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2002; Volume 12(3) from Clinical Autonomic Research                                           
Send comments or suggestions about Autonomic News to: italo.biaggioni@mcmail.vanderbilt.edu

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Autonomic Clocks  <<
       
Many physiological processes modulated by the autonomic nervous system are characterized by their periodicity.  Spectral analysis of heart rate and blood pressure, for example, are based on their relatively brief oscillations, presumably reflecting periodicity arising from pacemaker neurons located in brainstem autonomic centers.  A longer rhythm characterizes circadian clocks.  It has long been known that neurons in the suprachiasmatic nucleus (SCN) transmit circadian output to other brain areas by diurnal modulation of their spontaneous discharge frequency.  The molecular mechanisms that modulate the diurnal periodicity of SCN neurons were explored by Pennartz et al in rat brain slices.  They demonstrated a diurnal modulation of calcium current in SCN neurons.  This current strongly contributes to the generation of spontaneous oscillations in membrane potential, which occur selectively during daytime.  They proposed that this diurnal modulation of calcium current determines the periodic firing rate of SCN neurons.
        Sympathetic activity also has an important diurnal variation; plasma norepinephrine and blood pressure, reach a nadir during the night and a peak early in the morning, a phenomenon that could explain the higher incidence of stroke and cardiac events at that time of day.  The nocturnal decrease in blood pressure is partially loss in a subset of patients with essential hypertension (“non-dippers”).  Sherwood et al found that, compared to 116 dippers, the 56 non-dippers were more likely to be black and to have a family history of hypertension as well as higher body mass index.  The physiological decrease in nighttime norepinephrine excretion was reduced in non-dippers, who also had a heighten response to alpha agonists.  These results suggest that the circadian sympathetic clock is altered in these patients. 
        Patients with autonomic failure are the ultimate non-dippers, inasmuch as their supine blood pressure tends to be as high or higher during the night than during the day.  The resultant nocturnal pressure diuresis leads to worsening of orthostatic hypotension in the morning.  Omboni et al confirmed these earlier findings and showed profound orthostatic decreases in stroke volume in the morning of patients with neuropathic orthostatic hypotension. They suggest that, in addition to nocturnal polyuria, redistribution of fluid into the interstitium also contributes to the nocturnal loss of effective intravascular volume.
        Hirshoren et al explored periodicity of autonomic function in another biological clock, the menstrual cycle.  This comprehensive study monitored various autonomic parameters and fluid hormones throughout the menstrual cycle.  They found, e.g., that plasma norepinephrine decreased from the early to the late follicular phase.  The cardiac baroreflex sensitivity, obtained by spectral analysis, increased significantly along the luteal phase.  Heart rate sensitivity to isoproterenol decreased during the late luteal phase.  Of interest, blood pressure and heart rate remained unchanged throughout the menstrual cycle, either in the supine position or in responses to orthostatic stress.
        Pennartz CM, de Jeu MT, Bos NP, Schaap J, Geurtsen AM (2002). Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 416:286-290.
        Sherwood A, Steffen PR, Blumenthal JA, Kuhn C, Hinderliter AL (2002). Nighttime blood pressure dipping: the role of the sympathetic nervous system. Am J Hypertens 15:111-118.
        Omboni S, Smit AA, van Lieshout JJ, Settels JJ, Langewouters GJ, Wieling W (2001). Mechanisms underlying the impairment in orthostatic tolerance after nocturnal recumbency in patients with autonomic failure. Clin Sci 101:609-618.
        Hirshoren N, Tzoran I, Makrienko I et al (2002). Menstrual cycle effects on the neurohumoral and autonomic nervous systems regulating the cardiovascular system. J Clin Endocrinol Metab 87:1569-1575.

