Mental health and quality of life during weight loss in females with clinically severe obesity: a randomized clinical trial.

The purpose of this investigation was to explore the effects of dietary weight loss intervention, with and without the addition of exercise on health-related quality of life, depressive symptoms, and anxiety. As part of the EMPOWER study for women, sixty premenopausal women (BMI of 40.4 ± 6.7) were randomized to energy restriction only (ER) or to exercise plus energy restriction (EXER) for 12 months. Health-related quality of life was assessed using the SF-36, depressive symptoms were assessed using the Beck Depression Inventory II (BDI), and anxiety symptoms using the Spielberger state and trait anxiety questionnaire. All measures were completed at baseline, 3, 6 and 12 months. At 12 months, there were significant (p < 0.05) group-by-time interactions favouring the EXER group for five of the eight domains and the mental component summary score. At 12 months, a significant group-by-time interaction favouring the EXER group is reported for both state and trait anxiety (p = .005 and p = .001, respectively). At 12 months, there was a significant group-by-time interaction for depressive symptoms favouring EXER (p < 0.05). Within-group changes for BDI scores were improved at all follow-up time points in the EXER group. Exercise training confers an additional benefit to energy restriction in the absence of additional weight loss at 12 months for health-related quality of life, depressive symptoms, and state and trait anxiety scores when compared to energy restriction only. Exercise and an energy-restricted diet improve health-related quality of life and mental health. Exercise may protect mental health without further weight loss for women with severe obesity.

Sympathetic activation and endothelial dysfunction in polycystic ovary syndrome are not explained by either obesity or insulin resistance.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine condition underpinned by insulin resistance and associated with increased risk of obesity, type 2 diabetes and adverse cardiovascular risk profile. Previous data suggest autonomic imbalance [elevated sympathetic nervous system (SNS) activity and decreased heart rate variability (HRV)] as well as endothelial dysfunction in PCOS. However, it is not clear whether these abnormalities are driven by obesity and metabolic disturbance or whether they are independently related to PCOS. PARTICIPANTS AND METHODS: We examined multiunit and single-unit muscle SNS activity (by microneurography), HRV (time and frequency domain analysis) and endothelial function [ischaemic reactive hyperaemia index (RHI) using the EndoPAT device] in 19 overweight/obese women with PCOS (BMI: 31·3 ± 1·5 kg/m(2), age: 31·3 ± 1·6 years) and compared them with 21 control overweight/obese women (BMI: 33·0 ± 1·4 kg/m(2), age: 28·2 ± 1·6 years) presenting a similar metabolic profile (fasting total, HDL and LDL cholesterol, glucose, triglycerides, insulin sensitivity and blood pressure). RESULTS: Women with PCOS had elevated multiunit muscle SNS activity (41 ± 2 vs 33 ± 3 bursts per 100 heartbeats, P < 0·05). Single-unit analysis showed that vasoconstrictor neurons were characterized by elevated firing rate and probability and incidence of multiple spikes (P < 0·01 for all parameters). Women with PCOS also had impaired endothelial function (RHI: 1·77 ± 0·14 vs 2·18 ± 0·14, P < 0·05). HRV did not differ between the groups. CONCLUSION: Women with PCOS have increased sympathetic drive and impaired endothelial function independent of obesity and metabolic disturbances. Sympathetic activation and endothelial dysfunction may confer greater cardiovascular risk in women with PCOS.

Relation between QT interval variability and cardiac sympathetic activity in hypertension.

Elevated QT interval variability is a predictor of malignant ventricular arrhythmia, but the underlying mechanisms are incompletely understood. A recent study in dogs with pacing-induced heart failure suggests that QT variability is linked to cardiac sympathetic nerve activity. The aim of this study was to determine whether increased cardiac sympathetic activity is associated with increased beat-to-beat QT interval variability in patients with essential hypertension. We recorded resting norepinephrine (NE) spillover into the coronary sinus and single-lead, short-term, high-resolution, body-surface ECG in 23 patients with essential hypertension and 9 normotensive control subjects. To assess beat-to-beat QT interval variability, we calculated the overall QT variability (QTVN) as well as the QT variability index (QTVi). Cardiac NE spillover (12.2 ± 6.5 vs. 20.7 ± 14.7, P = 0.03) and QTVi (-1.75 ± 0.36 vs. -1.42 ± 0.50, P = 0.05) were significantly increased in hypertensive patients compared with normotensive subjects. QTVN was significantly correlated with cardiac NE spillover (r(2) = 0.31, P = 0.001), with RR variability (r(2) = 0.20, P = 0.008), and with systolic blood pressure (r(2) = 0.16, P = 0.02). Linear regression analysis identified the former two as independent predictors of QTVN. In conclusion, elevated repolarization lability is directly associated with sympathetic cardiac activation in patients with essential hypertension.

