Higher Plasma Norepinephrine Levels Research Articles

Decreased levels of hydrogen sulfide in the hypothalamic paraventricular nucleus contribute to sympathetic hyperactivity induced by cerebral infarction.

Paroxysmal sympathetic hyperactivity (PSH) is a common clinical feature secondary to ischemic stroke (IS), but its mechanism is poorly understood. We aimed to investigate the role of H2S in the pathogenesis of PSH. IS patients were divided into malignant (MCI) and non-malignant cerebral infarction (NMCI) group. IS in rats was induced by the right middle cerebral artery occlusion (MCAO). H2S donor (NaHS) or inhibitor (aminooxy-acetic acid, AOAA) were microinjected into the hypothalamic paraventricular nucleus (PVN). Compared with the NMCI group, patients in the MCI group showed PSH, including tachycardia, hypertension, and more plasma norepinephrine (NE) that was positively correlated with levels of creatine kinase, glutamate transaminase, and creatinine respectively. The 1-year survival rate of patients with high plasma NE levels was lower. The hypothalamus of rats with MCAO showed increased activity, especially in the PVN region. The levels of H2S in PVN of the rats with MCAO were reduced, while the blood pressure and renal sympathetic discharge were increased, which could be ameliorated by NaHS and exacerbated by AOAA. NaHS completely reduced the disulfide bond of NMDAR1 in PC12 cells. The inhibition of NMDAR by MK-801 microinjected in PVN of rats with MCAO also could lower blood pressure and renal sympathetic discharge. In conclusion, PSH may be associated with disease progression and survival in patients with IS. Decreased levels of H2S in PVN were involved in regulating sympathetic efferent activity after cerebral infarction. Our results might provide a new strategy and target for the prevention and treatment of PSH.

Selected sex related differences in pathophysiology of cardiovascular system.

The annual incidence of cardiovascular diseases is age-dependently increasing both in men and women, however, the prevalence is higher in men until midlife. The higher incidence of cardiovascular disease in men than in women of similar age, and the menopause-associated increase in cardiovascular disease in women, has led to speculation that gender-related differences in sex hormones might have a key role in the development and evolution of cardiovascular disease. There are several suggested pathways in which gender and sex hormones can affect human cardiovascular system to produce original sexually different pathophysiology between women and men. Sex steroid hormones and their receptors are critical determinants of cardiovascular gender differences. Also arterial blood pressure is typically lower in women than in men what could be explained particularly by greater synthesis of nitric oxide (NO) in women. Female cardiomyocytes have a greater survival advantage when challenged with oxidative stress, suggesting that female hormones may play an important role in antioxidative protection of myocardium. It was also demonstrated in animal models that combination of XX chromosomes versus an XY chromosomes enhances sex differences in higher HDL cholesterol. Women were found to have reduced sympathetic activity (reflected by lower total peripheral resistance) and pulmonary artery pressure and enhanced parasympathetic activity relative to men. Similarly, men were found to have higher plasma norepinephrine levels than women. Regarding differences between the sexes in electrophysiology of the heart, two principle mechanisms have been proposed to explain them: hormonal effects on the expression or function of ion channels or, conversely, differences in autonomic tone. To improve diagnosis and treatment of cardiovascular diseases, greater focus on understanding the molecular and cellular physiology of the sex steroid hormones and their receptors in the cardiovascular system will be required.

Pheochromocytoma and Paraganglioma Patients With Poor Survival Often Show Brown Adipose Tissue Activation.

Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on β-adrenoceptors (β-ARs). In some malignancies, BAT activation is associated with higher cancer activity. To study the relationship between BAT activation and PPGL clinical outcomes. A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT [7.80%; age 27.50 (15.00-45.50) years; 10 female/6 male; body mass index [BMI] 24.90 [19.60-25.35] kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 [25.4-45.5] years; 21 female/15 male; BMI 25.0 [22.0-26.0] kg/m2). Overall survival. The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05-32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group [4.65 vs 0.55 times above the upper limit of normal; P < 0.01]. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups. Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.

Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal.

Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following β‐adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic β‐adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and β‐blockade (AUCP ropranolol–AUCS aline, β‐REE) and as a percent (%) of control (AUCP ropranolol÷AUCS aline × 100). β‐REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: β‐REE R = −0.58, P = 0.03; %REE R = −0.56, P = 0.04; NE: β‐REE R = −0.55, P = 0.0535; %REE R = −0.54, P = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity.

Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study.

BackgroundChronic fatigue syndrome (CFS) is a common and disabling disorder, and a major threat against adolescent health. The pathophysiology is unknown, but alteration of neuroendocrine control systems might be a central element, resulting in attenuation of the hypothalamus–pituitary–adrenalin (HPA) axis and enhancement of the sympathetic/adrenal medulla (SAM) system. This study explored differences in neuroendocrine control mechanisms between adolescent CFS patients and healthy controls, and whether characteristics of the control mechanisms are associated with important clinical variables within the CFS group.MethodsCFS patients 12–18 years of age were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied. A comparable group of healthy controls were recruited from local schools. A total of nine hormones were assayed and subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and daily physical activity was recorded by an accelerometer.ResultsA total of 120 CFS patients and 68 healthy controls were included. CFS patients had significantly higher levels of plasma norepinephrine, plasma epinephrine and plasma FT4, and significantly lower levels of urine cortisol/creatinine ratio. Subgrouping according to other case definitions as well as adjusting for confounding factors did not alter the results. Multivariate linear regression models as well as network analyses revealed different interrelations between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls. Also, single hormone degree centrality was associated with clinical markers within the CFS group.ConclusionThis study reveals different interrelation between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls, and an association between hormone control characteristics and important clinical variables in the CFS group. These results add to the growing insight of CFS disease mechanisms.Trial registration Clinical Trials NCT01040429

The Role of Beta-Blockers in the Treatment of Hypertension.

Two major guide-line committees (JNC-8 and NICE UK) have dropped beta-blockers as first-line therapy in the treatment of hypertension. Also, recent meta-analyses (that do not take age into account) have concluded that beta-blockers are inappropriate first-line agents in the treatment of hypertension. This review seeks to shed some light on the "rights and wrongs" of such actions and conclusions. Because the pathophysiology of primary/essential hypertension differs in elderly and younger subjects, the latter being closely linked to obesity and increased sympathetic nerve activity, the author sought to clarify the efficacy of beta-blockers in the younger/middle-aged group in reducing the risk of death, and cardiovascular end-points. Four searches were undertaken, utilising PubMed up to 31st Dec 2015. One search was under the terms "hypertension AND obesity AND sympathetic nerve activity". A second was "hypertension AND plasma noradrenaline/norepinephrine AND survival". A third was "beta-blockers or adrenergic beta-antagonists AND hypertension AND age AND stroke or myocardial infarction or death". A fourth was "meta-analysis of beta-blockers AND hypertension AND age AND death, stroke, myocardial infarction" RESULTS: Diastolic (with or without systolic) hypertension, in contrast to isolated systolic hypertension, occurs primarily in younger subjects, and is linked to overweight/obesity and increased sympathetic nerve activity. In younger/middle-aged hypertensive subjects, high plasma norepinephrine levels are linked (independent of blood pressure) to an increased risk of future cardiovascular events and death. High resting heart rates (a surrogate for high sympathetic nerve activity) likewise predict premature all-cause death, coronary heart disease and cardiovascular events in younger hypertensive subjects. In this younger/middle-aged hypertensive group, antihypertensive agents that increase sympathetic nerve activity (diuretics, dihydropyridine calcium blockers, and angiotensin receptor blockers (ARBs)) do not decrease (and may increase) the risk of myocardial infarction, and are therefore inappropriate first-line agents in this age-group. By contrast, in younger/middle-aged hypertensive subjects (less than 60years old), meta-analysis has shown that beta-blockers are significantly superior to randomised placebo, and at least as effective as randomised comparator agents, in reducing death/stroke/myocardial infarction. In this younger/middle-aged hypertensive group beta-blockers have been shown (vs randomised placebo or diuretics) to reduce the risk of myocardial infarction by 35-50 %, and stroke by 50-55 % (vs placebo), in non-smoker men. Atenolol was at least as effective as ACE-inhibition (captopril) in reducing all 7 cardiovascular endpoints (including stroke which was reduced by 50 %), vs less tight control of blood pressure, in obese hypertensive subjects with type-2 diabetes (UKPDS study); and after 20 years follow-up, atenolol was significantly (23 %) superior to the ACE-inhibitor in reducing the risk of all-cause death (beta-blockers have anti-cancer properties, which maybe relevant). Primary/essential hypertension in younger/middle-age is underpinned by high sympathetic nerve activity. In this age-group high resting heart rates and high plasma norepinephrine levels (independent of blood pressure) are linked to premature cardiovascular events and death. Thus, anti-hypertensive agents that increase sympathetic nerve activity ie diuretics, dihydropyridine calcium blockers, and ARBs, are inappropriate first-line choices in this younger age-group. Beta-blockers perform well vs randomised placebo and other antihypertensive agents regarding reduced risk of death/stroke/myocardial infarction in younger (<60years) hypertensive subjects, and are a reasonable first-line choice of therapy (certainly in men). These facts should be reflected in the recommendations of guideline committees around the world.

