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Context:Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. Objective:To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone. Design:Double-blind, placebo-controlled trial. Setting:Twelve academic medical centers in the United States. Participants:In all, 788 men ≥65 years old with an average of two serum testosterone levels

ImportanceRecent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk.ObjectiveTo test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume.Design, setting, and participantsDouble-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014.InterventionTestosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.Main outcomes and measuresThe primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis).ResultsOf 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group.Conclusions and relevanceAmong older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.Trial registrationclinicaltrials.gov Identifier: NCT00799617.

The clinical implications of ankle-brachial index (ABI) cutpoints are not well defined in patients with chronic kidney disease (CKD) despite increased prevalence of high ABI attributed to arterial stiffness. We examined the relationship of ABI with cardiovascular disease (CVD) and all-cause mortality among CKD patients. Three thousand six hundred twenty-seven participants without clinical peripheral artery disease (PAD) at baseline from the Chronic Renal Insufficiency Cohort Study were included. ABI was obtained per standard protocol and CVD events were confirmed by medical record adjudication. A U-shaped association of ABI with PAD, myocardial infarction (MI), composite CVD, and all-cause mortality was observed. Individuals with an ABI between 1.0 and

BackgroundData from prior studies have yielded inconsistent results on the association of serum testosterone levels with the risk for cardiovascular disease. There are no clinical trial data on the effects of testosterone replacement therapy on plaque progression.ObjectiveWe designed a study to investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA). In this paper, we describe the study design, methods, and characteristics of the study population.MethodsThe Cardiovascular Trial of the Testosterone Trials (TTrials; NCT00799617) is a double-blind, placebo-controlled trial of 1 year of testosterone therapy in men 65 years or older with clinical manifestations of androgen deficiency and unequivocally low serum testosterone concentrations (

BackgroundData from prior studies have yielded inconsistent results on the association of serum testosterone levels with the risk for cardiovascular disease. There are no clinical trial data on the effects of testosterone replacement therapy on plaque progression.ObjectiveWe designed a study to investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA). In this paper, we describe the study design, methods, and characteristics of the study population.MethodsThe Cardiovascular Trial of the Testosterone Trials (TTrials; NCT00799617) is a double-blind, placebo-controlled trial of 1 year of testosterone therapy in men 65 years or older with clinical manifestations of androgen deficiency and unequivocally low serum testosterone concentrations (

BackgroundRisk factors for mitral annular calcification (MAC) and cardiovascular disease (CVD) demonstrate significant overlap in the general population. The aim of this paper is to determine whether there are independent relationships between MAC and demographics, traditional and novel CVD risk factors using cardiac CT in the Chronic Renal Insufficiency Cohort (CRIC) in a cross-sectional study.MethodsA sample of 2070 subjects underwent coronary calcium scanning during the CRIC study. Data were obtained for each participant at time of scan.Subjectswere dichotomized into the presence and absence of MAC. Differences in baseline demographic and transitional risk factor data were evaluated across groups. Covariates used in multivariable adjustment were age, gender, BMI, HDL, LDL, lipid lowering medications, smoking status, family history of heart attack, hypertension, diabetes mellitus, phosphate, PTH, albuminuria, and calcium.ResultsOur study consisted of 2070 subjects, of which 331 had MAC (prevalence of 16.0%). The mean MAC score was 511.98 (SD 1368.76). Age and white race remained independently associated with presence of MAC. Decreased GFR was also a risk factor. African American and Hispanic race, as well as former smoking status were protective against MAC. In multivariable adjusted analyses, the remaining covariates were not significantly associated with MAC. Among renal covariates, elevated phosphate was significant.ConclusionIn the CRIC population, presence of MAC was independently associated with age, Caucasian race, decreased GFR, and elevated phosphate. These results are suggested by mechanisms of dysregulation of inflammation, hormones, and electrolytes in subjects with renal disease.

BackgroundRisk factors for mitral annular calcification (MAC) and cardiovascular disease (CVD) demonstrate significant overlap in the general population. The aim of this paper is to determine whether there are independent relationships between MAC and demographics, traditional and novel CVD risk factors using cardiac CT in the Chronic Renal Insufficiency Cohort (CRIC) in a cross-sectional study.MethodsA sample of 2070 subjects underwent coronary calcium scanning during the CRIC study. Data were obtained for each participant at time of scan.Subjectswere dichotomized into the presence and absence of MAC. Differences in baseline demographic and transitional risk factor data were evaluated across groups. Covariates used in multivariable adjustment were age, gender, BMI, HDL, LDL, lipid lowering medications, smoking status, family history of heart attack, hypertension, diabetes mellitus, phosphate, PTH, albuminuria, and calcium.ResultsOur study consisted of 2070 subjects, of which 331 had MAC (prevalence of 16.0%). The mean MAC score was 511.98 (SD 1368.76). Age and white race remained independently associated with presence of MAC. Decreased GFR was also a risk factor. African American and Hispanic race, as well as former smoking status were protective against MAC. In multivariable adjusted analyses, the remaining covariates were not significantly associated with MAC. Among renal covariates, elevated phosphate was significant.ConclusionIn the CRIC population, presence of MAC was independently associated with age, Caucasian race, decreased GFR, and elevated phosphate. These results are suggested by mechanisms of dysregulation of inflammation, hormones, and electrolytes in subjects with renal disease.

