title: Effect of angiotensin II receptor blockade on autonomic nervous system function in patients with essential hypertension. Autonomic Blockade Reverses Endothelial Dysfunction in Obesity-Associated Hypertension Renal sympathetic denervation restores aortic distensibility in patients with resistant hypertension: data from a multi-center trial Evidence for Pressure‐Independent Sympathetic Modulation of Central Pulse Wave Velocity Effects of Bariatric Surgery in Obese Patients With Hypertension Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial Experimental Weight Gain Increases Ambulatory Blood Pressure in Healthy Subjects: Implications of Visceral Fat Accumulation Ethnic Differences in Insulinemia and Sympathetic Tone as Links Between Obesity and Blood Pressure Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans. Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects. The effect of metformin and insulin on sympathetic nerve activity, norepinephrine spillover and blood pressure in obese, insulin resistant, normoglycemic, hypertensive men. Adverse consequences of high sympathetic nervous activity in the failing human heart. Usefulness of brachial artery flow-mediated dilation to predict long-term cardiovascular events in subjects without heart disease. Differential effects of lipophilic and hydrophilic statins on muscle sympathetic nerve activity in heart failure with preserved left ventricular ejection fraction Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients Differential effects of renin–angiotensin–aldosterone system inhibition, sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension: a double-blind, placebo-controlled cross-over trial Glomerular hyperfiltration is a predictor of adverse cardiovascular outcomes.
abstract: It has long been proposed that the renin-angiotensin system exerts a stimulatory influence on the sympathetic nervous system , including augmentation of central sympathetic outflow and presynaptic facilitation of norepinephrine release from sympathetic nerves . We tested this proposition in 19 patients with essential hypertension , evaluating whether the angiotensin receptor blockers ( ARBs ) eprosartan and losartan had identifiable antiadrenergic properties . This was done in a prospect i ve , r and omized , three-way placebo-controlled study of crossover design . Patients were r and omized to 600 mg of eprosartan daily , 50 mg of losartan daily , or placebo . The treatment period was 4 wk , with 2-wk washout periods . Multiunit firing rates in efferent sympathetic nerves distributed to skeletal muscle vasculature ( muscle sympathetic nerve activity , MSNA ) were measured with microneurography , testing whether ARBs inhibit central sympathetic outflow . In parallel , isotope dilution methodology was used to measure whole body norepinephrine spillover to plasma . Mean blood pressure on placebo was 151/98 mmHg , with both ARBs causing reductions of approximately 11 mmHg systolic and 6 mmHg diastolic pressure , placebo corrected . Both MSNA [ 35 + /- 12 bursts/min ( mean + /- SD ) on placebo ] and whole body norepinephrine spillover [ 366 + /- 247 ng/min ] were unchanged by ARB administration , indicating that the ARBs did not material ly inhibit central sympathetic outflow or act presynaptically to reduce norepinephrine release at existing rates of nerve firing . These findings contrast with the easily demonstrable reduction in sympathetic nervous activity produced by antihypertensive drugs of the imidazoline-binding class , which are known to act within the brain to inhibit sympathetic nervous outflow . We conclude that sympathetic nervous inhibition is not a major component of the blood pressure-lowering action of ARBs in essential hypertension Impaired nitric oxide ( NO ) vasodilation ( endothelial dysfunction ) is associated with obesity and thought to be a factor in the development of hypertension . We previously found that NO synthesis inhibition had similar pressor effects in obese hypertensives compared with healthy control during autonomic blockade , suggesting that impaired NO vasodilation is secondary to sympathetic activation . We tested this hypothesis by determining the effect of autonomic blockade ( trimethaphan 4 mg/min IV ) on NO-mediated vasodilation ( increase in forearm blood flow to intrabrachial acetylcholine ) compared with endothelial-independent vasodilation ( intrabrachial sodium nitroprusside ) in obese hypertensive subjects ( 30<body mass index<40 kg/m2 ) .  Acetylcholine and sodium nitroprusside were given at equipotent doses ( 10 , 30 , and 50 & mgr;g/min and 1 , 2 , and 3 & mgr;g/min , respectively ) to 14 obese subjects ( 49±3.6 years , 34±1 kg/m2 , 165/94±7/6 mm Hg ) , on separate occasions 1 month apart , r and omly assigned . Autonomic blockade increased basal forearm blood flow ( from 3.9±0.7 to 5.2±1.2 mL/100 mL per minute , P=0.078 ) . As expected , NO-mediated vasodilation was blunted on the intact day compared with NO-independent vasodilation ; forearm blood flow increased from 3.6±0.6 to 10.1±1.1 with the highest dose of nitroprusside , but only from 3.7±0.4 to 7.2±0.8 mL/100 mL per minute with the highest dose of acetylcholine , P<0.05 . In contrast , forearm blood flow responses to acetylcholine  were restored by autonomic blockade and were no longer different to nitroprusside ( from 