Catheter-Based Renal Sympathetic Denervation Significantly Inhibits Atrial Fibrillation Induced by Electrical Stimulation of the Left Stellate Ganglion and Rapid Atrial Pacing

BackgroundSympathetic activity involves the pathogenesis of atrial fibrillation (AF). Renal sympathetic denervation (RSD) decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive. The aim of this study was to identify the effects of RSD on AF inducibility induced by hyper-sympathetic activity in a canine model.MethodsTo establish a hyper-sympathetic tone canine model of AF, sixteen dogs were subjected to stimulation of left stellate ganglion (LSG) and rapid atrial pacing (RAP) for 3 hours. Then animals in the RSD group (n = 8) underwent radiofrequency ablation of the renal sympathetic nerve. The control group (n = 8) underwent the same procedure except for ablation. AF inducibility, effective refractory period (ERP), ERP dispersion, heart rate variability and plasma norepinephrine levels were measured at baseline, after stimulation and after ablation.ResultsLSG stimulation combined RAP significantly induced higher AF induction rate, shorter ERP, larger ERP dispersion at all sites examined and higher plasma norepinephrine levels (P<0.05 in all values), compared to baseline. The increased AF induction rate, shortened ERP, increased ERP dispersion and elevated plasma norepinephrine levels can be almost reversed by RSD, compared to the control group (P<0.05). LSG stimulation combined RAP markedly shortened RR-interval and standard deviation of all RR-intervals (SDNN), Low-frequency (LF), high-frequency (HF) and LF/HF ratio (P<0.05). These changes can be reversed by RSD, compared to the control group (P<0.05).ConclusionsRSD significantly reduced AF inducibility and reversed the atrial electrophysiological changes induced by hyper-sympathetic activity.

391 BETA2-ADRENOCEPTOR POLYMORPHISMS (ARG16GLY) IS RELATED TO RESISTANCE TO WEIGHT LOSS INDUCED IMPROVEMENTS OF CARDIAC- AND RENAL COMPLICATIONS

