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BACKGROUND: Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric-oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin-mediated vasodilation in adult subjects with obesity. METHODS AND RESULTS: In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast-enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min, P=0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min, P=0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively, P=0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively, P=0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU2/s, respectively, P=0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin-induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively, P=0.031). CONCLUSIONS: We conclude that sympathetic activation impairs insulin-mediated microvascular recruitment in adult subjects with obesity.
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BACKGROUND: Supine hypertension affects most patients with orthostatic hypotension (OH) due to autonomic failure, but it is often untreated for fear of worsening OH. We hypothesized that increasing intrathoracic pressure with continuous positive airway pressure (CPAP) had a Valsalva-like blood-pressure-lowering effect that could be used to treat nocturnal supine hypertension in these patients, while reducing nocturnal pressure diuresis and improving daytime OH. METHODS: In Protocol 1, we determined the acute hemodynamic effects of increasing levels of CPAP (0, 4, 8, 12, and 16 cm H2O, 3 minutes each) in 26 patients with autonomic failure and supine hypertension studied while awake and supine. In Protocol 2 (n=11), we compared the effects of overnight therapy with CPAP (8-12 cm H2O for 8 hours) versus placebo on nocturnal supine hypertension, nocturnal diuresis and daytime OH in a 2-night crossover study. RESULTS: In Protocol 1, acute CPAP (4-16 cm H2O) decreased systolic blood pressure in a dose-dependent manner (maximal drop 22±4 mmHg with CPAP 16) due to reductions in stroke volume (-16+3%) and cardiac output (-14±3%). Systemic vascular resistance and heart rate remained unchanged. In Protocol 2, overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance (AUC upright SBP 642±121 versus placebo 410±109 mmHg*min; P=0.014). CONCLUSIONS: CPAP is a novel nonpharmacologic approach to treat the supine hypertension of autonomic failure while improving nocturia and daytime OH. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03312556.
Assuntos
Hipertensão , Hipotensão Ortostática , Insuficiência Autonômica Pura , Humanos , Pressão Positiva Contínua nas Vias Aéreas , Estudos Cross-Over , Hipertensão/tratamento farmacológico , Pressão SanguíneaRESUMO
[Figure: see text].
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Inibidores da Captação Adrenérgica/farmacologia , Cloridrato de Atomoxetina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipotensão Ortostática/fisiopatologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Doença de Parkinson/fisiopatologia , Insuficiência Autonômica Pura/fisiopatologia , Idoso , Feminino , Humanos , Hipotensão Ortostática/sangue , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/sangue , Norepinefrina/sangue , Doença de Parkinson/sangue , Insuficiência Autonômica Pura/sangue , Estudos RetrospectivosRESUMO
BACKGROUND: High sodium intake is recommended for the treatment of postural tachycardia syndrome (POTS) to counteract the hypovolemia and elevated plasma norepinephrine that contribute to excessive orthostatic tachycardia, but evidence of its efficacy is not available. OBJECTIVES: This study tested whether a high sodium (HS) diet reduces orthostatic tachycardia (Δ heart rate) and upright heart rate compared with a low sodium (LS) diet in POTS patients, and secondarily its effect on plasma volume (PV) and plasma norepinephrine. METHODS: A total of 14 POTS patients and 13 healthy control subjects (HC), age 23 to 49 years, were enrolled in a crossover study with 6 days of LS (10 mEq sodium/day) or HS (300 mEq sodium/day) diet. Supine and standing heart rate, blood pressure, serum aldosterone, plasma renin activity, blood volume, and plasma norepinephrine and epinephrine were measured. RESULTS: In POTS, the HS diet reduced upright heart rate and Δ heart rate compared with the LS diet. Total blood volume and PV increased, and standing norepinephrine decreased with the HS compared with the LS diet. However, upright heart rate, Δ heart rate, and upright norepinephrine remained higher in POTS than in HC on the HS diet (median 117 beats/min [interquartile range: 98 to 121 beats/min], 46 beats/min [interquartile range: 32 to 55 beats/min], and 753 pg/ml [interquartile range: 498 to 919 pg/ml] in POTS vs. 85 beats/min [interquartile range: 77 to 95 beats/min], 19 beats/min [interquartile range: 11 to 32 beats/min], and 387 pg/ml [interquartile range: 312 to 433 pg/ml] in HC, respectively), despite no difference in the measured PV. CONCLUSIONS: In POTS patients, high dietary sodium intake compared with low dietary sodium intake increases plasma volume, lowers standing plasma norepinephrine, and decreases Δ heart rate. (Dietary Salt in Postural Tachycardia Syndrome; NCT01547117).
