Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation

It has been reported that hypertension and obesity often coexist with hyperuricemia. To clarify the relations between serum uric acid, plasma norepinephrine, and insulin or leptin levels in subjects with weight gain-induced blood pressure elevation, we conducted the present longitudinal study. In 433 young, nonobese, normotensive men, body mass index, blood pressure, and levels of serum uric acid, fasting plasma norepinephrine, insulin, and leptin were measured every year for 5 years. Subjects were stratified by significant weight gain and/or blood pressure elevation (>10% in body mass index or mean blood pressure) for 5 years. At entry, blood pressure, uric acid, and norepinephrine values in subjects with blood pressure elevation were greater than in those without it, although body mass index, insulin, and leptin were similar. At entry, body mass index, blood pressure, uric acid, and norepinephrine in subjects with weight gain were greater than in those without weight gain. The increases in body mass index, mean blood pressure, uric acid, norepinephrine, insulin, and leptin for 5 years were greater in subjects with blood pressure elevation and/or weight gain than in subjects without, and those increases were greatest in subjects with weight gain whose blood pressure was elevated. By multiple regression analysis, basal mean blood pressure, norepinephrine, and uric acid were significant determinant factors of changes in mean blood pressure over 5 years, and basal body mass index, norepinephrine, and uric acid were significant determinant factors of changes in body mass index. These results demonstrate that serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation.     

Non‐interventional weight changes affect systolic blood pressure in normotensive individuals

The association between obesity and hypertension is well established. Weight loss has been shown to reduce blood pressure (BP) among hypertensive patients. Nevertheless, the effect of weight changes on BP in normotensive individuals is less clear. The author explored the association between non‐interventional weight alterations and BP changes in a large cohort of normotensive adults. This is a retrospective analysis of normotensive individuals, between 2010 and 2018. All weight changes were non‐interventional. Body mass index (BMI) and BP were measured annually. Patients were divided according to the change in BMI between visits: reduction of more than 5% ("large reduction"), between 2.5% and 5% ("moderate reduction"), reduction of <2.5% or elevation of <2.5% ("unchanged"), elevation between 2.5% and 5% ("moderate increase"), and elevation of more than 5% ("large increase"). The primary outcome was the change in systolic BP (SBP) between the visits. The final analysis included 8723 individuals. 20% of the patients reduced their BMI by at least 2.5% and 24.5% increased their BMI by more than 2.5%. "High reduction" inferred an absolute decrease of 3.6 mmHg in SBP, while "large increase" resulted in an absolute increase of 1.9 mmHg in SBP. The proportion of individuals with at least 10 mmHg decrease in SBP progressively declined according to the relative decrease in BMI, and the proportion of patients with at least 10 mmHg increase in SBP progressively increased. This effect was more pronounced in individuals with higher baseline SBP. Among normotensive adults, modest non‐interventional weight changes may have significant effects on SBP.     

Body weight and weight change in relation to blood pressure in normotensive men

We examined blood pressure (BP) in association with weight change since age 20, body mass index (BMI) at different ages and fat distribution in normotensive individuals using baseline survey data collected in the Shanghai Men's Health Study, an ongoing population-based prospective cohort study of Chinese men aged 40-74 years. All anthropometric and BP measurements were performed by medical professionals. Included in this analysis were 25 619 men who had no prior history of hypertension, diabetes or cardiovascular disease, never took any antihypertensive medication and had both normal systolic BP (SBP) and diastolic BP (DBP) (<140/90 mm Hg). Both SBP and DBP increased linearly across the whole range of weight gain since age 20. The adjusted mean differences between the highest and the lowest quintiles of weight gain were 6.0 mm Hg (95% confidence interval (CI): 5.6, 6.5) for SBP and 3.9 (95% CI: 3.6, 4.2) for DBP. When accounting for BMI at age 20, the multivariate-adjusted odds ratio of prehypertension (SBP, 120-139 and/or DBP, 80-89 mm Hg) was 4.1 (95% CI: 3.7, 4.5; P for trend <0.0001) comparing the extreme quintiles of weight gain. Similar positive associations were also observed for BMI at age 40, current BMI, circumferences of the waist and hips and waist-to-hip ratio. In conclusion, these data suggest that weight gain since age 20 and elevated adiposity may contribute significantly to the rise in BP in normotensive individuals, emphasizing the importance of weight control throughout adulthood in preventing high BP.     

