E. Lambert

Baseline Sympathetic Nervous System Activity Predicts Dietary Weight Loss in Obese Metabolic Syndrome Subjects

CONTEXTnThe sympathetic nervous system is an important physiological modulator of basal and postprandial energy expenditure.nnnOBJECTIVEnOur objective was to investigate whether the variability of weight loss attained during hypocaloric dietary intervention is related to individual differences in baseline sympathetic drive and nutritional sympathetic nervous system responsiveness.nnnPARTICIPANTS AND METHODSnUntreated obese subjects (n = 42; body mass index = 32.1 ± 0.5 kg/m(2)), aged 57 ± 1 yr, who fulfilled Adult Treatment Panel III metabolic syndrome criteria participated in a 12-wk weight loss program using a modified Dietary Approaches to Treat Hypertension (DASH) diet. Muscle sympathetic nerve activity (MSNA) was measured by microneurography at rest and in a subset of subjects during a standard 75-g oral glucose tolerance test.nnnRESULTSnWeight loss (6.7 ± 0.5 kg) was independently predicted by baseline resting MSNA burst incidence (r = 0.38; P = 0.019), which accounted for 14.3% of the variance after adjustment for age and baseline body weight. Weight loss-resistant subjects in the lower tertile of weight loss (4.4 ± 0.3%) had significantly blunted MSNA responses to oral glucose at baseline compared with successful weight losers (9.6 ± 0.8%). Absolute Δ MSNA averaged -7 ± 2, -6 ± 5, and -3 ± 3 bursts per 100 heartbeats at 30, 60, and 90 min after glucose in the weight loss-resistant group. Corresponding values in the successful weight loss group were 9 ± 3, 12 ± 3, and 15 ± 4 bursts per 100 heartbeats (time × group interaction, P = 0.004).nnnCONCLUSIONSnThese findings indicate that baseline sympathetic drive and nutritional sympathetic responsiveness may be important prognostic biological markers for weight loss outcome.

A Randomized Controlled Trial of the Effects of Pioglitazone Treatment on Sympathetic Nervous System Activity and Cardiovascular Function in Obese Subjects With Metabolic Syndrome

CONTEXTnInsulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk.nnnOBJECTIVEnThe 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.nnnPARTICIPANTS AND METHODSnA 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.nnnRESULTSnPIO 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).nnnCONCLUSIONSnCompared 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.

Soluble vascular endothelial growth factor receptor-1 is reduced in patients with resistant hypertension after renal denervation

Renal denervation (RDN) has been shown in several studies to reduce blood pressure (BP) in patients with resistant hypertension (RH). Data on potential biomarkers associated with BP changes remain scarce. We evaluated whether soluble vascular endothelial growth factor receptor (sVEGFR-1) is affected by the procedure. A total of 57 patients with RH participated in this study. BP and heart rate were recorded at baseline and at 3 months follow-up, at which time blood samples were collected to determine the levels of sVEGFR-1, VEGF-A, VEGF-C, nitric oxide (NO), soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1. None of the biomarkers had a predictive value that could identify responders vs non-responders to RDN. However, sVEGFR-1 concentration was dramatically reduced after RDN (5913±385 vs 280±57u2009pgu2009ml−1, P<0.001). At the same time VEGF-A levels were significantly increased (10.0±3.0 vs 55.5±7.9u2009pgu2009ml−1, P<0.001), without significant changes in VEGF-C. NO levels were significantly increased after RDN in the whole group (82.6±6.2 vs 106.9±7.8u2009μM, P=0.021). Interestingly, the elevation in NO levels at 3 months was only seen in patients who demonstrated a reduction in systolic BP of ⩾10u2009mm Hg (78.9±8.3 vs 111.6±11.7u2009μM, P=0.018). We report a significant reduction in sVEGFR-1 levels after RDN procedure, which was accompanied by a significant increase in VEGF-A concentration as well as NO. Changes in plasma cytokines were not quantitatively linked to magnitude of BP reduction. An RDN-induced reduction in sVEGFR-1 plasma levels and increase in VEGF-A would raise the VEGF-A/sVEGFR-1 ratio, thereby increasing VEGF-A bioavailability to act on its full-length receptor and may contribute to the BP-lowering effect potentially via NO-mediated pathways.

