusions: A high level of <beta>(2)AR overexpression results in cardiomyopathy and heart failure. The onset was slower and the expression levels of receptors required are much higher than previously described for the beta 
(1)AR overexpression. 
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Giasson BI, Duda JE, Murray IVJ et al. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000; 290: 985-9.
Abstract: Aggregated alpha -synuclein proteins form brain Lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha -synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha -synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha -synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha -synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies 
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Grassi G, Seravalle G, Dell'Oro R, Turri C, Bolla GB, Mancia G. Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension 2000; 36: 538-42.
Abstract: Previous studies have shown that essential hypertension and obesity are both characterized by sympathetic activation coupled with a baroreflex impairment. The present study was aimed at determining the effects of the concomitant presence of the 2 above-mentioned conditions on sympathetic activity as well as on baroreflex cardiovascular control. In 14 normotensive lean subjects (aged 33.5+/-2.2 years, body mass index 22.8+/-0.7 kg/m(2) [mean+/-SEM]), 16 normotensive obese subjects (body mass index 37.2+/-1.3 kg/m(2)), 13 lean hypertensive subjects (body mass index 24.0+/-0.8 kg/m(2)), and 16 obese hypertensive subjects (body mass index 37.5+/-1.3 kg/m(2)), all age-matched, we measured beat-to-beat arterial blood pressure (by Finapres device), heart rate (KR, by EGG), and postganglionic muscle sympathetic nerve activity (MSNA, by microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Blood pressure values were higher in lean hypertensive and obese hypertensive subjects than in normotensive lean and obese subjects. MSNA was significantly (P<0.01) greater in obese normotensive subjects (49.1+/-3.0 bursts per 100 heart beats) and in lean hypertensive subjects (44.5+/-3.3 bursts per 100 heart beats) than in lean normotensive control subjects (32.2+/-2.5 bursts per 100 heart beats); a further increase was detectable in individuals with the concomitant presence of obesity and hypertension (62.1+/-3.4 bursts per 100 heart beats). Furthermore, whereas in lean hypertensive subjects, only baroreflex control of HR was impaired, in obese normotensive subjects, both HR and MSNA baroreflex changes were attenuated, with a further attenuation being observed in obese hypertensive patients. Thus, the association between obesity and hypertension triggers a sympathetic activation and an impairment in baroreflex cardiovascular control that are greater in magnitude than those found in either of the above- mentioned abnormal conditions alone
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Kurbaan AS, Franzen AC, Heaven D et al. Cardioinhibition during tilt testing identifies patients who may benefit from pacing. Pace-Pacing and Clinical Electrophysiology 2000; 23: 1792-4.
Abstract: This study examined whether the various hemodynamic collapse patterns observed during tilt testing in patients with suspected neurocardiogenic syncope are relevant when planning therapy, particularly whether a predominantly cardioinhibitory response predicts a beneficial response from pacing. Methods: The effects of temporary atrioventricular (A-V) sequential pacing were studied during tilt testing in 34 patients 48.2 +/- 18.5 years of age. The patient population was divided into a cardioinhibitory group (VASlS classes 2A and 2B) or mixed group (VASIS classes 1 and 3) according to their response to baseline tilt testing. The test was then repeated during A-Vpacing with rate hysteresis. A positive response to A-V pacing was defined as a greater than or equal to 30-second increase between onset of symptoms and syncope, or mitigation of symptoms compared with the baseline tilt test. Results: The study protocol was not successfully completed in three patients. Among the remaining 31 patients, a baseline cardioinhibitory response was observed in 17, and a mixed response in 14 patients. A-V sequential pacing was successful in 13 of 17 patients with a cardioinhibitory response versus 5 of 14 patients with a mixed response (P = 0.024). Conclusion: The presence of a predominantly cardioinhibitory collapse pattern (VASIS 2A and 2B) during baseline tilt testing doubled the likelihood of successful temporary A-V sequential pacing, and may identify patients with neurocardiogenic syncope most likely to benefit from permanent dual chamber pacing
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Pankow JS, Rose KM, Oberman A et al. Possible locus on chromosome 18q influencing postural systolic blood pressure changes. Hypertension 2000; 36: 471-6.
Abstract: We conducted a genome-wide scan for quantitative trait loci influencing the systolic blood pressure, diastolic blood pressure, and pulse responses to a postural challenge in 498 white sibling-pairs from the Hypertension Genetic Epidemiology Network, a multicenter study of the genetic susceptibility to hypertension. 
