Publications by authors named "Carolina Sari"

35 Publications

Does moxonidine reduce Achilles tendon or musculoskeletal pain in women with polycystic ovarian syndrome? A secondary analysis of a randomised controlled trial.

BMC Endocr Disord 2020 Aug 26;20(1):131. Epub 2020 Aug 26.

University of Canberra Research Institute for Sport and Exercise (UCRISE), Canberra, ACT, Australia.

Background: Sympathetic activity and insulin resistance have recently been linked with chronic tendon and musculoskeletal pain. Polycystic ovarian syndrome is linked with insulin resistance and increased sympathetic drive and was therefore an appropriate condition to study the effects of modulating sympathetic activity on Achilles tendon and musculoskeletal symptoms.

Methods: A secondary analysis of a double-blinded, randomised controlled trial on women with polycystic ovarian syndrome was conducted. Participants received 12 weeks of moxonidine (n = 14) or placebo (n = 18). Musculoskeletal symptom and Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaires were distributed, and ultrasound tissue characterisation quantified tendon structure at 0 and 12 weeks. 2-way ANOVA was used for multiple comparisons.

Results: There was no difference in mean change in musculoskeletal symptoms (- 0.6 ± 1.7 vs - 0.4 ± 1.8, p = 0.69) or VISA-A (moxonidine - 0.2 ± 8.8 vs placebo + 4.2 ± 14.6, p = 0.24) attributable to the intervention. There was no difference in any measures of Achilles structure. Moxonidine did not reduce sympathetic drive when compared to placebo.

Conclusions: This was the first study to investigate the effects of blocking sympathetic drive on musculoskeletal and Achilles tendon symptoms in a metabolically diverse population. While the study was limited by small sample size and lack of sympathetic modulation, moxonidine did not change tendon pain/structure or musculoskeletal symptoms.

Trial Registration: ClinicalTrials.gov, NCT01504321 . Registered 5 January 2012.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12902-020-00610-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449016PMC
August 2020

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

Front Physiol 2019 18;10:1162. Epub 2019 Sep 18.

Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

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 ( < 0.05). Levels of plasma triglycerides and 5 lipid species were higher in group 2 ( < 0.05). Endothelial function was less in group 2 (RHI: 1.64 vs. 2.26, = 0.003) and heart rate was higher (76 vs. 67 bpm, = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.01162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759693PMC
September 2019

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

J Hypertens 2019 12;37(12):2333-2340

12 Pickworth Court, Rosanna, Victoria, Australia.

: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HJH.0000000000002198DOI Listing
December 2019

A polymorphism in the noradrenaline transporter gene is associated with increased blood pressure in patients with resistant hypertension.

J Hypertens 2018 07;36(7):1571-1577

Faculty of Health, Arts and Design, Iverson Health Innovation Research Institute, Swinburne University of Technology.

Objectives: Noradrenaline released from sympathetic nerves is rapidly inactivated via the action of the noradrenaline transporter (NET). We aimed to determine whether a single nucleotide polymorphism (SNP) in the NET gene, rs7194256, was associated with blood pressure and plasma noradrenaline concentration in patients with resistant hypertension.

Methods: Ninety-two consecutive patients with resistant hypertension participated in this study (age 62 ± 1.3 years, BMI 32 ± 0.6 kg/m, mean ± SEM). Blood pressure was assessed using 24-h ambulatory blood pressure monitoring. Genotyping of rs7194256 (C/T) was performed using a predeveloped TaqMan SNP Genotyping Assay. Plasma catecholamines were analyzed using high-performance liquid chromatography.

Results: There were no differences in anthropometric measures between those carrying a T allele or the CC genotype. Patients carrying a T allele had significantly higher SBP: 24-h mean 148 ± 2.6 vs. 140 ± 2.4; 24-h max 189 ± 3.2 vs. 179 ± 2.6; 24-h min 114 ± 3.0 vs. 105 ± 2.3; night mean 141 ± 3.0 vs. 131 ± 2.5; night max 170 ± 3.6 vs. 159 ± 3.1; night min 118 ± 3.4 vs. 109 ± 2.4 (all P < 0.05). T-allele carriers had a significantly higher arterial noradrenaline concentration: 573 ± 53 vs. 377 ± 35 pg/ml (P = 0.002) and lower ratio of the intraneuronal noradrenaline metabolite, 3,4-dihydroxyphenylglycol, to noradrenaline (3.01 ± 0.4 vs. 4.08 ± 0.3 pg/ml; P = 0.024).

