PubMed Health⌕ Search

Biomedical subjects

Gordon H Williams

Publications and source records attributed to Gordon H Williams.

At least 19 recordsLinked to original sources
PubMed2007

Ala92 type 2 deiodinase allele increases risk for the development of hypertension.

Accumulating evidence suggests that genes of the hypothalamic-pituitary-thyroid pathway influence susceptibility to hypertension. Type 2 iodothyronine deiodinase is responsible for the conversion of thyroxine to tri-iodothyronine for use in peripheral tissues. The present study evaluated whether a type 2 iodothyronine deiodinase nonsynonymous polymorphism, threonine 92 to alanine (Thr92Ala), is a determinant of hypertension susceptibility. A total of 372 euthyroid subjects were genotyped for Thr92Ala polymorphism using the Sequenom MassARRAY platform. Associations with hypertension and hypertension-related intermediate phenotypes were performed with generalized estimating equations. Type 2 iodothyronine deiodinase Thr92Ala allele frequencies differed significantly between hypertensive and normotensive subjects, with an excess of Ala92 carriers in hypertensive compared with normotensive subjects (64.8% versus 47.1%; P=0.011). Adjusted for age, gender and race, the estimated odds ratio for hypertension in Ala92 allele carriers compared with Thr92 homozygotes was 2.11 (95% CI: 1.15 to 3.89). Among euthyroid adults, the common Ala92 allele of the type 2 iodothyronine deiodinase increases risk for the development of hypertension. These data support an important role for genetic variation in the hypothalamic-pituitary-thyroid pathway in influencing susceptibility to hypertension.

Adult↗
PubMed2006

Uric acid and the development of hypertension: the normative aging study.

Experimental evidence supports a causative role for uric acid in the pathogenesis of hypertension. Prospective studies have variably adjusted for relevant confounders and have been of relatively limited duration. We prospectively examined the relationship between uric acid level and the development of hypertension in the Normative Aging Study, a longitudinal cohort of healthy adult men. Of the 2280 initial men in the Normative Aging Study, 2062 had available information for inclusion in the analysis. Cox proportional hazards model was used to examine the relationship between baseline serum uric acid level and the development of hypertension adjusting for age, body mass index, abdominal circumference, smoking, alcohol, plasma triglycerides, total cholesterol, and plasma glucose. A total of 892 men developed hypertension over a mean of 21.5 years of follow-up. Serum uric acid level independently predicted the development of hypertension in age-adjusted (relative risk [RR]: 1.10; 95% CI: 1.06 to 1.15: P<0.001) and multivariable (RR: 1.05; 95% CI: 1.01 to 1.10; P=0.02) models. Among 1277 men at risk for the development of hypertension at the time of their first serum creatinine measurement, 508 (39.8%) developed hypertension over a mean of 10.3+/-5.5 years of follow-up. Additionally adjusting for calculated glomerular filtration rate in this subset, serum uric acid remained associated with the development of hypertension (RR: 1.06; 95% CI: 1.01 to 1.12; P=0.03). The baseline serum uric acid level is a durable marker of risk for the development of hypertension. The association is independent of elements of the metabolic syndrome, alcohol intake, and renal function.

Adult↗
PubMed2006

Beta-2 adrenergic receptor diplotype defines a subset of salt-sensitive hypertension.

Two genetic variants of the beta-2 adrenergic receptor, 46G>A and 79C>G, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin-angiotensin-aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 beta-2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high- and low-sodium balance. The beta-2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes combined, 46AA/79CC was associated with a greater change in blood pressure. Furthermore, this diplotype was associated with low-renin (LR) hypertension (identifying 32% of the LR hypertensives), higher plasma aldosterone, and lower plasma renin and serum potassium levels. In conclusion, the 46AA/79CC diplotype is associated with greater blood pressure response to dietary sodium and higher odds of LR hypertension. We propose that the mechanism for the observed association is inadequate suppression of aldosterone with salt intake, implicating the beta-2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where beta-2 adrenergic receptor stimulation increased aldosterone secretion, whereas blockade reduced the stimulated aldosterone response. Importantly, this association could only be detected with an intermediate and not a distant phenotype.

Adolescent↗
PubMed2006

Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus.