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Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Síndrome da Taquicardia Postural Ortostática/terapia , Postura/fisiologia , Sódio na Dieta/administração & dosagem , Adulto , Biomarcadores/sangue , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Síndrome da Taquicardia Postural Ortostática/sangue , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Adulto JovemRESUMO
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
Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P<0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P=0.013 ) and cardiac output (-15±5% versus -2±4%, P=0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57, P=0.072) and an improvement in the morning upright systolic BP (r=-0.76, P=0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.
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Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea/fisiologia , Hipertensão/terapia , Hipertermia Induzida/métodos , Insuficiência Autonômica Pura/complicações , Idoso , Feminino , Temperatura Alta , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Insuficiência Autonômica Pura/fisiopatologia , Resultado do TratamentoRESUMO
The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet. All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow. Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus, P=0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls, P=0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01308099.
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Pressão Sanguínea/fisiologia , Endotélio Vascular/fisiopatologia , Frequência Cardíaca/fisiologia , Hipotensão Ortostática/fisiopatologia , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Artéria Braquial/fisiopatologia , Endotélio Vascular/metabolismo , Feminino , Força da Mão/fisiologia , Humanos , Perna (Membro)/irrigação sanguínea , Masculino , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
CONTEXT: Women with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can result in increased visceral adiposity (VAT) and impaired vascular function. GH-releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. OBJECTIVE: We tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. METHODS: Eighteen women with PCOS participated in a double-blind, crossover study. They received sitagliptin either 100 mg or placebo daily for 1 month, with crossover treatments separated by an 8-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT) and assessments of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm. RESULTS: During OGTT, sitagliptin increased glucagon-like peptide-1 (P < 0.001), early insulin secretion (from mean [± SD] insulinogenic index 1.9 ± 1.2 to 3.2 ± 3.1; P = 0.02), and decreased peak glucose (mean -17.2 mg/dL [95% CI, -27.7 to -6.6]; P < 0.01). At 1 month, sitagliptin decreased VAT (from 1141.9 ± 700.7 to 1055.1 ± 710.1 g; P = 0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9 ± 3.6 to 17.0 ± 6.8 min, N = 16; P = 0.04) and interpulse interval (from 53.2 ± 20.0 to 77.3 ± 38.2 min, N = 16; P < 0.05) but did not increase mean overnight GH (P = 0.92 vs placebo). CONCLUSIONS: Sitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval. CLINICAL TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov as NCT02122380 prior to enrollment of the first participant.