6.2±1.1 to 11.4±1.6 mL/100 mL per minute and from 5.2±0.9 to 12.5±0.9 , respectively , P=0.58 ) . Our results support the concept that sympathetic activation contributes to the impairment in NO-mediated vasodilation seen in obesity-associated hypertension and provides further rationale to explore it as a therapeutic target Renal sympathetic denervation ( RDN ) is under investigation as a treatment option in patients with resistant hypertension ( RH ) . Determinants of arterial compliance may , however , help to predict the BP response to therapy . Aortic distensibility ( AD ) is a well-established parameter of aortic stiffness and can reliably be obtained by CMR . This analysis sought to investigate the effects of RDN on AD and to assess the predictive value of pre-treatment AD for BP changes . We analyzed data of 65 patients with RH included in a multicenter trial .  RDN was performed in all participants . A st and ardized CMR protocol was utilized at baseline and at 6-month follow-up . AD was determined as the change in cross-sectional aortic area per unit change in BP . Office BP decreased significantly from 173/92 ± 24/16 mmHg at baseline to 151/85 ± 24/17 mmHg ( p < 0.001 ) 6 months after RDN . Maximum aortic areas increased from 604.7 ± 157.7 to 621.1 ± 157.3 mm2 ( p = 0.011 ) . AD improved significantly by 33 % from 1.52 ± 0.82 to 2.02 ± 0.93 × 10−3 mmHg−1 ( p < 0.001 ) . Increase of AD at follow-up was significantly more pronounced in younger patients ( p = 0.005 ) and responders to RDN ( p = 0.002 ) . Patients with high-baseline  AD were significantly younger ( 61.4 ± 10.1 vs. 67.1 ± 8.4 years , p = 0.022 ) . However , there was no significant correlation of baseline AD to response to RDN . AD is improved  after RDN across all age groups . Importantly , these improvements appear to be unrelated to observed BP changes , suggesting that RDN may have direct effects on the central vasculature Background Whether the sympathetic nervous system can directly alter central aortic stiffness remains controversial , mainly because of the difficulty in experimentally augmenting peripheral vasoconstrictor activity without changing blood pressure . Methods and Results To address this limitation , we utilized low‐level cardiopulmonary baroreflex loading and unloading shown previously to alter sympathetic outflow without evoking parallel hemodynamic modulation . Blood pressure and carotid‐femoral aortic pulse wave velocity ( cf‐PWV ) were measured in 32 healthy participants ( 24±2 years ; women : n=15 ) before and during 12‐minute applications of low‐level lower body negative pressure ;  −7 mm Hg ) and lower body positive pressure ; + 7 mm Hg ) , applied in a r and om order . Fibular nerve microneurography was used to collect muscle sympathetic nerve activity ( MSNA ) in a subset ( n=8 ) to confirm peripheral sympathetic responses . During lower body negative pressure , heart rate , blood pressure , stroke volume , cardiac output , and total peripheral resistance were not statistically different ( all P>0.05 ) ; MSNA burst frequency ( + 15 % ; P=0.007 ) , total MSNA ( + 44 % ; P=0.006 ) , and cf‐PWV ( ∆+0.3±0.2 m/s ; P<0.001 ) increased . In total , 28 ( 88 % ) of participants observed an increase in cf‐PWV greater than the baseline typical error of measurement . During lower body positive pressure , heart rate , stroke volume , cardiac output , and total peripheral resistance were not statistically different ( all P>0.05 ) , though blood pressure increased ( P<0.05 ) and pulse pressure decreased ( P=0.01 ) ; MSNA burst frequency ( −4 % ; P=0.37 ) , total MSNA ( −7 % ; P=0.89 ) , and cf‐PWV ( ∆0.0±0.2 m/s ; P=0.68 ) were not statistically different . Conclusions These findings provide evidence that acute elevations in peripheral sympathetic activity can increase central aortic PWV  in young participants independent of a change in distending or pulsatile blood pressure or heart rate Background : Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution . R and omized trials design ed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed . Methods : In this r and omized , single-center , nonblinded trial , we included patients with hypertension ( using ≥2 medications at maximum doses or > 2 at moderate doses ) and a body mass index between 30.0 and 39.9 kg/m2 . Patients  were r and omized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone . The primary end point was reduction of ≥30 % of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure < 140 mm Hg and 90 mm Hg , respectively , at 12 months . Results : We included 100 patients ( 70 % female , mean age 43.8±9.2 years , mean body mass index 36.9±2.7 kg/m2 ) , and 96 % completed follow-up .  