Conclusion: A SNP in the NET gene in patients with resistant hypertension is associated with higher plasma noradrenaline concentration and elevated SBP. Impaired NET function may be a contributor to the pronounced activation of the sympathetic nervous system characteristic of patients with resistant hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HJH.0000000000001736DOI Listing
July 2018

Inverse association between sympathetic nervous system activity and bone mass in middle aged overweight individuals.

Bone 2018 06 29;111:123-128. Epub 2018 Mar 29.

Iverson Health Innovation Research Institute, Faculty of Health, Arts and Design, Swinburne University of Technology, Hawthorn, Victoria, Australia; Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Background/purpose: Sympathetic nervous system activation in obesity is associated with impaired cardiovascular and metabolic function. Animal studies have shown a direct link between sympathetic nervous activation and bone health but little is known about this link in humans. This study examined whether sympathetic activation may impact bone health in overweight adults.

Methods: This cross sectional study included 96 overweight or obese middle-aged adults (51 males, mean body mass index: 32.8 kg/m, mean age: 55.3 years). Multivariate linear regression models evaluated associations between whole body and leg bone mineral density (BMD) and bone mineral content (BMC) derived from dual-energy X-ray absorptiometry and muscle sympathetic nervous system activity (MSNA) measured by microneurography.

Results: Older age, male sex and higher weight were associated with higher leg and body BMC and BMD. After adjustment for age, sex and weight, MSNA was significantly inversely associated with total BMC (p = 0.012) and with leg BMC (p < 0.01) but was not associated with either total or leg BMD (p = 0.159 and p = 0.063 respectively). When the analysis was sex specific, the relationships between MSNA and total and leg BMC were only significant in males.

Conclusions: Our study indicates that in middle aged overweight or obese males, sympathetic activation may have a deleterious effect on bone mineral content.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2018.03.025DOI Listing
June 2018

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

Fertil Steril 2018 03 7;109(3):532-539. Epub 2018 Feb 7.

Monash Centre for Health Research and Implementation, Monash University, Clayton, Victoria, Australia; Diabetes and Vascular Medicine Unit, Monash Health, Melbourne, Victoria, Australia. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fertnstert.2017.11.020DOI Listing
March 2018

Endothelial Function in Healthy Young Individuals Is Associated with Dietary Consumption of Saturated Fat.

Front Physiol 2017 9;8:876. Epub 2017 Nov 9.

Faculty of Health, Arts and Design, Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC, Australia.

A diet rich in fat, in particular saturated fat (SF), may be linked to cardiovascular disease development, possibly due to a detrimental effect of fat on endothelial function (EF). We aimed to determine whether the habitual SF intake [as a ratio to total fat (the sum of saturated, polyunsaturated, and monounsaturated fat)] might influence endothelial function in young, overweight but otherwise healthy adults. Sixty-nine young adults (49 males, mean age: 23 ± 1 years, mean BMI: 29.1 ± 0.8 kg/m) were classified into three tertiles according to their habitual SF intake consumption (low SF: <39%, medium SF 39.1-43.7%, and high SF: >43.7% of total fat). Endothelial function was assessed using digital amplitude tonometry. The three groups of individuals were comparable for total energy intake and calories from: fat, protein, and carbohydrates. There was no difference in anthropometric and hemodynamic variables among the groups. Those in the high SF group presented with impaired endothelial function [reactive hyperemia index (RHI): high SF: 1.60 ± 0.08 compared to 2.23 ± 0.16 in the medium SF and 2.12 ± 0.14 in the low SF group, < 0.01]. Regression analysis, including gender, age, ethnicity, body mass index indicated that the ratio of SF to total fat was an independent predictor of the RHI ( < 0.05). The habitual consumption of a diet high in SF in relation to polyunsaturated and monounsaturated fat was strongly associated with impaired endothelial function in young overweight adults, potentially contributing to increased risk of developing cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2017.00876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684178PMC
November 2017

Does sympathetic dysfunction occur before denervation in pure autonomic failure?

Clin Sci (Lond) 2018 01 2;132(1):1-16. Epub 2018 Jan 2.

Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, P.O. Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia

Pure autonomic failure (PAF) is a rare sporadic disorder characterized by autonomic failure in the absence of a movement disorder or dementia and is associated with very low plasma norepinephrine (NE) levels-suggesting widespread sympathetic denervation, however due to its rarity the pathology remains poorly elucidated. We sought to correlate clinical and neurochemical findings with sympathetic nerve protein abundances, accessed by way of a forearm vein biopsy, in patients with PAF and in healthy controls and patients with multiple systems atrophy (MSA) in whom sympathetic nerves are considered intact. The abundance of sympathetic nerve proteins, extracted from forearm vein biopsy specimens, in 11 patients with PAF, 8 patients with MSA and 9 age-matched healthy control participants was performed following a clinical evaluation and detailed evaluation of sympathetic nervous system function, which included head-up tilt (HUT) testing with measurement of plasma catecholamines and muscle sympathetic nerve activity (MSNA) in addition to haemodynamic assessment to confirm the clinical phenotype. PAF participants were found to have normal abundance of the NE transporter (NET) protein, together with very low levels of tyrosine hydroxylase (TH) (<0.0001) and reduced vesicular monoamine transporter 2 (VMAT2) (<0.05) protein expression compared with control and MSA participants. These findings were associated with a significantly higher ratio of plasma 3,4-dihydroxyphenylglycol (DHPG):NE in PAF participants when compared with controls (<0.05). The finding of normal NET abundance in PAF suggests intact sympathetic nerves but with reduced NE synthesis. The finding of elevated plasma ratio of DHPG:NE and reduced VMAT2 in PAF indicates a shift towards intraneuronal NE metabolism over sequestration in sympathetic nerves and suggests that sympathetic dysfunction may occur ahead of denervation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20170240DOI Listing
January 2018

Obesity Paradox in Hypertension: Is This Because Sympathetic Activation in Obesity-Hypertension Takes a Benign Form?

Hypertension 2018 01 20;71(1):22-33. Epub 2017 Nov 20.

From the Baker Heart and Diabetes Institute, Melbourne, Australia (M.E., J.D., C.I.S.); Swinburne University of Technology, Melbourne, Australia (G.L., E.L.); and School of Medicine, Royal Perth Hospital Unit, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth (M.S.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09790DOI Listing
January 2018

Effects of Moxonidine and Low-Calorie Diet: Cardiometabolic Benefits from Combination of Both Therapies.

Obesity (Silver Spring) 2017 11 2;25(11):1894-1902. Epub 2017 Sep 2.

Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Objective: Because sympathetic nervous system activity plays a detrimental role in metabolic and cardiovascular health, this study compared the effects of a centrally acting sympatholytic agent, the effects of a weight loss (WL) program using a low-calorie diet, and the effects of a combination of both.

Methods: Young (18-30 years) male subjects with overweight (BMI > 25 kg/m ) were allocated to a WL program (n = 10), a moxonidine treatment course (M; n = 10, 0.4 mg/d), a combination of both (WL + M; n = 11), or to a control (C) group (n = 6) for 6 months. Muscle sympathetic nerve activity (MSNA), endothelial function, renal function (Cockcroft-Gault formula), and the metabolic profile were assessed before and after intervention.

Results: WL occurred in the WL and WL + M groups (-7.6 ± 1.9 kg, P < 0.001 in both). MSNA and systolic blood pressure decreased similarly in the WL, M, and WL + M groups (by ∼10 bursts/min, P < 0.001, and by ∼9 mm Hg, P < 0.05). All other parameters for the WL, C, and M groups remained unchanged. In the WL + M group, decreased total cholesterol (-0.78 ± 0.23 mmol/L, P < 0.001), decreased low-density lipoprotein cholesterol (-0.49 ± 0.16 mmol/L, P < 0.01), decreased insulin (-6.5 ± 2.8 mmol/L, P < 0.05), and attenuated glomerular hyperfiltration (-19 ± 5 mL/min, P < 0.01) occurred.

Conclusions: The combination of moxonidine with a WL program has beneficial effects on aspects of the metabolic profile and end organ damage in young males with overweight.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.21962DOI Listing
November 2017

Neck Circumference Is Associated with Muscle Sympathetic Nerve Activity in Overweight and Obese Men but Not Women.

Front Physiol 2017 6;8:203. Epub 2017 Apr 6.

Human Neurotransmitters Laboratory, Baker Heart and Diabetes InstituteMelbourne, VIC, Australia.

