RESUMO
Norepinephrine released from sympathetic nerves is removed from the neuroeffector junction via the action of the norepinephrine transporter (NET). NET impairment is evident in several clinically important conditions including major depressive disorder (MDD), panic disorder (PD), essential hypertension and the postural orthostatic tachycardia syndrome (POTS). We aimed to determine whether a single nucleotide polymorphism (SNP) in the 3' untranslated region (UTR) of the NET gene is associated with NET impairment and to elucidate the mechanisms involved. The analyses were carried out in two cohorts of European ancestry, which included healthy controls and MDD, PD, hypertensive and POTS patients. Compared with controls, cases had significantly higher prevalence of the T allele of rs7194256 (C/T), arterial norepinephrine, depression and anxiety scores, larger left ventricular mass index, higher systolic and diastolic blood pressures, and heart rate. Bioinformatic analysis identified that the microRNA miR-19a-3p could bind preferentially to the sequence created by the presence of the T allele. This was supported by results of luciferase assays. Compared with controls, cases had significantly lower circulating miR-19a-3p, which was associated with pathways related to blood pressure and regulation of neurotransmission. In vitro norepinephrine downregulated miR-19a-3p. In conclusion, the T allele of the rs7194256 SNP in the 3'UTR of the NET gene is more prevalent in diseases where NET impairment is evident. This might be explained by the creation of a binding site for the microRNA miR-19a-3p. A defect in NET function may potentiate the sympathetic neurochemical signal, predisposing individuals with affective diseases to increased risk of cardiovascular disease development.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Regiões 3' não Traduzidas/genética , Adulto , Alelos , Sítios de Ligação , Doenças Cardiovasculares , Estudos de Coortes , Biologia Computacional , Transtorno Depressivo Maior/genética , Hipertensão Essencial , Feminino , Frequência Cardíaca , Humanos , Hipertensão/genética , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Transtorno de Pânico/genética , Polimorfismo de Nucleotídeo Único/genética , Síndrome da Taquicardia Postural Ortostática/genética , População Branca/genéticaRESUMO
Renal denervation (RDN) has been shown in several studies to reduce blood pressure (BP) in patients with resistant hypertension (RH). Data on potential biomarkers associated with BP changes remain scarce. We evaluated whether soluble vascular endothelial growth factor receptor (sVEGFR-1) is affected by the procedure. A total of 57 patients with RH participated in this study. BP and heart rate were recorded at baseline and at 3 months follow-up, at which time blood samples were collected to determine the levels of sVEGFR-1, VEGF-A, VEGF-C, nitric oxide (NO), soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1. None of the biomarkers had a predictive value that could identify responders vs non-responders to RDN. However, sVEGFR-1 concentration was dramatically reduced after RDN (5913±385 vs 280±57 pg ml-1, P<0.001). At the same time VEGF-A levels were significantly increased (10.0±3.0 vs 55.5±7.9 pg ml-1, P<0.001), without significant changes in VEGF-C. NO levels were significantly increased after RDN in the whole group (82.6±6.2 vs 106.9±7.8 µM, P=0.021). Interestingly, the elevation in NO levels at 3 months was only seen in patients who demonstrated a reduction in systolic BP of ⩾10 mm Hg (78.9±8.3 vs 111.6±11.7 µM, P=0.018). We report a significant reduction in sVEGFR-1 levels after RDN procedure, which was accompanied by a significant increase in VEGF-A concentration as well as NO. Changes in plasma cytokines were not quantitatively linked to magnitude of BP reduction. An RDN-induced reduction in sVEGFR-1 plasma levels and increase in VEGF-A would raise the VEGF-A/sVEGFR-1 ratio, thereby increasing VEGF-A bioavailability to act on its full-length receptor and may contribute to the BP-lowering effect potentially via NO-mediated pathways.