Genetics of Autonomic Disorders <<
       
We have seen exponential progress in molecular biology techniques needed for the identification of genetic disorders.  Familial dysautonomia is now known to be due to mutations in the I-kappaB kinase-associated protein (IBKAP).  It is not yet know, however, how this gene defect results in the sensory and autonomic neuropathy that characterizes this syndrome, and an animal model would be useful for this purpose.  Cuajangco et al report the cloning and genomic characterization of the mouse homologue of the IKBKAP gene.  The gene contains 37 exons that span approximately 51 kb.  Like its human counterpart, the mouse gene encodes a protein of 1332 amino acids  and a molecular weight of 150 kDa.  It shows 80% amino acid identity with the human IKAP.  The discovery of this mouse gene will help in the development of an animal model of familial dysautonomia. 
        Deficiency of dopamine-beta-hydroxylase (DBH), the enzyme that converts dopamine into norepinephrine, was the first congenital defect of catecholamine metabolism described, on the basis of clinical and biochemical characteristics (undetectable circulating levels of norepinephrine, epinephrine and their metabolites, elevated levels of dopamine, and undetectable serum DBH). Kim et al identified seven novel variants of the human DBH gene, including four potentially pathogenic mutations, in two unrelated patients and their families. Both patients were compound heterozygotes for variants affecting expression of the DBH protein. Each patient carried one copy of a T/C transversion in intron 1, creating a premature stop codon. In addition, a missense mutation in exon 2 was identified in patient 1, and missense mutations in exons 1 and 6 were identified in patient 2.  Thus, NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH.
        Hereditary paragangliomas are tumors of the autonomic nervous system that often arise in cervical autonomic ganglia and are usually functionally silent.  However, tumors may be bilateral, may recur, and their growth may require surgical removal, leading to iatrogenic baroreflex failure due to surgical trauma of the carotid sinus nerves.  Abnormalities in three genes (SDHD, SDHC, and SDHB), which encode three protein subunits of cytochrome b of complex II in the mitochondrial respiratory chain, are responsible for this disorder.  Gimenez-Roqueplo et al studied a family in which the father and two sons had multiple paragangliomas.  A nonsense mutation (R22X) in the SDHD gene was found in these three affected subjects. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor but not in peripheral leukocytes. A selective loss of complex II enzymatic activity was found in tissue of affected patients, but not in six sporadic tumors.  In situ hybridization, immunohistochemistry experiments and mRNA quantitation showed high level of expression of the angiogenic factors vascular endothelial growth factor (VEGF) and endothelial PAS domain protein 1 in herediary paraganglioma compared to sporadic tumors.  Thus, inactivation of the SDHD gene in hereditary paraganglioma was associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors. It is proposed that these abnormalities lead to tumorogenesis.   
        Cuajungco MP, Leyne M, Mull J, Gill SP, Gusella JF, Slaugenhaupt SA (2001). Cloning, characterization, and genomic structure of the mouse Ikbkap gene. DNA Cell Biol 20:579-586.
        Kim CH, Zabetian CP, Cubells JF et al (2002). Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. Am J Med Genet 108:140-147.
        Gimenez-Roqueplo AP, Favier J, Rustin P et al (2001). The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 69:1186-1197.

Electrical Stimulation of Cardiac Parasympathetic Nerves in Humans  <<
        Schauerte et al report the use of an intravascular catheter inserted into the superior vena cava or the coronary sinus to produce electric stimulation of cardiac parasympathetic nerves adjacent these vascular structures.  Catheter stimulation in the coronary sinus was more effective in producing selective cardiac parasympathetic stimulation, resulting in bradycardia and AV block.  The authors speculate that this procedure may be useful in slowing ventricular rate in patients with atrial fibrillation in whom pharmacological approaches may be contraindicated because of the negative inotropic effects of drugs used to control heart rate.  Cardiac parasympathetic activation may also be useful as a diagnostic tool during electrophysiological studies.  Electrical stimulation, however, also stimulates vagal afferents leading to chest discomfort and pain.  It is unlikely, therefore, that this procedure can be used as long-term therapy.  In the current proof-of-concept study, electrical stimulation was applied for a few seconds only, and the safety of longer-term stimulation in humans is not known.  
        Schauerte P, Mischke K, Plisiene J et al (2001). Catheter stimulation of cardiac parasympathetic nerves in humans: a novel approach to the cardiac autonomic nervous system. Circulation 104:2430-2435.

 Sympathetic Nervous System Activity and Cardiac Hypertrophy.  The Good, the Bad, and the Uncertain  <<
       