Reduction of ≥30 % of the total number of antihypertensive medications while maintaining controlled blood pressure occurred in 41 of 49 patients from the gastric bypass group ( 83.7 % ) compared with 6 of 47 patients ( 12.8 % ) from the control group with a rate ratio of 6.6 ( 95 % confidence interval , 3.1–14.0 ; P<0.001 ) . Remission of hypertension was present in 25 of 49 ( 51 % ) and 22 of 48 ( 45.8 % ) patients r and omized to gastric bypass , considering office and 24-hour ambulatory blood pressure monitoring , respectively , whereas no patient su bmi tted to medical therapy was free of antihypertensive drugs at 12 months . A post hoc analysis for the primary end point considering the SPRINT ( Systolic Blood Pressure Intervention Trial ) target reached consistent results , with a rate ratio of 3.8 ( 95 % confidence interval , 1.4–10.6 ; P=0.005 ) . Eleven patients ( 22.4 % ) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives . Waist circumference , body mass index , fasting plasma glucose , glycohemoglobin , low-density lipoprotein cholesterol , triglycerides , high-sensitivity C-reactive protein , and 10-year Framingham risk score were lower in the gastric bypass than in the control group . Conclusions : Bariatric surgery represents an effective strategy for blood pressure control in a broad population of patients with obesity and hypertension . Clinical Trial Registration : URL : https:// clinical trials.gov . Unique identifier : NCT01784848 Objective The increase in blood pressure that accompanies the obese state is almost invariably associated with alterations in metabolism ( insulin resistance and dyslipidaemia ) and the neurohumoral profile ( activation of the renin – angiotensin system , sympathetic overactivity ) , which potentiate the cardiovascular risk associated with hypertension . However , debate remains as to the antihypertensive drug on which treatment of obesity-related hypertension should be based . The CROSS ( C and esartan Role on Obesity and on Sympathetic System ) study was undertaken to examine the antihypertensive , neuroadrenergic , and metabolic effects of an angiotensin II receptor blocker in comparison with a diuretic in obese hypertensive individuals . Methods In 127 obese hypertensive individuals aged 50.7 ± 5.1 years ( mean ± SD ) , we measured clinic blood pressure , heart rate , plasma glucose , and insulin at rest and during an oral glucose load before and 12 weeks after treatment with either c and esartan cilexetil ( 8–16 mg once daily ) or hydrochlorothiazide ( HCTZ , 25–50 mg once daily ) , administered orally in accordance with a double-blind , r and omized , placebo-controlled , two-parallel-groups study design . Insulin sensitivity was expressed as insulin resistance index ( IRI ) , calculated as the ratio of the area under the curve ( AUC ) for glucose to that for insulin . In a subgroup of patients , measurements also included direct microneurographic recording of muscle sympathetic nerve activity ( MSNA ) in the peroneal nerve . Results C and esartan cilexetil caused a significant ( P < 0.01 ) reduction in both mean blood pressure ( from 114.2 ± 5.1 to 99.6 ± 6.0 mmHg ) and MSNA ( from 51.0 ± 12.3 to 40.4 ± 12.5 bursts per 100 heart beats ) , and a significant ( P < 0.02 ) increase in insulin sensitivity ( AUC IRI : from −23.2 ± 22.1 to −17.6 ± 12.2 ) . In contrast , HCTZ did not significantly affect MSNA and worsened insulin sensitivity , while achieving blood pressure reductions similar to those produced by c and esartan cilexetil . Conclusions These data provide evidence that , in obese hypertensive individuals , treatment with c and esartan cilexetil has an antihypertensive effect similar to that of HCTZ . Unlike diuretic treatment , however , treatment with c and esartan cilexetil improves insulin sensitivity and exerts sympathoinhibitory effects BACKGROUND In the 2.8 years of the Diabetes Prevention Program ( DPP ) r and omised clinical trial ,  diabetes incidence  in high-risk adults was reduced by 58 % with intensive lifestyle intervention and by 31 % with metformin , compared with placebo . We investigated the persistence of these effects in the long term . METHODS All active DPP participants were eligible for continued follow-up . 2766 of 3150 ( 88 % ) enrolled for a median additional follow-up of 5.7 years ( IQR 5.5 - 5.8 ) . 910 participants were from the lifestyle , 924 from the metformin , and 932 were from the original placebo groups .  On the basis of the benefits from the intensive lifestyle intervention in the DPP , all three groups were offered group-implemented lifestyle intervention . Metformin treatment was continued in the original metformin group ( 850 mg twice daily as tolerated ) , with participants unmasked to assignment , and the original lifestyle intervention group was offered additional lifestyle support . The primary outcome was development of diabetes according to American Diabetes Association criteria . Analysis was by intention-to-treat . This study is registered with Clinical Trials.gov , number NCT00038727 . FINDINGS During the 10.0-year ( IQR 9.0 - 10.5 ) follow-up since r and omisation to DPP , the original lifestyle group lost , then partly regained weight . The modest weight loss with metformin was maintained . Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years ( 95 % CI 4.1 - 5.7 ) in the intensive lifestyle intervention group , 7.8 ( 6.8 - 8.8 ) in the metformin group , and 11.0 ( 9.8 - 12.3 ) in the placebo group . Diabetes incidence rates in this follow-up study were similar between treatment groups : 5.9 per 100 person-years ( 5.1 - 6.8 ) for lifestyle , 4.9 ( 4.2 - 5.7 ) for metformin , and 5.6 ( 4.8 - 6.5 ) for placebo . Diabetes incidence in the 10 years since DPP r and omisation was reduced by 34 % ( 24 - 42 ) in the lifestyle group and 18 % ( 7 - 28 ) in the metformin group compared with placebo . INTERPRETATION During follow-up after DPP , incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group , but the cumulative incidence of diabetes remained lowest in the lifestyle group . Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years . FUNDING National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) BACKGROUND Lifestyle interventions produce short-term improvements in glycemia and cardiovascular disease ( CVD ) risk factors in individuals with type 2 diabetes mellitus , but no long-term data are available . We examined the effects of lifestyle intervention on changes in weight , fitness , and CVD risk factors during a 4-year study . METHODS The Look AHEAD ( Action for Health in Diabetes ) trial is a multicenter r and omized clinical trial comparing the effects of an intensive lifestyle intervention ( ILI ) and diabetes support and education ( DSE ; the control group ) on the incidence of major CVD events in 5145 overweight or obese individuals ( 59.5 % female ; mean age , 58.7 years ) with type 2 diabetes mellitus . More than 93 % of participants provided outcomes data at each annual assessment . RESULTS Averaged across 4 years , ILI participants had a greater percentage of weight loss than DSE participants ( -6.15 % vs -0.88 % ; P < .001 ) and greater improvements in treadmill fitness ( 12.74 % vs 1.96 % ; P < .001 ) , hemoglobin A(1c ) level ( -0.36 % vs -0.09 % ; P < .001 ) , systolic ( -5.33 vs -2.97 mm Hg ; P < .001 ) and diastolic ( -2.92 vs -2.48 mm Hg ; P = .01 ) blood pressure , and levels of high-density lipoprotein cholesterol ( 3.67 vs 1.97 mg/dL ; P < .001 ) and triglycerides ( -25.56 vs -19.75 mg/dL ; P < .001 ) . Reductions in low-density lipoprotein cholesterol levels were greater in DSE than ILI participants ( -11.27 vs -12.84 mg/dL ; P = .009 ) owing to greater use of medications to lower lipid levels in the DSE group . At 4 years , ILI participants maintained greater improvements than DSE participants in weight , fitness , hemoglobin A(1c ) levels , systolic blood pressure , and high-density lipoprotein cholesterol levels . CONCLUSIONS Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness , glycemic control , and CVD risk factors in individuals with type 2 diabetes . Whether these differences in risk factors translate to reduction in CVD events will ultimately be addressed by the Look AHEAD trial . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00017953 BACKGROUND Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infa rct ion and stroke . There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma ( PPAR gamma ) could reduce macrovascular complications . Our aim , therefore , was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes . METHODS We did a prospect i ve , r and omised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease .  We recruited patients from primary -care practice s and hospitals . We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg ( n=2605 ) or matching placebo ( n=2633 ) , to be taken in addition to their glucose-lowering drugs and other medications . Our primary endpoint was the composite of all-cause mortality , non fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) , stroke , acute coronary syndrome , endovascular or surgical intervention in the coronary or leg arteries , and amputation above the ankle . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N NCT00174993 . FINDINGS Two patients were lost to follow-up , but were included in analyses . The average time of observation was 34.5 months . 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint ( HR 0.90 , 95 % CI 0.80 - 1.02 , p=0.095 ) . The main secondary endpoint was the composite of all-cause mortality , non-fatal myocardial infa rct ion , and stroke . 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint ( 0.84 , 0.72 - 0.98 , p=0.027 ) . Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified . 6 % ( 149 of 2065 ) and 4 % ( 108 of 2633 ) of those in the pioglitazone and placebo groups , respectively , were admitted to hospital with heart failure ; mortality rates from heart failure did not differ between groups . INTERPRETATION Pioglitazone reduces the composite of all-cause mortality , non-fatal myocardial infa rct ion , and stroke in patients with type 2 diabetes who have a high risk of macrovascular events Objective : To examine whether experimentally induced weight gain raises ambulatory blood pressure ( BP ) in healthy subjects and identify any relationship between changes in BP and changes in regional fat distribution . Patients and Methods : Twenty‐six normal weight subjects were r and omized to 8 weeks of weight gain through overfeeding ( n=16 ; age , 30.4±6.6 years ) or to weight maintenance ( controls ; n=10 ; age , 27.1±7.7 years ) between July 2004 and August 2010 . Measures of body composition via dual energy X‐ray absorptiometry and computed tomography , circulating biomarkers , and 24‐hour ambulatory BP were obtained at baseline and after the 8‐week experimental phase . Results : Overfeeding result ed in 3.7 kg ( 95 % CI , 2.9‐4.5 ) increase in body weight in weight gainers , with increments in total ( 46.2 cm2 ; 95 % CI , 27.6‐64.9 ) , visceral ( 13.8 cm2 ; 95 % CI , 5.8‐21.9 ) , and subcutaneous fat ( 32.4 cm2 ; 95 % CI , 13.5‐51.3 ) . No changes occurred in the maintenance group . Increases in 24‐hour systolic BP ( 4 mm Hg ; 95 % CI , 1.6‐6.3 ) , mean BP ( 1.7 mm Hg ; 95 % CI , 0.3‐3.3 ) , and pulse pressure ( 2.8 mm Hg ; 95 % CI , 1.1‐4.4 ) were evident after weight gain in the experimental group , whereas BP remained unchanged in controls . Changes in mean BP correlated only with changes in visceral fat ( & rgr;=0.45 ; P=.02 ) , but not with changes in other body composition measures . Conclusion : Modest weight gain causes elevation in 24‐hour BP in healthy subjects . The association between increased BP and abdominal visceral fat accumulation suggests that visceral deposition of adipose tissue may contribute specifically to the enhanced risk of hypertension associated with weight gain Hyperinsulinemia and increased sympathetic nervous system ( SNS ) activity are thought to be pathophysiological links between obesity and hypertension . In the present study , we examined the relation among heart rate ( HR ) , blood pressure ( BP ) , and percent body fat ( hydrodensitometry or DEXA ) , fasting plasma insulin concentration , and muscle sympathetic nerve activity ( MSNA , microneurography )  in male , normotensive whites ( n=42 ) and Pima Indians ( n=77 ) . Pima Indians have a high prevalence of obesity and hyperinsulinemia but a relatively low prevalence of hypertension . Compared with whites , Pima Indian men had a higher percent body fat ( 28 % versus 21 % ) and higher fasting insulin concentrations ( 210 versus 132 pmol/L ) but lower MSNA ( 27 versus 33 bursts/min ) ( all P < 0.001 ) . In both ethnic groups , HR and BP were positively related to percent body fat and MSNA , and both were significant independent determinants of HR and BP in multiple regression analyses . However , MSNA was positively related to percent body fat and the fasting insulin concentration in whites ( r = 0.60 and r = 0.47 , both P < 0.01 ) but not in Pima Indians ( r = 0.15 and r = 0.03 , NS ) ( P < 0.01 for ethnic differences in the slope of the regression lines ) . These results confirm the physiological importance of the SNS in normal BP regulation but indicate that the roles of hyperinsulinemia and increased SNS activity as mediators for the relation between obesity and hypertension can differ between different ethnic groups . The lack of an increase in SNS activity with increasing adiposity and insulinemia in Pima Indians may contribute to the low prevalence of hypertension in this population Glucagon-like peptide-1 ( GLP-1 ) , an incretin , which is used to treat diabetes mellitus in humans , inhibited vagal activity and activated nitrergic pathways . In rats , GLP-1 also increased sympathetic activity , heart rate , and blood pressure ( BP ) . However , the effects of GLP-1 on sympathetic activity in humans are unknown . Our aims were to assess the effects of a GLP-1 agonist with or without alpha(2)-adrenergic or -nitrergic blockade on autonomic nervous functions in humans . In this double-blind study , 48 healthy volunteers were r and omized to GLP-1-(7 - 36 ) amide , the nitric oxide synthase ( NOS ) inhibitor N(G)-monomethyl-l-arginine acetate ( l-NMMA ) , the alpha(2)-adrenergic antagonist yohimbine , or placebo ( i.e. , saline ) , alone or in combination . Hemodynamic parameters , plasma catecholamines , and cardiac sympathetic and parasympathetic modulation were measured by spectral analysis of heart rate . Thereafter , the effects of GLP-1-(7 - 36 ) amide on muscle sympathetic nerve activity ( MSNA ) were assessed by microneurography in seven subjects . GLP-1 increased ( P = 0.02 ) MSNA but did not affect cardiac sympathetic or parasympathetic indices , as assessed by spectral analysis . Yohimbine increased plasma catecholamines and the low-frequency ( LF ) component of heart rate power spectrum , suggesting increased cardiac sympathetic activity . l-NMMA increased the BP and reduced the heart rate but did not affect the balance between sympathetic and parasympathetic activity .  GLP-1 increases skeletal muscle sympathetic nerve activity but does not appear to affect cardiac sympathetic or parasympathetic activity in humans The purpose of this study was to determine the contribution of the adrenergic system in mediating hypertension in obese and lean patients . Thirteen obese , hypertensive patients with a body mass index ( BMI ) > or = 28 kg/m2 ( obese ) and nine lean patients with a BMI < or = 25 kg/m2 ( lean ) were recruited . After a 1-week washout period , participants underwent daytime ambulatory blood pressure monitoring  ( ABPM ) . Participants were then treated with the alpha-adrenergic antagonist doxazosin , titrating to 4 mg QHS in 1 week . In the next week , the beta-adrenergic antagonist atenolol was added at an initial dose of 25 mg/day and titrated to 50 mg/day within 1 week . One month after the addition of atenolol , all patients underwent a second ABPM session . There were no differences between the obese and lean subjects in baseline systolic ( SBP ) , diastolic ( DBP ) , or mean arterial pressures ( MAP ) measured by office recording or ABPM . However , obese subjects had higher heart rates than lean subjects ( 87.5+/-2.4 v 76.8+/-4.9 beats/min ) . After 1 month of treatment with the adrenergic blockers , obese patients had a significantly lower SBP ( 130.0+/-2.5 v 138.9+/-2.1 mm Hg , P = .02 ) and MAP ( 99.6+/-2.3 v 107.0+/-1.5 mm Hg , P = .02 ) than lean patients . Obese patients also tended to have a lower DBP than lean patients ( 84.3+/-2.5 