Fitness, Strength and Body Composition during Weight Loss in Women with Clinically Severe Obesity: A Randomised Clinical Trial.

INTRODUCTION: To determine whether combined exercise training with an energy-restricted diet leads to improved physical fitness and body composition when compared to energy restriction alone in free-living premenopausal women with clinically severe obesity. METHODS: Sixty premenopausal women (BMI of 40.4 ± 6.7) were randomised to energy restriction only (ER) or to exercise plus energy restriction (EXER) for 12 months. Body composition and fitness were measured at baseline, 3, 6 and 12 months. RESULTS: VO2 peak improved more for EXER compared to ER at 3 (mean difference ± SEM 2.5 ± 0.9 mL ∙ kg-1 ∙ min-1, p = 0.006) and 6 (3.1 ± 1.2 mL ∙ kg-1 ∙ min-1, p = 0.007) but not 12 months (2.3 ± 1.6 mL ∙ kg-1 ∙ min-1, p = 0.15). Muscle strength improved more for EXER compared to ER at all time points. No differences between groups for lean mass were observed at 12 months. CONCLUSION: Combining exercise training with an energy-restricted diet did not lead to greater aerobic power, total body mass, fat mass or limit lean body mass loss at 12 months when compared to energy restriction alone for premenopausal women with clinically severe obesity in free-living situations. Future research should aim to determine an effective lifestyle approach which can be applied in the community setting for this high-risk group.

Evaluation of elevated heart rate as a sympathetic nervous system biomarker in essential hypertension.

BACKGROUND: There is a need for an easily accessible biomarker of sympathetic nervous activation in essential hypertension, but none exists. Heart rate (HR) has been suggested, but requires validation, now doubly important as an elevated HR in hypertension has emerged as an independent cardiovascular risk factor. METHODS: Isotope dilution methodology was used to measure total and regional noradrenaline spillover and adrenaline secretion rates in 30 patients with unmedicated essential hypertension and in a comparator group of 48 healthy participants with normal blood pressure. The particular interest was in the relationship of measured HR to cardiac noradrenaline spillover, the measure of cardiac sympathetic activity. RESULTS: Sympathetic activation was present in the patients with essential hypertension, evident in significantly increased mean cardiac, renal and total noradrenaline spillover rates. Adrenaline secretion was normal. HR in hypertension correlated directly with cardiac noradrenaline spillover (r = 0.82, P = 9.3 × 10), but not with renal noradrenaline spillover or adrenaline secretion. 67% of the variance in HR was attributable to differences in cardiac sympathetic activity. Among hypertensive patients there was no internal correlation between cardiac noradrenaline spillover, renal noradrenaline spillover and adrenaline secretion; the sympathetic activation commonly was not 'global'. In healthy participants HR did not correlate with measures of sympathetic activity or adrenaline secretion. CONCLUSION: When sympathetic activation exists in essential hypertension it is differentiated, not necessarily involving all sympathetic outflows. An elevated HR proved to be a biomarker of cardiac sympathetic activation but not activation of the renal sympathetic outflow. Identifying activation of the cardiac sympathetic outflow as the prime mechanism of hypertension tachycardia is relevant to therapies which should now be considered to minimize cardiovascular risk in this clinical setting. Is an elevated HR a valid biomarker of sympathetic activation in essential hypertension? Yes, but only for the cardiac sympathetic outflow. The unavoidable principle is that regional differentiation of sympathetic responses in essential hypertension means that no simple test can ever represent each and every sympathetic outflow.

Effect of Central Sympathoinhibition With Moxonidine on Sympathetic Nervous Activity in Polycystic Ovary Syndrome-A Randomized Controlled Trial.

Sympathetic nervous system (SNS) activity is increased in polycystic ovary syndrome (PCOS). Moxonidine is a centrally acting sympatholytic drug with known beneficial effects on hypertension, insulin sensitivity, dyslipidemia and inflammation. In this double-blind placebo controlled randomized clinical trial we examined the effect of moxonidine on modulating sympathetic activity and downstream metabolic abnormalities in 48 pre-menopausal women with PCOS (Rotterdam diagnostic criteria), recruited from the community (January 2013-August 2015). Participants received moxonidine (0.2 mg daily initially, up titrated to 0.4 mg daily in 2 weeks) (n = 23) or placebo (n = 25) for 12 weeks. Multiunit muscle sympathetic activity (by microneurography) and plasma noradrenaline levels were measured (primary outcomes). Fasting lipids, insulin resistance, serum androgens, and inflammatory markers were measured as secondary outcomes. Forty three women completed the trial (19 moxonidine, 24 placebo). Mean change in burst frequency (-3 ± 7 vs. -3 ± 8 per minute) and burst incidence (-3 ± 10 vs. -4 ± 12 per 100 heartbeat) did not differ significantly between moxonidine and placebo groups. Women on moxonidine had a significant reduction in hs-CRP compared to placebo group (-0.92 ± 2.3 vs. -0.04 ± 1.5) which did not persist post Bonferroni correction. There was a significant association between markers of insulin resistance at baseline and reduction in sympathetic activity with moxonidine. Moxonidine was not effective in modulating sympathetic activity in PCOS. Anti-inflammatory effects of moxonidine and a relationship between insulin resistance and sympathetic response to moxonidine are suggested which need to be further explored. Clinical Trial Registration Number: (NCT01504321).