Cardiac hypertrophy may result from a physiological process in “athelete’s heart” or as a pathological process in hypertension.  Eccentric hypertrophy occurs predominantly in endurance athletes (e.g., runners, swimmers) as a result of a volume-loading effect, whereas concentric hypertrophy is seen in athletes performing isometric exercises (e.g., weight lifters) resulting in a pressure-loading effect, and in hypertension.  Neri Serneri et al, compared a group of Italian soccer players with sedentary controls matched for variables known to affect sympathetic activity, including age and body mass index.  They found that endurance athletes had increased cardiac production (cardiac AV gradient) of insulin-like growth factor (but not of endothelin-I or angiotensin II) than controls.  Athletes also had greater cardiac norepinephrine spillover, but similar whole body norepinephrine spillover, compared to controls.  They speculate that both factors contribute to the “physiological” cardiac hypertrophy that develops in athletes.  The increase in cardiac sympathetic activity is, in a way, paradoxical, because it is generally believed that athletes also have increase cardiac parasympathetic tone.
        Greenwood et al, measured muscle sympathetic nerve activity, as a surrogate indicator for cardiac sympathetic tone, in patients with essential hypertension with or without left ventricular hypertrophy.  They were able to measure single unit impulses in these patients, and found increased muscle sympathetic nerve activity in those patients with ventricular hypertrophy.  There was, however, significant overlap between groups and differences were significant only if sympathetic activity was corrected for heart rate. 
        These association studies do not proof causality, but suggest that the increased sympathetic tone leads to compensatory ventricular hypertrophy as a way to maintain cardiac function.  Once heart failure ensues, however, there is substantial evidence that sympathetic activity is detrimental.  It is now clear that blockade of beta adrenergic receptors is beneficial in dilated cardiomyopathy.  Lowes et al, report changes in cardiac gene expression in 26 patients who responded to beta-blockers with improved cardiac function (defined as an increase in left ventricular ejection fraction of at least 5 units) compared to those who did not improve on this treatment (6 patients).  Those who responded had an increase in mRNA levels (from right side ventricular septum biopsies) of sarcoplasmic reticulum calcium ATPase and alpha-myosin heavy chain, and a decrease in beta-myosin heavy chain. Some of these changes were not seen in patients who improved spontaneously on placebo.  No differences were found between patients on metoprolol (selective beta1-blocker) compared to carvedilol (combined beta1-, beta2- and alpha1-blocker), suggesting that blockade of beta1 receptors is sufficient to observe a beneficial effect.  There were no significant changes in blood pressure between groups, suggesting that changes in gene expression were not due to differences in cardiac work load.
        Neri Serneri GG, Boddi M, Modesti PA et al (2001). Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes. Circ Res 89:977-982.
        Greenwood JP, Scott EM, Stoker JB, Mary DA (2001). Hypertensive left ventricular hypertrophy: relation to peripheral sympathetic drive. J Amer Coll Cardiol 38:1711-1717.
        Lowes BD, Gilbert EM, Abraham WT et al (2002). Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. New Engl J Med 346:1357-1365.


Pennartz CM, de Jeu MT, Bos NP, Schaap J, Geurtsen AM (2002). Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature.416:286-290.

Abstract: The central biological clock of the mammalian brain is located in the suprachiasmatic nucleus. This hypothalamic region contains neurons that generate a circadian rhythm on a single-cell basis. Clock cells transmit their circadian timing signals to other brain areas by diurnal modulation of their spontaneous firing rate. The intracellular mechanism underlying rhythm generation is thought to consist of one or more self-regulating molecular loops, but it is unknown how these loops interact with the plasma membrane to modulate the ionic conductances that regulate firing behaviour. Here we demonstrate a diurnal modulation of Ca2+ current in suprachiasmatic neurons. This current strongly contributes to the generation of spontaneous oscillations in membrane potential, which occur selectively during daytime and are tightly coupled to spike generation. Thus, day-night modulation of Ca2+ current is a central step in transducing the intracellular cycling of molecular clocks to the rhythm in spontaneous firing rate

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Sherwood A, Steffen PR, Blumenthal JA, Kuhn C, Hinderliter AL (2002). Nighttime blood pressure dipping: the role of the sympathetic nervous system. Am J Hypertens.15:111-118.

Abstract: There is a marked diurnal variation in blood pressure (BP), with BP dipping to its lowest levels during nighttime sleep. A day-night dip in systolic BP (SBP) of <10% has been used to characterize individuals as nondippers, and is associated with an increased risk for cardiovascular disease. The present study examined the contribution of the sympathetic nervous system (SNS) to BP dipping in a biracial sample of 172 men and women aged 25 to 45 years. Assessments included 24-h ambulatory BP monitoring and both waking and sleeping urinary catecholamines. In addition, cardiovascular alpha- and beta-adrenergic receptor (AR) responsiveness was determined by the doses of isoproterenol and phenylephrine required to attain an increase in heart rate of 25 points (CD25) and BP (PD25), respectively. Compared with dippers (n = 116), nondippers (n = 56) were more likely to be African American and to have a family history of hypertension as well as a higher body mass index (BMI). The nighttime fall in both norepinephrine (NE) and epinephrine (EPI) excretion rates was reduced in nondippers compared with dippers (NE dip 9.3 v 13.1 microg/mg; EPI dip 2.7 v 4.0 microg/mg; both P < .05). Nondippers also were characterized by heightened alpha1-AR responsiveness compared with dippers (PD25 = 252 v 321 microg, P < .05). These data suggest that the SNS may contribute to individual differences in nighttime BP dipping, and appears to account in part for blunted BP dipping in African Americans