Although subjects with chronic kidney disease (CKD) are at markedly increased risk for cardiovascular mortality, the relation between CKD and aortic valve calcification has not been fully elucidated. Also, few data are available on the relation of aortic valve calcification and earlier stages of CKD. We sought to assess the relation of aortic valve calcium (AVC) with estimated glomerular filtration rate (eGFR), traditional and novel cardiovascular risk factors, and markers of bone metabolism in the Chronic Renal Insufficiency Cohort (CRIC) Study. All patients who underwent aortic valve scanning in the CRIC study were included. The relation between AVC and eGFR, traditional and novel cardiovascular risk factors, and markers of calcium metabolism were analyzed using both unadjusted and adjusted regression models. A total of 1,964 CRIC participants underwent computed tomography for AVC quantification. Decreased renal function was independently associated with increased levels of AVC (eGFR 47.11, 44.17, and 39 ml/min/1.73 m2, respectively, p

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a critical resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best available national data on heart disease, stroke, and other cardiovascular disease-related morbidity and mortality and the risks, quality of care, use of medical procedures and operations, and costs associated with the management of these diseases in a single document. Indeed, since 1999, the Statistical Update has been cited >10 500 times in the literature, based on citations of all annual versions. In 2012 alone, the various Statistical Updates were cited ≈3500 times (data from Google Scholar). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas, as well as increasing the number of ways to access and use the information assembled. For this year's edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year. This year's edition includes a new chapter on peripheral artery disease, as well as new data on the monitoring and benefits of cardiovascular health in the population, with additional new focus on evidence-based approaches to changing behaviors, implementation strategies, and implications of the AHA's 2020 Impact Goals. Below are a few highlights from this year's Update. © 2013 American Heart Association, Inc.

Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a critical resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best available national data on heart disease, stroke, and other cardiovascular disease-related morbidity and mortality and the risks, quality of care, use of medical procedures and operations, and costs associated with the management of these diseases in a single document. Indeed, since 1999, the Statistical Update has been cited >10 500 times in the literature, based on citations of all annual versions. In 2012 alone, the various Statistical Updates were cited ≈3500 times (data from Google Scholar). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas, as well as increasing the number of ways to access and use the information assembled. For this year's edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year. This year's edition includes a new chapter on peripheral artery disease, as well as new data on the monitoring and benefits of cardiovascular health in the population, with additional new focus on evidence-based approaches to changing behaviors, implementation strategies, and implications of the AHA's 2020 Impact Goals. Below are a few highlights from this year's Update. © 2013 American Heart Association, Inc.

BackgroundThe clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.MethodsWe randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.ResultsAt 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.ConclusionsGenotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update*The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on heart disease, stroke, and other cardiovascular disease-related morbidity and mortality and the risks, quality of care, medical procedures and operations, and costs associated with the management of these diseases in a single document*Indeed, since 1999, the Statistical Update has been cited >10 500 times in the literature, based on citations of all annual versions*In 2011 alone, the various Statistical Updates were cited ≈1500 times (data from ISI Web of Science)*In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas, as well as increasing the number of ways to access and use the information assembled*For this year's edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year*This year's edition also implements a new chapter organization to reflect the spectrum of cardiovascular health behaviors and health factors and risks, as well as subsequent complicating conditions, disease states, and outcomes*Also, the 2013 Statistical Update contains new data on the monitoring and benefits of cardiovascular health in the population, with additional new focus on evidence-based approaches to changing behaviors, implementation strategies, and implications of the AHA's 2020 Impact Goals*Below are a few highlights from this year's Update . © 2013 American Heart Association, Inc.

Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update.*The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on heart disease, stroke, and other cardiovascular disease-related morbidity and mortality and the risks, quality of care, medical procedures and operations, and costs associated with the management of these diseases in a single document Indeed, since 1999, the Statistical Update has been cited >10 500 times in the literature, based on citations of all annual versions. In 2011 alone, the various Statistical Updates were cited ∼1500 times (data from ISI Web of Science). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas, as well as increasing the number of ways to access and use the information assembled. For this year's edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year. This year's edition also implements a new chapter organization to reflect the spectrum of cardiovascular health behaviors and health factors and risks, as well as subsequent complicating conditions, disease states, and outcomes. Also, the 2013 Statistical Update contains new data on the monitoring and benefits of cardiovascular health in the population, with additional new focus on evidence-based approaches to changing behaviors, implementation strategies, and implications of the AHA's 2020 Impact Goals. Below are a few highlights from this year's Update. © 2013 American Heart Association, Inc.

Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p

Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P

Increased lipoprotein-associated phospholipase [A.sub.2] (Lp-[PLA.sub.2]) activity is associated with increased risk of cardiac events, but it is not known whether Lp-[PLA.sub.2] is a causative agent. Here we show that selective inhibition of Lp-[PLA.sub.2] with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-[PLA.sub.2] activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-[PLA.sub.2] inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke., Atherosclerosis, the most common cause of myocardial infarction, stroke and cardiovascular death, is an inflammatory-immunomodulatory disease (1,2). A key early step in its development is the accumulation and subsequent oxidation [...]