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We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6-22 and HR: 3.6, 95% CI: 1.1-12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2-6), trouble swallowing (HR 2.5, 95% CI: 1.4-4.5) and changes in speech (HR:2.4, 95% CI:1.1-4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1-5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2-38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6-46), preserved olfaction (HR: 8.7, 95% CI: 1.7-45), anhidrosis (HR: 1.8, 95% CI: 1-3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1-2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.
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Doença de Parkinson , Insuficiência Autonômica Pura , Humanos , Masculino , Feminino , Idoso , Estudos Longitudinais , Pessoa de Meia-Idade , Insuficiência Autonômica Pura/fisiopatologia , Estudos Prospectivos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Progressão da Doença , Doença por Corpos de Lewy/fisiopatologia , Estudos de Coortes , Atrofia de Múltiplos Sistemas/fisiopatologia , Atrofia de Múltiplos Sistemas/epidemiologiaRESUMO
PURPOSE: Hypertension is one of the major causes of cardiovascular morbidity and mortality in the USA and disproportionately affects Black women. Endothelial-derived nitric oxide (eNO) substantially regulates blood pressure in humans, and impaired NO-mediated vasodilation has been reported in the Black population. Previous studies using an NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) did not fully determine the NO contribution to blood pressure because of baroreflex buffering. Therefore, in the present study we used trimethaphan, a ganglionic blocker, to inhibit baroreflex buffering and study NO modulation of blood pressure in Black women during L-NMMA infusion. METHODS: L-NMMA at doses of 250 µg/kg per minute was infused in combination with trimethaphan at doses of 4 mg/min to eliminate baroreflex mechanisms. Heart rate (HR) was obtained with continuous electrocardiogram monitoring, and continuous blood pressure was measured with the volume clamp method. The increase in systolic blood pressure (SBP) during both infusions was used to estimate the contribution of NO to blood pressure. RESULTS: Ten Black (age range 30-50 years, body mass index [BMI] 30-45 kg/m2), and nine White women (age range 30-50 years, body mass index 30-45 kg/m2) were enrolled in this study. During autonomic blockade, there was no difference in the decrease in SBP between Black and White women (- 20 ± 16.45 vs. - 24 ± 15.49 mm Hg, respectively; P = 0.659). When autonomic blockade was combined with L-NMMA, Black women had a significant increase in SBP compared to White women (54 ± 13.62 vs. 39 ± 09.64 mm Hg, respectively; P = 0.022, respectively). CONCLUSION: Autonomic blood pressure regulation was similar between Black and White women. However, NO contribution to blood pressure was significantly greater in Black women compared to White women. REGISTRATION: ClinicalTrials.gov: NCT01122407.
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PURPOSE: The specific characteristics of autonomic involvement in patients with early Parkinson's disease (PD) are unclear. This study aimed to evaluate the characteristics of autonomic dysfunction in drug-naïve patients with early-stage PD without orthostatic hypotension (OH) by analyzing Valsalva maneuver (VM) parameters. METHODS: We retrospectively analyzed drug-naïve patients without orthostatic hypotension (n = 61) and controls (n = 20). The patients were subcategorized into early PD (n = 35) and mid-PD (n = 26) groups on the basis of the Hoehn and Yahr staging. VM parameters, including changes in systolic blood pressure at late phase 2 (∆SBPVM2), ∆HRVM3, Valsalva ratio (VR), pressure recovery time, adrenergic baroreflex sensitivity, and vagal baroreflex sensitivity, were assessed. RESULTS: In the early PD group, ∆SBPVM2, a marker of sympathetic function, was significantly lower compared with that in controls (risk ratio = 0.95, P = 0.027). Receiver operating characteristic (ROC) curve analysis showed an optimal cut-off value of -10 mmHg for ∆SBPVM2 [P = 0.002, area under the curve (AUC): 0.737]. VR exhibited an inverse relationship with Unified Parkinson's Disease Rating Scale Part 3 scores in the multivariable regression analysis (VR: P = 0.038, ß = -28.61), whereas age showed a positive relationship (age: P = 0.027, ß = 0.35). CONCLUSION: The ∆BPVM2 parameter of the VM may help detect autonomic nervous system involvement in early-PD without OH. Our results suggest that sympathetic dysfunction is an early manifestation of autonomic dysfunction in patients with PD.
