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Summary Objectives 25-Hydroxyvitamin D (25(OH)D) deficiency and excess activity of the renin–angiotensin system (RAS) are both associated with cardiovascular disease. Vitamin D interacts with the vitamin D receptor (VDR) to negatively regulate renin expression in mice; however, human studies linking genetic variation in the VDR with renin are lacking. We evaluated (i) whether genetic variation in the VDR at the Fok1 polymorphism was associated with plasma renin activity (PRA) in a population of hypertensives and a separate population of normotensives and (ii) whether the association between Fok1 genotype and PRA was independent of 25(OH)D levels. Design/Patients/Measurements Genetic association study, assuming an additive model of inheritance, of 375 hypertensive and 146 normotensive individuals from the HyperPATH cohort, who had PRA assessments after 1 week of high dietary sodium balance (HS) and l week of low dietary sodium balance (LS). Results The minor allele (T) at the Fok1 polymorphism was significantly associated with lower PRA in hypertensives (LS: β = −0·22, P

The purpose of this study was to elucidate the relationship between fasting plasma glucose (FPG), development of diabetes, and incident heart failure (HF) in a large, community sample of nondiabetic subjects.From Kaiser Permanente Northwest medical records, we identified 10,113 subjects with an FPG level of 100-125 mg/dl in 1997 or 1998 who were free of diabetes and HF and matched them to an equal number of subjects with an FPG level of100 mg/dl on sex and 5-year age groups. Subjects were followed until a new diagnosis of HF was entered into the medical record, death, termination of health plan membership, or December 31, 2005, whichever came first.After controlling for known HF risk factors, each 10 mg/dl increase in FPG was independently associated with an 8% increase in the risk of HF over a mean follow-up of 79 months [hazard ratio (HR)=1.08, 95% confidence interval (CI) 1.03-1.13, P=.003]. However, in a subsequent analysis that included only those HF cases that occurred prior to diabetes onset and censored follow-up at the time of diabetes development, FPG was not a significant predictor of HF risk (HR=1.01, 95% CI 0.96-1.07, P=.621). Age, male sex, body mass index, smoking, and cardiovascular disease were highly predictive of HF incidence.Although the risk of HF is increased among subjects with higher FPG, the increased risk is explained by greater likelihood of developing diabetes. Risk factors other than FPG are much stronger independent predictors of incident HF.

Background Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. Methods APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitozone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. Result A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body 2 mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. Conclusions APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitozone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease. (Am Heart J 2008; 156:1074-9.)

Emerging evidence suggests a role for cortisol in essential hypertension, and preliminary reports indicate that urinary free cortisol (UFC) may be an intermediate phenotype.The objectives of this study were: 1) confirm bimodality of UFC, 2) assess whether UFC variations aggregate in hypertensive families, and 3) compare low-mode and high-mode UFC groups for distinguishing features.Subjects included 390 hypertensives and 166 normotensives from the general community.Subjects had blood pressure and laboratory measurements on high- and low-salt diets. Familial aggregation was evaluated in 250 hypertensive siblings from 117 families.Hypertensives had higher UFC than normotensives (P0.001) and bimodal distribution of UFC (P0.0001). Analyses were controlled for gender and dietary sodium, which are confounding determinants of UFC. Mean low-mode UFC (33.8+/-10.6 microg per 24 h) was similar to that of normotensives. The high mode, comprising 31.3% of hypertensives, had less change in mean arterial pressure between diets than the low mode (P=0.01) without any other significant differences. Observed proportions of concordance and discordance for UFC mode differed significantly from that expected (P0.001). Observed concordance for the high mode was twice that expected, whereas for the low mode, it was similar to that expected by chance. Family membership explained a significant proportion of variance in UFC classification (P=0.027). UFC mode of one sibling was a significant predictor of the UFC mode of the other sibling [odds ratio 6.6, 95% confidence interval (2.4-18.0), P0.001].High-mode UFC is an intermediate phenotype of hypertension associated with salt resistance and a strong familial component supporting heritability.

Osteoporosis is an increasingly prevalent condition that, currently, is underdiagnosed and thus undertreated, so that improved screening and preventative dietary and lifestyle changes are needed. For more-severe cases, there are also several drug classes available or in development that work in different ways; these are detailed in this Review. Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1–34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.

Two genetic variants of the β-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 β-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 β-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 β-2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where β-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.

This case study examined the utility of regular expressions to identify clinical data relevant to the epidemiology of treatment of hypertension. We designed a software tool that employed regular expressions to identify and extract instances of documented blood pressure values and anti-hypertensive treatment intensification from the text of physician notes. We determined sensitivity, specificity and precision of identification of blood pressure values and anti-hypertensive treatment intensification using a gold standard of manual abstraction of 600 notes by two independent reviewers. The software processed 370 Mb of text per hour, and identified elevated blood pressure documented in free text physician notes with sensitivity and specificity of 98%, and precision of 93.2%. Anti-hypertensive treatment intensification was identified with sensitivity 83.8%, specificity of 95.0%, and precision of 85.9%. Regular expressions can be an effective method for focused information extraction tasks related to high-priority disease areas such as hypertension.

