RESUMEN
BACKGROUND: The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program. METHODS: Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m(2), underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry. RESULTS: Weight loss averaged -8.3 ± 0.6% of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9%, P = 0.04) and exogenous insulin clearance (by 12 ± 5%, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by -12 ± 5%, whole-body norepinephrine spillover rate by -14 ± 8%, and MSNA by -9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = -0.63, P = 0.01) which explained 40% of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64% of the variance. CONCLUSIONS: Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850.
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Restricción Calórica , Dedos/irrigación sanguínea , Hiperinsulinismo/dietoterapia , Insulina/sangre , Hígado/metabolismo , Obesidad/dietoterapia , Resistencia Vascular , Pérdida de Peso , Anciano , Biomarcadores/sangre , Glucemia/metabolismo , Índice de Masa Corporal , Péptido C/sangre , Femenino , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Hiperinsulinismo/sangre , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/etiología , Hiperinsulinismo/fisiopatología , Cinética , Masculino , Manometría , Persona de Mediana Edad , Músculo Esquelético/inervación , Norepinefrina/sangre , Obesidad/sangre , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/fisiopatología , Pletismografía , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatología , Resultado del Tratamiento , VictoriaRESUMEN
INTRODUCTION: We aimed to determine the accuracy of the echocardiographic assessment of cardiac index (CI) in subjects with preserved left ventricular ejection fraction (LVEF). METHODS: Thirty-three subjects with LVEF >50%, normal sinus rhythm, and a broad spectrum of hemodynamic profiles underwent echocardiography immediately followed by right heart catheterization. As gold standards, CI was assessed using thermodilution [CI (TD)] and the Fick method [CI (F)]. Echocardiographic CI was assessed by four methods: from the left ventricular outflow tract (LVOT) velocity time integral and the LVOT diameter as measured [CI (LVOTm)] as well as estimated from body surface area [CI (LVOTe)], and from stroke volume indices assessed using the biplane [CI (BP)] and monoplane [CI (MP)] methods. RESULTS: The mean CI (TD), CI (F), CI (LVOTm), CI (LVOTe), CI (BP), and CI (MP) were 3.0 ± 0.9, 3.1 ± 0.7, 2.8 ± 0.6, 3.3 ± 0.6, 2.0 ± 0.6, and 2.2 ± 0.7 L/min/m(2) . There were modest correlations between CI (TD) and CI (F) and all four noninvasive measures of CI with r(2) values ranging from 0.09 to 0.30. CI (LVOTm) underestimated CI (TD) and CI (F) by 0.3 and 0.3 L/min/m(2) , CI (LVOTe) overestimated CI (TD) and CI (F) by 0.3 and 0.2 L/min/m(2) , and CI (BP) and CI (MP) underestimated CI (TD) and CI (F) by 1.1 and 1.1 L/min/m(2) and 0.9 and 0.9 L/min/m(2) , respectively, with large limits of agreement for all comparisons. CONCLUSIONS: In subjects with nondilated left ventricles with preserved LVEF, flow- or volume-based measures of CI by 2D echocardiography may not accurately reflect CI (TD) and CI (F). Further larger studies are required to verify our findings and to evaluate the accuracy of contrast and 3D echocardiography in this setting.
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Gasto Cardíaco/fisiología , Ventrículos Cardíacos/diagnóstico por imagen , Volumen Sistólico/fisiología , Función Ventricular Izquierda/fisiología , Anciano , Cateterismo Cardíaco , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Estudios Prospectivos , Reproducibilidad de los Resultados , Termodilución , UltrasonografíaRESUMEN
CONTEXT: Impaired insulin clearance contributes to the hyperinsulinemia of obesity, yet relatively little is known concerning the pathophysiological determinants of insulin clearance in obese populations. OBJECTIVE: To examine the cross-sectional relationship between insulin clearance and resting sympathetic nervous system activity in a cohort of obese subjects with metabolic syndrome. PARTICIPANTS AND METHODS: Unmedicated, nonsmoking subjects (31 male, 27 female; aged 56 ± 1 year; body mass index 33.7 ± 0.6 kg/m(2)) underwent euglycemic hyperinsulinemic clamp to determine insulin sensitivity (M) and insulin clearance, assessment of norepinephrine kinetics, peripheral arterial tonometry, Doppler echocardiography, and oral glucose tolerance test. RESULTS: Univariate correlation analyses showed inverse associations between insulin clearance and arterial norepinephrine concentration (r = -0.44, P = .0006), calculated norepinephrine spillover rate (r = -0.33, P = .01), augmentation index (AI, r = -0.37, P = .005), and positive associations with M (r = 0.30, P = .02), Matsuda insulin sensitivity index (r = 0.27, P = .04), and cardiac output (r = 0.27, P = .04). Insulin clearance and sensitivity did not differ between genders, however females had higher AI compared to males (35 ± 3% versus 14 ± 2%, P < .001). In age and gender adjusted stepwise regression analyses, arterial norepinephrine concentration alone explained 19% of the variance in insulin clearance. When all significant variables were entered into the regression model, arterial norepinephrine, AI, gender, and M were independent predictors of insulin clearance, together explaining 41% of the variance. CONCLUSIONS: Arterial norepinephrine concentration is inversely and independently associated with whole-body insulin clearance rate in obese individuals with metabolic syndrome. Prospective studies are needed to determine the direction of causality and the chronology of interactions between insulin clearance and sympathetic neural activity.