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Doenças do Sistema Nervoso Autônomo , Barorreflexo , Doença de Parkinson , Manobra de Valsalva , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Masculino , Feminino , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/etiologia , Manobra de Valsalva/fisiologia , Barorreflexo/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Pressão Sanguínea/fisiologiaRESUMO
OBJECTIVE: To evaluate the relationship between postural orthostatic tachycardia syndrome (POTS) and pregnancy. DESIGN: Cross-sectional survey. SETTING: International. SAMPLE: A total of 8941 female patients with a diagnosis of POTS. METHODS: Data from the survey were analysed using descriptive measures and stratified for comparisons. MAIN OUTCOME MEASURES: Symptom course of POTS during pregnancy. Secondary outcomes included pregnancy loss, POTS onset during pregnancy and the impacts of a comorbid diagnosis of Ehlers-Danlos syndrome or an autoimmune disorder on symptoms during pregnancy. RESULTS: Overall, 40.8% (n = 3652) of participants reported one or more pregnancies. Most participants experienced worsening of symptoms in the first (62.6%) and third (58.9%) trimesters and 3 months after pregnancy (58.7%), and 81.1% experienced worsening symptoms at any point in their pregnancy. Most participants with worsening symptoms in the first trimester also experienced worsening symptoms in the second (61.6%) and third (68.1%) trimesters, but if they improved in the first trimester then this improvement persisted in the second and third trimesters. Of participants who reported that POTS was triggered by a specific event (41.3%), 8.1% reported pregnancy as the trigger for the onset. CONCLUSIONS: Postural orthostatic tachycardia syndrome symptoms in the first trimester of pregnancy may help predict symptom course throughout the duration of pregnancy. Some individuals may experience an initial onset of POTS during pregnancy. This novel information may guide clinicians in counselling patients with POTS who are planning pregnancy.
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Aborto Espontâneo , Síndrome de Ehlers-Danlos , Síndrome da Taquicardia Postural Ortostática , Gravidez , Humanos , Feminino , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Síndrome da Taquicardia Postural Ortostática/epidemiologia , Estudos Transversais , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/epidemiologia , ComorbidadeRESUMO
We propose a consensus definition of "an exaggerated orthostatic pressor response" in subjects in whom systolic blood pressure increases ≥ 20 mmHg when going from supine to standing posture. This definition can be extended for seated to standing measurements. We reserve the term "orthostatic hypertension" for when this pressor response leads to an upright systolic blood pressure ≥ 140 mmHg. We believe this consensus definition will help in the study of the pathophysiology, clinical impact, and potential treatment of these entities, and identification of patients who are at greater cardiovascular risk.
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Hipertensão , Hipotensão Ortostática , Humanos , Sistema Nervoso Autônomo , Pressão Sanguínea , Hipotensão Ortostática/tratamento farmacológico , Postura/fisiologia , Estados Unidos , JapãoRESUMO
PURPOSE OF REVIEW: Patients with neurogenic orthostatic hypotension (OH) frequently have hypertension in the supine position (sHTN). We review the controversies surrounding the need and safety of treating sHTN in patients with OH. RECENT FINDINGS: The presence of sHTN complicates the management of OH because treatment of one can worsen the other. New approaches have been developed to treat OH without worsening sHTN by preferentially improving standing blood pressure, such as medications that harness the patient's residual sympathetic tone like pyridostigmine and atomoxetine, and devices such as an automated abdominal binder that targets the inappropriate splanchnic venous pooling causing OH. There is a reluctance to treat sHTN for fear of increasing the risks of falls and syncope associated with OH, thought to be more immediate and dangerous than the late complications of organ damage associated with sHTN. This, however, does not take into account that nighttime sHTN induces natriuresis, volume loss, and begets daytime orthostatic hypotension. It is possible to treat sHTN in ways that reduce the risk of worsening OH. Furthermore, novel approaches, such as the use of local heat can control nighttime sHTN, reduce nocturia, and improve OH. Although continued progress is needed, recent findings offer hope that we can treat nocturnal sHTN and at the same time improve daytime OH, lessening the controversy whether to treat or not sHTN.