Background: Obesity is an independent risk factor for cardiovascular and renal complications. We previously reported that the Arg16Gly, β2-adrenoceptor (ADRB2) polymorphism, accompanying high plasma norepinephrine (NE) could predict future weight gain, BP elevation and renal injury. The 1st line of treatment for obesity is weight loss (WL). In this study, we evaluated the relationships between ADRB2 polymorphisms (Arg16Gly), prevalence of LVH and renal function (creatinine clearance) over 2 years with WL program. Methods: Obese Japanese men (n = 154) were measured BMI, BP, plasma NE, leptin, creatinine, creatinine clearance (CCr), LVH determined by ECG and ADRB2 polymorphisms (Arg16Gly, Gln27Glu) before and after WL program (low caloric diet + exercise) over 2 years. Significant WL was defined >10% WL of entry BMI. Results: Significant WL was noted in 97 (63%) subjects and the frequencies of Gly16 were 39% for WL group vs. 54% for non-WL group (P < 0.05). At entry, subjects with Gly16 allele had higher levels of plasma NE, leptin, creatinine, higher prevalence of LVH, and lower CCr compared to those without Gly16 allele. WL group had lower fat-mass, NE, leptin and creatinine and LVH prevalence and higher CCr at entry compare dto non-WL group. WL group had greater changes in BMI, fat-mass, creatinine and CCr, and greater % reductions in NE and leptin over a 2-year period. Changes in fat-mass correlated with changes in creatinine, CCr, NE and BP over 2 years. Changes in plasma NE correlated with changes in CCr. In multiple regression analysis, plasma NE, fat-mass and BP levels were determinants for prevalence of LVH at entry and 2-year period. Conclusions: ADRB2 polymorphisms (Arg16Gly) accompanying high plasma NE is related to the prevalence of LVH and improving CCr with WL. Arg16Gly associated with high plasma NE may play an important role in cardio- and renal-complications in obesity.

Orthostatic Hypertension

See related article, pp 167–173 Orthostatic hypertension (OHT) is beneath the radar of many health care professionals. In the clinic, it is generally both unexpected and counterintuitive. After recheck, it may sometimes regress toward the mean. However, at other times the OHT can be dramatic and persistent. Nevertheless, our knowledge about its causes and significance remains circumscribed. It is in many ways the last hemodynamic frontier. Recently, there has been increasing interest in OHT and its possible consequences on health. The spectrum of degree and clinical context of OHT is very broad.1 In some cases, it can be a dramatic physical manifestation of 50 mm Hg or more in a disorder such as baroreflex failure. In other situations, it may only be an incidental physical finding. OHT is usually defined as an increase in blood pressure with upright posture or tilt, but precise criteria have not been established. Furthermore, few studies have entailed direct measurement of blood pressure in people with OHT. Such measurements would more faithfully reflect intraarterial pressure and would avoid the introduction of potential artifacts. Sphygmomanometers can underestimate blood pressure when it is perturbed by pressor reflexes, such as those engaged by upright posture, or if it is increased by pressor agents. Therefore, the magnitude of the blood pressure increase after standing might be even larger than is generally reported in patients with OHT. OHT has been long recognized. Some of the most thoughtful early studies were conducted by David Streeten …

Are Electrocardiographic Changes in Patients with Acute Subarachnoid Hemorrhage Associated with Takotsubo Cardiomyopathy?

Background: Subarachnoid hemorrhage (SAH) has been associated with electrocardiographic (ECG) changes, arrhythmias, and release of cardiac enzymes. Recently, Takotsubo cardiomyopathies, presenting typical ECG changes and left ventricular (LV) regional wall-motion abnormalities (RWMAs), have been reported and considered to be a result of high norepinephrine (NE) levels. We hypothesized that ST-T-wave changes in patients with SAH may be manifestations of Takotsubo cardiomyopathy and associated with RWMAs. Methods: We instituted consecutive echocardiographic screening of all patients with acute aneurysmal SAH. A standard 12-lead ECG and blood samples for creatine kinase (CK) MB isoenzyme and troponin-T (Tn-T) were obtained. To evaluate sympathetic nervous activity, we obtained blood samples and urine samples for NE. Results: Of 42 patients with acute aneurysmal SAH, 26 had abnormal ECG including rhythm abnormalities. Ten of 12 patients with ST-T-wave changes had severe neurologic deficits, but 1 patient had RWMAs on echocardiography. Another patient with LV dysfunction showed a normal ST-T wave. In patients with ST-T-wave changes, elevated Tn-T (8.3 vs. 3.3%), CK-MB (8.3 vs. 10.0%), plasma and urine NE (16.7 and 33.3% vs. 16.7 and 50.0%), and mortality (8.3 vs. 13.3%) were not significantly higher. All 5 deaths resulted from noncardiac causes. High plasma and urine NE levels were not related to neurologic severity or mortality. Conclusions: Although ECG abnormalities are frequently seen in SAH patients, the incidence of RWMAs is very low. Electrocardiographic manifestations in patients with SAH and Takotsubo cardiomyopathy are similar, but ECG abnormalities in patients with SAH are mostly not related to LV dysfunction.