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Glicemia/metabolismo , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Adolescente , Adulto , Biomarcadores/análise , Glicemia/análise , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Teste de Tolerância a Glucose , Hormônio do Crescimento Humano/metabolismo , Humanos , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/patologia , Prognóstico , Adulto JovemRESUMO
Context: Abnormal fatty acid (FA) metabolism contributes to diabetes and cardiovascular disease. The FA receptor CD36 has been linked to risk of metabolic syndrome. In rodents CD36 regulates various aspects of fat metabolism, but whether it has similar actions in humans is unknown. We examined the impact of a coding single-nucleotide polymorphism in CD36 on postprandial hormone and bile acid (BA) responses. Objective: To examine whether the minor allele (G) of coding CD36 variant rs3211938 (G/T), which reduces CD36 level by â¼50%, influences hormonal responses to a high-fat meal (HFM). Design: Obese African American (AA) women carriers of the G allele of rs3211938 (G/T) and weight-matched noncarriers (T/T) were studied before and after a HFM. Setting: Two-center study. Participants: Obese AA women. Intervention: HFM. Main Outcome Measures: Early preabsorptive responses (10 minutes) and extended excursions in plasma hormones [C-peptide, insulin, incretins, ghrelin fibroblast growth factor (FGF)19, FGF21], BAs, and serum lipoproteins (chylomicrons, very-low-density lipoprotein) were determined. Results: At fasting, G-allele carriers had significantly reduced cholesterol and glycodeoxycholic acid and consistent but nonsignificant reductions of serum lipoproteins. Levels of GLP-1 and pancreatic polypeptide (PP) were reduced 60% to 70% and those of total BAs were 1.8-fold higher. After the meal, G-allele carriers displayed attenuated early (-10 to 10 minute) responses in insulin, C-peptide, GLP-1, gastric inhibitory peptide, and PP. BAs exhibited divergent trends in G allele carriers vs noncarriers concomitant with differential FGF19 responses. Conclusions: CD36 plays an important role in the preabsorptive hormone and BA responses that coordinate brain and gut regulation of energy metabolism.
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Ácidos e Sais Biliares/sangue , Antígenos CD36/genética , Jejum/sangue , Hormônios/sangue , Absorção Intestinal/fisiologia , Adulto , Negro ou Afro-Americano/genética , Antígenos CD36/fisiologia , Estudos de Casos e Controles , Metabolismo Energético/genética , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Black women have one of the highest prevalence rates of hypertension and obesity in the United States. We previously reported that sympathetic activation induced by obesity is a significant contributor to hypertension in white patients. It is unknown whether sympathetic activity similarly contributes to hypertension in obese black women. METHODS AND RESULTS: We studied 42 obese women (16 white, body mass index 36±4 kg/m2, 44% with hypertension; 26 black, body mass index 35±4 kg/m2, 46% with hypertension). Antihypertensive medications were discontinued for 2 weeks before the day of the study. All patients underwent complete autonomic blockade with trimethaphan at a dosage of 4 mg/min. Resting sympathetic activity determined from muscle sympathetic nerve recordings was similar between obese black women with hypertension and those with normotension. In whites, sympathetic activity was elevated in obese patients with hypertension compared with normotension; the decrease in mean arterial blood pressure produced by trimethaphan was greater in obese white patients with hypertension compared with those with normotension (-26.8±9.7 mm Hg versus -14.8±7.9 mm Hg, P=0.02). In contrast, there was no difference in the depressor responses induced by trimethaphan between obese black women with hypertension and those with normotension (-15.5±10.5 mm Hg versus -12.3±10.2 mm Hg, P=0.45). Mean arterial blood pressure remained elevated in obese blacks with hypertension compared with those with normotension during trimethaphan infusion (83.7±15.0 mm Hg versus 71.7±9.8 mm Hg, P=0.02). Heart rate increased similarly with trimethaphan between white (P=0.11) and black (P=0.76) women with hypertension and normotension. CONCLUSIONS: These findings suggest that sympathetic activity does not contribute to hypertension in obese black women and provide further evidence for racial differences in hypertension mechanisms.
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Pressão Sanguínea/fisiologia , Etnicidade , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Obesidade/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Hipertensão/complicações , Hipertensão/etnologia , Obesidade/complicações , Obesidade/etnologia , Prevalência , Estados Unidos/epidemiologiaRESUMO
Context: Dopamine ß-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown. Case Description: We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 µU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis. Conclusions: We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism.