Consequences of the evolutionary cardiovascular challenge of human bipedalism: orthostatic intolerance syndromes, orthostatic hypertension.

: In quadrupeds, the arterial baroreflex has dominance in the reflex homeostatic responses, which protect against haemorrhage. In humans, it is the low pressure cardiopulmonary reflex, which protects against the analogous cardiovascular challenge of gravity-dependent venous pooling with standing. To preserve orthostatic cardiovascular homeostasis with the emergence of bipedalism in humans the low pressure reflex, a minor, subsidiary reflex in quadripeds, was co-opted. Mirroring the imperfect skeletal evolution to bipedalism, this cardiovascular development has been problematic, with dysregulation manifesting as disabling orthostatic intolerance syndromes and, paradoxically, an orthostatic hypertensive response that appears to play a role in the development of essential hypertension in some people. Improved understanding of these evolutionary faults provides new options for postural and pharmacological treatments.

Android Fat Deposition and Its Association With Cardiovascular Risk Factors in Overweight Young Males.

OBJECTIVE: Excess adiposity increases the risk of type-2 diabetes and cardiovascular disease development. Beyond the simple level of adiposity, the pattern of fat distribution may influence these risks. We sought to examine if higher android fat distribution was associated with different hemodynamic, metabolic or vascular profile compared to a lower accumulation of android fat deposits in young overweight males. METHODS: Forty-six participants underwent dual-energy X-ray absorptiometry and were stratified into two groups. Group 1: low level of android fat (<9.5%) and group 2: high level of android fat (>9.5%). Assessments comprised measures of plasma lipid and glucose profile, blood pressure, endothelial function [reactive hyperemia index (RHI)] and muscle sympathetic nerve activity (MSNA). RESULTS: There were no differences in weight, BMI, total body fat and lean mass between the two groups. Glucose tolerance and insulin resistance (fasting plasma insulin) were impaired in group 2 (p < 0.05). Levels of plasma triglycerides and 5 lipid species were higher in group 2 (p < 0.05). Endothelial function was less in group 2 (RHI: 1.64 vs. 2.26, p = 0.003) and heart rate was higher (76 vs. 67 bpm, p = 0.004). No difference occurred in MSNA nor blood pressure between the 2 groups. CONCLUSION: Preferential fat accumulation in the android compartment is associated with increased cardiovascular and metabolic risk via alteration of endothelial function.

High-molecular-weight adiponectin is inversely associated with sympathetic activity in polycystic ovary syndrome.

OBJECTIVE: To examine the role of high-molecular-weight (HMW) adiponectin and its relationship to sympathetic activity in women with polycystic ovary syndrome (PCOS). DESIGN: Cross sectional study using biobanked samples. SETTING: Not applicable. PATIENT(S): Premenopausal women with PCOS (n = 46, Rotterdam diagnostic criteria) and without PCOS (n = 22). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): High-molecular-weight adiponectin levels with secondary outcomes of sympathetic activity and leptin levels. RESULT(S): The high-molecular-weight adiponectin level was lower in women with PCOS (median 2.2 [interquartile range (IQR)2.3] µg/mL) than in controls (median 3 [IQR2.5] µg/mL) (age and BMI adjusted), and it correlated inversely with the values measured for homeostatic model of assessment of insulin resistance (HOMA-IR), fasting insulin, triglycerides, and free androgen index and positively with sex hormone-binding globulin (SHBG) and high-density lipoprotein cholesterol in all participants and in the PCOS group. In the PCOS group, sympathetic activity (burst frequency) was statistically significantly higher than in controls (median 26 [IQR11] vs. median 22 [IQR14], respectively) and correlated inversely with HMW adiponectin (r = -0.230). The leptin levels were similar between the women with PCOS and controls and did not statistically significantly correlate with HMW adiponectin or sympathetic activity. On multiple regression analysis, burst frequency and SHBG explained 40% of the HMW adiponectin variability (B = -0.7; 95% CI -1.2 to -0.2; and B = 0.01; 95% CI 0.004-0.01) in PCOS. CONCLUSION(S): Alongside insulin resistance, increased sympathetic activity is associated with and may modulate HMW adiponectin levels in women with PCOS.