Assuntos
Hipertensão/sangue , Óxido Nítrico/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Biomarcadores/sangue , Estudos de Coortes , Denervação , Feminino , Humanos , Hipertensão/cirurgia , Molécula 1 de Adesão Intercelular/sangue , Rim/inervação , Masculino , Pessoa de Meia-Idade , Molécula 1 de Adesão de Célula Vascular/sangueRESUMO
Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained. Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (n=11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (n=11, P<0.05). In a rat model of CHF, a 40% reduction (P<0.05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content (P<0.05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 micromol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. The full text of this article is available at http://www.circresaha.org.
Assuntos
Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Fator de Crescimento Neural/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Adulto , Animais , Células Cultivadas , Regulação para Baixo , Humanos , Pessoa de Meia-Idade , Fator de Crescimento Neural/efeitos dos fármacos , Fator de Crescimento Neural/genética , Norepinefrina/farmacologia , Prazosina/farmacologia , Proteína Quinase C/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The objective of this study was to examine the cross-sectional relationship between the expression of norepinephrine transporter (NET), the protein responsible for neuronal uptake-1, and indices of glycaemia and hyperinsulinaemia, in overweight and obese individuals. METHODS: Thirteen non-medicated, non-smoking subjects, aged 58 ± 1 years (mean ± standard error of the mean), body mass index (BMI) 31.4 ± 1.0 kg m-2, with wide-ranging plasma glucose and haemoglobin A1c (HbA1c, range 5.1% to 6.5%) participated. They underwent forearm vein biopsy to access sympathetic nerves for the quantification of NET by Western blot, oral glucose tolerance test (OGTT), euglycaemic hyperinsulinaemic clamp, echocardiography and assessments of whole-body norepinephrine kinetics and muscle sympathetic nerve activity. RESULTS: Norepinephrine transporter expression was inversely associated with fasting plasma glucose (r = -0.62, P = 0.02), glucose area under the curve during OGTT (AUC0-120, r = -0.65, P = 0.02) and HbA1c (r = -0.67, P = 0.01), and positively associated with steady-state glucose utilization during euglycaemic clamp (r = 0.58, P = 0.04). Moreover, NET expression was inversely related to left ventricular posterior wall dimensions (r = -0.64, P = 0.02) and heart rate (r = -0.55, P = 0.05). Indices of hyperinsulinaemia were not associated with NET expression. In stepwise linear regression analysis adjusted for age, body mass index and blood pressure, HbA1c was an independent inverse predictor of NET expression, explaining 45% of its variance. CONCLUSIONS: Hyperglycaemia is associated with reduced peripheral NET expression. Further studies are required to identify the direction of causality.
RESUMO
BACKGROUND: Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and beta-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of further therapeutic approaches is warranted. Recent data suggest that continuous positive airway pressure (CPAP) may be of benefit in the treatment of CHF, although the mechanism for this action is incompletely understood. METHODS AND RESULTS: In the present study, we examined the effect of short-term CPAP (10 cm H(2)O for 10 minutes) on hemodynamics (Swan Ganz catheter) and total systemic and cardiac sympathetic activity (norepinephrine spillover method) in 14 CHF patients in New York Heart Association class III. The application of CPAP was associated with a fall in cardiac output (4.8+/-0.3 to 4.4+/-0.2 L/min; P<0.05) and a significant reduction in cardiac norepinephrine spillover (370+/-58 to 299+/-55 pmol/min; P<0.05), although total systemic norepinephrine spillover was unchanged. CONCLUSION: The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.