Neck circumference (NC) is a predictor of cardiometabolic risk. The objective of this study was to explore the relationship of NC to muscle sympathetic nerve activity (MSNA) within an overweight and obese population. The study design was a retrospective cross-sectional analysis. Un-medicated persons (72 men, 53 postmenopausal women) aged 56 ± 1 years (mean ± SEM) with body mass index (BMI) 32.8 ± 0.4 kg/m, were studied. NC was measured together with traditional anthropometric measures, supine blood pressure, fasting blood lipids, insulin, and glucose. Insulin sensitivity was assessed by homeostasis model (HOMA-IR) and Matsuda Insulin Sensitivity Index (ISI) derived from 75-g oral glucose tolerance test. Resting multiunit MSNA was recorded by microneurography in the peroneal nerve and expressed as burst frequency and burst incidence. Men within the highest tertile of NC had significantly higher fasting and post-glucose plasma insulin levels (insulin AUC), HOMA-IR, non-esterified fatty acids, MSNA (45 ± 2 vs. 36 ± 2 bursts per min; 69 ± 3 vs. 58 ± 3 bursts per 100 hb) and heart rate, and lower Matsuda ISI compared to men in the lowest tertile ( all <0.05). In stepwise regression analyses, NC alone explained 12%, and together with insulin AUC it accounted for 22%, of the variance in MSNA in men. In women, NC was associated with anthropometric measures but not with MSNA or metabolic indices. Among overweight and obese men, NC was independently associated with elevated MSNA and hyperinsulinemia, and thus may be relevant to cardiometabolic risk prediction. The biological basis of gender differences merits further elucidation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2017.00203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382191PMC
April 2017

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

J Clin Endocrinol Metab 2017 06;102(6):2059-2068

Human Neurotransmitters, Baker Heart & Diabetes Institute, Melbourne, Victoria 3004, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2016-3738DOI Listing
June 2017

Serum uric acid and the relationship with subclinical organ damage in adults.

J Hypertens 2017 04;35(4):745-752

aHuman Neurotransmitters Laboratory, Baker IDI Heart & Diabetes Institute bDepartment of Physiology, Monash University, Melbourne, Victoria cRoyal Perth Hospital Unit, School of Medicine and Pharmacology, Perth, Western Australia dFaculty of Medicine, Nursing and Health Sciences eDepartment of General Practice, Monash University, Melbourne, Victoria, Australia.

Aims: Elevated serum uric acid (SUA) is often present in conditions associated with increased cardiovascular risk yet it is not recognized as a marker of risk. We evaluated whether SUA was associated with evidence of early markers of cardiovascular risk factor including subclinical early organ damage, sympathetic tone and metabolic profile in a healthy population with a high prevalence of obesity.

Material And Methods: Data from 281 patients (175 women and 106 men, mean age: 35.5 ± 0.8 years, mean BMI: 33.2 ± 0.5 kg/m) were retrieved from a database. All participants were healthy, nonsmoker and free of medication. Available data included metabolic profile, muscle sympathetic nervous activity (MSNA, microneurography), endothelial function (pulse amplitude tonometry, augmentation index), estimated glomerular filtration rate (eGFR) and echocardiography.

Results: With participants grouped into sex-adjusted tertiles of SUA, those in the third tertile of SUA had increased waist circumference, worse metabolic profile (fasting glucose, total cholesterol, triglycerides and HDL), elevated MSNA, decreased endothelial function, increased augmentation index and decreased eGFR compared with those in the first tertile of SUA. In multiple regression analysis adjusted for age, sex, BMI and ethnicity, SUA was independently associated with waist circumference, low-density lipoprotein, triglycerides, augmentation index, MSNA and eGFR, providing a combined adjusted R = 0.599 or 60% of the overall variance.

Conclusion: In a healthy population with a high proportion of obesity, SUA is associated with measures of metabolic, end-organ damage and sympathetic tone indicating the potential value of SUA as a marker of early cardiovascular disease development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HJH.0000000000001212DOI Listing
April 2017

Comparable Attenuation of Sympathetic Nervous System Activity in Obese Subjects with Normal Glucose Tolerance, Impaired Glucose Tolerance, and Treatment Naïve Type 2 Diabetes following Equivalent Weight Loss.

Front Physiol 2016 3;7:516. Epub 2016 Nov 3.