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Omboni S, Smit AA, van Lieshout JJ, Settels JJ, Langewouters GJ, Wieling W (2001). Mechanisms underlying the impairment in orthostatic tolerance after nocturnal recumbency in patients with autonomic failure. Clin Sci (Lond).101:609-618.

Abstract: In the present study, we have assessed in patients with neurogenic orthostatic hypotension the haemodynamics underlying the reduced tolerance to standing after prolonged recumbency at night. In 10 patients with neurogenic orthostatic hypotension (age 33-68 years), of which seven were being treated with fludrocortisone and/or sleeping in the 12 degrees head-up tilt position, 24 h continuous non-invasive finger blood pressure was recorded by a Portapres device. Beat-to-beat blood pressure, heart rate, stroke volume, cardiac output and total peripheral vascular resistance obtained by pulse contour analysis were assessed during 5 min of standing in the evening (at 22.30 hours) and in the morning (at 06.30 hours). On average, the inverse of the normal 24 h blood pressure profile was found, with a large diversity in blood pressure profiles among patients. Supine blood pressure values were similar, but standing blood pressure values were lower in the morning than in the evening (P<0.01). This resulted from larger falls in stroke volume and cardiac output upon standing in the morning compared with the evening, while total peripheral resistance did not change. There was no relationship between the decrease in body weight during the night (mean 0.9 kg; range 0.2-1.6 kg) and the evening-morning difference in standing blood pressure. We conclude that, in patients with neurogenic orthostatic hypotension, the impaired tolerance to standing in the morning is due to larger falls in stroke volume and cardiac output. Not only nocturnal polyuria, but also a redistribution of body fluid, are likely mechanisms underlying the pronounced decreases in stroke volume and cardiac output after prolonged recumbency at night

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Hirshoren N, Tzoran I, Makrienko I et al (2002). Menstrual cycle effects on the neurohumoral and autonomic nervous systems regulating the cardiovascular system. J Clin Endocrinol Metab.87:1569-1575.

Abstract: Gonadal hormones may affect homeostatic mechanisms regulating the cardiovascular system. We investigated this relationship at five different crucial hormonal time points along the menstrual cycle. Eight eumenorrheic healthy subjects underwent a battery of autonomic tests, hemodynamics, and volume-regulatory hormone measurements. Fluid-regulatory hormones, plasma renin activity, and aldosterone increased along the luteal phase (P = 0.003 and 0.02, respectively), whereas rest supine-corrected hematocrit declined in the course of the menstrual cycle (P = 0.001). Plasma norepinephrine decreased from 1.4 +/- 0.2 to 0.95 +/- 0.1 nmol/liter (P < 0.02) [early follicular (EF) to late follicular]. Thereafter, concentrations gradually returned to EF levels. Lf to Hf domain ratio (spectral analysis of electrocardiogram) showed a difference from that of norepinephrine. The cardiovagal baroreflex sensitivity increased significantly along the luteal phase (P = 0.04). The dose of isoproterenol required to increase heart rate (HR) 15 beats per minute was 0.19 +/- 0.04 microg during the EF time point, and it increased to 0.39 +/- 0.06 microg during the late luteal time point (P = 0.05). However, blood pressure, HR, and their responses to orthostatic stress remained unchanged. Fluctuations in the ovarian hormones along the menstrual cycle are associated with unchanged blood pressure and HR, despite the significant variations in the different homeostatic mechanisms regulating the cardiovascular system

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Cuajungco MP, Leyne M, Mull J, Gill SP, Gusella JF, Slaugenhaupt SA (2001). Cloning, characterization, and genomic structure of the mouse Ikbkap gene. DNA Cell Biol.20:579-586.