Assuntos
Insuficiência Cardíaca/terapia , Coração/fisiopatologia , Respiração com Pressão Positiva , Sistema Nervoso Simpático/fisiopatologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/fisiologia , Humanos , Norepinefrina/metabolismoRESUMO
OBJECTIVES: The aim of this study was to investigate the role of peripheral presynaptic alpha-2 adrenergic receptors in modulating norepinephrine (NE) release in congestive heart failure (CHF). BACKGROUND: Activation of the sympathetic nervous system is a hallmark of CHF. Clonidine, an imidazoline and adrenergic agonist with high selectivity for the alpha-2 adrenoceptor, has been shown to reduce generalized sympathetic activity in heart failure after parenteral administration. If it could be shown that peripheral presynaptic alpha-2 adrenoceptors are inhibitory to NE release, then they could be targeted for future therapy, and as a corollary, potentially circumvent unwanted side effects arising from stimulation of alpha-2 adrenoceptors in the brain. Additionally, it could be concluded that these receptors form the basis for an auto-inhibitory feedback to further NE release. METHODS: Fifteen healthy volunteers and 10 patients with heart failure received intra-arterial clonidine via the brachial artery (0.05 microg and 0.48 microg/100 ml forearm/min). Radio-tracer techniques were employed for studying NE kinetics. RESULTS: Intra-arterial clonidine caused a dose-dependent decrease in forearm spillover of NE in healthy individuals (low dose, high dose: 26%, 49%: p < 0.05, p < 0.001, respectively). In the patient group, no decrease in forearm spillover was demonstrated after local administration. The difference in response between the two groups was statistically significant (p = 0.004). CONCLUSIONS: Peripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/fisiologia , Receptores Adrenérgicos alfa 2/fisiologia , Receptores Pré-Sinápticos/fisiologia , Idoso , Clonidina/administração & dosagem , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Pré-Sinápticos/efeitos dos fármacosRESUMO
OBJECTIVES: The present study was designed to identify the hemodynamic factor or factors that reflexly contribute to activation of the cardiac sympathetic nerves in patients with severe congestive heart failure (CHF). BACKGROUND: We and others have previously shown that activation of the sympathetic nervous system is a key feature of CHF in humans. Furthermore, the degree of sympathetic activation shows marked regional heterogeneity and is most pronounced in the heart. Recent studies have shown a significant positive relation between pulmonary artery pressure and the magnitude of cardiac sympathetic activation. Of particular importance, the degree of cardiac sympathoexcitation has also been shown to be strongly associated with mortality in CHF. METHODS: We assessed total systemic and cardiac sympathetic activity (norepinephrine [NE] spillover method) in nine patients with severe CHF and significantly elevated pulmonary artery pressure (mean [+/-SEM] pulmonary artery pressure 46 +/- 3 mm Hg) at rest and during a titrated infusion of sodium nitroprusside (SNP). RESULTS: SNP infusion significantly reduced mean arterial blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. During SNP infusion, the total body NE spillover rate (NESR) increased (from 7.9 +/- 1.7 to 11.2 +/- 3.1 nmol/min, p < 0.01), whereas the cardiac NESR decreased (from 522 +/- 86 to 409 +/- 71 pmol/min, p < 0.05). The ratio of cardiac/total NE spillover was also substantially reduced (from 7.8 +/- 1.3 to 4.9 +/- 0.9%, p < 0.001). CONCLUSIONS: There is a directionally opposite change in whole-body (increase) and cardiac (reduction) sympathetic nervous activity during SNP infusion, most likely due to unloading of arterial baroreceptors and specific cardiopulmonary baroreceptors, respectively, in severe CHF. These observations support the concept of a positive feedback relation between pulmonary artery pressure/filling pressure and cardiac sympathetic tone in CHF and serve to reinforce the importance of vasodilator therapy in this condition.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Nitroprussiato/farmacologia , Norepinefrina/sangue , Pressorreceptores/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Feminino , Insuficiência Cardíaca/sangue , Humanos , Hipertensão Pulmonar/sangue , Masculino , Pessoa de Meia-Idade , DescansoRESUMO
One possible intervention to interrupt the deleterious effects of the renin-angiotensin system is suppression of angiotensin II (Ang II) formation by inhibition of angiotensin-converting enzyme (ACE). However, ACE inhibition incompletely suppresses Ang II formation and also leads to accumulation of bradykinin. Angiotensin II type 1 (AT1) receptors are believed to promote the known deleterious effects of Ang II. Therefore, AT1 receptor antagonists have been recently introduced into therapy for hypertension and congestive heart failure (CHF). Although there are significant differences between the effects of AT1 receptor antagonists and ACE inhibitors including the unopposed stimulation of angiotensin II type 2 (AT2) receptors by AT1 receptor antagonists, the discussion of whether ACE inhibitors, AT1 receptor antagonists or the combination of both are superior in the pharmacotherapy of CHF is still largely theoretical. Accordingly, AT1 receptor antagonists are still investigational. Angiotensin-converting enzyme inhibitors remain first line therapy in patients with CHF due to systolic dysfunction. However, in patients not able to tolerate ACE inhibitor induced side effects, in particular cough, AT1 receptor antagonism is a good alternative. In clinical practice, emphasis should be placed on increasing the utilization of ACE inhibitors, as more than 50% of patients with CHF do not receive ACE inhibitors. In addition, the majority of those on ACE inhibitors receive doses lower than the dosage used in the large clinical trials. Although not yet completely proved, it is likely that high doses of ACE inhibition are superior to low doses with respect to prognosis and symptoms.