Human Neurotransmitters Laboratory, Baker IDI Heart and Diabetes InstituteMelbourne, VIC, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash UniversityMelbourne, VIC, Australia.

Elevated sympathetic nervous system (SNS) activity is a characteristic of obesity and type 2 diabetes (T2D) that contributes to target organ damage and cardiovascular risk. In this study we examined whether baseline metabolic status influences the degree of sympathoinhibition attained following equivalent dietary weight loss. Un-medicated obese individuals categorized as normal glucose tolerant (NGT, = 15), impaired glucose tolerant (IGT, = 24), and newly-diagnosed T2D ( = 15) consumed a hypocaloric diet (29% fat, 23% protein, 45% carbohydrate) for 4-months. The three groups were matched for baseline age (56 ± 1 years), body mass index (BMI, 32.9 ± 0.7 kg/m), and gender. Clinical measurements included whole-body norepinephrine kinetics, muscle sympathetic nerve activity (MSNA, by microneurography), spontaneous cardiac baroreflex sensitivity (BRS), and oral glucose tolerance test. Weight loss averaged -7.5 ± 0.8, -8.1 ± 0.5, and -8.0 ± 0.9% of body weight in NGT, IGT, and T2D groups, respectively. T2D subjects had significantly greater reductions in fasting glucose, 2-h glucose and glucose area under the curve (AUC) compared to NGT and IGT (group effect, <0.001). Insulinogenic index decreased in IGT and NGT groups and increased in T2D (group × time, = 0.04). The magnitude of reduction in MSNA (-7 ± 3, -8 ± 4, -15 ± 4 burst/100 hb, respectively) and whole-body norepinephrine spillover rate (-28 ± 8, -18 ± 6, and -25 ± 7%, respectively), time effect both <0.001, did not differ between groups. After adjustment for age and change in body weight, Δ insulin AUC was independently associated with reduction in arterial norepinephrine concentration, whilst Δ LDL-cholesterol and improvement in BRS were independently associated with decrease in MSNA. Equivalent weight loss through hypocaloric diet is accompanied by similar sympathoinhibition in matched obese subjects with different baseline glucose tolerance. Attenuation of hyperinsulinemia and hyperlipidemia, rather than glycemic indices, is associated with reduction in SNS activity following weight loss intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2016.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093133PMC
November 2016

Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss.

Cardiovasc Diabetol 2015 Aug 22;14:113. Epub 2015 Aug 22.

Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-015-0276-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546319PMC
August 2015

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

Clin Endocrinol (Oxf) 2015 Dec 13;83(6):812-9. Epub 2015 May 13.

Human Neurotransmitters Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Vic., Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.12803DOI Listing
December 2015

Pioglitazone treatment enhances the sympathetic nervous system response to oral carbohydrate load in obese individuals with metabolic syndrome.

Metabolism 2015 Jul 18;64(7):797-803. Epub 2015 Mar 18.

Laboratory of Human Neurotransmitters, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia; Department of Physiology, Monash University, Melbourne, Victoria, Australia.

Context: Insulin resistance is associated with blunted sympathetic nervous system (SNS) response to carbohydrate ingestion which may contribute to postprandial hypotension and impaired body weight homeostasis.

Objective: This study was conducted to examine the effects of pharmacological insulin sensitization on whole-body norepinephrine kinetics during a standard 75-g oral glucose tolerance test (OGTT) in obese, insulin resistant subjects with metabolic syndrome.

Methods: Un-medicated individuals (n=42, mean age 56±0.8 yrs, body mass index 34±0.6 kg/m(2)) were randomised to 12-weeks pioglitazone (PIO, 15 mg for 6 weeks, then 30 mg daily) or placebo using a double-blind, parallel group design. Whole-body norepinephrine kinetics (arterial norepinephrine concentration, calculated spillover and clearance rates), spontaneous cardiac baroreflex sensitivity, heart rate and blood pressure were measured at times 0, 30, 60, 90 and 120 minutes during OGTT. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M) and Matsuda index.

Results: PIO increased clamp derived glucose utilisation by 35% (P<0.001) and there were concurrent reductions in inflammatory status and plasma triglycerides (P<0.05). Fasting norepinephrine kinetic parameters were unaltered. PIO treatment was associated with lower plasma insulin incursions, greater reduction in diastolic blood pressure and enhanced baroreflex sensitivity during OGTT (P all <0.05). The overall norepinephrine spillover response (AUC(0-120)) increased significantly in the PIO group (group × time interaction, P=0.04), with greatest increment at 30 minutes post-glucose (101±38 ng/min at baseline versus 241±48 ng/min post treatment, P=0.04) and correlated with percent improvement in M.