To determine whether mineralocorticoid receptor (MR) activation plays a role in diabetic renal injury and whether this role differs in types 1 and 2 diabetes mellitus, we examined the effect of a MR antagonist on renal injury in rodent models of type 1 (streptozotocin-treated rat) and type 2 (db/db mouse) diabetes. We studied three groups of 8-wk-old, uninephrectomized Wistar rats for 4 wk: diabetic streptozotocin- (55 mg/kg) treated rats (n = 11), diabetic streptozotocin-treated rats receiving the MR antagonist eplerenone (n = 15), and nondiabetic rats (n = 9). In addition, we studied three groups of 8-wk-old mice for 16 wk: diabetic db/db mice (n = 10), diabetic db/db mice treated with eplerenone (n = 8), and nondiabetic, db/+ littermates (n = 11). Diabetic rats and mice developed albuminuria and histopathological evidence of renal injury, including glomerular hypertrophy, mesangial expansion, and tubulointerstitial injury as well as increased renal cortical levels of MR protein, MR mRNA, TGFbeta mRNA, and osteopontin mRNA. All of these changes were significantly reduced by treatment with eplerenone except for the elevated MR levels. The beneficial effects of eplerenone were not attributable to changes in blood pressure or glycemia. In summary, MR expression was increased in kidneys of diabetic rodents, and MR antagonists effectively reduced diabetic renal injury irrespective of the species or specific cause of the diabetes. Thus, these data suggest that MR activation is a critical factor in the early pathogenesis of renal disease in both type 1 and type 2 diabetes mellitus.

Albuminuria↗
PubMed2006

Effect of acute aldosterone administration on gene expression profile in the heart.

Aldosterone is known to have a number of direct adverse effects on the heart, including fibrosis and myocardial inflammation. However, genetic mechanisms of aldosterone action on the heart remain unclear. This paper describes an investigation of temporal changes in gene expression profile of the whole heart induced by acute administration of a physiologic dose of aldosterone in the mouse. mRNA levels of 34,000 known mouse genes were measured at eight time points after aldosterone administration using oligonucleotide microarrays and compared with those of the control animals who underwent a sham injection. A novel software tool (CAGED) designed for analysis of temporal microarray experiments using a Bayesian approach was used to identify genes differentially expressed between the aldosterone-injected and control group. CAGED analysis identified 12 genes as having significant differences in their temporal profiles between aldosterone-injected and control groups. All of these genes exhibited a decrease in expression level 1-3 h after aldosterone injection followed by a brief rebound and a return to baseline. These findings were validated by quantitative RT-PCR. The differentially expressed genes included phosphatases, regulators of steroid biosynthesis, inactivators of reactive oxygen species, and structural proteins. Several of these genes are known to functionally mediate biochemical phenomena previously observed to be triggered by aldosterone administration, such as phosphorylation of ERK1/2. These results provide the first description of cardiac genetic response to aldosterone and identify several potential mediators of known biochemical sequelae of aldosterone administration in the heart.

Aldosterone↗
PubMed2006

Cortisol circadian rhythm alterations in psychotic major depression.

BACKGROUND: Increased hypothalamic-pituitary-adrenal axis activity is well described in psychotic depression with an emphasis on 24-hour, urinary free cortisol levels or dexamethasone suppression tests. There are limited data on cortisol levels during specific times of the day. METHODS: Patients with depression with (PMD) and without (NPMD) psychosis and healthy control subjects were studied using rating scales of depression and psychosis and measures of HPA activity, including overnight cortisol and adrenocorticotropin levels. We used analysis of variance to determine group differences and regression analyses to assess contributions of specific measures to cortisol levels. RESULTS: PMDs had higher cortisol during the evening hours than did NPMDs or control subjects, who did not differ from one another. Regression analyses suggest that depression and the combination of depressive and psychotic symptoms were important contributors to variance in evening cortisol. CONCLUSIONS: PMD is associated with increased cortisol levels during the quiescent hours. Enhanced cortisol activity, particularly a higher nadir, was related to depression severity and the interaction of depressive and psychotic symptoms. This increase suggests a defect in the action of the circadian timing system and HPA axis, creating a hormonal milieu similarly seen in early Cushing's syndrome and potentially an (im)balance of mineralocorticoid and glucocorticoid receptor activity.

Adrenocorticotropic Hormone↗
PubMed2006

Nonmodulation and essential hypertension.

Nonmodulation is a process in which there is a disorder in angiotensin-dependent control of the renal circulation and adrenal aldosterone release. The abnormalities are associated with an inability to handle a sodium load and salt-sensitive hypertension. All of the features are corrected by angiotensin-converting enzyme inhibition. A striking family history of hypertension and concordance of responses to angiotensin II in sibling pairs have suggested a familial factor. Genes governing renin substrate (angiotensinogen) production showed gene polymorphisms in nonmodulators. As nonmodulation occurs in approximately 40% of patients with essential hypertension, clearly other genes must contribute.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Familial aggregation of insulin resistance and cardiovascular risk factors in hypertension.