Renal nerve ablation reduces augmentation index in patients with resistant hypertension.

OBJECTIVE: Renal denervation (RDN) has been demonstrated to reduce muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant hypertension. Whether alterations of arterial stiffness may contribute to BP-lowering effects of RDN is unknown. METHODS: We measured office BP and arterial stiffness using fingertip tonometry-derived augmentation index (EndoPAT2000) at baseline and at 3-month follow-up in 50 consecutive patients with resistant hypertension. Forty patients received RDN and 10 patients served as controls. MSNA was obtained in 20 RDN and 10 non-RDN patients. RESULTS: Baseline BP averaged 170/92 ± 19/15 mmHg (RDN) and 171/93 ± 14/8 mmHg (non-RDN) despite the use of 4.9 ± 1.9 and 4.4 ± 2.0 antihypertensive drugs, respectively. RDN significantly reduced SBP (170  ± 19 vs. 154 ± 25 mmHg; P < 0.001) and DBP (92 ± 15 vs. 84 ± 16 mmHg; P<0.001), augmentation index (30.6  ± 23.8 vs. 22.7 ± 22.4%; P=0.002), AI@75 corrected for heart rate (22.4 ± 21.6 vs. 14.4 ± 20.7; P=0.002) and MSNA (80 ± 15 vs. 71 ± 18  bursts/100 heartbeats; P<0.01). Changes in AI@75 with RDN were unrelated to SBP (r=0.043; P = 0.79), and DBP (r = 0.092; P = 0.57) and MSNA changes (r = -0.17; P = 0.49). No changes in BP, augmentation index, AI@75 or MSNA were observed in the non-RDN group. CONCLUSION: RDN results in a substantial and rapid reduction in augmentation index, which appears to be independent of BP and MSNA changes. These findings are indicative of a beneficial effect of RDN on arterial stiffness in patients with resistant hypertension and may contribute to the sustained BP-lowering effect of RDN.

Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease.

BACKGROUND AND OBJECTIVES: Sympathetic activation is a hallmark of ESRD and adversely affects cardiovascular prognosis. Efferent sympathetic outflow and afferent neural signalling from the failing native kidneys are key mediators and can be targeted by renal denervation (RDN). Whether this is feasible and effective in ESRD is not known. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: In an initial safety and proof-of-concept study we attempted to perform RDN in 12 patients with ESRD and uncontrolled blood pressure (BP). Standardized BP measurements were obtained in all patients on dialysis free days at baseline and follow up. Measures of renal noradrenaline spillover and muscle sympathetic nerve activity were available from 5 patients at baseline and from 2 patients at 12 month follow up and beyond. RESULTS: Average office BP was 170.8 ± 16.9/89.2 ± 12.1 mmHg despite the use of 3.8 ± 1.4 antihypertensive drugs. All 5 patients in whom muscle sympathetic nerve activity and noradrenaline spillover was assessed at baseline displayed substantially elevated levels. Three out of 12 patients could not undergo RDN due to atrophic renal arteries. Compared to baseline, office systolic BP was significantly reduced at 3, 6, and 12 months after RDN (from 166 ± 16.0 to 148 ± 11, 150 ± 14, and 138 ± 17 mmHg, respectively), whereas no change was evident in the 3 non-treated patients. Sympathetic nerve activity was substantially reduced in 2 patients who underwent repeat assessment. CONCLUSIONS: RDN is feasible in patients with ESRD and associated with a sustained reduction in systolic office BP. Atrophic renal arteries may pose a problem for application of this technology in some patients with ESRD.

Change in sympathetic nerve firing pattern associated with dietary weight loss in the metabolic syndrome.