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Insulina/metabolismo , Síndrome Metabólico/metabolismo , Norepinefrina/sangre , Obesidad/metabolismo , Arterias , Glucemia/metabolismo , Estudios de Cohortes , Estudios Transversales , Femenino , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Obesidad/complicacionesRESUMEN
CONTEXT: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. OBJECTIVE: The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake. PARTICIPANTS AND METHODS: A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography. RESULTS: PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08). CONCLUSIONS: Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.
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Presión Sanguínea/efectos de los fármacos , Síndrome Metabólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Sistema Nervioso Simpático/efectos de los fármacos , Tiazolidinedionas/administración & dosificación , Diástole/efectos de los fármacos , Método Doble Ciego , Ecocardiografía Doppler , Endotelio Vascular/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hiperinsulinismo/tratamiento farmacológico , Hiperinsulinismo/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipoglucemiantes/administración & dosificación , Masculino , Síndrome Metabólico/fisiopatología , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/sangre , Metoxihidroxifenilglicol/farmacocinética , Persona de Mediana Edad , Modelos Biológicos , Norepinefrina/sangre , Norepinefrina/farmacocinética , Obesidad/fisiopatología , Pioglitazona , Placebos , TritioRESUMEN
Chronic HIV infection is associated with increased risk of cardiovascular disease (CVD), including in patients with virological suppression. Persistent innate immune activation may contribute to the development of CVD via activation of monocytes in these patients. We investigated whether changes in monocyte phenotype predict subclinical atherosclerosis in virologically suppressed HIV-positive individuals with low cardiovascular risk. We enroled 51 virologically suppressed HIV-positive individuals not receiving protease inhibitors or statins and 49 age-matched uninfected controls in this study. Carotid artery intima-media thickness (cIMT) was used as a surrogate marker for CVD, and traditional risk factors, including Framingham risk scores, were recorded. Markers of monocyte activation (CD14, CD16, CCR2, CX3CR1, CD38, HLA-DR and CD11b) were measured in whole-blood samples by flow cytometry. Associations were assessed using univariate and multivariate median regressions. Median cIMT was similar between HIV-positive and HIV-negative participants (P=0.3), although HIV-positive patients had significantly higher Framingham risk score (P=0.009) and systemic inflammation. Expression of two monocyte markers, CD11b and CX3CR1, independently predicted carotid artery thickness in HIV-positive individuals after controlling for Framingham risk score (P=0.025 and 0.015, respectively). These markers were not predictive of carotid artery thickening in controls. Our study indicates that monocyte surface markers may serve as novel predictors of CVD in HIV-positive individuals and is consistent with an important role for monocyte activation in the progression of HIV-related cardiovascular pathology.
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Antígenos de Diferenciación/inmunología , Enfermedades de las Arterias Carótidas/inmunología , Seropositividad para VIH/inmunología , VIH-1/inmunología , Monocitos/inmunología , Adulto , Antígenos de Diferenciación/sangre , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/patología , Femenino , Seropositividad para VIH/sangre , Seropositividad para VIH/patología , VIH-1/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Monocitos/patología , Estudios ProspectivosRESUMEN
CONTEXT: Altered cardiac structure and function have been reported in prediabetic and diabetic populations; however, the contribution of the sympathetic nervous system (SNS) to these changes has yet to be delineated. OBJECTIVE: Our objective was to examine interrelationships between glucose metabolism, left ventricular mass and function, and SNS activity in obese metabolic syndrome subjects. PARTICIPANTS AND METHODS: Unmedicated impaired glucose tolerant (IGT) (n = 31) or treatment-naive type 2 diabetic (T2D) (n = 25) subjects, matched for age (mean 58 ± 1 years), gender, body mass index (32.2 ± 0.5 kg/m(2)), and blood pressure, participated. They underwent echocardiography and assessments of whole-body norepinephrine kinetics, muscle sympathetic nerve activity, and insulin sensitivity by euglycemic clamp (M value). RESULTS: T2D subjects had higher left ventricular mass index (LVMI) (93.6 ± 3.5 vs 77.2 ± 3.4 g/m(2), P = .002) and Doppler-derived isovolumetric relaxation and deceleration times (both P < .05) and lower early/late transmitral inflow velocities (E/A) (P = .02) compared with IGT. Total muscle sympathetic nerve activity and arterial norepinephrine concentration were higher in the T2D group (by 18% and 32%, respectively, both P ≤ .05), whereas plasma norepinephrine clearance was reduced (1.94 ± 0.11 vs 2.26 ± 0.10 L/min, P = .02). M value correlated inversely with left ventricular septal thickness (r = -0.46, P = .007). Whole-body noradrenaline spillover rate correlated with LVMI in the T2D subgroup (r = 0.47, P = .03). In the pooled cohort, LVMI was independently predicted by pulse pressure (r = 0.38, P = .004) and E/A ratio by 2-hour glucose (r = -0.38, P = .005). CONCLUSIONS: Transition from IGT to T2D is associated with cardiac enlargement and diastolic dysfunction, which relate to metabolic, hemodynamic, and SNS alterations.