A Case of Malignant Pheochromocytoma with Holt-Oram Syndrome

A 23-year-old female patient with malignant pheochromocytoma was admitted to the Tokyo Women's Medical University. The patient had been clinically diagnosed with Holt-Oram syndrome at birth. Since she had complex congenital heart disease, chronic heart failure, and severe hypoxia, the risk surrounding surgery to remove the primary tumor was predicted to be very high, and subsequently, chemotherapy was performed. The patient was not able to continue chemotherapy due to adverse effects. However, for one year, both her hypertension and catecholamine-dependent symptoms were well controlled by an alpha-adrenergic and beta-adrenergic receptor blockade, although the patient did experience high plasma norepinephrine levels. To our knowledge, this is the first report of a patient with the combination of malignant pheochromocytoma and Holt-Oram syndrome. A correlation between chronic hypoxia and pheochromocytoma has been reported. This instructive case reminds us to consider the possibility of pheochromocytoma with congenital heart disease when these types of unexpected or unusual symptoms are encountered.

Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: A population-based study

Autonomic nervous system (ANS) dysfunction has been suggested in patients with chronic fatigue syndrome (CFS). In this study, we sought to determine whether increased heart rate (HR) and reduced heart rate variability (HRV) parameters observed in CFS patients during wakefulness persist during sleep. To this end, we compared heart rate (HR) and HRV as indicators of ANS function in CFS subjects and non-fatigued (NF) controls in a population-based, case-control study. Thirty subjects with CFS and 38 NF controls, matched for age-, sex- and body mass index, were eligible for analysis. Main outcome measures included mean RR interval (RRI), HR, and HRV parameters derived from overnight ECG. Plasma aldosterone and norepinephrine levels, medicines with cardiovascular effect, and reported physical activity were examined as covariates. General Linear Models were used to assess significance of associations and adjust for potential confounders. Compared to controls, CFS cases had significantly higher mean HR (71.4 vs 64.8 bpm), with a shorter mean RRI [840.4 (85.3) vs 925.4(97.8) ms] ( p < 0.0004, each), and reduced low frequency (LF), very low frequency (VLF), and total power (TP) of HRV ( p < 0.02, all). CFS cases had significantly lower plasma aldosterone ( p < 0.05), and tended to have higher plasma norepinephrine levels. HR correlated weakly with plasma norepinephrine ( r = 0.23, p = 0.05) and moderately with vitality and fatigue scores ( r = − 0.49 and 0.46, respectively, p < 0.0001). Limitation in moderate physical activity was strongly associated with increased HR and decreased HRV. Nevertheless, among 42 subjects with similar physical activity limitations, CFS cases still had higher HR (71.8 bpm) than respective controls (64.9 bpm), p = 0.023, suggesting that reduced physical activity could not fully explain CFS-associated differences in HR and HRV. After adjusting for potential confounders case-control differences in HR and TP remained significant ( p < 0.05). Conclusion: the presence of increased HR and reduced HRV in CFS during sleep coupled with higher norepinephrine levels and lower plasma aldosterone suggest a state of sympathetic ANS predominance and neuroendocrine alterations. Future research on the underlying pathophysiologic mechanisms of the association is needed.

Environmental influences on hypothalamic–pituitary–thyroid function and behavior in Antarctica