Assuntos
Angiotensina II/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Bradicinina/metabolismo , Relação Dose-Resposta a Droga , Fibrinólise/efeitos dos fármacos , Seguimentos , Insuficiência Cardíaca/sangue , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de AngiotensinaRESUMO
OBJECTIVES: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. BACKGROUND: Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. METHODS: To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. RESULTS: Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. CONCLUSIONS: These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.
Assuntos
Antagonistas Adrenérgicos/administração & dosagem , Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas Adrenérgicos/efeitos adversos , Adulto , Idoso , Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Catecolaminas/sangue , Feminino , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
OBJECTIVES: We sought to assess the effects of brain natriuretic peptide (BNP) on systemic and regional sympathetic nervous activity (SNA) in both patients with congestive heart failure (CHF) and healthy control subjects. BACKGROUND: Although the response of SNA to atrial natriuretic peptide (ANP) has been well documented, the response of SNA to BNP is largely unknown. METHODS: We assessed cardiac and whole-body SNA using the norepinephrine (NE) tracer dilution method before and after infusion of two doses of BNP (3 and 15 ng/kg body weight per min) in 11 patients with stable CHF (ejection fraction 24 +/- 2%) and 12 age-matched healthy control subjects. In addition, renal SNA and hemodynamic variables were assessed at baseline and after the higher BNP dose. RESULTS: Low dose BNP did not change blood pressure or whole-body NE spillover, but reduced cardiac NE spillover in both groups by 32 +/- 13 pmol/min (p < 0.05). In both groups, high dose BNP reduced pulmonary capillary pressure by 5 +/- 1 mm Hg (p < 0.001) and mean arterial pressure by 6 +/- 3 mm Hg (p < 0.05), without a concomitant increase in whole-body NE spillover; however, cardiac NE spillover returned to baseline levels. Renal NE spillover remained virtually unchanged in healthy control subjects (501 +/- 120 to 564 +/- 115 pmol/min), but was reduced in patients with CHF (976 +/- 133 to 656 +/- 127 pmol/min, p < 0.01). CONCLUSIONS: Our results demonstrate a sympathoinhibitory effect of BNP. Cardiac sympathetic inhibition was observed at BNP concentrations within the physiologic range, whereas high dose BNP, when arterial and filling pressures fell and reflex sympathetic stimulation was expected, systemic and cardiac SNA equated to baseline values. There was inhibition of renal SNA in patients with CHF, but not in healthy control subjects. Whether this effect is specific to BNP or related to reduced filling pressure remains to be determined.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/administração & dosagem , Sistema Nervoso Simpático/efeitos dos fármacos , Doença Crônica , Relação Dose-Resposta a Droga , Feminino , Coração/inervação , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Infusões Intravenosas , Rim/inervação , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/efeitos adversos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Norepinefrina/sangue , Valores de Referência , Sistema Nervoso Simpático/fisiopatologiaRESUMO
OBJECTIVES: The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone. BACKGROUND: Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear. METHODS: Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow. RESULTS: Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons. CONCLUSIONS: Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.