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Glucosa/metabolismo , Ventrículos Cardíacos/fisiopatología , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Sistema Nervioso Simpático/fisiopatología , Función Ventricular Izquierda/fisiología , Presión Sanguínea/fisiología , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Técnica de Clampeo de la Glucosa , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/metabolismo , Humanos , Resistencia a la Insulina/fisiología , Masculino , Síndrome Metabólico/complicaciones , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Norepinefrina/metabolismo , Obesidad/complicaciones , Obesidad/fisiopatología , Sistema Nervioso Simpático/metabolismo , UltrasonografíaRESUMEN
BACKGROUND: Haemodialysis results in a left ventricular hypertrophic response. It is unclear whether tight blood pressure control or particular medications might attenuate this response. We sought to determine, in a pre-dialysis cohort on atenolol, whether Losartan might attenuate left ventricular hypertrophy post arteriovenous fistula creation in end stage kidney disease. MATERIALS AND METHODS: Placebo controlled double blind randomisation of 26 patients to fixed dose atenolol plus fixed dose losartan or placebo occurred 1 day prior to fistula creation. Pre-randomisation echocardiography was repeated at 1 week and 1-month. Measurement was undertaken of blood pressure, heart rate, brain natriuretic peptide, serum creatinine and estimated glomerular filtration rate. The primary pre-specified endpoint was the change in left ventricular mass at 1 month. Non-parametric statistical comparison was performed within and between groups. RESULTS: There was no difference in left ventricular mass between our groups 1-month post fistula creation. In the entire cohort, change in left ventricular mass was driven by changes in blood pressure and volume loading. Blood pressure changes correlated with left ventricular mass changes seen shortly post arteriovenous fistula creation, suggesting blood pressure control during this time period may be an important part of the management of end stage kidney disease. CONCLUSIONS: We did not see an advantage with the use of losartan with respect to diminution of the LVM response. However, our demonstrated change in LVM was relatively small compared to previous literature and suggests a possible role for beta blockade as a neurohormonal modulator around the time of arteriovenous fistula creation. TRIAL REGISTRATION: Clinical trials.gov (NCT00602004).
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Antihipertensivos/uso terapéutico , Derivación Arteriovenosa Quirúrgica/efectos adversos , Presión Sanguínea , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/etiología , Losartán/uso terapéutico , Adulto , Anciano , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Modelos Lineales , Losartán/farmacología , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/metabolismo , Placebos , UltrasonografíaRESUMEN
BACKGROUND: The accuracy of Doppler echocardiography to estimate key hemodynamic parameters in subjects with normal left ventricular ejection fraction (LVEF) has not been fully investigated. METHODS AND RESULTS: Thirty-six subjects with LVEF >50% (median age 62 years), with a broad clinical profile, underwent Doppler echocardiography immediately followed by right heart catheterization. Correlation coefficients between invasive and noninvasive right atrial pressure (RAP), systolic (sPAP) and mean (mPAP) pulmonary artery pressure, cardiac output (CO), and pulmonary vascular resistance (PVR) were 0.39, 0.70, 0.72, 0.57, and 0.60 (P < .001 for all). There was no significant correlation between invasive and noninvasive (based on the peak early transmitral to peak early septal mitral annular velocity ratio) pulmonary capillary wedge pressure (PCWP; r = 0.23; P = .18). Bland-Altman plots revealed variable bias but with consistently large limits of agreement for all noninvasive parameters, particularly PCWP. Areas under the receiver operating characteristic curve for noninvasive sPAP, CO, PVR, and PCWP to predict an invasively assessed mPAP ≥25 mm Hg, cardiac index <2.5 L min(-1) m(-2), PVR >3 Wood units, and PCWP ≤15 mm Hg, respectively, were 0.92, 0.83, 0.70, and 0.58. CONCLUSIONS: Single Doppler echocardiography parameters are not accurate enough to reliably estimate key hemodynamic parameters, particularly PCWP, in subjects with normal LVEF.