We examined the physiological and psychological status of men and women who spent the summer ( n = 100) and/or winter ( n = 85) seasons in Antarctica at McMurdo (latitude 78.48 S, elevation 12 m) and South Pole (latitude 90 S, elevation 3880 m) stations to determine whether there were any significant differences by severity of the stations' physical environment. Physiological measures (body mass index, blood pressure, heart rate, tympanic temperature), serum measures of thyroid hormones, cortisol, and lipids and plasma catecholamines were obtained at predeployment (Sep–Oct) and the beginning of the summer (November) and winter (Mar–Apr) seasons. Cognitive performance and mood were assessed using the Automatic Neuropsychological Assessment Metric — Isolated and Confined Environments (ANAM-ICE), a computerized test battery. South Pole residents had a lower body mass index ( p < 0.05) and body temperature ( p < 0.01) and higher levels of plasma norepinephrine ( p < 0.05) in summer and winter than McMurdo residents. Upon deployment from the United States and during the summer, South Pole residents experienced significantly higher thyroid hormone values (free and total T 3 and T 4) ( p < 0.01) than McMurdo residents; in summer they also experienced lower levels of triglycerides ( p < 0.01) cortisol ( p < 0.05) and LDL ( p < 0.05). In winter, South Pole residents also experienced a 39% decrease in serum TSH compared with a 31.9% increase in McMurdo ( p < 0.05). South Pole residents also were significantly more accurate ( p < 0.05) and efficient ( p < 0.01) in performance of complex cognitive tasks in summer and winter. Higher thyroid hormone levels, combined with lower BMI and body temperature, may reflect increased metabolic and physiological responses to colder temperatures and/or higher altitude at South Pole with no apparent adverse effect on mood and cognition.

.BETA.2- and .BETA.3-Adrenoceptor Polymorphisms Relate to Subsequent Weight Gain and Blood Pressure Elevation in Obese Normotensive Individuals

High blood pressure (BP) is a major determinant of cardiovascular events in obesity. The beta2- and beta3-adrenoceptor polymorphisms are associated with obesity and hypertension. In the present study, we examine the relationships of beta2- and beta3-adrenoceptor polymorphisms with further weight gain-induced BP elevation in obese subjects. Changes in BP, body weight, total body fat-mass, waist-to-hip ratio, plasma norepinephrine (NE) and leptin levels, and beta2(Arg16Gly)- and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured periodically over a 5-year period in 55 entry obese (body mass index [BMI]> or =25.0 kg/m(2)) normotensive (BP<140/90 mmHg) men. BP elevation and weight gain were defined as > or =10% increases from entry levels over 5 years in mean BP or BMI. Obese subjects with weight gain, BP elevation or weight gain-induced BP elevation had higher frequencies of the Gly16 allele of Arg16GIy and Arg64 allele of Trp64Arg. Subjects carrying the Gly16 or Arg64 alleles had significantly greater total fat-mass and waist-to-hip ratio at entry and over a 5-year period compared to the subjects who did not carry these polymorphisms. Subjects carrying the Gly16 allele had similar levels of plasma NE, higher levels of plasma leptin and a lower slope of the regression lines between plasma leptin and NE levels. Those carrying the Arg64 allele had higher plasma NE levels at entry and over a 5-year period compared to the subjects without the Arg64 allele, but plasma leptin levels and slopes were similar. The findings demonstrate that the Arg64 allele of the beta3-adrenoceptor polymorphisms relates to weight gain-induced BP elevation accompanying high plasma NE (heightened sympathetic activity) in obese men. The Gly16 allele of the beta2-adrenoceptor polymorphisms links to weight gain-induced BP elevation associated with leptin resistance. beta2- and beta3-adrenoceptor polymorphisms could predict the future BP elevation and further weight gain-induced BP elevation in originally obese subjects.

Rebound Weight Gain as Associated With High Plasma Norepinephrine Levels That Are Mediated Through Polymorphisms in the β2-Adrenoceptor