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Hipertensão , Hipotensão Ortostática , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipotensão Ortostática/complicações , Hipotensão Ortostática/terapiaRESUMO
BACKGROUND: Sublingual nitroglycerin (SL NTG) is useful for treating acute decompensated heart failure, possibly by increasing splanchnic capacitance and reducing left ventricular (LV) preload. We evaluated a radionuclide method to study these effects, initially in subjects without heart failure. METHODS AND RESULTS: Red blood cells were labelled by an in vitro method. Abdominal and chest images were obtained at rest, showing relative regional blood volumes. The abdomen was then re-imaged during progressive escalation of intrathoracic pressure using continuous positive airway pressure to assess baseline splanchnic capacitance (pressure-volume relationship, PVR) and compliance (slope of PVR). The procedure was repeated after 0.6 mg SL NTG, followed by chest images. Relative splanchnic blood volume increased at rest after SL NTG (P < .002), signifying an increase in splanchnic capacitance. The slope of the splanchnic PVR decreased in proportion to the baseline PVR (P = .0014), signifying increased compliance. The relative pulmonary blood volume decreased in proportion to the increase in splanchnic blood volume (P = .01). CONCLUSIONS: A semi-quantitative radionuclide method demonstrated the effect of SL NTG for increasing splanchnic capacitance and compliance, with a proportional decrease in pulmonary blood volume. These data may be applied to quantitatively evaluate the importance of splanchnic vasodilation as a mechanism of LV preload reduction in the treatment of heart failure. CLINICAL TRIALS REGISTRATION: NCT02425566.
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Insuficiência Cardíaca , Nitroglicerina , Humanos , Pressão Sanguínea , Volume Sanguíneo , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Pulmão , Nitroglicerina/farmacologia , Radioisótopos/farmacologiaRESUMO
BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a debilitating form of chronic orthostatic intolerance that primarily affects women and causes substantial impairment in quality of life and function. Yet, there is minimal literature describing the employment and economic consequences of POTS. We explored these aspects of the POTS patient experience through a self-reported study designed using community-based participatory research principles. METHODS AND RESULTS: A comprehensive questionnaire, including employment and economic consequences, was developed in partnership with Dysautonomia International, a patient advocacy organization. The POTS community engaged in all stages of the research design and analysis. Participants were recruited through Dysautonomia International's website and social media channels. The analysis included 5,556 adult (age ≥18 years) participants with a physician-confirmed diagnosis of POTS. The majority of participants were female (95%). Forty-eight per cent of participants reported employment during the three months prior to the survey, and of these participants, 66.8% would work greater hours if not for illness limitations. Over two-thirds (70.5%) of participants have lost income due to POTS symptoms, with 36.0% of the total cohort losing more than $10,000 USD in the 12 months prior to the survey. Almost all (95%) participants reported POTS-related out-of-pocket medical expenses since diagnosis, with 51.1% of participants spending $10,000 USD or more. CONCLUSIONS: This is the largest study reporting the employment and economic challenges experienced by individuals with POTS. Exposure of these challenges emphasizes the need for earlier diagnosis and improved therapeutic strategies to reduce the negative individual and societal consequences of this disorder.
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Emprego , Síndrome da Taquicardia Postural Ortostática/economia , Efeitos Psicossociais da Doença , Feminino , Humanos , Renda , Masculino , Síndrome da Taquicardia Postural Ortostática/complicações , Síndrome da Taquicardia Postural Ortostática/diagnósticoRESUMO
PURPOSE: Neurogenic orthostatic hypotension (nOH) is the hallmark of neurodegenerative forms of autonomic failure, including pure autonomic failure, multiple system atrophy, and Parkinson's disease. Studies have shown autonomic physiological differences in Africans Americans (AA) such as lower heart rate variability, enhanced blood pressure reactivity, and blunted sympathetic neural response compared to non-Hispanic whites. However, the clinical characteristics and neurohormonal profile of autonomic failure in AA is unknown. METHODS: A total of 65 patients with nOH participated in this study (9 AA and 56 non-Hispanic whites). Both groups were of similar age and comorbidity status, and they underwent standardized autonomic testing and assessment of neurohormonal levels and renin activity and aldosterone in supine and upright positions. RESULTS: There were no significant differences in baseline autonomic clinical characteristics between non-Hispanic whites and AA with nOH. Non-Hispanic whites demonstrated a significant increase in upright renin activity compared to AA (295 ± 88% vs. 13 ± 13%, respectively). AA showed a blunted increase in aldosterone compared to non-Hispanic whites (188 ± 27% vs. 59 ± 38%, respectively). These results indicated persistent suppression of the renin-angiotensin system in AA, particularly during upright posture. CONCLUSION: Our findings demonstrate that AA with nOH have similar clinical characteristics and hemodynamic autonomic profiles, but lower upright renin activity and aldosterone levels, compared to non-Hispanic whites. Renin suppression persists in AA with severe autonomic failure and can potentially contribute to postural changes and supine hypertension.