The authors assessed the familial aggregation of cardiometabolic abnormalities (elevated homeostasis model assessment [HOMA], triglycerides [TG], and low-density lipoprotein [LDL] and reduced high-density lipoprotein [HDL]) among hypertensive siblings (N=287 from 138 families). Evidence for familial aggregation required sibling-pair concordance of outcome variables dichotomized according to predefined values (concordance for highest-quartile HOMA [>3.3], TG [>170 mg/dL], and LDL [>138 mg/dL] and lowest-quartile HOMA for HDL [<32 mg/dL]). Hypertensive individuals with insulin resistance (high-quartile HOMA) had higher TG and lower HDL and LDL levels compared with insulin-sensitive hypertensives. High-quartile HOMA, TG, and LDL aggregated in hypertensive families, and TG plus HOMA coaggregated. HDL did not show aggregation. In a multivariate logistic regression, the only significant predictor of an individual's HOMA status was a sibling's HOMA status in a model including age, sex, race, and body mass index (odds ratio=9.12; 95% confidence interval, 3.64-23.14; P<.001). Cardiometabolic variables demonstrate heritability in hypertensive families. Further exploration of common genetic susceptibility loci in hypertension involving these factors is warranted.

Cholesterol, HDL↗
PubMed2006

Why is orthostatic tolerance lower in women than in men? Renal and cardiovascular responses to simulated microgravity and the role of midodrine.

BACKGROUND: Exposure to microgravity induces cardiovascular deconditioning, manifested by orthostatic intolerance (OI). We assessed the renal, cardioendocrine, and cardiovascular responses of women and men to simulated microgravity to examine the impact of gender on OI. METHODS: Fifteen healthy female and 14 healthy male subjects were given a constant diet for 3 to 5 days, after which they underwent a tilt-stand test (pre-TST) and began 14 to 16 days of head-down tilt bed rest (HDTB), followed by a repeat tilt-stand test (post-TST). Female subjects began HDTB so that the post-TST was at the same time in their menstrual cycle as their pre-TST. Twenty-four-hour urine collections (daily), hormonal measurements, plethysmography, and cardiovascular system identification were performed. RESULTS: The times to presyncope were significantly different for men and women before (p= .005) and after HDTB (p= .001), with all of the women but only 50% of the men experiencing presyncope during the pre-TST (p= .002) and all of the women but only 64% of the men experiencing presyncope during the post-TST. At baseline, the following differences between women and men were observed: women had higher serum aldosterone levels (p = .02), higher parasympathetic responsiveness (p = .01), lower sympathetic responsiveness (p = .05), and lower venous compliance (p = .05). Several parameters changed with HDTB in both men and women. In a double-blinded randomized trial, midodrine (5 mg orally) or placebo given to female subjects 1 hour before post-TST was ineffective in preventing 01. CONCLUSION: In conclusion, the frequency of OI is higher in women than in men and is not modified by midodrine at the dose used. This increased susceptibility is likely secondary to intrinsic basal differences in the activity of volume-mediated parasympathetic and adrenergic systems and in venous tone. Thus, approaches to reduce OI in women are likely to differ from those effective in men.

Adaptation, Physiological↗
PubMed2005

Aggregation of high-normal thyroid-stimulating hormone in hypertensive families.

BACKGROUND: Studies suggest that there are genetic variants that influence both blood pressure regulation and serum TSH levels. We investigated whether high-normal TSH values aggregate in hypertensive families. The influence of hypertension family history on serum TSH levels in healthy normotensive individuals was also examined. METHODS: All subjects were euthyroid (TSH, 0.5-5.0 mIU/liter). The study subjects were 333 hypertensives, including 229 members of multiple sibling families. The subjects had blood samples for serum TSH determination drawn in the morning after overnight bed rest. High-normal TSH was defined as values above 2.0 mIU/liter and equal to or less than 5.0 mIU/liter. Thirty-one healthy normotensives provided information about their family history of hypertension by telephone. RESULTS: The concordance for high-normal TSH values among hypertensive, multiple sibling families was greater than expected by chance (P = 0.009). There were nearly twice as many families concordant for high-normal TSH status as expected (13.2% vs. 7.0%), whereas the observed proportion concordant for normal TSH status was similar to that expected (58.3% vs. 54.1%). Family membership explained a significant proportion of variance in TSH status (P = 0.038). Healthy normotensives with a family history of hypertension had significantly higher TSH values (2.2 +/- 1.2 mIU/liter) than those with a negative family history of hypertension (TSH 1.3 +/- 0.7 mIU/liter) independent of other characteristics (P = 0.025). CONCLUSIONS: There is familial aggregation of high-normal TSH values in hypertensive families, and a hypertension family history influences serum TSH levels in healthy individuals. These findings are consistent with the existence of genetic variants affecting both blood pressure regulation and serum TSH levels.