A successful weight loss program is essential treatment for obesity-related diseases, but it is well known that the majority of individuals do not succeed in weight loss maintenance. The present study evaluates hormonal mechanisms and the relationship of beta2-adrenoceptor polymorphisms involved in individuals who regain weight after initially successful weight loss. Overweight Japanese men (n = 154) were enrolled in a 24-month weight loss program. Body mass index (BMI), total body fat mass, plasma norepinephrine (NE) and leptin levels, and beta2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu) were measured every 6 months for the 24-month period. Maintenance of weight loss was defined as significant weight loss (>or=10% reduction) from entry weight at 6 months and maintenance of the weight loss for an additional 18 months. Rebound weight gain was defined as significant weight loss at 6 months but subsequent regain of body weight during the next 18 months. The results showed that 37 subjects maintained weight loss during 24 months, whereas 36 subjects had rebound weight gain. The BMI at entry and calorie intake and physical activity at each period were similar between the two groups. Subjects who maintained weight loss had at entry a significantly lower fat mass and plasma NE levels compared to those with rebound weight gain. Body fat mass, NE, and leptin levels at entry predicted the degree of change in body weight during the 24-month study period. Subjects with rebound weight gain had a significantly higher frequency of the Gly16 allele for the beta2-adrenoceptor polymorphism compared to subjects who had a 24-month maintenance of weight loss. Subjects carrying the Gly16 allele also had significantly higher plasma NE, leptin, and body fat mass levels and a greater waist-to-hip ratio both at entry and throughout the study. A high initial degree of body fat mass and high plasma NE levels as determined by the Gly16 allele for the beta2-adrenoceptor polymorphisms predict those individuals who will have rebound weight gain after their initial successful weight loss.

β 2 - and β 3 -Adrenergic Receptor Polymorphisms Are Related to the Onset of Weight Gain and Blood Pressure Elevation Over 5 Years

The genes responsible for obesity are candidate genes for obesity-related diseases, such as hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with hypertension and obesity. To longitudinally clarify the relevance to alterations in beta-adrenergic receptor polymorphisms related to weight gain, blood pressure (BP) elevation, and sympathetic nerve activity as measured by plasma norepinephrine level, we studied 160 young, nonobese, normotensive men. Changes in body weight, BP, plasma norepinephrine levels, and beta2-adrenergic (Arg16Gly, Gln27Glu) and beta3-adrenergic (Trp64Arg) receptor polymorphisms were measured periodically over a 5-year period. Weight gain and BP elevation were defined as > or =10% increases from entry levels over 5 years in body mass index or mean BP. The presence of the Gly16 allele of Arg16Gly was associated with a higher frequency of weight gain and BP elevation over the 5-year period. The subjects carrying the Glu27 allele of Gln27Glu and the Trp64 allele of Trp64Arg had a higher frequency of BP elevation. Significantly higher levels of plasma norepinephrine at entry and at year 5 were observed in the subjects with the Gly16 allele of Arg16Gly and the Glu27 allele of Gln27Glu compared with those without the Gly16 or the Glu27 alleles. These results demonstrate that the Gly16 allele is related to greater weight gain and BP elevation. Additionally, Glu27 and Trp64 alleles are linked to BP elevation. The subjects carrying the beta2-polymorphisms linked to weight gain and BP elevation also have higher plasma norepinephrine levels that are present at entry before weight gain and BP elevation. These findings suggest that beta2-adrenergic receptor polymorphisms in association with a heightened sympathetic nerve activity could predict the future onset of obesity and hypertension, as shown in the 5-year longitudinal study.

Radionuclide Imaging Metabolic Activity of Brown Adipose Tissue in a Patient with Pheochromocytoma

We describe a patient with extra-adrenal pheochromocytoma and high plasma norepinephrine levels. Radionuclide images of this patient obtained using (18)F-fluorodeoxyglucose and (123)I-metaiodobenzylguanidine revealed bilateral tracer accumulation in the shoulder and lower neck. The regions of radiotracer uptake corresponded to the location of human brown adipose tissue (BAT). Excessive sympathetic stimulation by high circulating catecholamine concentrations augmented the metabolic activity and tracer uptake in the BAT. This study showed that radionuclide imaging can noninvasively visualize human BAT in terms of metabolic and functional activity.