HIGHER MICRORNA-132 IS ASSOCIATED WITH BLOOD PRESSURE AND LIVER STEATOSIS IN OBESE INDIVIDUALS

Objective: Obesity is associated with numerous comorbidities including cardiovascular disease, diabetes and non-alcoholic fatty liver disease (NAFLD). Obesity pathogenesis is complex and incompletely understood and hence therapeutic options to address the global epidemic of obesity are lacking. In addition, NAFLD is strongly linked to cardiovascular disease. Our recent findings in experimental models have shown that microRNA miR-132 is an important regulator of liver homeostasis. Here, we aimed to assess miR-132 expression in liver and fat tissue of obese individuals and its association with blood pressure and hepatic steatosis. Design and method: Obese individuals undergoing bariatric surgery for weight management (nu200a=u200a14u200afemales/5 males) comprised the cohort of this study. They were 39u200a±u200a2 years old (meanu200a±u200aSEM) with a body mass index (BMI) of 42u200a±u200a1u200akg/m2. Extensive clinical and demographic information was collected for each patient. Supine blood pressure, measured with Omron HEM-907 device, was on average 127u200a±u200a4 mmHg (systolic) and 74u200a±u200a2 mmHg (diastolic) and heart rate 67u200a±u200a24u200abeats/min. According to Adult Treatment Panel III, the participants had 2.2u200a±u200a0.3 metabolic abnormalities. Quantitative PCR was performed to determine tissue expression of miR-132 in liver and matched subcutaneous and visceral fat biopsies in these patients. Liver biopsies were read by a single hepatopathologist using a standardised pathological approach and graded in terms of steatosis, inflammation and fibrosis. Results: Hepatic and visceral fat expression of miR-132 were strongly correlated (ru200a=u200a0.729, Pu200a=u200a0.005). Hepatic miR-132 expression was also correlated with BMI (ru200a=u200a0.641, Pu200a=u200a0.018), triglycerides (ru200a=u200a0.604, Pu200a=u200a0.029), systolic blood pressure (ru200a=u200a0.577, Pu200a=u200a0.039) and heart rate (ru200a=u200a0.694, Pu200a=u200a0.009). Visceral fat miR-132 expression was associated with BMI (ru200a=u200a0.746, Pu200a<u200a0.001) and liver steatosis (ru200a=u200a0.533, Pu200a=u200a0.33). There was no correlation between subcutaneous and visceral expression of miR-132 (Pu200a=u200a0.210). Conclusions: Our data supports that miR-132 may play a causal role in the cardiovascular and metabolic implications of obesity in humans. Given the increasing public burden of obesity and associated comorbidities, novel therapeutic approaches are needed for prevention and treatment of these diseases. In addition, further targeted search for biomarkers in complex diseases such as obesity, cardiovascular disease and NAFLD are warranted.