Sympathetic activation in subjects with the metabolic syndrome (MS) plays a role in the pathogenesis of cardiovascular disease development. Diet-induced weight loss decreases sympathetic outflow. However the mechanisms that account for sympathetic inhibition are not known. We sought to provide a detailed description of the sympathetic response to diet by analyzing the firing behavior of single-unit sympathetic nerve fibers. Fourteen subjects (57 ± 2 years, nine men, five females) fulfilling ATP III criteria for the MS underwent a 3-month low calorie diet. Metabolic profile, hemodynamic parameters, and multi-unit and single-unit muscle sympathetic nerve activity (MSNA, microneurography) were assessed prior to and at the end of the diet. Patients' weight dropped from 96 ± 4 to 88 ± 3 kg (P < 0.001). This was associated with a decrease in systolic and diastolic blood pressure (-12 ± 3 and -5 ± 2 mmHg, P < 0.05), and in heart rate (-7 ± 2 bpm, P < 0.01) and an improvement in all metabolic parameters (fasting glucose: -0.302.1 ± 0.118 mmol/l, total cholesterol: -0.564 ± 0.164 mmol/l, triglycerides: -0.414 ± 0.137 mmol/l, P < 0.05). Multi-unit MSNA decreased from 68 ± 4 to 59 ± 5 bursts/100 heartbeats (P < 0.05). Single-unit MSNA indicated that the firing rate of individual vasoconstrictor fibers decreased from 59 ± 10 to 32 ± 4 spikes/100 heart beats (P < 0.05). The probability of firing decreased from 34 ± 5 to 23 ± 3% of heartbeats (P < 0.05), and the incidence of multiple firing decreased from 14 ± 4 to 6 ± 1% of heartbeats (P < 0.05). Cardiac and sympathetic baroreflex function were significantly improved (cardiac slope: 6.57 ± 0.69 to 9.57 ± 1.20 ms·mmHg(-1); sympathetic slope: -3.86 ± 0.34 to -5.05 ± 0.47 bursts/100 heartbeats·mmHg(-1), P < 0.05 for both). Hypocaloric diet decreased sympathetic activity and improved hemodynamic and metabolic parameters. The sympathoinhibition associated with weight loss involves marked changes, not only in the rate but also in the firing pattern of active vasoconstrictive fibers.

Ghrelin modulates sympathetic nervous system activity and stress response in lean and overweight men.

Ghrelin is a growth hormone-releasing peptide secreted by the stomach with potent effects on appetite. Experimental and clinical studies indicate that ghrelin also influences cardiovascular regulation and metabolic function and mediates behavioral responses to stress. We investigated the effects of ghrelin on blood pressure (BP), sympathetic nervous system activity, and mental stress responses in lean (n=13) and overweight or obese (n=13) individuals. Subjects received an intravenous infusion of human ghrelin (5 pmol/kg per minute for 1 hour) and saline in a randomized fashion. Ghrelin decreased systolic (-6 and -11 mm Hg) and diastolic BP (-8 mm Hg for both), increased muscle sympathetic nervous system activity (18±2 to 28±3 bursts per min, P<0.05 and from 21±2 to 32±3 bursts per min, P<0.001) in lean and overweight or obese subjects, respectively, without a significant change in heart rate, calf blood flow, or vascular resistance. Ghrelin induced a rise in plasma glucose concentration in lean individuals (P<0.05) and increased cortisol levels in both groups (P<0.05). Stress induced a significant change in mean BP (+22 and +27 mm Hg), heart rate (+36 and +29 bpm), and muscle sympathetic nervous system activity (+6.1±1.6 and +6.8±2.7 bursts per min) during saline infusion in lean and overweight or obese subjects, respectively. During ghrelin infusion, the changes in BP and muscle sympathetic nerve activity in response to stress were significantly reduced in both groups (P<0.05). In conclusion, ghrelin exerts unique effects in that it reduces BP and increases muscle sympathetic nervous system activity and blunts cardiovascular responses to mental stress. These responses may represent a combination of peripheral (baroreflex-mediated) and central effects of ghrelin.

Renal denervation: a potential new treatment modality for polycystic ovary syndrome?

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with sympathetic nervous system activation, insulin resistance, and blood pressure elevation. Renal nerve ablation has been demonstrated to reduce sympathetic outflow and improve blood pressure control. Here we report on the effects of renal denervation on hemodynamic, metabolic, and renal parameters in two obese PCOS patients with hypertension. METHODS: Sympathetic nerve activity was assessed at baseline using microneurography and norepinephrine spillover measurements. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Measurements of cystatin-C, creatinine clearance, and urinary albumin-creatinine ratio were also obtained. All measurements were repeated 3 months after bilateral renal denervation achieved via percutaneous endovascular radiofrequency ablation. RESULTS: Muscle sympathetic nerve activity and whole body norepinephrine spillover were substantially elevated at baseline in both patients by approximately 2.5-3-fold. Bilateral renal nerve ablation reduced both indices of sympathetic nerve activity. This was associated with moderate reductions in blood pressure and a substantial improvement in insulin sensitivity by approximately 17.5% in the absence of weight changes at 3-month follow-up. Glomerular hyperfiltration and urinary albumin excretion were also reduced. CONCLUSION: These findings corroborate the relevance of sympathetic activation in PCOS and suggest that renal denervation exerts beneficial effects not only on blood pressure control but also on insulin sensitivity, renal, and endocrine abnormalities characteristic of PCOS.