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Doenças do Sistema Nervoso Autônomo , Hipertensão , Hipotensão Ortostática , Negro ou Afro-Americano , Pressão Sanguínea , HumanosRESUMO
PURPOSE: In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension. METHODS: A multicenter ascending-dose trial (range 1-20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine/seated/standing blood pressure, and safety. RESULTS: Thirty-four patients (age 66 ± 8 years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6-52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration. CONCLUSION: Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure. TRIAL REGISTRATION: NCT02705755 (first posted March 10, 2016).
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Droxidopa , Hipotensão Ortostática , Idoso , Pressão Sanguínea , Tontura/induzido quimicamente , Método Duplo-Cego , Droxidopa/efeitos adversos , Humanos , Hipotensão Ortostática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , NorepinefrinaRESUMO
PURPOSE: Pure autonomic failure (PAF) results from an impaired peripheral autonomic nervous system, and clinical symptoms present with orthostatic hypotension. While the impact on cardiovascular indices of orthostatic intolerance are well-characterized, more limited information is available regarding cerebral hemodynamic dysfunction in PAF. The objective of this study was to test the hypothesis that cerebral blood flow (CBF) is reduced in PAF, and to quantify the relationship between CBF and clinical indicators of disease severity, including peripheral supine arterial blood pressure. METHODS: Participants with PAF (n = 17) and age- and sex-matched normotensive healthy controls (n = 17) were examined using established clinical rating scales, cardiovascular autonomic function tests, and 3T MRI measurements of CBF. CBF-weighted images were also used to determine the prevalence of venous hyperintensities from the major dural sinuses as evidence of abnormal capillary flow. Nonparametric tests and general linear models were used to evaluate differences and correlations between study variables. RESULTS: Gray matter CBF was higher in PAF (51.1 ± 13.4 mL/100 g/min) compared to controls (42.9 ± 6.5 mL/100 g/min, p = 0.007). Venous hyperintensities were more prevalent in PAF relative to controls, and the presence and degree of venous hyperintensities was associated with higher mean CBF (p = 0.027). In PAF participants, CBF and supine systolic blood pressure were inversely related (Spearman's rho = -0.545, p = 0.024). CONCLUSIONS: Findings suggest that PAF patients may exhibit elevated CBF and provide evidence that this condition exerts a hemodynamic impact in the central nervous system.
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Doenças do Sistema Nervoso Autônomo , Hipotensão Ortostática , Insuficiência Autonômica Pura , Sistema Nervoso Autônomo , Pressão Sanguínea , Circulação Cerebrovascular , Humanos , Insuficiência Autonômica Pura/diagnóstico por imagemRESUMO
PURPOSE: The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. METHODS: Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations. RESULTS: The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. CONCLUSIONS: Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.
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Hipotensão Ortostática , Atrofia de Múltiplos Sistemas , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/terapia , Avaliação de Resultados em Cuidados de Saúde , Índice de Gravidade de DoençaRESUMO
PURPOSE: Postural tachycardia syndrome (POTS), a syndrome characterized by orthostatic symptoms and a heart rate increase of at least 30 beats per minute in the absence of hypotension upon standing, is often accompanied by increased sympathetic activity and low blood volume. A common non-pharmacologic recommendation for patients with POTS is a high-sodium (HS) diet with the goal of bolstering circulating blood volume. The objective of this study is to assess the effects of 6 days of a HS diet on endothelial function in POTS. METHODS: A total of 14 patients with POTS and 13 age-matched healthy controls, all females, were studied following 6 days on a low-sodium (LS) diet (10 mEq/day) and 6 days on a HS diet (300 mEq/day) in a crossover design. We measured endothelial function following reactive hyperemia in the brachial artery using flow-mediated dilation (FMD), leg blood flow (LBF) using strain gauge plethysmography in the calf, and reactive hyperemic index (RHI) in the microcirculation of the hand using pulsatile arterial tonometry. RESULTS: On the LS diet, FMD% did not differ between patients with POTS and the healthy controls although peak brachial artery diameter was lower for the patient group. RHI was higher for the patient group than for the controls, but there were no differences in post-ischemic LBF increase. On the HS diet, there were no between-group differences in FMD%, LBF increase, or RHI. CONCLUSION: In summary, a HS diet for 6 days did not induce endothelial dysfunction. This non-pharmacologic treatment used for patients with POTS does not negatively affect endothelial function when used for a sub-acute duration. TRIAL REGISTRATION: ClinicalTrials.gov NCT01550315; March 9, 2012.