Conclusions: PIO enhances the early postprandial SNS response to carbohydrate ingestion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2015.03.006DOI Listing
July 2015

Arterial norepinephrine concentration is inversely and independently associated with insulin clearance in obese individuals with metabolic syndrome.

J Clin Endocrinol Metab 2015 Apr 15;100(4):1544-50. Epub 2015 Jan 15.

Laboratories of Human Neurotransmitters (N.E.S., M.T.G., E.A.L., C.I.A., N.E., S.E.P., J.B.D., G.W.L.), Cardiovascular Nutrition (P.J.N.) and Neurovascular Hypertension and Kidney Disease (D.H., M.P.S.), and Alfred Baker Medical Unit (S.K.), Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2014-3796DOI Listing
April 2015

Cognitive function, health-related quality of life, and symptoms of depression and anxiety sensitivity are impaired in patients with the postural orthostatic tachycardia syndrome (POTS).

Front Physiol 2014 25;5:230. Epub 2014 Jun 25.

Baker IDI Heart & Diabetes Institute Melbourne, VIC, Australia ; Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University Melbourne, VIC, Australia.

The Postural Orthostatic Tachycardia Syndrome (POTS) is a condition in which heart rate increases abnormally when the individual assumes an upright position. In addition to the marked tachycardia, presyncope, and syncope, patients with POTS often complain of light-headedness, fatigue, and difficulty in concentrating. The present study assessed individuals with POTS for psychiatric comorbidity, anxiety sensitivity and health related quality of life and examined general cognitive ability. Data was obtained from patients with POTS (n = 15, 12 female, aged 30 ± 3 years) and age matched healthy subjects (n = 30, 21 female, aged 32 ± 2 years). Patients with POTS commonly presented with symptoms of depression, elevated anxiety and increased anxiety sensitivity, particularly with regards to cardiac symptoms, and had a poorer health related quality of life in both the physical and mental health domains. While patients with POTS performed worse in tests of current intellectual functioning (verbal and non-verbal IQ) and in measures of focused attention (digits forward) and short term memory (digits back), test results were influenced largely by years of education and the underlying level of depression and anxiety. Acute changes in cognitive performance in response to head up tilt were evident in the POTS patients. From results obtained, it was concluded that participants with POTS have an increased prevalence of depression and higher levels of anxiety. These underlying symptoms impact on cognition in patients with POTS, particularly in the cognitive domains of attention and short-term memory. Our results indicate that psychological interventions may aid in recovery and facilitate uptake and adherence of other treatment modalities in patients with POTS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2014.00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070177PMC
July 2014

A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome.

J Clin Endocrinol Metab 2014 Sep 17;99(9):E1701-7. Epub 2014 Jun 17.

Laboratories of Human Neurotransmitters (N.E.S., M.T.G., C.L.S., N.E., G.W.L., K.R., J.B.D., E.A.L.), Cardiovascular Nutrition (P.J.N.), and Neurovascular Hypertension and Kidney Disease (P.M., M.P.S.) and Alfred Baker Medical Unit (S.K., C.W.), Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 8008, Australia; Faculty of Medicine, Nursing, and Health Sciences (G.W.L., M.P.S.) and the Departments of Physiology (E.A.L.) and Primary Health Care (J.B.D.), Monash University, Melbourne, Victoria 3800, Australia; and the Department of Physiology (E.A.L.), University of Melbourne, Melbourne 3010, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2014-1976DOI Listing
September 2014

The effects of dietary weight loss on indices of norepinephrine turnover: modulatory influence of hyperinsulinemia.

Obesity (Silver Spring) 2014 Mar 6;22(3):652-62. Epub 2013 Dec 6.

Laboratories of Human Neurotransmitters, Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia.

Objectives: This study was conducted to examine (1) the effects of dietary weight loss on indices of norepinephrine (NE) turnover and (2) whether baseline hyperinsulinemia modulates sympathetic neural adaptations.