Muscle Sympathetic Nerve Activity Is Associated With Elements of the Plasma Lipidomic Profile in Young Asian Adults.

Background: Asian subjects are at increased cardio-metabolic risk at comparatively lower body mass index (BMI) compared with white subjects. Sympathetic nervous system activation and dyslipidemia, both characteristics of increased adiposity, appear to be related. We therefore analyzed the association of muscle sympathetic nerve activity (MSNA) with the plasma lipidomic profile in young adult Asian and white subjects. Methods: Blood samples were collected from 101 participants of either Asian or white background (age, 18 to 30 years; BMI, 28.1 ± 5.9 kg/m2). Lipids were extracted from plasma and analyzed using electrospray ionization-tandem mass spectrometry. MSNA was quantified using microneurography. The association of MSNA and obesity with lipid species was examined using linear regression analysis. Results: The plasma concentrations of total dihydroceramide, ceramide, GM3 ganglioside, lysoalkylphosphatidylcholine, alkenylphosphatidylethanolamine, and lysophosphatidylinositol were elevated in the Asian subjects relative to the white subjects. After adjustment for confounders, diacylglycerols and triacylglycerols, cholesterol esters, phosphatidylinositols, phosphatidylethanolamines, and phosphatidylglycerols bore significant associations with MSNA but only in the Asian subjects. These associations remained significant after further adjustment for the participants' degree of insulin resistance and appeared not to be related to differences in diet macronutrient content between groups. Conclusions: The lipidomic profile differs between Asian and white subjects. There exists a strong relationship between certain lipid species and MSNA. The association is stronger in Asian subjects, despite their lower BMI. This study demonstrates an association between circulating lipids and central sympathetic outflow. Whether the stronger association between the lipid profile and sympathetic activation underpins the apparent greater risk posed by increased adiposity in Asian individuals merits further attention.

Dyslipidemia is associated with sympathetic nervous activation and impaired endothelial function in young females.

BACKGROUND: Dyslipidemia is one the most well-established risk factors for cardiovascular disease development. Moreover, hypercholesterolemia and plasma cholesterol level in the high to normal range are established triggers for impairment in endothelial function. Evidence indicates that endothelial function is closely linked with sympathetic nervous activity in healthy individuals. We therefore investigated whether both endothelial and sympathetic functions may be impaired in young females with abnormal plasma cholesterol levels. METHODS: Baseline endothelial function (digital pulse amplitude) and muscle sympathetic nervous activity (microneurography) were retrospectively analyzed in 14 young healthy females with dyslipidemia as indicated by total cholesterol ≥197mg/dL, high-density lipoprotein ≤39mg/dL, or low-density lipoprotein >116mg/dL, and in 13 females with lipids in the healthy range. RESULTS: Subjects with dyslipidemia had significantly impaired endothelial function compared to those with a normal cholesterol profile (reactive hyperemia index; 1.61±0.10 vs. 2.32±0.14, P < 0.001), increased muscle sympathetic nervous activity (after adjusting for body mass and age, 36±3 vs. 27±3 bursts per 100 heartbeats, P = 0.049) and elevated high-sensitivity C-reactive protein (4.13±0.77 vs. 1.92±0.61mg/L, P = 0.03). DISCUSSION: Our results indicate that young healthy females with dyslipidemia present with a strong impairment of endothelial function and increased sympathetic drive. The sympathetic activation observed in the subjects with an elevated cholesterol profile may play a role in the development of cardiovascular disease development.

Sympathetic and vascular dysfunction in adult patients with Fontan circulation.