All participants were hypertensive (systolic blood pressure greater than or equal to 140 mm Hg, diastolic blood pressure greater than or equal to 90 mm Hg, or on antihypertensive medications) with diagnosis before age 60. Blood pressure and pulse were measured by an oscillometric method after a 5-minute rest in a supine position and again immediately on standing. The genome scan included a total of 387 autosomal short-tandem-repeat polymorphisms typed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield, We used multipoint variance-components linkage analysis to identify possible quantitative trait loci influencing postural change phenotypes after adjusting for sex, age, and use of antihypertensive medications. There was suggestive evidence for linkage on chromosome 18q for the postural systolic blood pressure response (maximum logarithm of the odds score=2.6 at 80 centiMorgans). We also observed a maximum logarithm of the odds score of 1.9 for the systolic blood pressure response and 1.7 for the diastolic blood pressure response on chromosome 6p, The marker that demonstrated the strongest evidence for linkage for the systolic blood pressure response (D18S858) lies within 20 centiMorgans of a marker previously linked to rare familial orthostatic hypotensive syndrome. Our findings indicate that there may be 1 or more genes on chromosome 18q that regulate systolic blood pressure during the physiological recovery period after a postural stressor
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Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Archives of Internal Medicine 2000; 160: 3461-8.
Abstract: Background: The pathogenesis of chronic fatigue syndrome (CFS) is unknown. Neurally mediated hypotension (NMH) has been suggested as a common comorbid condition or a potential underlying cause. Methods: We conducted a cotwin control study of 21 monozygotic twins who were discordant for CFS. One twin met the 1994 Centers for Disease Control and Prevention criteria for CFS, and the other twin was healthy and denied chronic fatigue. The twins were selected from a volunteer twin registry in which at least 1 member reported persistent fatigue. As part of a 7-day clinical evaluation, all 21 twin pairs were evaluated with a 3-stage tilt table test with isoproterenol hydrochloride for the assessment of NMH. The presence of NMH was defined as syncope or presyncope associated with a decrease of 25 mm Hg in blood pressure and no associated increase in heart rate. Results: A positive tilt table test result was observed in 4 twins with CFS (19%) and in 4 healthy twins (19%). This difference was not statistically significant (matched-pair odds ratio, 1.0; 95% confidence interval, 0.2- 5.4, P>.90). Compared with the healthy twins, the twins with CFS reported more severe symptoms of CFS and NMH both in the week before and during the tilt table test. Conclusions: These results do not support a major role for NMH in CFS. They highlight the importance of selecting well-matched control subjects, as well as the unique value of  the monozygotic cotwin control design in the study of this illness
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Shapiro RE, Winters B, Hales M et al. Endogenous circulating sympatholytic factor in orthostatic intolerance. Hypertension 2000; 36: 553-60.
Abstract: Sympathotonic orthostatic hypotension (SOH) is an idiopathic syndrome characterized by tachycardia, hypotension, elevated plasma norepinephrine, and symptoms of orthostatic intolerance provoked by assumption of an upright posture. We studied a woman with severe progressive SOH with blood pressure unresponsive to the presser effects of alpha (1)-adrenergic receptor (AR) agonists, We tested the hypothesis that a circulating factor in this patient interferes with vascular adrenergic neurotransmission. Preincubation of porcine pulmonary artery vessel rings with patient plasma produced a dose-dependent inhibition of vasoconstriction to phenylephrine in vitro, abolished vasoconstriction to direct electrical stimulation, and had no effect on nonadrenergic vasoconstrictive stimuli 
(endothelin-1), PGF-2 alpha (or KCl), Preincubation of vessels with control plasma was devoid of these effects. SOH plasma inhibited the binding of an alpha (1)-selective antagonist radioligand ([I-125]HEAT) to membrane fractions derived from porcine pulmonary artery vessel rings, rat liver, and cell lines selectively overexpressing human ARs of the alpha (1B) subtype but not other AR subtypes (alpha (1A) and alpha (1D)), We conclude that a factor in SOH plasma can selectively and irreversibly inhibit adrenergic ligand binding to alpha (1B) ARs, We propose that this factor contributes to a novel pathogenesis for SOH in this patient. This patient's syndrome represents a new disease entity, and her plasma may provide a unique tool for probing the selective functions of alpha (1)-ARs
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Zuscik MJ, Sands S, Ross SA et al. Overexpression of the alpha1B-adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy. Nat.Med. 2000; 6: 1388-94.
Abstract: Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor 
impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown
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