v 90.9+/-1.6 mm Hg , P = .057 ) , but there was no significant difference in heart rate after 1 month of adrenergic blockade . These results indicate that blood pressure is more sensitive to adrenergic blockade in obese than in lean hypertensive patients and suggest that increased sympathetic activity may be an important factor in the maintenance of hypertension in obesity To evaluate the effect of metformin on insulin sensitivity and to further examine the relationship between insulin resistance , sympathetic nerve activity and blood pressure , 6 obese insulin resistant , normoglycemic hypertensive men were investigated ( age 49 + /- 2 years , BMI 27.6 + /- 1.2 , mean + /- SEM ) . The study had a placebo controlled , double blind , cross over design with 6 weeks ' metformin treatment ( 850 mg b.i.d ) vs placebo .  Blood pressure was measured weekly . At the end of each treatment period , glucose infusion rate ( GIR ) , muscle sympathetic nerve activity ( MSA ) and renal and total body norepinephrine ( NE ) kinetics ( radioisotope dilution ) were examined during euglycemic hyperinsulinemic clamp . Fasting insulin was 13 + /- 3 and 10 + /- 2 mU/l and fasting glucose 5.3 + /- 0.2 and 5.1 + /- 0.1 mmol/l after placebo and metformin treatment , respectively ( ns ) . GIR during the last hour of the insulin clamp was 3.7 + /- 0.6 vs 3.6 + /- 0.6 mg/kg x min ( ns ) . Resting MSA , total body and right renal NE spillover did not differ significantly after placebo and metformin treatment . Systolic and diastolic blood pressures were 151 + /- 10/95 + /- 5 mmHg after placebo and 146 + /- 5/94 + /- 5 mmHg after metformin treatment ( ns ) . Thus metformin treatment did not have any significant effect on insulin sensitivity , blood pressure or sympathetic activity in this small group of patients . Renal plasma flow and MSA increased significantly during the insulin clamp , whereas renal NE and total body NE spillover remained unchanged , suggesting nonuniform regional sympathetic nerve responses to acute hyperinsulinemia OBJECTIVES In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias , we prospect ively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure . BACKGROUND Despite recent therapeutic advances , patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias . It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive , potentially contributing to subsequent adverse events . METHODS Sixty patients with moderate to severe heart failure ( left ventricular ejection fraction 18.9 + /- 0.9 % [ mean + /- SE ] ) were studied prospect ively . In addition to the compilation of a hemodynamic , biochemical and electrocardiographic profile for each patient , whole-body and cardiac sympathetic activity were determined by isotope dilution . The relation of these variables to outcome was determined by Cox proportional hazards analysis . RESULTS The mean follow-up period of the study group was 7 + /- 1 months ( range 1 to 24 ) with a 12-month actuarial survival of 75 % . Deaths ( 14 in all ) were accounted for either by sudden death or progressive heart failure in equal numbers . The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects ( 402 + /- 37 vs. 105 + /- 19 pmol/min , p < 0.01 ) , although the values for heart failure ranged widely from normal to 10 times normal . By univariate Cox proportional hazards analysis , pulmonary capillary wedge pressure ( p < 0.01 ) , mean pulmonary artery pressure ( p < 0.001 ) , serum sodium levels ( p < 0.01 ) and cardiac norepinephrine spill-over rate ( p < 0.001 ) were identified as significant prognostic markers . In a multivariate analysis , cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker ( p = 0.0006 ) of those evaluated in this study . CONCLUSIONS These results suggest that activation of the sympathetic nervous system in patients with heart failure , specifically the cardiac sympathetic nerves , may contribute to the poor prognosis associated with severe heart failure . The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure Endothelial dysfunction is considered an important prognostic factor in atherosclerosis . To determine the long-term association of brachial artery flow-mediated dilation ( FMD ) and adverse cardiovascular ( CV ) events in healthy subjects , we prospect ively assessed brachial FMD in 618 consecutive healthy subjects with no apparent heart disease , 387 men ( 63 % ) , and mean age 54 ± 11 years . After overnight fasting and discontinuation of all medications for ≥12 hours , FMD was assessed using high-resolution linear array ultrasound . Subjects were divided into 2 groups : FMD ≤11.3 % ( n = 309 ) and > 11.3 % ( n = 309 ) , where 11.3 % is the median FMD , and were comparable regarding CV risk factors , lipoproteins , fasting glucose , C-reactive protein , concomitant medications , and Framingham 10-year risk score . In a mean clinical follow-up of 4.6 ± 1.8 years , the composite CV events ( all-cause mortality , nonfatal myocardial infa rct ion , hospitalization for heart failure or angina pectoris , stroke , coronary artery bypass grafting , and percutaneous coronary interventions ) were significantly more common in subjects with FMD ≤11.3 % rather than > 11.3 % ( 15.2 % vs 1.2 % , p = 0.0001 , respectively ) . Univariate analysis demonstrated that the median FMD significantly predicted CV events ( odds ratio 2.78 , 95 % CI 1.35 to 5.71 , p < 0.001 ) . Multivariate analysis , controlling for traditional CV risk factors , demonstrated that median FMD was the best independent predictor of long-term CV adverse events ( odds ratio 2.93 , 95 % CI 1.28 to 6.68 , p < 0.001 ) . In conclusion , brachial artery median FMD independently predicts long-term adverse CV events in healthy subjects with no apparent heart disease in addition to those derived from traditional risk factor assessment Augmented sympathetic nerve activity is associated with heart failure with preserved left ventricular ejection fraction ( HFpEF ) .  