BACKGROUND: Patients with Fontan circulation are known to have increased systemic vascular resistance (SVR) however the underlying mechanisms are uncertain. We therefore further investigated the haemodynamic and vascular profile of Fontan patients. METHODS: Eighteen adult subjects aged 25 ± 1 years who had undergone the Fontan procedure in their childhood (at age 6 ± 1 years) and not in clinical failure at the time of study were assessed for: 1) autonomic function, including direct muscle sympathetic nerve activity (MSNA) recording and sympathetic and cardiac baroreflex function, 2) endothelial function by means of reactive hyperaemia using the Endopat peripheral arterial tonometry (PAT) technique and plasma endothelin concentration and gene expression, 3) pulse wave reflections (digital and central augmentation index (AI)) and 4) haemodynamic changes to head-up tilt. Data were compared to that obtained in a group of 23 age- and weight-matched healthy subjects. RESULTS: Fontan participants presented with elevated MSNA compared with controls (40 ± 5 vs 27 ± 3 bursts per 100 heartbeats), decreased cardiac baroreflex function (16.0 ± 3.3 versus 30.9 ± 3.7 ms · mm Hg(-1)), normal sympathetic baroreflex function, decreased endothelial function (PAT ratio=0.35 ± 0.09 vs 0.77 ± 0.11), and increased digital (5.9 ± 3.0% vs -9.7 ± 2.3%) and central (1.4 ± 2.7% vs -10.2 ± 3.9%) AI. Ten minute head-up tilt (60°) induced greater reductions in cardiac output (CO) and stroke volume (SV) in Fontan patients (CO: -28% vs -11%, SV: -40% vs -25%). CONCLUSION: Adult Fontan patients have increased MSNA and altered endothelial function that are likely to contribute to their known increased SVR. Therapies aiming at reducing the peripheral resistances should target endothelial function and sympathetic activity.

Cardiac repolarization variability in patients with postural tachycardia syndrome during graded head-up tilt.

OBJECTIVE: The aim of this study was to assess cardiac ventricular repolarization in patients with postural tachycardia syndrome (POTS) and further the possible link between ventricular repolarization and sympathetic nervous system activity. METHODS: We recorded body surface ECGs together with plasma noradrenaline (NE) spillover, and muscle sympathetic nerve activity (MSNA) in twelve healthy control subjects (CON; 5 males; age: 23±2 yrs) and 13 subjects with postural tachycardia syndrome (POTS; 4 males; 32±13 yrs) during graded head-up tilt (0°-20°-30°-40°). Ventricular repolarization was assessed by computing various measures of beat-to-beat QT interval variability and T wave amplitude. RESULTS: In patients with POTS, baseline heart rates were higher and MSNA increases during tilt were more pronounced than in CON. None of the QT variability measures was significantly affected by tilt or different between CON and POTS when corrected for heart rate. Contrary, the T wave amplitude flattened due to tilt (p<0.001) and this effect was significantly more pronounced in POTS (32% at 40°) than in CON (21% at 40°; p=0.03). CONCLUSIONS: Beat-to-beat variability of the QT interval is normal in patients with POTS. However, significantly more attenuated T waves during head-up tilt together with elevated MSNA levels suggest increased sympathetic outflow to the ventricular myocardium in patients with POTS. SIGNIFICANCE: Monitoring of the T wave during tilt test may provide a non-invasive tool for assessing excessive sympathetic outflow to the ventricular myocardium.

Sympathetic nervous system activity is associated with obesity-induced subclinical organ damage in young adults.

Excess weight is established as a major risk factor for cardiovascular diseases, particularly in young individuals. To get a better understanding of the pathophysiology underlying increased cardiovascular disease risk, we evaluated early signs of organ damage and their possible relationship to sympathetic nervous activity. Eighteen lean (body mass index <25 kg/m(2)) and 25 overweight or obese (body mass index >25 kg/m(2)) healthy university students were included in the study. We comprehensively assessed subclinical target organ damage, including the following: (1) assessment of renal function; (2) left ventricular structure and systolic and diastolic function; and (3) endothelial function. Muscle sympathetic nervous activity was assessed by microneurography. Participants with excess weight had decreased endothelial function (P<0.01), elevated creatinine clearance (P<0.05), increased left ventricular mass index (P<0.05), increased left ventricular wall thickness (P<0.01), lower systolic and diastolic function (P<0.01), and elevated muscle sympathetic nervous activity (P<0.001) compared with lean individuals. In multiple regression analysis, endothelial function was inversely related to muscle sympathetic nervous activity (R(2)=0.244; P<0.05), whereas creatinine clearance and left ventricular mass index were positively related to muscle sympathetic nervous activity, after adjustment for body mass index, sex, and blood pressure (R(2)=0.318, P<0.01 and R(2)=0.312, P<0.05, respectively). Excess weight in young individuals is associated with subclinical alterations in renal and endothelial function, as well as in the structure of the heart, even in the absence of hypertension. Sympathetic activity is closely associated with cardiovascular and renal alterations observed in these subjects.