Abstract: Our laboratory recently reported that mutations in the human I-kappaB kinase-associated protein (IKBKAP) gene are responsible for familial dysautonomia (FD). Interestingly, amino acid substitutions in the IKAP correlate with increased risk for childhood bronchial asthma. Here, we report the cloning and genomic characterization of the mouse Ikbkap gene, the homolog of human IKBKAP. Like its human counterpart, Ikbkap encodes a protein of 1332 amino acids with a molecular weight of approximately 150 kDa. The Ikbkap gene product, Ikap, contains 37 exons that span approximately 51 kb. The protein shows 80% amino acid identity with human IKAP. It shows very high conservation across species and is homologous to the yeast Elp1/Iki3p protein, which is a member of the Elongator complex. The Ikbkap gene maps to chromosome 4 in a region that is syntenic to human chromosome 9q31.3. Because no animal model of FD currently exists, cloning of the mouse Ikbkap gene is an important first step toward creating a mouse model for FD. In addition, cloning of Ikbkap is crucial to the characterization of the putative mammalian Elongator complex

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Kim CH, Zabetian CP, Cubells JF et al (2002). Mutations in the dopamine beta-hydroxylase gene are associated with human norepinephrine deficiency. American Journal of Medical Genetics.108:140-147.

Abstract: Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta- hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. (C) 2002 Wiley-Liss, Inc

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Gimenez-Roqueplo AP, Favier J, Rustin P et al (2001). The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet.69:1186-1197.

Abstract: Hereditary paragangliomas are usually benign tumors of the autonomic nervous system that are composed of cells derived from the primitive neural crest. Even though three genes (SDHD, SDHC, and SDHB), which encode three protein subunits of cytochrome b of complex II in the mitochondrial respiratory chain, have been identified, the molecular mechanisms leading to tumorigenesis are unknown. We studied a family in which the father and his eldest son had bilateral neck paragangliomas, whereas the second son had a left carotid-body paraganglioma and an ectopic mediastinal pheochromocytoma. A nonsense mutation (R22X) in the SDHD gene was found in these three affected subjects. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, that was not detected in six sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. Real-time quantitative reverse transcriptase (RT)-PCR measurements confirmed that vascular endothelial growth factor and endothelial PAS domain protein 1 mRNA levels were significantly higher (three- and sixfold, respectively) than those observed in three sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma is associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors

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Schauerte P, Mischke K, Plisiene J et al (2001). Catheter stimulation of cardiac parasympathetic nerves in humans: a novel approach to the cardiac autonomic nervous system. Circulation.104:2430-2435.

Abstract: BACKGROUND: Cardiac parasympathetic nerves run alongside the superior vena cava (SVC) and accumulate particularly epicardially adjacent to the orifice of the coronary sinus (CS). In animals, these nerves can be electrically stimulated inside the SVC or CS, which results in negative chronotropic/dromotropic effects and negative inotropic effects in the atria but not the ventricles. Parasympathetic nerve stimulation (PS) with 20 Hz in the CS, however, also excites the atria, thereby inducing atrial fibrillation. The present study overcomes this limitation by applying high-frequency nerve stimuli within the atrial refractory period. Using this technique, we investigated for the first time whether neurophysiological effects similar to those in animals can be obtained in humans. METHODS AND RESULTS: In 25 patients, parasympathetic nerves were stimulated via a multipolar electrode catheter placed in the SVC (stimulation with 20 Hz; n=14) or CS (pulsed 200-Hz stimuli; n=11). A significant sinus rate decrease and prolongation of the antegrade Wenckebach period was achieved during PS in the SVC. During PS in the CS, a graded-response prolongation of the antegrade Wenckebach interval was observed with increasing PS voltage until third-degree AV block occurred in 8 of 11 patients. The negative chronotropic/dromotropic effects started and terminated immediately after the onset and termination of PS, respectively. Atropine abolished these effects (n=11). CONCLUSIONS: Human parasympathetic efferent nerve stimulation induces reversible negative chronotropic and dromotropic effects. PS may serve as an adjunctive tool for the diagnosis/treatment of supraventricular tachycardias and may be beneficial for ventricular rate slowing during tachycardic atrial fibrillation in patients with congestive heart failure

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Neri Serneri GG, Boddi M, Modesti PA et al (2001). Increased cardiac sympathetic activity and insulin-like growth factor-I formation are associated with physiological hypertrophy in athletes. Circulation Research.89:977-982.