Objectives: This project was developed to identify ways to support hospital-based improvements for the identification and management of osteoporosis following treament of a fragility fracture.Design: This is a retrospective review of medical records of sets of consecutive patients who were admitted for surgical treatment of fragility fracture following introduction of several versions of admission and discharge care pathways. Effectiveness of the admission pathway was defined as % subjects with measurement of serum 25-hydroxyvitamin D (25(OH)D) during hospitalization; effectiveness of the discharge pathway was defined as % subjects with documentation of instructions for calcium and/or vitamin D supplementation.Setting: This study reviewed medical records of patients admitted to hospital for surgical treatment of a fragility fracture.Participants: Medical records were evaluated for 98 patients older than 50-years who were admitted with a fragility fracture of the hip or femur.Measurements: Medical records were reviewed for the % subjects with documentation of an in-hospital order for serum 25(OH)D and with documentation of instructions to patients upon discharge concerning calcium and vitamin D intake. Median value of serum 25(OH)D was calculated.Results: In accordance with the admission pathway, serum 25(OH)D was measured in 37% (36/98). The median 25(OH)D level was 19.5 ng/mL; 78% were vitamin D insufficient [serum 25(OH)D≤ 32 ng/mL] and 58% were vitamin D deficient [serum 25(OH)D ≤20 ng/mL]. In accordance with the discharge pathway, 74% (71/96) were discharged on calcium and/or vitamin D.Conclusion: The high prevalence of vitamin D insufficiency (78%) observed in this study affirms the importance of incorporating vitamin D supplementation in hospital-based fracture care pathways. The discharge pathway was more effective than the newer admission pathway, a finding attributable to effects of familiarity, retraining, and introduction of computer-prompts. These evolving pathways represent a much-needed paradigm shift in the care of fragility fracture patients.

Celiac disease is associated with decreased bone density; however, the risk of fractures in celiac disease patients is unclear. We compared the prevalence of celiac disease between a group of women with hip fractures and a group of women undergoing elective joint replacement surgery and the association between celiac disease and vitamin D levels.Two hundred eight community dwelling and postmenopausal women were recruited from Boston, MA (n=81) and Baltimore, MD (n=127). We measured tissue transglutaminase IgA by ELISA to diagnose celiac disease and 25-hydroxyvitamin D (25(OH)D) levels by radioimmunoassay in both women with hip fractures (n=157) and a control group (n=51) of total hip replacement subjects from Boston. Subjects were excluded if they took any medications or had medical conditions that might affect bone.Median serum 25(OH)D levels were significantly lower (p0.0001) in the hip fracture cohorts compared to the elective joint replacement cohort (14.1 ng/ml vs. 21.3 ng/ml, respectively). There were no differences in the percentage of subjects with a positive tissue transglutaminase in the women with hip fractures versus the control group (1.91% vs. 1.96%, respectively).Vitamin D levels are markedly reduced in women with hip fractures, however hip fracture patients did not show a higher percentage of positive tissue transglutaminase levels compared with controls. These data suggest that routine testing for celiac disease among hip fracture patients may not be necessary in the absence of clinical signs and symptoms, although data from larger studies among hip fracture subjects are needed.

Objectives Post-hoc analyses have shown an increase incidence of fractures among type 2 diabetes (T2DM) patients treated with thiazolidinediones (TZDs). The mechanisms by which TZDs may be associated with increased fracture risk is not well understood. This article describes the study design and baseline characteristics for a prospective, randomized, double-blind, active-controlled trial to evaluate the effects of rosiglitazone on changes in measures of skeletal structure, surrogates of bone strength and metabolism. Methods Postmenopausal women without osteoporosis and diagnosed with T2DM were randomized in a double-blind design to either rosiglitazone or metformin for 52 weeks, then all subjects received open-label metformin for 24 weeks. Study endpoints included changes in bone mineral density (BMD), quantitative computed tomography (QCT), digitized hip radiography (HXR) and high resolution magnetic resonance imaging (hrMRI). Serum markers of bone metabolism and indices of glycemic control were assessed within and between treatment groups. Results A total of 226 subjects were randomized. Baseline characteristics included: age 63.8 ± 6.5 years; years postmenopausal 16.9 ± 8.4; duration of diabetes 3.5 (1.8–7.8) years; body mass index (BMI) 31.4 ± 5.9 kg/m2; and glycated hemoglobin (HbA1c) 6.4 ± 0.65%. At baseline, mean T-scores were −0.95 ± 0.91 at the femoral neck, −0.02 ± 0.97 at the total hip and −0.55 ± 1.25 at the total spine. Since there are no well recognized techniques to determine bone mass and structure at the distal limbs (cortical bone sites where fractures were reported in RSG subjects), using the femoral neck as a surrogate for these areas may be a potential limitation of the study. Conclusion This is the first randomized trial utilizing multiple techniques to evaluate bone mass, structure, serum markers of bone remodeling, and potential reversibility of changes after discontinuation of rosiglitazone. This study will provide information about RSG bone effects in a population of postmenopausal women at risk for bone loss and subsequent fracture. ClinicalTrials.gov number NCT00679939