Lipophilic statins reduce sympathetic nerve activity in patients with heart failure with reduced left ventricular ejection fraction . However , little is known about whether all types of statins , regardless of solubility , reduce sympathetic nerve activity in HFpEF . We evaluated the effect of atorvastatin , a lipophilic statin , and rosuvastatin , a hydrophilic statin , on muscle sympathetic nerve activity ( MSNA ) in HFpEF patients . This study was conducted as a prospect i ve , r and omized , open-label , crossover trial . Ten HFpEF patients with untreated hyperlipidemia participated in this study . Subjects were assigned to either the atorvastatin ( lipophilic ) or the rosuvastatin ( hydrophilic ) group with each drug administered for 8 weeks . Atorvastatin and rosuvastatin treatment result ed in a similar reduction in low-density lipoprotein cholesterol ( LDL-C ) levels . There was no difference in the effect of either treatment on blood pressure , heart rate , or left ventricular function . Atorvastatin significantly decreased MSNA frequency compared with baseline ( 31.5 ± 6.3 vs. 47.5 ± 10.7 bursts/min , p < 0.01 ) , but rosuvastatin had no effect on MSNA ( 40.9 ± 7.3 bursts/min ) . MSNA was significantly lower in the atorvastatin group than rosuvastatin group ( p < 0.05 ) . However , the reduction in MSNA seen in either group did not correlate with the reduction in LDL-C. No significant differences were observed in either the baroreflex control of heart rate or MSNA between the two groups . These results suggest that lipophilic statins have a favorable effect on sympathetic nerve activity beyond lowering LDL-C in HFpEF , but hydrophilic statins do not Background Lorcaserin , a selective serotonin 2C receptor agonist that modulates appetite , has proven efficacy for weight management in overweight or obese patients . The cardiovascular safety and efficacy of lorcaserin are undefined . Methods We r and omly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin ( 10 mg twice daily ) or placebo . The primary safety outcome of major cardiovascular events ( a composite of cardiovascular death , myocardial infa rct ion , or stroke ) was assessed at an interim analysis to exclude a noninferiority boundary of 1.4 . If noninferiority was met , the primary cardiovascular efficacy outcome ( a composite of major cardiovascular events , heart failure , hospitalization for unstable angina , or coronary revascularization [ extended major cardiovascular events ] ) was assessed for superiority at the end of the trial . Results At 1 year , weight loss of at least 5 % had occurred in 1986 of 5135 patients ( 38.7 % ) in the lorcaserin group and in 883 of 5083 ( 17.4 % ) in the placebo group ( odds ratio , 3.01 ; 95 % confidence interval [ CI ] , 2.74 to 3.30 ; P<0.001 ) . Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors ( including blood pressure , heart rate , glycemic control , and lipids ) than those in the placebo group . During a median follow‐up of 3.3 years , the rate of the primary safety outcome was 2.0 % per year in the lorcaserin group and 2.1 % per year in the placebo group ( hazard ratio , 0.99 ; 95 % CI , 0.85 to 1.14 ; P<0.001 for noninferiority ) ; the rate of extended major cardiovascular events was 4.1 % per year and 4.2 % per year , respectively ( hazard ratio , 0.97 ; 95 % CI , 0.87 to 1.07 ; P=0.55 ) . Adverse events of special interest were uncommon , and the rates were generally similar in the two groups , except for a higher number of patients with serious hypoglycemia in the lorcaserin group ( 13 vs. 4 , P=0.04 ) . Conclusions In a high‐risk population of overweight or obese patients , lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events  than that with placebo . ( Funded by Eisai ; CAMELLIA – TIMI 61 Clinical Trials.gov number , NCT02019264 . Objectives : The objective of this study is to determine the effects of renin -- angiotensin -- aldosterone system inhibition , sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension . Methods : A r and omized , four-way , double-blind , crossover study in 31 adults with previously untreated obesity-related hypertension , in which the effects of 8 weeks ’ inhibition of the renin -- angiotensin -- aldosterone system ( using aliskiren 300 mg ) , sympathoinhibition ( using moxonidine 0.4 mg ) , diuretic therapy ( using hydrochlorothiazide 25 mg ) or placebo on flow-mediated dilation and 24-h blood pressure were compared . Results : The median flow-mediated dilation during placebo was 4.0 % [ interquartile range ( IQR ) 2.9–5.5 % ] and was increased by aliskiren [ 0.81 % , 95 % confidence interval ( CI ) 0.02–1.79 ] , but not by moxonidine ( 0.20 % , 95 % CI −0.46 to 1.03 ) or hydrochlorothiazide ( 0.39 % , 95%CI −0.31%–1.26 % ) . Similarly , compared with placebo  , mean 24-h blood pressure was most reduced by aliskiren ( −9.8/−6.3 mmHg ) and to a lesser degree by hydrochlorothiazide ( −5.9/−2.6 mmHg ) . Moxonidine did not significantly affect blood pressure despite reduction of muscle sympathetic nerve activity . Insulin sensitivity deteriorated during hydrochlorothiazide treatment and was unaffected by aliskiren or moxonidine . Unlike aliskiren and moxonidine , hydrochlorothiazide  reduced urinary 8-iso-prostagl and in F2&agr;-VI , a marker of oxidative stress . Vascular stiffness , systemic inflammation , leptin , adiponectin and other oxidative stress markers ( plasma malondialdehyde , myeloperoxidase activity and urinary 8-hydroxydeoxyguanosine ) were unaffected by treatment . Conclusion : Renin inhibition , but not sympathoinhibition or diuretic therapy , improves endothelial function and results in larger reductions of 24-h , office , and central blood pressure in obesity-related hypertension . This adds weight to the hypothesis that inhibition of the renin -- angiotensin -- aldosterone system is an effective first step in the treatment of obesity-related hypertension The association between glomerular hyperfiltration and cardiovascular events is not well known . To investigate whether glomerular hyperfiltration is independently associated with risk of adverse outcome  we analyzed 8794 participants , average age 52 years enrolled in 8 prospect i ve studies . Of these , 89 % had hypertension . Using the 5th and 95th percentiles of the age- and sex-specific quintiles of CKD-EPI-calculated estimated glomerular filtration rate ( eGFR ) , we identified three participant groups with low , high and normal eGFR . The ambulatory pulse pressure interval was wider and nighttime blood pressure fall was smaller in both the low and high than in the normal eGFR participants . During a mean follow-up of 6.2 years , there were 722 cardiovascular events . Crude event rates were significantly higher for both high ( 1.8 per 100-person-year ) and low eGFR groups ( 2.1 per 100 person-year ) as compared with group with normal eGFR ( 1.2 per 100 person-year ) . In multivariable Cox models including age , sex , average 24-hour blood pressure , smoking , diabetes , and cholesterol , both high eGFR ( hazard ratio 1.5 ( 95 % confidence interval 1.2 - 2.1 ) and low eGFR ( 2.0 [ 1.5 - 2.6 ] ) participants had a significantly higher risk of cardiovascular events as compared to those with normal eGFR . Addition of body mass index to the multivariable survival model did not change the magnitude of hazard estimates . Thus , glomerular hyperfiltration is a strong and independent predictor of cardiovascular events in a large multiethnic population of predominantly hypertensive individuals . Our findings support a U-shaped relationship between eGFR and adverse outcome
target: This indicates that even in the absence of metabolic abnormalities , overweight and obesity are not innocuous , perhaps because the traditional cardiovascular risk factors are either not present early or remain undetected using routine clinical assessment .
  This raises the concept that early or sub clinical organ damage assessment s may be better at identifying subjects who are more likely to progress to develop cardiovascular disease .
background: Obesity and Consequences The prevalence of overweight and obesity has reached epidemic proportion , with the recent figures from the World Health Organization indicating that in 2016 39 % of adults aged ≥18 years ( 39 % of men and 40 % of women ) were overweight and 13 % ( 11 % of men and 15 % of women ) obese .
  The World Health Organization states that raised body mass index ( BMI ) is a major risk factor for noncommunicable diseases such as cardiovascular diseases ( mainly heart disease and stroke ) , which were the leading causes of death in 2012 , diabetes mellitus , musculoskeletal disorders , and some cancers .
  The Framingham Heart Study data have indicated that overweight and obesity are associated with significantly decreased life expectancy .
  Nevertheless , and against these strong evidence s , the relationship between BMI and mortality has been challenged by several studies , indicating a survival advantages for those who are overweight and class I obese .
  However , the determinants of these observations are poorly understood and continue to be debated because BMI may not be the ideal index of adiposity and fat distribution and fitness and disease prevention may obscure the link between BMI and mortality .
  Overweight or obesity is not always accompanied by traditional risk factors .
  In fact , a systematic review and meta analysis revealed that about 35 % of obese individuals are metabolically healthy .
  There is evidence that an important factor driving at least some of the obesity-associated end-organ damage is overactivity of the sympathetic nervous system ( SNS ) , an observation that suggests that targeting SNS in obesity may help reduce the cardiovascular risk associated with obesity .
  In this review , we highlight the current knowledge of the potential role of SNS function in obesity-induced organ damage and examine whether interventions aim ed at reducing cardiovascular risk in obesity may be mediated via alterations in SNS activity .