Beta2-adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals

BACKGROUND: The genes responsible for insulin resistance are also candidate genes for insulin resistance-related diseases, such as obesity and hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with diabetes, hypertension, and obesity. To clarify the relevance of the beta-adrenergic receptor polymorphisms to insulin resistance, we studied their association with polymorphisms of beta2 (Arg16Gly, Gln27Glu) and beta3 (Trp64Arg) adrenoceptor genes. METHODS: We studied 155 young, nonobese Japanese men using the homeostasis model assessment of insulin resistance (HOMA-IR) to divide individuals into insulin-sensitive and insulin-resistant groups. Insulin resistance in the participants was defined as HOMA-IR equal to or greater than the average plus 1 SD of 3.1. There were 69 men who were insulin resistant and 86 men who were insulin sensitive. Body mass index (BMI), blood pressure (BP), plasma glucose, insulin, leptin, norepinephrine (NE) levels, and the polymorphisms of Arg16Gly and Gln27Glu of the beta2- and Trp64Arg of the beta3-adrenoceptor polymorphisms were measured in all participants. RESULTS: The insulin-resistant group had higher frequency of the Gly16 allele of Arg16Gly compared with the insulin-sensitive group, whereas the frequencies of genotypes or alleles of Gln27Glu and Trp64Arg were similar. The insulin-resistant group had a higher mean HOMA-IR, fasting insulin, NE, and total fat mass compared with levels in the insulin-sensitive group, but the BMI and leptin levels were similar. The subjects carrying the Gly16 allele of the beta2-adrenoceptor gene had a higher mean HOMA-IR, fasting insulin, NE, body fat mass, and BP than those without the Gly16 allele. CONCLUSIONS: The Gly16 mutation of the beta2-adrenoceptor gene is associated with increased insulin resistance, adiposity, and BP accompanied by higher plasma NE levels early in the metabolic disease in developing obesity. These findings show an important role of beta2-adrenoceptor gene polymorphisms in the association of insulin resistance in hypertension and obesity.     

High plasma norepinephrine levels associated with beta2-adrenoceptor polymorphisms predict future renal damage in nonobese normotensive individuals.

Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and beta2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years. beta2 (Arg16Gly, Gln27Glu)-adrenoceptor polymorphisms were determined. The subjects were stable in body weight and BP (<10%) for 5 years. High plasma NE was defined as > or =mean+1 SD at entry. Thirty-seven subjects had entry-high plasma NE and 182 were entry-normal. Entry-high plasma NE subjects had significantly greater total body fat mass and plasma NE and significantly lower creatinine clearance at entry and throughout the study. Increases in BMI, fat mass, BP, plasma NE, BUN, and creatinine, as well as the reduction in creatinine clearance in the 5 years, were significantly greater in entry-high NE subjects. These subjects had significantly higher frequencies of the Gly16 allele of beta2-adrenoceptor polymorphisms. Throughout the study, subjects carrying the Gly16 allele had higher plasma NE, HOMA-IR, and fat mass, and significantly greater reductions in creatinine clearance. Plasma NE at entry was a determinant variable for changes in BUN, creatinine, and creatinine clearance over the 5-year period in multiple regression analysis. In conclusion, high plasma NE at entry, associated with the Gly16 allele of the beta2-adrenoceptor polymorphisms, predict renal function deterioration (seen in elevations of BUN and creatinine and reduction of creatinine clearance) over a 5-year period accompanying further heightened sympathetic nerve activity and deterioration of insulin resistance.     

beta2-adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist-stimulated blood pressure and peripheral blood flow in normal individuals

BACKGROUND: The Gly16 beta(2)-adrenergic receptor (beta(2)AR) polymorphism is a common variant of the beta(2)AR that displays depressed function caused by enhanced receptor downregulation in vitro compared with the Arg16 receptor. METHODS AND RESULTS: We studied 20 healthy, normotensive, nonsmoking white individuals who were homozygous for either the Arg16 (n = 10) or the Gly16 (n = 10) genotype. Plethysmographic lower-limb blood flow, blood pressure, and 2-dimensional echocardiograms were recorded at baseline and after 15-minute incremental infusions of terbutaline (100 to 300 ng/kg per minute). Baseline heart rates, blood pressures, and flows were similar in both groups, but at the maximum dose of terbutaline, limb blood flow was less (P <.05), calculated vascular resistance was greater (P <.05), and systolic and diastolic blood pressures were greater in patients with Gly16 than in those with Arg16 (both P <.05). In contrast, terbutaline-stimulated heart rates were not different. In a separate group of 20 homozygous individuals (12 Arg16, 8 Gly16), there were no differences in 2-dimensional echocardiographically determined ventricular function. CONCLUSIONS: We conclude that the Gly16 beta(2)AR polymorphism imparts attenuated vasodilatory responses to catecholamines in normal human beings and is an important genetic component in the regulation of peripheral blood flow and systemic arterial pressure.     

