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Aims: Obesity is associated with an increased incidence of mortality. The Sibutramine Cardiovascular Outcomes (SCOUT) trial can provide the first evidence of the effect of intentional weight loss on mortality in an obese population at high risk., Methods: SCOUT was a randomized, double-blind, placebo-controlled trial testing sibutramine vs. placebo. Eligibility for the trial required both men and women aged at least 55 years, with BMI of at least 27 kg/m and 45 kg/m or less. Study participants with type 2 diabetes mellitus (T2DM) only should have at least one other risk factor defined as hypertension, dyslipidaemia, smoking, or diabetic nephropathy, and/or they had a history of cardiovascular disease. Study participants were stratified in three groups: patients with T2DM, patients with a prior cardiovascular event but without diabetes, and patients with both T2DM and a prior cardiovascular event.The relationship between weight loss and mortality (all-cause, cardiovascular, and noncardiovascular) was investigated with Cox regression models., Results: The main study showed that all-cause mortality was not different in patients allocated to sibutramine or placebo. This ancillary analysis demonstrates that there is a general trend showing higher mortality in patients with the greatest weight loss (weight reduction >10 kg) and in those with increasing weight (>1 kg). If integrated weight loss (area under the curve from baseline to 12 months) is used, these observations are confirmed. The impact of substantial weight loss on mortality is marked in those dying of noncardiovascular causes, specifically cancer., Conclusion: The relationship between weight change and mortality differs for cardiovascular and noncardiovascular mortality.

Objective: We aim to systematically review the bariatric surgery literature with regards to adequacy of patient follow-up, meeting the McMaster criteria of ≥80% follow-up., Background: Loss to follow-up is a major concern and can potentially bias the outcome and interpretation of a study. The quality of follow-up in bariatric surgery is quite variable with recent systematic reviews criticizing the field for its lack of overall follow-up., Methods: A complete search of PubMed was performed. Literature was restricted to a range of 5 years (2007-2012), English language, and publications listed in PubMed. The McMaster Evidence-based Criteria for High Quality Studies was used to assess the follow-up data adequacy and a logistic meta-regression was performed to identify factors associated with high quality follow-up studies., Results: Ninety-nine published manuscripts were included. For follow-up at study end, only 40/99 (40.4%) of papers had adequate patient follow-up, 42/99 (42.4%) failed to meet the McMaster criteria and 17/99 (17.2%) failed to report any follow-up results. On average, 31% were lost to follow-up at the study's end. Only shorter study duration, and if the study was performed in the US, were associated with studies meeting the McMaster criteria., Conclusions: Only 40% of studies in the bariatric surgery literature meet criteria for adequate follow-up. On average, studies have 30% of patients lost to follow-up at the stated end-point. Identified study characteristics associated with high quality follow-up included shorter study duration and studies performed in the US.

Background: Multidisciplinary bariatric care is increasingly being delivered in Canada within publicly funded regional programs. Demand is high, wait lists are long, and clinical effectiveness is unknown., Objective: To examine the "real-world" outcomes associated with a publicly funded, population-based regional bariatric (medical and surgical) program., Research Design: Prospective observational cohort., Subjects: Five hundred consecutive patients (150 wait-listed, 200 medically treated, 150 surgically treated) from the Edmonton Weight Wise program were enrolled., Measures: The primary outcome was weight change (kg). Between-group changes were analyzed using multivariable regression adjusted for age, sex, and baseline weight and "last-observation-carried-forward" was used for missing data. Subjects transitioning between groups (wait-list to medical or medical to surgery) were censored when crossing over., Results: At baseline, mean age was 43.7 ± 9.6 years, mean body mass index was 47.9 ± 8.1 kg/m, and 88% were female. A total of 412 subjects (82%) completed 2-year follow-up and 143 (29%) subjects crossed over to the next treatment phase. Absolute and relative (% of baseline) mean weight reductions were 1.5 ± 8.5 kg (0.9 ± 6.1%) for wait-listed, 4.1 ± 11.6 kg (2.8 ± 8.1%) for medically treated, and 22.0 ± 19.7 kg (16.3 ± 13.5%) for surgically treated (P<0.001) subjects. For surgery, weight reductions were 7.0 ± 9.7 kg (5.8 ± 7.9%) with banding, 21.4 ± 16.0 kg (16.4 ± 11.6%) with sleeve gastrectomy, and 36.6 ± 19.5 kg (26.1 ± 12.2%) with gastric bypass (P<0.001). Rates of hypertension, diabetes, and dyslipidemia decreased to a significantly greater degree with surgery than medical management (P<0.001) and stayed the same or increased in wait-listed subjects., Conclusions: Population-based bariatric care, particularly bariatric surgery, was clinically effective. Weight and cardiometabolic risk was relatively stable wait-listed patients receiving "usual care."

Uncertainties about the cardiovascular safety of sibutramine led to the SCOUT trial that is investigating sibutramine plus weight management in high-risk, overweight/obese patients. A 6-week lead-in period during which all patients received sibutramine permitted an initial assessment of tolerability. A total of 10,742 patients received sibutramine and 3.1% of these discontinued due to an adverse event; issues affecting more than 10 patients were drug intolerance, headache, insomnia, nausea, dry mouth, and constipation-, tachycardia-, and hypertension-related events. Serious adverse events, most commonly associated with the System Organ Class, Cardiac disorders, were reported by 2.7% of patients; however, the majority was not considered sibutramine-related. Adverse events relating to high blood pressure and/or pulse rate, whether reported as adverse events leading to discontinuation, or serious adverse events were reported by less than 0.2% of patients. No serious or individual events leading to discontinuation occurred in more than 25 patients. There were 15 (0.1%) deaths; 10 were attributed to a cardiovascular cause. Discontinuations for adverse events were lower than anticipated. Serious adverse events generally reflected sibutramine's known pharmacology or were related to cardiac disorders already present in this high-risk population. When compared with epidemiological data, overall mortality rate was low and sibutramine was well tolerated in this mainly off-label population. No new safety issues were detected.