Methods: Obese individuals aged 56 ± 1 year, BMI 32.5 ± 0.4 kg/m(2) , with metabolic syndrome, underwent a 12-week hypocaloric diet (HCD, n = 39) or no treatment (n = 26). Neurochemical measurements comprised arterial dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylglycol (DHPG), and NE concentrations, the steady-state ratio of [3H]-DHPG to [3H]-NE, as an index of neuronal uptake, and calculated whole-body plasma NE clearance and spillover rates.

Results: Body weight decreased by -7.4 ± 0.5% in HCD group (P < 0.001) and was accompanied by reductions in DOPA, NE, and DHPG averaging -14 ± 5% (P = 0.001), -23 ± 4% (P <0.001), and -5 ± 4% (P = 0.03), respectively. NE spillover rate decreased by -88 ± 39 ng/min (P = 0.01), whereas neuronal uptake and NE plasma clearance were unchanged. Despite similar weight loss, hyperinsulinemic subjects exhibited greater reductions in NE and NE spillover rate, compared to normoinsulinemic subjects (group by time interaction P < 0.05).

Conclusions: Weight loss is associated with down-regulation of sympathetic nervous activity but no overall alteration in disposition indices. Hyperinsulinemic subjects derive a greater sympathoinhibitory benefit during weight loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.20614DOI Listing
March 2014

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

Am J Hypertens 2013 Feb 28;26(2):250-6. Epub 2012 Dec 28.

Human Neurotransmitters Laboratory, Baker IDI Heart & Diabetes Institute, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajh/hps016DOI Listing
February 2013

The relation of glucose metabolism to left ventricular mass and function and sympathetic nervous system activity in obese subjects with metabolic syndrome.

J Clin Endocrinol Metab 2013 Feb 27;98(2):E227-37. Epub 2012 Dec 27.

Laboratories of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, PO Box 6492, St. Kilda Road Central, Melbourne, Victoria, Australia. A.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2012-3277DOI Listing
February 2013

Neuroadrenergic dysfunction along the diabetes continuum: a comparative study in obese metabolic syndrome subjects.

Diabetes 2012 Oct 4;61(10):2506-16. Epub 2012 Jun 4.

Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m(2)), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = -0.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = -0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db12-0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447913PMC
October 2012

Sympathetic and vascular dysfunction in adult patients with Fontan circulation.

Int J Cardiol 2013 Aug 21;167(4):1333-8. Epub 2012 Apr 21.

Human Neurotransmitters Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2012.04.015DOI Listing
August 2013

Baseline sympathetic nervous system activity predicts dietary weight loss in obese metabolic syndrome subjects.

J Clin Endocrinol Metab 2012 Feb 16;97(2):605-13. Epub 2011 Nov 16.

Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia.

Context: The sympathetic nervous system is an important physiological modulator of basal and postprandial energy expenditure.

Objective: Our 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.

Participants And Methods: Untreated 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.

Results: Weight 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).

Conclusions: These findings indicate that baseline sympathetic drive and nutritional sympathetic responsiveness may be important prognostic biological markers for weight loss outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2011-2320DOI Listing
February 2012

Audiogenic seizure proneness requires the contribution of two susceptibility loci in mice.

Neurogenetics 2011 Aug 18;12(3):253-7. Epub 2011 Jun 18.

Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.

Juvenile mice of the DBA/2J strain undergo generalised seizures when exposed to a high-intensity auditory stimulus. Genetic analysis identified three different loci underlying this audiogenic seizure proneness (ASP)-Asp1, Asp2 and Asp3 on chromosomes 12, 4 and 7, respectively. Asp1 is thought to have the strongest influence, and mice with only Asp1 derived from the DBA/2J strain are reported to exhibit ASP. The aim of this study was to characterise more accurately the contributions of the Asp1 and Asp3 loci in ASP using congenic strains. Each congenic strain contains a DBA/2J-derived interval encompassing either Asp1 or Asp3 on a C57BL/6J genetic background. A double congenic C57BL/6J strain containing both Asp loci derived from DBA/2J was also generated. Here, we report that DBA/2J alleles at both of these Asp loci are required to confer ASP because congenic C57BL/6 mice harbouring DBA/2J alleles at only Asp1 or Asp3 do not exhibit ASP, whereas DBA/2J alleles at both loci resulted in increased susceptibility for audiogenic seizure in double congenic C57BL/6 mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-011-0289-2DOI Listing
August 2011

Single-unit muscle sympathetic nervous activity and its relation to cardiac noradrenaline spillover.