[PP.18.22] EFFECTS OF MOXONIDINE AND LOW CALORIE DIET IN YOUNG OVERWEIGHT MALES

Objective: Elevated sympathetic nervous system activity in overweight individuals is believed to play a detrimental role in metabolic and cardiovascular health in early adulthood. We therefore aimed to compare the effects of a treatment with either a low calorie diet, a sympatholytic agent or a combination of both on hemodynamic and metabolic parameters and renal and endothelial function. Design and method: Overweight (BMI>25u200akg/m2), young (18–30 years) otherwise healthy males were randomly allocated to receive either a low calorie diet (LCD; n=10), moxonidine (MOX; nu200a=u200a10, 0.4u200amg/day), a combination of both (LCD+MOX; nu200a=u200a11) or to act as controls (CONT; nu200a=u200a6) for a period of 6 months. Muscle sympathetic nerve activity (MSNA) was measured by microneurography, endothelial function was assessed using digital pulse tonometry and renal function using creatinine clearance derived from the Cockcroft Gault formula before and after intervention. Results: Weight loss occurred in the LCD and LCD+MOX (−7.5u200a±u200a1.9 and −7.6u200a±u200a1.9u200akg). MSNA significantly decreased in the LCD, MOX and LCD+MOX groups (−14u200a±u200a3, −14u200a±u200a3, −14u200a±u200a2 bursts per 100 heartbeats) and this was associated with a decrease in systolic blood pressure (−8.9u200a±u200a3.3; −8.8u200a±u200a5.5;−9.8u200a±u200a3.2 mmHg). All other metabolic parameters for both LCD, CON and MOX groups remained unchanged. Endothelial function remained unchanged in all groups. In the LCD + MOX, additional benefits included decreased waist circumference (−8.3u200a±u200a1.9u200acm), decreased total cholesterol (−0.78u200a±u200a0.23u200ammol/l) and LDL cholesterol (−0.49u200a±u200a0.16u200ammol/l) and fasting insulin (−6.5u200a±u200a2.8u200ammol/l) and attenuated glomerular hyperfiltration from 187u200a±u200a4 to 167u200a±u200a4u200aml/min). Conclusions: The addition of moxonidine to a LCD may have beneficial effects on the metabolic profile and renal function of overweight young males.

[OP.7D.10] THE EFFECT OF RENAL DENERVATION ON ADIPOKINES IN PATIENTS WITH RESISTANT HYPERTENSION.

Objective: We have previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. Obesity also contributes to hypertension. A number of adipocyte-derived factors (collectively termed ‘adipokines’) have been implicated in BP control. The aim of this study was to examine the effect of RDN on adipokines. In particular, whether BP reduction, associated with RDN treatment, has a favourable outcome on adipokine profile in patients with resistant hypertension (RH). Design and method: Fifty seven patients with RH undergoing RDN have been recruited for the study (65% males, age 60.8u200a±u200a1.5 years, BMI 32.6u200a±u200a0.7u200akg/m2, meanu200a±u200aSEM). At recruitment the patients were on an average of 4.8u200a±u200a2.1 antihypertensive drugs and were asked to refrain from changing their medication regimen for the duration of the study. Automated seated office BP measurements were taken with an Omron HEM-705 monitor at baseline and 3 months follow up visit. Leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were measured in plasma at baseline and 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75u200a±u200a2.57 vs 155.23u200a±u200a3.17 mmHg, pu200a<u200a0.001) and diastolic (90.68u200a±u200a2.31 vs 83.74u200a±u200a2.36 mmHg, pu200a<u200a0.001) BP 3 months after RDN. Body weight and heart rate remained unchanged. There were no significant differences in plasma leptin levels post RDN. Fasting insulin concentration significantly increased 3 months after the procedure (20.05u200a±u200a1.46 vs 29.70u200a±u200a2.51u200auU/ml, pu200a=u200a0.002). There was a significant drop in circulating NEFA at follow up (1.01u200a±u200a0.07 vs 0.47u200a±u200a0.04u200amEq/l, pu200a<u200a0.001). While there were no changes in resistin, adiponectin concentration was significantly higher after RDN (5654u200a±u200a800 vs 6644u200a±u200a967u200ang/ml, pu200a=u200a0.024). Conclusions: We have previously shown a decrease in BP following RDN. This is the first study to demonstrate that RDN is associated with potentially beneficial effects on the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via metabolic pathways.

Panic disorder : sympathetic nervous mechanisms and net gene epigenetics underlying increased cardiac risk

s for The Royal Australian and New Zealand College of Psychiatrists Joint CINP/ASPR Scientific Meeting Brisbane Convention & Exhibition Centre, Brisbane, Australia