Assuntos
Encéfalo/metabolismo , Insuficiência Cardíaca/fisiopatologia , Coração/inervação , Norepinefrina/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Di-Hidroxifenilalanina/metabolismo , Insuficiência Cardíaca/etiologia , Humanos , Metoxi-Hidroxifenilglicol/metabolismo , Pessoa de Meia-Idade , Neuropeptídeo Y/metabolismo , Pressão Propulsora Pulmonar/fisiologia , TermodiluiçãoRESUMO
OBJECTIVES: In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure. BACKGROUND: Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events. METHODS: Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9 +/- 0.9% [mean +/- SE]) were studied prospectively. In addition to the compilation of a hemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis. RESULTS: The mean follow-up period of the study group was 7 +/- 1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 +/- 37 vs. 105 +/- 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capillary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepinephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study. CONCLUSIONS: These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Norepinefrina/sangue , Sistema Nervoso Simpático/fisiopatologia , Adulto , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Análise de Sobrevida , Sistema Nervoso Simpático/metabolismoRESUMO
BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.
Assuntos
Epinefrina/fisiologia , Norepinefrina/fisiologia , Transtorno de Pânico/diagnóstico , Transtorno de Pânico/fisiopatologia , Estresse Psicológico/diagnóstico , Estresse Psicológico/fisiopatologia , Sistema Nervoso Simpático/fisiologia , Medula Suprarrenal/inervação , Medula Suprarrenal/fisiologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Epinefrina/sangue , Feminino , Coração/inervação , Coração/fisiopatologia , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/química , Músculos/inervação , Miocárdio/química , Norepinefrina/sangue , Transtorno de Pânico/sangue , Inventário de Personalidade , Técnica de Diluição de Radioisótopos , Estresse Psicológico/sangueRESUMO
OBJECTIVE: To seek direct evidence for a cause-effect relation between sympathetic activation and arrhythmogenesis. METHODS: Rats underwent open-chest surgery with either coronary artery occlusion or sham operation, and were studied 8 weeks later using in situ heart perfusion and nerve stimulation methods. RESULTS: Infarcted rats showed cardiac functional impairment and increased heart and lung weight. The extent of these changes correlated well with infarct size (IS). In in situ perfused hearts, sympathetic nerve stimulation (2 and 4 Hz, 45 s duration) induced a frequency-dependent release of norepinephrine (NE). NE release was lower in MI than that in control groups. In hearts with large IS (> or = 40%, n = 19) ventricular arrhythmias were rare at baseline, but nerve stimulation evoked the onset of ventricular premature beats (95%), tachycardia (37%) and fibrillation (26%), IS and stimulation frequency were key determinants for the inducibility of arrhythmias. Lower K- concentration enhanced arrhythmia inducibility. beta-blockade inhibited the frequency of arrhythmias produced by nerve stimulation. CONCLUSION: In infarcted rat hearts sympathetic activation is a potent trigger for the onset of ventricular tachyarrhythmias.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Taquicardia Ventricular/etiologia , Inibidores da Captação Adrenérgica/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Análise de Variância , Animais , Atenolol/farmacologia , Estimulação Cardíaca Artificial , Desipramina/farmacologia , Estimulação Elétrica , Eletrocardiografia , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Pulmão/patologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Perfusão , Potássio/metabolismo , Propanolaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Sexo , Estatísticas não Paramétricas , Sistema Nervoso Simpático/efeitos dos fármacos , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologiaRESUMO
Estrogens are reported to provide protection against the development of cardiovascular disease in women, but the mechanisms underlying these effects are not well defined. We hypothesized that estrogen might affect the hormonal responses to stress. We therefore studied cortisol, ACTH, epinephrine, norepinephrine, and norepinephrine spillover and hemodynamic responses to a 10-min mental arithmetic test in 12 perimenopausal women randomized to 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily; n = 7) or placebo (n = 5). Total body and forearm norepinephrine spillover were measured by radiotracer methodology. After supplementation with estradiol, the increases in both systolic and diastolic blood pressure in response to mental stress were reduced, and cortisol, ACTH, plasma epinephrine and norepinephrine, and total body norepinephrine spillover responses to stress were significantly attenuated (P < 0.05 in each case). Forearm norepinephrine spillover was unchanged by estrogen, and there was no change in any of the responses after placebo. We conclude that estrogen supplementation in perimenopausal women attenuates blood pressure, glucocorticoid, and catecholamine responses to psychological stress.