Effect of weight loss on blood pressure, arterial compliance, and insulin resistance in normotensive obese subjects

BACKGROUND: Obesity is characterized by insulin resistance and hyperinsulinemia that may elevate arterial pressure due to sympathetic overactivity and volume overload. The aim of the study is to measure hemodynamic parameters and metabolic variables in obese normotensive subjects. METHODS: Twenty-four normotensive, overweight subjects from our medical staff were enrolled. They had personal and group meetings with a physician, dietician, and psychologist to improve their compliance with regard to physical activity and personal low-calorie diet. In addition, each subject was given orlistat 120 mg three times daily for 12 weeks. Noninvasive hemodynamic parameters including arterial compliance were measured using radial artery pulse wave analysis, at the beginning and 1 month after taking the last dose of Orlistat, and insulin resistance was calculated using HOMA score. RESULTS: At the end of the 3-month period, the average weight was reduced from 89.5 +/- 12 kg to 81.5 +/- 9 kg. The systolic arterial pressure was reduced from 128 +/- 12 mm Hg to 121 +/- 10 mm Hg and diastolic arterial pressure was reduced from 75.4 +/- 9 mm Hg to 69.6 +/- 7 mm Hg. Arterial compliance measurements showed significant improvement in large artery compliance from 13 +/- 4 to 15.8 +/- 3.6 while no change occurred in small arteries. The insulin sensitivity assessed by HOMA score improved significantly from 6.5 +/- 4.5 to 4.8 +/- 3.1 with weight reduction. CONCLUSIONS: Our data show that weight loss is accompanied by lowering of blood pressure, even in normotensive obese patients. This weight loss brings about an improvement in insulin resistance and a rise in large artery compliance, whereas no change occurs in small artery compliance.     

beta2-adrenoceptor gene polymorphisms and blood pressure variations in East Anglian Caucasians

OBJECTIVE: The amino-terminal polymorphisms, Arg16Gly and Gln27Glu, of the beta2-adrenergic receptor (beta2AR) have been shown to affect regulation of the receptor expression by an agonist in cell culture studies. The Arg16Gly polymorphism has also been recently shown to be associated with essential hypertension. We therefore evaluated whether the amino-terminal polymorphisms of beta2AR are associated with hypertension in a Caucasian population. SUBJECTS AND METHODS: We performed an association study in 298 hypertensive patients and an equal number of age-matched normotensive controls from the East Anglian region, with blood pressure assessed categorically and quantitatively. We also examined the influence of the amino-terminal polymorphisms on blood pressure response to beta-blockade in 144 of the patients randomly assigned to this class of drug. Genotyping of the Arg16Gly polymorphism was undertaken by a newly designed mismatched polymerase chain reaction (PCR) and digestion with Nde I, whereas the Gln27Glu polymorphism was genotyped by PCR followed by Fnu4H I cleavage. RESULTS: We found no differences in the genotype or allele frequencies of the beta2AR polymorphisms between hypertensive and normotensive participants. There was also no association between the beta2AR genotypes and variations in either basal blood pressure or the blood pressure response to a beta-blocker. CONCLUSION: These findings suggest that the amino-terminal polymorphisms of the beta2AR gene are unlikely to constitute major susceptibility for essential hypertension in the East Anglian population.     