J Physiol 2011 May 14;589(Pt 10):2597-605. Epub 2011 Mar 14.

Human Neurotransmitters Laboratory, Baker IDI Heart & Diabetes Institute, PO Box 6492 St Kilda Road Central, Melbourne, Vic 8008, Australia.

Recent work using single-unit sympathetic nerve recording techniques has demonstrated aberrations in the firing pattern of sympathetic nerves in a variety of patient groups. We sought to examine whether nerve firing pattern is associated with increased noradrenaline release. Using single-unit muscle sympathetic nerve recording techniques coupled with direct cardiac catheterisation and noradrenaline isotope dilution methodology we examined the relationship between single-unit firing patterns and cardiac and whole body noradrenaline spillover to plasma. Participants comprised patients with hypertension (n=6), depression (n=7) and panic disorder (n =9) who were drawn from our ongoing studies. The patient groups examined did not differ in their single-unit muscle sympathetic nerve firing characteristics nor in the rate of spillover of noradrenaline to plasma from the heart. The median incidence of multiple spikes per beat was 9%. Patients were stratified according to the firing pattern: low level of incidence (less than 9% incidence of multiple spikes per beat) and high level of incidence (greater than 9% incidence of multiple spikes per beat). High incidence of multiple spikes within a cardiac cycle was associated with higher firing rates (P <0.0001) and increased probability of firing (P <0.0001). Whole body noradrenaline spillover to plasma and (multi-unit) muscle sympathetic nerve activity in subjects with low incidence of multiple spikes was not different to that of those with high incidence of multiple spikes. In those with high incidence of multiple spikes there occurred a parallel activation of the sympathetic outflow to the heart, with cardiac noradrenaline spillover to plasma being two times that of subjects with low nerve firing rates (11.0 ± 1.5 vs. 22.0 ± 4.5 ng min⁻¹, P <0.05). This study indicates that multiple within-burst firing and increased single-unit firing rates of the sympathetic outflow to the skeletal muscle vasculature is associated with high cardiac noradrenaline spillover.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/jphysiol.2011.205351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115828PMC
May 2011

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

Am J Physiol Heart Circ Physiol 2011 Apr 21;300(4):H1412-7. Epub 2011 Jan 21.

School of Electrical and Electronic Engineering, University of Adelaide, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpheart.01184.2010DOI Listing
April 2011

The effects of weight loss versus weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components.

J Clin Endocrinol Metab 2011 Mar 22;96(3):E503-8. Epub 2010 Dec 22.

Laboratories of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria 8008, Australia.

Context: Sympathetic nervous system (SNS) overactivity participates in both the pathogenesis and adverse clinical complications of metabolic syndrome (MetS) obesity.

Objective: We conducted a prospective lifestyle intervention trial to compare the effects of active weight loss and extended weight loss maintenance on SNS function and MetS components.

Methods: Untreated subjects (14 males, four females; mean age, 53 ± 1 yr; body mass index, 30.9 ± 0.9 kg/m(2)) who fulfilled Adult Treatment Panel III criteria were randomized to 12-wk hypocaloric diet alone (n = 8) or together with aerobic exercise training (n = 10). This was followed by a 4-month weight maintenance period. Measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics, substrate oxidation by indirect calorimetry, baroreflex sensitivity, plasma renin activity (PRA), and MetS components were performed.

Results: Body weight decreased by 9.3 ± 0.8% at wk 12 (P < 0.001), and this was maintained. During active weight loss, norepinephrine spillover rate decreased by 23 ± 16% (P = 0.004), MSNA by 25 ± 3 bursts per 100 heartbeats (P < 0.001), and PRA by 0.25 ± 0.09 ng/ml · h (P = 0.007), whereas baroreflex sensitivity increased by 5.2 ± 2.2 msec/mm Hg (P = 0.005). After weight maintenance, beneficial effects of weight loss on norepinephrine spillover rate were preserved, whereas PRA and MSNA rebounded (by 0.24 ± 0.11 ng/ml · h, P = 0.02; and 20 ± 5 bursts/100 heartbeats, P = 0.0003), and baroreflex sensitivity was attenuated.

Conclusions: Divergent effects of successful weight loss maintenance on whole-body norepinephrine spillover rate and MSNA suggest organ-specific differentiation in SNS adaptation to weight loss under conditions of negative vs. stable energy balance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2010-2204DOI Listing
March 2011
-->