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Doenças do Sistema Nervoso Autônomo/complicações , Dopamina beta-Hidroxilase/deficiência , Hiperinsulinismo/etiologia , Resistência à Insulina , Norepinefrina/deficiência , Adolescente , Animais , Droxidopa/uso terapêutico , Feminino , Humanos , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/tratamento farmacológico , Insulina/metabolismo , Camundongos , PrognósticoRESUMO
CONTEXT: The scavenger receptor CD36 influences the endothelial nitric oxide-cGMP pathway in vitro. Genetic variants that alter CD36 level are common in African Americans (AAs), a population at high risk of endothelial dysfunction. OBJECTIVE: To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences endothelial function, insulin sensitivity (IS), and the response to treatment with the nitric oxide-cGMP potentiator sildenafil. DESIGN: IS (frequently sampled iv glucose tolerance) and endothelial function (flow mediated dilation [FMD]) were determined in age- and body mass index-matched obese AA women with or without the G allele of rs3211938 (protocol 1). Effect of chronic sildenafil treatment on IS and FMD was tested in AA women with metabolic syndrome and with/without the CD36 variant, using a randomized, placebo-controlled trial (protocol 2). SETTING: Two-center study. PARTICIPANTS: Obese AA women. INTERVENTION: A total of 20-mg sildenafil citrate or placebo thrice daily for 4 weeks. MAIN OUTCOME: IS, FMD. RESULTS: G allele carriers have lower FMD (P = .03) and cGMP levels (P = .01) than noncarriers. Sildenafil did not improve IS, mean difference 0.12 (95% confidence interval [CI], -0.33 to 0.58; P = .550). However, there was a significant interaction between FMD response to sildenafil and rs3211938 (P = .018). FMD tended to improve in G carriers, 2.9 (95% CI, -0.9 to 6.8; P = .126), whereas it deteriorated in noncarriers, -2.6 (95% CI, -5.1 to -0.1; P = .04). CONCLUSIONS: The data document influence of a common genetic variant on susceptibility to endothelial dysfunction and its response to sildenafil treatment.
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Antígenos CD36/genética , Endotélio Vascular/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Polimorfismo de Nucleotídeo Único , Citrato de Sildenafila/uso terapêutico , Vasodilatação/efeitos dos fármacos , Adulto , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Resistência a Medicamentos/genética , Endotélio Vascular/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Resistência à Insulina/genética , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Obesidade/fisiopatologia , Resultado do Tratamento , Vasodilatação/genéticaRESUMO
BACKGROUND: Flow-mediated dilation (FMD) is used to assess endothelial function through changes in vascular diameter after hyperemia. High-fat meal (HFM) has been shown to induce endothelial dysfunction; recent studies, however, reported conflicting results in obese African American women (AAW). Differences in the method used to analyze FMD may explain these discrepancies. METHODS AND RESULTS: In protocol 1, we assessed the time course of FMD and compared the repeatability of FMD using the individual maximum peak dilation (FMDpeak) and the dilation at 60 seconds (FMD60). Sixteen AAW (age, 42±10.4 years; body mass index [BMI], 39±5.8 kg/m(2)) were studied on 2 occasions, 4 weeks apart, under fasting conditions (study 1 and study 2). In protocol 2, we used the most repeatable measurement from protocol 1 to assess changes in endothelial function after an HFM in 17 AAW (agen 42±11.1 years; BMIn 38±5.6 kg/m(2)). We found that FMDpeak was the most repeatable measurement (N=16; study 1, 5.31±3.12% and study 2, 5.80±2.91%; r=0.94). After an HFM, the baseline brachial artery diameter significantly increased at 2 hours (0.10 mm; 95% confidence interval [CI], 0.01-0.18; P=0.03) and at 4 hours (0.17 mm; 95% CI, 0.09-0.25; P<0.001). At 2 hours, the FMDpeak decreased compared with pre-HFM (-1.76; 95% CI, -3.55-0.02; P≤0.05). CONCLUSIONS: The individual's maximum peak dilation after hyperemia is the most consistent measure to assess the effect of an HFM on endothelial function. Endothelial dysfunction occurred at 2 hours after an HFM in AAW. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ Unique identifiers: NCT01334554 and NCT02126735.