Assuntos
Catecolaminas/sangue , Estradiol/análogos & derivados , Glucocorticoides/sangue , Menopausa/fisiologia , Estresse Psicológico/sangue , Hormônio Adrenocorticotrópico/sangue , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Epinefrina/sangue , Estradiol/administração & dosagem , Estradiol/sangue , Estradiol/uso terapêutico , Feminino , Hormônio Foliculoestimulante/sangue , Antebraço/irrigação sanguínea , Frequência Cardíaca , Humanos , Hidrocortisona/sangue , Pessoa de Meia-Idade , Norepinefrina/sangueRESUMO
The failure of plasma norepinephrine to rise during upright posture is accepted as a diagnostic sign of autonomic nervous failure in patients with postural hypotension. Our clinical experience has been that this test is misleading, with an increase in plasma norepinephrine commonly occurring. To test whether this might result from absent reflex postural venous constriction lowering cardiac output and plasma norepinephrine clearance, we measured norepinephrine plasma kinetics during recumbency and 30 degrees head-up tilting in six patients with pure autonomic failure and eight healthy subjects. Mean arterial pressure fell by 54 +/- 8 mm Hg with head-up tilt in the patients with pure autonomic failure. The plasma norepinephrine concentration (arterial sampling) increased 73 +/- 29 pg/ml (mean difference +/- SED, p less than 0.02), solely because of a 36% reduction in the clearance of norepinephrine from plasma (0.78 +/- 0.09 l/min, p less than 0.0001). In normal subjects, plasma norepinephrine concentration rose by 112 +/- 20 pg/ml (p less than 0.001), largely because of a 24% increase in norepinephrine spillover to plasma (190 +/- 20 ng/min, p less than 0.005). When the postural fall in blood pressure and cardiac output in the pure autonomic failure patients was prevented by the selective venoconstrictor dihydroergotamine (10 micrograms/kg i.v.), no fall in plasma clearance or rise in plasma concentration of norepinephrine occurred. Measurement of the change in plasma norepinephrine with postural stimulation in patients with orthostatic hypotension is not a reliable diagnostic test for autonomic failure because elevations can occur in the plasma concentration that are entirely attributable to reduced plasma norepinephrine clearance.