Insulin and blood pressure during weight loss in obese adolescents

The role of insulin in the regulation of blood pressure was evaluated in 50 obese adolescents before and after a 20-week weight loss program. When compared with 10 nonobese adolescents, the obese subjects had significantly higher systolic, diastolic, and mean arterial pressures (p = 0.005), an elevated 24-hour urinary sodium excretion (p = 0.002), an elevated fasting insulin concentration (p = 0.001), and an abnormal insulin response to an oral glucose tolerance test (sum of the insulins at 0, 1, and 2 hours post-oral glucose load; p = 0.001). We also observed a significant correlation between systolic and diastolic blood pressure (age and sex normalized) and body weight (r = 0.57, p less than 0.01 and r = 0.7, p less than 0.01), fasting insulin (r = 0.49, p less than 0.01 and r = 0.54, p less than 0.01), and sum of insulins (r = 0.42, p less than 0.01 and r = 0.46, p less than 0.01). To study the effect of weight loss on the relationship between blood pressure and insulin, the obese subjects were randomly assigned to three groups: 15 to a diet and behavior change group, 18 to a diet, behavior change, and exercise group, and 17 to an obese control group. Compared with the obese control group, the two weight loss groups each experienced a significant decrease in insulin (p less than 0.01), sum of the insulins (p less than 0.01), and blood pressure (p less than 0.01). The decrease in blood pressure during the weight loss program significantly correlated with the change in both insulin and body weight.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of weight loss on clinic and ambulatory blood pressure in normotensive men

Obesity and physical inactivity are associated with both elevated cardiovascular risk and blood pressure (BP), but the interrelation of exercise, weight loss and BP is poorly understood. This study examines the independent effects of exercise and weight loss on both standard clinic and automated, ambulatory BP in 115 overweight, sedentary, normotensive men (aged 30 to 59 years) who were randomly assigned to control status or to lose weight over 1 year by moderate caloric restriction (dieting) or by increased caloric expenditure (exercise). Median daytime and evening BP were determined from measurements made every 20 minutes while the subjects were awake. After 1 year, the control group gained (mean +/- standard deviation) 0.5 +/- 3.8 kg while the diet group lost 6.9 +/- 4.4 kg and the exercise group lost 4.6 +/- 3.5 kg. Clinic BP decreased similarly in all 3 groups, but daytime and evening ambulatory BP decreased in both intervention groups and increased in the control group. Relative to the 1-year change in control subjects, net change in daytime ambulatory BP averaged -2 to -3 mm Hg in both dieters and exercisers, while net change in evening ambulatory BP averaged -3 to -4 mm Hg. These changes were all statistically significant (p less than 0.05) when compared with control subjects except for daytime systolic BP in both intervention groups and evening diastolic BP in dieters. Weight loss achieved through caloric restriction or expenditure may cause important decreases in BP in normotensive men; exercise appears to confer no unique benefit. If confirmed, these results have important public health implications for the prevention of cardiovascular disease.     

The relationship between weight gain and blood pressure in children and adolescents

BACKGROUND: The aim of this study was to determine the relationship between the trajectories of weight gain and systolic blood pressure (SBP) in youth. METHODS: Annual surveys of anthropometry, fitness, SBP, and its determinants (cardiac output, systemic vascular resistance, and arterial compliance) were conducted in youth (aged 5 to 19 years) in a school-based setting between 2004 and 2006. Children were stratified according to change in body mass index (BMI) over time. RESULTS: Within the entire cohort (n = 2089), mean SBP (121 +/- 16 SD v 112 +/- 15 SD mm Hg; P < .01) and the prevalence of high blood pressure (48% v 18%, P < .01) were significantly higher and fitness levels were lower (P < .01) in obese children, relative to healthy-weight peers. After 2 years of follow-up, despite similar SBP and BMI at baseline, the average change in SBP was approximately 4.5-fold greater in children with the largest increase in BMI, relative to children who experienced minimal weight gain. This group also experienced a significantly greater increase in stroke volume (P < .05), while the change in heart rate, arterial compliance, and systemic vascular resistance was comparable with that of children who experienced minimal weight gain. Multiple linear regression analysis revealed that SBP increased 0.77 mm Hg for every kilogram of weight gain over a period of 2 years (P < .01). CONCLUSIONS: Overweight and disproportionate weight gain in children are associated with elevated SBP. These data support the need for interventions to prevent excessive weight gain and obesity in children and adolescents.     

Association between blood pressure and insulin resistance in obese females during weight loss and weight rebound phenomenon.