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Negro ou Afro-Americano , Artéria Braquial/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/fisiopatologia , Refeições , Obesidade/fisiopatologia , Vasodilatação , Adulto , Índice de Massa Corporal , Artéria Braquial/diagnóstico por imagem , Endotélio Vascular/diagnóstico por imagem , Feminino , Humanos , Hiperemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Obesidade/etnologia , Valor Preditivo dos Testes , Fluxo Sanguíneo Regional , Reprodutibilidade dos Testes , Fatores de Tempo , UltrassonografiaRESUMO
PURPOSE: Parkinson disease, an α-synucleinopathy, is associated with reduced insulin sensitivity, impaired glucose tolerance, and diabetes mellitus. Importantly, these metabolic alterations have been shown to contribute to disease progression. The purpose of this study was to determine if reduced insulin sensitivity is also present in other α-synucleinopathies associated with autonomic failure. METHODS: We studied 19 patients with multiple system atrophy and 26 patients with pure autonomic failure. For comparison, we studied 8 healthy controls matched for body mass index. Insulin sensitivity and beta cell function were calculated using fasting glucose and insulin levels according to the homeostatic model assessment 2. A multiple linear regression model was performed to determine factors that predict insulin sensitivity in autonomic failure. RESULTS: There was a significant difference in insulin sensitivity among groups (P = 0.048). This difference was due to lower insulin sensitivity in multiple system atrophy patients: 64% [interquartile range (IQR), 43 to 117] compared to healthy controls 139% (IQR, 83 to 212), P = 0.032. The main factor that contributed to the reduced insulin sensitivity was the presence of supine hypertension and residual sympathetic tone. CONCLUSIONS: Multiple system atrophy patients have reduced insulin sensitivity that is associated with residual sympathetic activation and supine hypertension. These patients may therefore be at high risk for development of impaired glucose tolerance and diabetes mellitus.
Assuntos
Resistência à Insulina/fisiologia , Atrofia de Múltiplos Sistemas/sangue , Atrofia de Múltiplos Sistemas/diagnóstico , Insuficiência Autonômica Pura/sangue , Insuficiência Autonômica Pura/diagnóstico , Sistema Nervoso Simpático/metabolismo , Idoso , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Estudos de Coortes , Feminino , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/sangue , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/epidemiologia , Insuficiência Autonômica Pura/epidemiologiaRESUMO
Postural tachycardia syndrome (POTS) is a form of chronic orthostatic intolerance for which the hallmark physiological trait is an excessive increase in heart rate with assumption of upright posture. The orthostatic tachycardia occurs in the absence of orthostatic hypotension and is associated with a >6-month history of symptoms that are relieved by recumbence. The heart rate abnormality and orthostatic symptoms should not be caused by medications that impair autonomic regulation or by debilitating disorders that can cause tachycardia. POTS is a "final common pathway" for a number of overlapping pathophysiologies, including an autonomic neuropathy in the lower body, hypovolemia, elevated sympathetic tone, mast cell activation, deconditioning, and autoantibodies. Not only may patients be affected by more than one of these pathophysiologies but also the phenotype of POTS has similarities to a number of other disorders, e.g., chronic fatigue syndrome, Ehlers-Danlos syndrome, vasovagal syncope, and inappropriate sinus tachycardia. POTS can be treated with a combination of non-pharmacological approaches, a structured exercise training program, and often some pharmacological support.