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Síndrome da Taquicardia Postural Ortostática , Pressão Sanguínea , Estudos Cross-Over , Dieta , Feminino , Frequência Cardíaca , Humanos , SódioRESUMO
RATIONALE: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. OBJECTIVE: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. METHODS AND RESULTS: As in dopamine ß-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine ß-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine ß-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine. CONCLUSIONS: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.
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Códon sem Sentido , Grupo dos Citocromos b/genética , Hipotensão Ortostática/genética , Glândulas Suprarrenais/metabolismo , Adulto , Animais , Ácido Ascórbico/metabolismo , Encéfalo/metabolismo , Catecolaminas/metabolismo , Feminino , Humanos , Hipotensão Ortostática/patologia , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Linhagem , Vesículas Secretórias/metabolismo , SíndromeRESUMO
This review provides recommendations for the treatment of neurogenic orthostatic hypotension (nOH), postprandial hypotension, and supine hypertension. It focuses on novel treatment strategies and new insights into the mechanism underlying these conditions. Our goal is to provide practical advice for clinicians on how to screen, diagnose, and treat these conditions with nonpharmacological and pharmacological approaches. For each disorder, we offered a stepwise recommendation on how to apply these new concepts to successfully ameliorate the symptoms associated with OH to prevent syncope and falls. The management of OH in patients who also have supine hypertension requires special considerations and pharmacotherapy. It is noteworthy that there are few therapeutic options for OH and only two Food and Drug Administration-approved drugs for the treatment of OH and nOH based on randomized clinical trials. We will use these studies to develop evidence-based guidelines for OH. The research is limited for postprandial hypotension and supine hypertension, and therefore the recommendations will be based on small studies, clinical expertise, and, above all, an understanding of the underlying pathophysiology.
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Doenças do Sistema Nervoso Autônomo , Hipertensão , Hipotensão Ortostática , Hipotensão , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/terapia , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Hipertensão/terapia , Hipotensão/diagnóstico , Hipotensão/fisiopatologia , Hipotensão/terapia , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/fisiopatologia , Hipotensão Ortostática/terapiaRESUMO
INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. CONCLUSION: Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.
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Doenças do Sistema Nervoso Autônomo/epidemiologia , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Sociedades Médicas/tendências , Doenças do Sistema Nervoso Autônomo/induzido quimicamente , Doenças do Sistema Nervoso Autônomo/diagnóstico , Síndrome de Fadiga Crônica/induzido quimicamente , Síndrome de Fadiga Crônica/diagnóstico , Síndrome de Fadiga Crônica/epidemiologia , Humanos , Vacinas contra Papillomavirus/efeitos adversos , Síndrome da Taquicardia Postural Ortostática/induzido quimicamente , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Síndrome da Taquicardia Postural Ortostática/epidemiologia , Disautonomias Primárias/induzido quimicamente , Disautonomias Primárias/diagnóstico , Disautonomias Primárias/epidemiologia , Estados Unidos/epidemiologiaRESUMO
Primary neurodegenerative autonomic disorders are characterized clinically by loss of autonomic regulation of blood pressure. The clinical picture is dominated by orthostatic hypotension, but supine hypertension is also a significant problem. Autonomic failure can result from impairment of central autonomic pathways (multiple system atrophy) or neurodegeneration of peripheral postganglionic autonomic fibers (pure autonomic failure, Parkinson's disease). Pharmacologic probes such as the ganglionic blocker trimethaphan can help us in the understanding of the underlying pathophysiology and diagnosis of these disorders. Conversely, understanding the pathophysiology is crucial in the development of effective pharmacotherapy for these patients. Autonomic failure patients provide us with an unfortunate but unique research model characterized by loss of baroreflex buffering. This greatly magnifies the effect of stimuli that would not be apparent in normal subjects. An example of this is the discovery of the osmopressor reflex: ingestion of water increases blood pressure by 30-40 mm Hg in autonomic failure patients. Animal studies indicate that the trigger of this reflex is related to hypo-osmolality in the portal circulation involving transient receptor potential vanilloid 4 receptors. Studies in autonomic failure patients have also revealed that angiotensin II can be generated through noncanonical pathways independent of plasma renin activity to contribute to hypertension. Similarly, the mineralocorticoid receptor antagonist eplerenone produces acute hypotensive effects, highlighting the presence of non-nuclear mineralocorticoid receptor pathways. These are examples of careful clinical research that integrates pathophysiology and pharmacology to advance our knowledge of human disease.