Abstract: Physiological hypertrophy represents the adaptive changes of the heart required for supporting the increased hemodynamic load in regularly trained healthy subjects. Mechanisms responsible for the athlete's hypertrophy still remain unknown. In 15 trained competitive soccer players and in 15 healthy men not engaged in sporting activities (sedentary control subjects) of equivalent age, we investigated the relationship among cardiac growth factor formation, cardiac sympathetic activity, and left ventricular morphology and function. Cardiac formation of insulin-like growth factor (IGF)-I, endothelin (ET)-1, big ET-1, and angiotensin (Ang) II was investigated at rest by measuring artery-coronary sinus concentration gradients. Cardiac sympathetic activity was studied by [(3)H]norepinephrine (NE) kinetics. Cardiac IGF-I, but not ET-1, big ET-1, and Ang II, formation was higher in athletes than in control subjects (P<0.01). NE levels in arterial and peripheral venous blood did not differ between groups. In contrast, coronary sinus NE concentration was higher in athletes than in control subjects (P<0.01). Cardiac, but not total systemic, NE spillover was also increased in athletes (P<0.01), whereas cardiac [(3)H]NE reuptake and clearance were not different. Echocardiographic modifications indicated a volume overload-induced hypertrophy associated with increased myocardial contractility. Multivariate stepwise analysis selected left ventricular mass index as the most predictive independent variable for cardiac IGF-I formation and velocity of circumferential fiber shortening for cardiac NE spillover. In conclusion, increased cardiac IGF-I formation and enhanced sympathetic activity selectively confined to the heart appear to be responsible for the physiological hypertrophy in athletes performing predominantly isotonic exercise

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Greenwood JP, Scott EM, Stoker JB, Mary DA (2001). Hypertensive left ventricular hypertrophy: relation to peripheral sympathetic drive. J Am Coll Cardiol.38:1711-1717.

Abstract: OBJECTIVESThis study was designed to examine whether the occurrence of left ventricular hypertrophy (LVH) in moderate to severe essential hypertension (EHT) was associated with alteration in peripheral sympathetic drive.BACKGROUNDIn hypertension, LVH is an independent predictor of increased morbidity and mortality. The reported mechanisms leading to LVH remain unclear but include hemodynamic and humoral factors. The sympathetic nervous system may be important, particularly as catecholamines have been shown to have trophic properties. We tested the hypothesis that sympathetic activity measured using microneurography could be different in patients with hypertension depending on the presence of LVH.METHODSWe examined 28 subjects with moderate to severe EHT (stages 2 to 3; Joint National Committee [JNC]-VI classification). Fourteen had echocardiographic evidence of LVH (EHT + LVH), while the other 14 subjects (EHT) did not. Subjects were matched in terms of age, body mass index and levels of arterial blood pressure. Peripheral muscle sympathetic nerve activity was measured from both multiunit bursts (MSNA) and single unit (s-MSNA) vasoconstrictor impulses via the peroneal nerve.RESULTSThe mean frequency of s-MSNA and MSNA was greater in the EHT + LVH group than it was in the EHT group (mean +/- SEM; 75.9 +/- 6.9 impulses/100 beats vs. 52.1 +/- 2.9 impulses/100 beats, p < 0.001 and 64.2 +/- 5.7 bursts/100 beats vs. 48.9 +/- 2.8 bursts/100 beats, p < 0.05).CONCLUSIONSThese results indicate that, in subjects with moderate to severe hypertension, the presence of LVH is associated with higher sympathetic discharge, evidenced by an increase in unitary firing frequency and also by fiber recruitment

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Lowes BD, Gilbert EM, Abraham WT et al (2002). Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. [see comments.]. New England Journal of Medicine.346:1357-1365.

Abstract: BACKGROUND: Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy. METHODS: We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mRNA) for contractility-regulating genes (those encoding beta1- and beta2-adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and alpha- and beta-myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of beta-adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography. RESULTS: Twenty-six of 32 beta-blocker-treated patients (those with complete mRNA measurements) had an improvement in left ventricular ejection fraction of at least 5 ejection-fraction (EF) units (mean [+/-SE] increase, 18.8+/-1.8). As compared with the six beta-blocker-treated patients who did not have a response (mean change, a decrease of 2.5+/-1.8 EF units), those who did have a response had an increase in sarcoplasmic-reticulum calcium ATPase mRNA and alpha-myosin heavy chain mRNA and a decrease in beta-myosin heavy chain mRNA. The change in sarcoplasmic-reticulum calcium ATPase was not present in the patients in the placebo group who had a spontaneous response. There were no differences between those who had a response and those who did not in terms of the change in mRNA or protein expression of beta-adrenergic receptors. CONCLUSIONS: In idiopathic dilated cardiomyopathy, functional improvement related to treatment with beta-blockers is associated with changes in myocardial gene expression

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