Failure of benefit and early hazard of bucindolol for Class IV heart failure

Objectives: The risks and benefits of β-blockade with bucindolol were assessed in heart failure (HF) patients with Class IV symptoms within the Beta-blocker Evaluation of Survival Trial (BEST). Background: β-blockade is accepted therapy for mild to moderate HF, but its safety and efficacy in advanced HF have not been established. Methods: BEST recruited 2708 HF patients; of these, 226 with Class IV symptoms (n = 114 randomized to bucindolol, n = 112 to placebo) formed the basis of this study. All-cause death, HF hospitalization, and drug discontinuations occurring early during therapy (≤6 months) and overall during follow-up were assessed. Compared with Class III, Class IV patients were older and had higher plasma norepinephrine levels, prevalence of coronary disease, S3 gallops, and lower ejection fractions, but characteristics of the 2 Class IV treatment groups were similar. Results: During a mean of 1.6 years, 49% Class IV patients died, and 54% were hospitalized for HF. Bucindolol increased the combined endpoint of death or HF hospitalization within the first 6 months (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.1-2.7) and did not result in benefit overall (HR = 1.2, 95% CI = 0.9-1.6). HF hospitalization alone within 6 months was increased by bucindolol (HR = 1.7), and an early adverse trend for death was seen (HR = 1.6) with no benefit overall (HR = 1.1). Bucindolol was discontinued more frequently than placebo for worsening HF (11% versus 4%) and hypotension (3% versus 0%). Conclusions: Class IV HF patients in BEST were at high risk. Bucindolol did not reduce death or HF hospitalization and was associated with early hazard.

Familial Obesity, Sympathetic Activation and Blood Pressure Level

This study was conducted to evaluate the relative contributions of existing obesity and a family history of obesity (FHOB) to blood pressure (BP) level, sympathetic activity, plasma leptin and insulin levels in young men without a family history of hypertension. The study was of "four-corner" design according to body mass index (BMI). A positive FHOB (FHOB+) was defined as both parents being obese (BMI>26.0 kg/m 2 ), and a negative FHOB (FHOB–) was defined as both parents being lean (BMI<22.0 kg/ m 2 ). The cutoff limits of BP for the subjects and their parents enrolled in present study was defined as a supine reading of <140/90 mmHg. In 12 lean young subjects with FHOB–, 9 obese young subjects with FHOB–, 8 lean young subjects with FHOB+ and 16 obese young subjects with FHOB+, BMI, BP, plasma norepinephrine (NE), insulin and leptin were measured. All subjects were men and non-diabetic. Obese subjects, irrespective of FHOB, had higher levels of BMI, BP, plasma NE, leptin and insulin compared to lean subjects. In subjects with FHOB+, regardless of their current degree of adiposity, there was a higher level of BP and plasma NE than in subjects with FHOB–. In lean subjects, FHOB+ was associated with a higher plasma NE level and BP, but similar levels of plasma leptin and insulin were found when compared with FHOB– subjects. These results suggest that existing obesity and a positive family history of obesity appear to have an association with sympathetic overactivity and BP elevation.

High urinary catecholamine excretion predicts mortality and functional decline in high-functioning, community-dwelling older persons: MacArthur Studies of Successful Aging.

Catecholamine release is a marker of stress, and high plasma norepinephrine levels have been associated with increased mortality. The predictive value of high urinary catecholamine excretion for functional decline and mortality in healthier older persons has not been determined. We used data from the MacArthur Studies of Successful Aging to determine the effects of high urinary catecholamine excretion on 3- and 7-year mortality and functional decline. In 1988, 765 high-functioning older subjects provided complete overnight urine samples for norepinephrine and epinephrine, and 199 of these provided repeat samples in 1991. Subjects who were in the top tertile of urinary norepinephrine or epinephrine excretion in 1988 were considered high excreters; those in the top tertile in both 1988 and 1991 were considered sustained high excreters. We used bivariate and multivariate analysis to examine the relations between high catecholamine excretion and mortality and Rosow-Breslau functional decline in 1991 and 1995. In multivariate analyses, subjects with high baseline urinary excretion of epinephrine, norepinephrine, or either catecholamine were at higher risk for mortality and functional decline at 3 and 7 years, although the magnitude of risk (adjusted odds-ratios ranged from 1.1 to 3.1) varied depending upon specific catecholamine and outcome measure. Subjects who had sustained high urinary norepinephrine excretion were also at increased risk for 4-year mortality or functional decline. High urinary catecholamine excretion in high-functioning, community-dwelling older persons likely reflects subclinical sympathetic stimulation and is a marker of increased risk for functional decline and mortality.