Background: Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease., Methods and Results: In 11 healthy subjects (7 men, age 27+/-2 years, body mass index 23.1+/-0.7 kg/m2), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113+/-3 mm Hg with placebo, 121+/-3 mm Hg with sibutramine (P<0.001 versus placebo), and 111+/-2 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position., Conclusions: The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.

Purpose of Review: Obesity is a major public health issue, and hypertension is one of the most common associated co-morbidities. Here, recent developments in the treatment of obesity-related hypertension, published during the past year, are reviewed., Recent Findings: Several recent studies have examined the effect of dietary and lifestyle changes on hypertension. These studies uniformly confirm that weight reduction together with salt restriction and increased physical exercise can lower blood pressure. Several studies have shown that pharmacologically induced weight reduction with orlistat or sibutramine can likewise be beneficial in the management of obese hypertensive patients. The role of surgery in obesity remains to be defined., Summary: Both non-pharmacologically and pharmacologically induced weight loss can lower blood pressure in obese hypertensive patients. The effects of weight loss and pharmacological management on morbidity and mortality in obese hypertensive patients remains to be addressed in prospective trials.

Background: Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown., Methods and Results: We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was approximately 3.5 times greater than the maximal response to entacapone., Conclusions: COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.

Background: The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known., Methods and Results: We characterized baroreflex function and responses to vasoactive drugs in patients with idiopathic orthostatic intolerance, patients with essential hypertension, patients with monogenic hypertension and brachydactyly, patients with multiple system atrophy, and control subjects. We used phenylephrine sensitivity during ganglionic blockade as a measure of baroreflex buffering. Phenylephrine (25 microg) increased systolic blood pressure 6+/-1.6 mm Hg in control subjects, 6+/-1.1 mm Hg in orthostatic intolerance patients, 18+/-3.9 mm Hg in patients with essential hypertension, 31+/-3.4 mm Hg in patients with monogenic hypertension, and 25+/-3.4 mm Hg in patients with multiple system atrophy. Similar differences in sensitivities between groups were observed with nitroprusside. The sensitivity to vasoactive drugs was highly correlated with baroreflex buffering function and to a lesser degree with baroreflex control of heart rate. In control subjects, sensitivities to nitroprusside and phenylephrine infusions were correlated with baroreflex heart rate control and sympathetic nerve traffic., Conclusions: Our findings are consistent with an important effect of baroreflex blood pressure buffering on the sensitivity to vasoactive drugs. They suggest that even moderate changes in baroreflex function may have a substantial effect on the sensitivity to vasoactive medications.

Background: Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance., Methods and Results: We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65+/-2 bpm with placebo and 71+/-3 bpm with reboxetine. At 75 degrees HUT, heart rate was 84+/-3 and 119+/-4 bpm with placebo and with reboxetine (P<0.0001). Mean arterial pressure was 85+/-2 with placebo and 91+/-2 mm Hg with reboxetine while supine (P<0.01) and 88+/-2 mm Hg and 90+/-3 mm Hg at 75 degrees HUT. Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine. Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine. Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine., Conclusions: Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.

Objective: Neurovascular compression of the rostral ventrolateral medulla (RVLM) has been implicated in the pathogenesis of essential hypertension. Although MRI has been widely used to evaluate the morphologic relation of structures in this region, spatial resolution of the previously used techniques was limited. This article describes the use of a new MRI protocol that combines two sequences with improved spatial resolution and complementary image information as well as a set of defined criteria for image analysis., Methods: MRI of the brain stem was performed in 60 hypertensive and 50 normotensive subjects using a 3D-CISS and a 3D-FISP-MRA sequence. Neurovascular contact in the RVLM was independently assessed by four readers using predefined criteria and compared with a consensus finding. Agreement was expressed by kappa statistics on a 0 to 1 scale., Results: Left-sided neurovascular contact within the RVLM was found in 13 (22%) hypertensive and 6 (12%) control subjects. The inter-reader agreement for positive and negative findings ranged from 0.47 to 0.79; agreement to the consensus finding ranged from 0.65 to 0.90., Conclusions: The combination of 3D-CISS and arterial flow-sensitive 3D-FISP, together with the evaluation criteria defined in this study, can be used for describing the finer anatomic features of the brain stem, and in particular for investigation of neurovascular contact of the IX/X cranial nerve root-entry zone. The high quality of images and the substantial or almost perfect reader-consensus agreement should make this protocol useful for future investigations of the neurovascular compression syndrome in patients with essential hypertension and possibly in other neurovascular compression syndromes, such as trigeminal neuralgia and hemifacial spasm.

Hyperinsulinemia and insulin resistance have been implicated to play a role in the development of hypertension and to contribute to the increased risk for cardiovascular disease in diabetic, obese, hypertensive, and normotensive salt-sensitive humans. Reviewed herein are the effects of nonpharmacological measures, including exercise, weight loss, diet, and changes in lifestyle, on insulin resistance. Based on the evidence from both experimental and clinical studies, regular exercise, moderate weight reduction, and a low-fat, high-carbohydrate, high-fiber diet can markedly improve insulin sensitivity. The possible mechanisms involved are discussed. Because these nonpharmacological measures have also been shown to lower blood pressure and correct dyslipidemia, they can contribute substantially to the reduction of major cardiovascular risk factors and should be implemented in all patients who may be at risk for cardiovascular disease.