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Fármacos do Sistema Nervoso Autônomo/farmacologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Fármacos Cardiovasculares/farmacologia , Sistema Cardiovascular/inervação , Hipertensão/fisiopatologia , Hipotensão/fisiopatologia , Neurotransmissores/farmacologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/metabolismo , Barorreflexo/efeitos dos fármacos , Bloqueadores Ganglionares/farmacologia , Humanos , Hipertensão/etiologia , Hipertensão/metabolismo , Hipotensão/etiologia , Hipotensão/metabolismo , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Decúbito Dorsal , Simpatomiméticos/farmacologia , Vasoconstritores/farmacologiaRESUMO
OBJECTIVE: Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS: Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS: We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 ± 25 vs -21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION: A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522-531.
Assuntos
Frequência Cardíaca/fisiologia , Hipotensão Ortostática/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Insuficiência Autonômica Pura/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/epidemiologia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/epidemiologia , Estudos Prospectivos , Insuficiência Autonômica Pura/diagnóstico , Insuficiência Autonômica Pura/epidemiologia , Posição OrtostáticaRESUMO
PURPOSE OF REVIEW: Patients with severe orthostatic hypotension due to autonomic failure may be hypertensive in the supine position. Until recently, there were no internationally recognized diagnostic criteria for supine hypertension. This review covers diagnostic criteria, mechanisms, and management of supine hypertension in autonomic failure patients. RECENT FINDINGS: Recently, an international consensus group defined supine hypertension in patients with neurogenic orthostatic hypotension as brachial SBP at least 140âmmHg and/or DBP at least 90âmmHg while supine. Using these criteria, a large proportion of patients with orthostatic hypotension is diagnosed with supine hypertension. Recent research supports the concept that the hypertension can be mediated through residual sympathetic nervous system function and independently from sympathetic activity, for example via mineralocorticoid receptor activation. SUMMARY: The clear definition of supine hypertension is an important step that will hopefully foster clinical research in this area. Supine hypertension promotes renal sodium excretion, thus, worsening orthostatic hypotension the next morning. Supine hypertension may promote cardiovascular and renal disease. Yet, long-term benefits of treating supine hypertension be it through non pharmacological or pharmacological means have not been proven by sufficiently large clinical trials.
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Hipertensão , Pressão Sanguínea , Humanos , Hipotensão Ortostática , Decúbito Dorsal , Sistema Nervoso SimpáticoRESUMO
BACKGROUND: Droxidopa is a norepinephrine precursor that improves symptoms of neurogenic orthostatic hypotension in conditions such as Parkinson disease, multiple system atrophy, and pure autonomic failure by inducing a pressor effect. Unlike other pressor agents, droxidopa crosses the blood-brain barrier; however, its central effects are, as of yet, uncharacterized. OBJECTIVE: We present the results of a retrospective cohort study examining cognitive and behavioral side effects linked to droxidopa therapy. METHODS: We performed a review of 101 patients who had been treated with droxidopa at an academic tertiary care center and identified cases of cognitive and behavioral changes associated with the therapy. RESULTS: We identified six patients who had developed cognitive and behavioral symptoms, including memory difficulties, confusion, mania, and irritability, shortly after droxidopa initiation. All six patients displayed symptoms of synucleinopathy, manifesting with autonomic failure, rapid eye movement sleep behavior disorder, and parkinsonism. Patients had no significant cognitive or behavioral symptoms before droxidopa initiation. Behavioral disturbances were observed early in the droxidopa titration period and at relatively low doses. Symptoms resolved with dose reduction in four patients, and droxidopa was discontinued in two patients due to persistent irritability. No other medical comorbidities or alternative etiologies were identified to explain the symptoms. CONCLUSIONS: Droxidopa is designed to act peripherally as a pressor agent but may also exert important central effects. We hypothesize that the cognitive and behavioral manifestations observed in the patients with orthostatic hypotension resulted from an "overdose" of key noradrenergic networks linking orbitofrontal and mesolimbic regions.