Assuntos
Doenças do Sistema Nervoso Autônomo/fisiopatologia , Norepinefrina/sangue , Postura , Doenças do Sistema Nervoso Autônomo/sangue , Pressão Sanguínea , Humanos , Pessoa de Meia-Idade , Concentração Osmolar , Valores de ReferênciaRESUMO
Neuronal uptake is an important mechanism for the removal of norepinephrine, but its contribution to the removal of epinephrine is unknown. This study compared the neuronal removal of circulating epinephrine and norepinephrine by examination of the cardiac extractions or plasma clearances of [3H]norepinephrine and endogenous or 3H-labeled epinephrine in healthy subjects, patients with cardiovascular disorders, and subjects administered desipramine to block neuronal uptake. In rabbits the plasma clearances of [3H]epinephrine and [3H] norepinephrine by neuronal uptake and the formation of dihydroxyphenylglycol (DHPG) from simultaneously infused [3H] norepinephrine and epinephrine were compared. In normal patients 51 +/- 3% of plasma epinephrine was extracted during one pass through the coronary circulation, significantly less than the cardiac extraction of [3H]norepinephrine (78 +/- 1%). In patients with cardiovascular disorders extractions of epinephrine (34 +/- 3%) remained lower than those of [3H]norepinephrine (63 +/- 2%). After desipramine, cardiac extraction of epinephrine was reduced to 12 +/- 2% and [3H]norepinephrine to 20 +/- 3%. In subjects infused simultaneously with [3H]epinephrine and [3H] norepinephrine, desipramine reduced the cardiac extraction of [3H]epinephrine by 28 +/- 6%, significantly less than the 49 +/- 7% reduction in [3H]epinephrine extraction; the plasma clearance of [3H]epinephrine was reduced by 4 +/- 5%, significantly less than the 20 +/- 6% reduction in [3H]norepinephrine clearance. In rabbits desipramine reduced the plasma clearance of [3H] epinephrine by 18%, significantly less than the 42% reduction in [3H]norepinephrine clearance; production of DHPG from epinephrine was less than half the production of [3H]DHPG from [3H]norepinephrine. The above differences indicated that epinephrine was removed 44-64% less avidly than norepinephrine by uptake into and metabolism within sympathetic neurons.
Assuntos
Epinefrina/farmacocinética , Neurônios/metabolismo , Norepinefrina/farmacocinética , Animais , Circulação Coronária/fisiologia , Doença das Coronárias/metabolismo , Desipramina/farmacologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/sangue , CoelhosRESUMO
Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED +/- 3.4, p less than 0.01), associated with an increased cardiac output (5.85-7.73 l/min, SED +/- 0.46, p less than 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED +/- 1.03, p less than 0.05). Resting forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED +/- 6.4, p less than 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/min) was also significantly greater after hydrocortisone, increasing from an average of 14.9 +/- 2.4 R units before treatment to 35.1 +/- 5.5 R units after hydrocortisone (SED +/- 6.0, p less than 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hidrocortisona/efeitos adversos , Hipertensão/induzido quimicamente , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Creatinina/sangue , Creatinina/urina , Antebraço , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Infusões Intra-Arteriais , Masculino , Norepinefrina/administração & dosagem , Placebos , Potássio/sangue , Potássio/urina , Sódio/sangue , Sódio/urina , Resistência Vascular/efeitos dos fármacosRESUMO
In essential hypertension sympathetic nerve firing is commonly increased. A central nervous system origin has been presumed but not tested directly. To estimate cerebral norepinephrine release in essential hypertension, spillover of norepinephrine into the cerebrovascular circulation was measured by isotope dilution, with high internal jugular venous sampling. Norepinephrine was released into the cerebrovascular circulation in both hypertensive patients and healthy volunteers and was present after administration of the ganglion blocker trimethaphan and in patients with sympathetic nervous failure, indicating that brain neurons and not cerebrovascular sympathetic nerves were the probable source. Although differing among hypertensive patients, norepinephrine spillover on average was higher in the hypertensive patients (153 +/- 41 pmol/min) than in healthy subjects (59 +/- 12 pmol/min; p less than 0.05), and was elevated in six of 17 patients, in whom the accompanying whole body norepinephrine spillover rate was higher than in the remaining 11 patients (p less than 0.01). To test for a possible link between brain norepinephrine release and human sympathetic nervous function, the effect of the tricyclic antidepressant desipramine (0.3 mg/kg i.v.) on both brain and whole body norepinephrine spillover was measured in healthy volunteers. Desipramine lowered the cerebrovascular spillover of norepinephrine, its precursor dihydroxyphenylalanine, and its metabolite dihydroxyphenylglycol by 50-80% and produced a mean fall of 35% in whole body norepinephrine spillover. One interpretation of these results is that human sympathetic nerve firing is dependent on norepinephrine release within the brain and that increased cerebral norepinephrine release may possibly be present in some patients with essential hypertension, underlying their higher sympathetic nerve firing rates.