Adult↗
PubMed2005

Sex differences in the genetic basis of morning serum cortisol levels: genome-wide screen identifies two novel loci specific to women.

CONTEXT: Relatively little is known about the influence of specific genes on cortisol levels, particularly morning cortisol levels. OBJECTIVE: The objective of this study was to identify quantitative trait loci associated with morning serum cortisol levels. DESIGN: We carried out a genome screen for morning serum cortisol using linkage and association methods tailored for use in large pedigrees. We conducted these analyses both in the whole sample and partitioned by sex. SETTING: This study was conducted on nine communal Hutterite farms in South Dakota. PARTICIPANTS: The Hutterites are a young founder population who practice a communal, farming lifestyle in the western United States and in Canada. Hutterites (n = 504, 53% female) aged 11-89 yr from a single pedigree participated in this study. MAIN OUTCOME MEASURES: The main outcome measures were markers significantly linked or associated with variation in morning serum cortisol levels. RESULTS: One genome-wide significant association was identified in the whole sample on 11p (D11S1981, P = 0.000092). Results of sex-partitioned analyses indicated that this association was restricted to females (females, P = 0.000084; males, P = 0.20). The 146-bp allele at this locus accounted for 7% of the variance in morning cortisol values in females, and females homozygous for the allele had an 89% increase in morning cortisol levels compared with female noncarriers. A second genome-wide significant association in females was identified on 14q (D14S74, P = 0.000091). CONCLUSIONS: Our results suggest that the genetic determinants of morning cortisol levels may be different for men and women and that loci on 11p and 14q influence morning cortisol levels in women.

Adolescent↗
PubMed2005

Aldosterone biosynthesis, regulation, and classical mechanism of action.

Circulating aldosterone is principally made in the glomerulosa zone of the adrenal cortex by a series of enzyme steps leading to the conversion of cholesterol to aldosterone. Uniquely, aldosterone's production is regulated at two critical enzyme steps: (1) early in its biosynthetic pathway (the conversion of cholesterol to pregnenolone cholesterol side chain cleavage enzyme) and (2) late (the conversion of corticosterone to aldosterone by aldosterone synthase). A variety of factors modify aldosterone secretion--the most important are angiotensin II (AngII), the end-product of the renin-angiotensin system (RAS), and potassium. However ACTH, neural mediators and natriuretic factors also contribute at least over the short run. Aldosterone's classical epithelial effect is to increase the transport of sodium across the cell in exchange for potassium and hydrogen ions. Although still controversial, there is an increasing body of data that supports the hypothesis that aldosterone can be synthesized in tissues outside of the adrenal cortex, specifically in the heart and the vasculature. Aldosterone's biosynthesis appears to be regulated in these tissues similar to what occurs in the adrenal cortex. The role of this extra adrenal aldosterone production in health and disease is as of yet undetermined.

Adrenal Cortex↗
PubMed2005

Genetics of human hypertension.

Hypertension is a complex genetic disorder caused by interplay between several "risk" genes and environmental factors (genetic heritability approximately 30%). Most genetic studies of hypertension use a candidate gene approach and two conclusions have been made: there is no association or linkage with the genes studied, or the hypertension phenotype is heterogeneous and subgroups with hypertension related to certain polymorphisms cannot be identified because of background noise. Studies using intermediate phenotypes suggest the latter is most likely. Another problem is the reliability of gene structure assessment: usually only one or two gene polymorphisms are assessed. The use of intermediate phenotypes and dense mapping of candidate genes would provide a better approach for identifying genotype-phenotype correlations, which might enable the use of genotypes to identify more-specific therapeutic and preventative measures for hypertensives.

Aldosterone↗
PubMed2005

Results of the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial by geographical region.