The purpose of this study was to investigate the effect of weight loss on blood pressure and its related variables in moderately obese Japanese females, including an investigation of the rebound phenomenon. Study I examined the effects of weight loss on blood pressure in 138 moderately obese, nondiabetic females (BMI 29.3+/-0.3 kg/M2; age, 46.3+/-0.8 years) during a 3-month therapeutic dietary and exercise program. Study II investigated the effect of weight rebound on blood pressure over an additional 21 months of exercise in 48 subjects from Study I subjects. After 3 months, the BMI significantly decreased to 27.9+/-0.3 kg/m2. Abdominal total fat, visceral fat (V), and subcutaneous fat (S) also decreased significantly. In addition, the summation of insulin (sigmaIRI), plasma glucose (sigmaPG) and HOMA during 75 g oral glucose tolerance test also all significantly decreased. Significant decreases in both the SBP and DBP were observed after the 3 month weight reduction program. Multiple regression analysis revealed that the reduction in SBP was significantly and positively associated with the reduction in log sigmaIRI and the reduction in log 24h-urinary norepinephrine excretion at the end of Study I. The DBP showed a significantly positive association with the log sigmaIRI. With regard to the weight rebound phenomenon, Study II showed that the SBP, DBP and sigmaIRI all increased significantly, and a positive correlation was observed between the changes in the SBP and those in the log sigmaIRI. However, no such correlation was observed regarding the abdominal total fat and visceral fat during both periods. These results suggest that weight loss therefore caused the BP to decrease due to both an improvement in hyperinsulinemia and a decrease in the adrenergic activity which may be involved in the urinary catecholamine. As a result, hyperinsulinemia is thus considered to play an important role in the pathogenesis of blood pressure due to obesity not only during weight loss, but also during the weight rebound phenomenon.     

Differences in mechanisms between weight loss-sensitive and -resistant blood pressure reduction in obese subjects.

This study was conducted to clarify the mechanisms involved in the sensitivity for blood pressure (BP) reduction in response to weight loss. In particular, we focused on the contributions of sympathetic nervous system activity and fasting plasma leptin and insulin levels to BP levels during weight loss in obese subjects with weight loss-sensitive and -resistant BP reduction. Sixty-one young, obese untreated hypertensive men (HT) and 52 obese normotensive men (NT) were enrolled in a weight loss program consisting of a low caloric diet and aerobic exercise over a 24-week period. At entry and at week 24, body mass index (BMI), BP, plasma norepinephrine (NE), leptin and insulin were measured. Successful weight loss and BP reduction were respectively defined as a more than a 10% reduction in BMI or mean BP from baseline at week 24. More than 60% of subjects in either group successfully achieved weight loss by this definition. The percentage of subjects who successfully achieved BP reduction was higher (64%) among those subjects who achieved weight loss than among those who did not (22%). Plasma NE level at entry in subjects who failed to achieve BP reduction despite weight loss was significantly higher than that in subjects who succeeded in BP reduction. Plasma leptin and insulin levels were similar between subjects with and without BP reduction. In addition, the absolute decrement and percent decrement in plasma NE in subjects who succeeded in BP reduction were significantly greater than those in subjects who failed to reduce their BP. Absolute and percent decrements in plasma leptin and insulin were similar in both groups. These results suggest that individuals who are resistant to weight loss-induced BP reduction have more sympathetic overactivity both at the outset of and during weight loss.     

Prospective study of predictive factors determining borderline hypertensive individuals who develop sustained hypertension: Prognostic value of increased diastolic orthostatic blood pressure tilt-test response and subsequent weight gain

Repeat hemodynamic determinations in supine and tilting positions were performed in 23 young men with borderline hypertension (HBP). The mean duration of follow-up was 48 months. During the study 11 patients had no change in hemodynamic parameters (group II), while 12 patients exhibited significant increase in systolic (p < 0.001) and mean (p < 0.01) arterial pressures (BP) and in body weight (p < 0.05) (group I). In this latter group, the initial hemodynamic pattern included supine elevations in cardiac output (CO) and heart rate (HR) and significant increase in diastolic orthostatic BP. After follow-up, the group I primary supine increases in CO and HR were followed by secondary supine increases in total peripheral resistance (p < 0.01) and systolic (p < 0.001) and mean (p < 0.01) BP with lower CO (p < 0.05) and HR (p < 0.001). In addition, it was shown during long-term follow-up in group I patients that: (1) the increase in systolic BP per unit age was negatively correlated with initial age (p < 0.001), (2) the increase in BP was positively correlated with weight gain (p < 0.05), and (3) the diastolic orthostatic hypertension disappeared. This study provides evidence that, in patients with borderline HBP having supine elevations of CO and HR, the subsequent development of sustained HBP can be expected, with follow-up observation of lower supine HR and disappearance of diastolic orthostatic hypertension accompanied by rapid weight gain.