Assuntos
Síndrome da Taquicardia Postural Ortostática , Doença Crônica , Frequência Cardíaca , Humanos , Mastócitos , Intolerância Ortostática , Síndrome da Taquicardia Postural Ortostática/diagnóstico , Síndrome da Taquicardia Postural Ortostática/fisiopatologia , PosturaRESUMO
OBJECTIVE: To evaluate whether mandatory fortification of grain products with folic acid in the US is associated with changes in histone methylation in cells involved in cervical carcinogenesis. METHODS: Cervical specimens obtained before (1990 to 1992) and after mandatory folic acid fortification (2000 to 2002) were used to examine the degree of histone methylation (H3 Lys-9) by immunohistochemistry. 91 women (51 before and 40 after fortification) were diagnosed with cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS) and sections utilized in the study also contained normal, reactive or metaplastic cervical epithelium, CIN 1 or CIN 2. 64 women (34 before and 30 after fortification) were free of CIN and these sections contained only normal or reactive cervical epithelium. Immunohistochemical staining for H3 Lys-9, its assessment in different cell or lesion types and data entry were blinded for fortification status. For each cell type or lesion category we used PROC MIXED in SAS with the specimen identifier as a random effect and the robust variance estimator to estimate age- and race-adjusted intensity score for H3 Lys-9 in the pre- and post-fortification periods. RESULTS: Degree of H3 Lys-9 methylation was significantly higher (P < 0.0001) in ≥CIN 2 lesions (CIN 2, CIN 3 and CIS) than in ≤CIN 1 lesions (CIN 1, normal, reactive and metaplastic), in both pre- and post-fortification CIN 3/CIS specimens. Age- and race-adjusted mean H3 Lys-9 score was significantly higher in all cell or lesion types in CIN 3/CIS specimens obtained in the post-fortification period compared to pre-fortification period (P < 0.05, all comparisons). In contrast, in specimens obtained from women free of CIN, Lys-9 methylation in normal/reactive cervical epithelium was significantly lower in post-fortification specimens than in pre-fortification specimens (P = 0.03). CONCLUSIONS: Higher levels of Lys-9 methylation in ≥CIN 2 compared to ≤CIN 1 lesions suggest that higher Lys-9 methylation is associated with progression of lower grade CIN to higher grade CIN. Higher Lys-9 methylation in cervical tissues of women diagnosed with CIN 3 in the post-fortification period than in pre-fortification period suggest that fortification may adversely affect histone methylation in already initiated cells. Lower Lys-9 methylation in normal/reactive cervical cells of women free of CIN in the post-fortification period than pre-fortification on the other hand suggests that fortification is likely to protect against initiation of carcinogenic process in the cervix. These results suggest that mandatory fortification with folic acid in the US seems to have different effects on cancer depending on the stage of carcinogenesis. Because this is the first study to report folic acid fortification-associated differences in histone methylation and because of the limitations inherent to the approach we have taken to demonstrate these differences, validation of the results in other study populations or with other techniques for assessing histone methylation is necessary.
RESUMO
OBJECTIVE: The objective of this study was to evaluate whether mandatory fortification of grain products with folic acid in the United States is associated with changes in DNA methyltransferase-1 (Dnmt-1) expression in cells involved in cervical carcinogenesis. METHODS: Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-1992) and after (2000-2002) mandatory folic acid fortification were used to examine the expression of Dnmt-1 in specific lesions involved in cervical carcinogenesis by immunohistochemistry. The total number of lesions examined was 101 in the prefortification period and 96 in the postfortification period. Immunohistochemical staining for Dnmt-1, its assessment, and data entry were blinded with regard to the fortification status. RESULTS: Age- and race-adjusted mean percentage of cells positive for Dnmt-1 or the Dnmt-1 score was significantly higher in all lesion types (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN, or carcinoma in situ) detected in the postfortification period compared with the prefortification period (P < 0.05, all comparisons). The degree of Dnmt-1 was significantly higher (P < 0.0001) in CIN > or = 2 lesions compared with CIN < or = 1 lesions, regardless of the fortification group. CONCLUSION: These results suggest that mandatory fortification with folic acid in the United States seems to have resulted in a change in the degree of expression of Dnmt-1 in cells involved in cervical carcinogenesis. Because the approach we have taken to demonstrate these differences have limitations inherent to a study of this nature and this is the first study to report a folate fortification associated change in Dnmt-1, validating these results in other study populations and/or with other techniques of assessing Dnmt-1 will increase the scientific credibility of these findings.