OBJECTIVE: To examine regional differences in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) trial. DESIGN: Double-blind, randomized, international clinical trial. SETTING: Six hundred and sixty-one clinical centers in 15 countries. PATIENTS: Hypertensive volunteers (n = 16,602) with > or =1 additional cardiovascular risk factor, grouped into four regions: USA (n = 8144), Canada (n = 3405), Western Europe (Spain, UK, Italy, Sweden, Germany; n = 2048) or 'other' (Bulgaria, Israel, Mexico, Czech Republic, Hungary, Poland, Slovakia, Brazil; n = 2879); subgroupings included country and state/province within the USA and Canada. INTERVENTIONS: Randomized to COER-verapamil or the investigator's choice of either atenolol or hydrochlorothiazide, titrated and additional drugs added as required. MAIN OUTCOME MEASURES: Baseline characteristics; blood pressure control, medication adherence and lost-to-follow-up at 2 years; and composite primary endpoint (stroke, myocardial infarction, cardiovascular death) by regional groupings. RESULTS: Regional differences were found at baseline for age, gender, blood pressure, percentage receiving antihypertensive drug therapy, initial choice of atenolol or hydrochlorothiazide, and risk factor profile. Blood pressure control rates increased markedly during follow-up in all regions, but varied significantly by region. Blood pressure control, medication adherence and lost-to-follow-up rates were poorest in the USA. After adjustment for baseline differences, the primary-event rate for each region was significantly lower than for the USA. Although baseline factors, blood pressure control and event rates varied by region, treatment differences did not. CONCLUSION: Despite differences in baseline and follow-up measures across geographical regions, the absence of treatment differences by region suggests that the overall findings of CONVINCE are robust.

Aged↗
PubMed2005

Simulated microgravity induces microvolt T wave alternans.

BACKGROUND: There are numerous anecdotal reports of ventricular arrhythmias during spaceflight; however, it is not known whether spaceflight or microgravity systematically increases the risk of cardiac dysrhythmias. Microvolt T wave alternans (MTWA) testing compares favorably with other noninvasive risk stratifiers and invasive electrophysiological testing in patients as a predictor of sudden cardiac death, ventricular tachycardia, and ventricular fibrillation. We hypothesized that simulated microgravity leads to an increase in MTWA. METHODS: Twenty-four healthy male subjects underwent 9 to 16 days of head-down tilt bed rest (HDTB). MTWA was measured before and after the bed rest period during bicycle exercise stress. For the purposes of this study, we defined MTWA outcome to be positive if sustained MTWA was present with an onset heart rate<or=125 bpm. During various phases of HDTB, the following were also performed: daily 24-hour urine collections, serum electrolytes and catecholamines, and cardiovascular system identification (measure of autonomic function). RESULTS: Before HDTB, 17% of the subjects were MTWA positive [95%CI: (0.6%, 37%)]; after HDTB, 42% of the subjects were MTWA positive [95%CI: (23%, 63%)] (P=0.03). The subjects who were MTWA positive after HDTB compared with MTWA negative subjects had an increased versus decreased sympathetic responsiveness (P=0.03) and serum norepinephrine levels (P=0.05), and a trend toward higher potassium excretion (P=0.06) after bed rest compared to baseline. CONCLUSIONS: HDTB leads to an increase in MTWA, providing the first evidence that simulated microgravity has a measurable effect on electrical repolarization processes. Possible contributing factors include loss in potassium and changes in sympathetic function.

Adult↗
PubMed2005

Readaptation from simulated microgravity as a stimulus for improved orthostatic tolerance: role of the renal, cardioendocrine, and cardiovascular systems.

BACKGROUND: Microgravity and simulated microgravity (SM) lead to important changes in orthostatic tolerance (OT), the autonomic nervous system (ANS), and the volume-regulating systems. After one is exposed to microgravity or SM, a period of readaptation to gravity is known to take place, but it is not certain if orthostatic function returns to baseline within the initial recovery and what mechanisms are involved. We hypothesized that after a period of recovery, OT, ANS, and volume-regulating systems would return to pre-SM levels. METHODS: To test this hypothesis, 24 healthy men were placed on a constant diet for 3 to 5 days, after which a tilt-stand test (pre-TST) was performed. The TST was repeated after 14 to 16 days of head-down tilt bed rest (HDTB) (post-TST) and a 3-day period of recovery (rec-TST), at which times measurements of renal, cardioendocrine, and cardiovascular systems were conducted. RESULTS: Presyncope occurred in 46% of subjects pre-TST, in 72% post-TST, and in 23% during rec-TST. OT was significantly better during the recovery period than at baseline (p = .03). There was a significant decrease in urinary sodium and potassium excretion, along with a decrease in plasma renin activity and serum and urine aldosterone compared with baseline. Serum norepinephrine and sympathetic responsiveness remained below baseline values. CONCLUSION: In summary, OT improved compared with baseline after a period of readaptation. Retention of electrolytes (sodium, potassium) could be involved. These findings indicate that recovery after SM is not simply a gradual return to baseline values but is instead a dynamic process reflecting interaction of multiple regulatory systems.

Adaptation, Physiological↗