Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model

Context  Recent studies have suggested a link between inhaled particulate matter exposure in urban areas and susceptibility to cardiovascular events; however, the precise mechanisms remain to be determined. Objective  To test the hypothesis that subchronic exposure to environmentally relevant particulate matter, even at low concentrations, potentiates atherosclerosis and alters vasomotor tone in a susceptible disease model. Design, Setting, and Participants  Between July 21, 2004, and January 12, 2005, 28 apolipoprotein E^–/– (apoE^–/–) mice were, based on randomized assignments, fed with normal chow or high-fat chow and exposed to concentrated ambient particles of less than 2.5 µm (PM_2.5) or filtered air (FA) in Tuxedo, NY, for 6 hours per day, 5 days per week for a total of 6 months. Main Outcome Measures  Composite atherosclerotic plaque in the thoracic and abdominal aorta and vasomotor tone changes. Results  In the high-fat chow group, the mean (SD) composite plaque area of PM_2.5 vs FA was 41.5% (9.8%) vs 26.2% (8.6%), respectively (P<.001); and in the normal chow group, the composite plaque area was 19.2% (13.1%) vs 13.2% (8.1%), respectively (P = .15). Lipid content in the aortic arch measured by oil red-O staining revealed a 1.5-fold increase in mice fed the high-fat chow and exposed to PM_2.5 vs FA (30.0 [8.2] vs 20.0 [7.0]; 95% confidence interval [CI], 1.21-1.83; P = .02). Vasoconstrictor responses to phenylephrine and serotonin challenge in the thoracic aorta of mice fed high-fat chow and exposed to PM_2.5 were exaggerated compared with exposure to FA (mean [SE], 134.2% [5.2%] vs 100.9% [2.9%], for phenylephrine, and 156.0% [5.6%] vs 125.1% [7.5%], for serotonin; both P = .03); relaxation to the endothelium-dependent agonist acetylcholine was attenuated (mean [SE] of half-maximal dose for dilation, 8.9 [0.2] x 10^-8 vs 4.3 [0.1] x 10^-8, respectively; P = .04). Mice fed high-fat chow and exposed to PM_2.5 demonstrated marked increases in macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine (all P<.001). Conclusion  In an apoE^–/– mouse model, long-term exposure to low concentration of PM_2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.      

Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes

Context  Glycemic disorders, one of the main risk factors for cardiovascular disease, are associated with activation of oxidative stress. Objective  To assess the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes. Design, Setting, and Participants  Case-control study of 21 patients with type 2 diabetes (studied 2003-2005) compared with 21 age- and sex-matched controls (studied in 2001) in Montpellier, France. Main Outcome Measures  Oxidative stress, estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F₂ (8-iso PGF₂). Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values (mean postprandial incremental area under the curve [AUCpp]). Long-term exposure to glucose was estimated from hemoglobin A_1c, from fasting glucose levels, and from mean glucose concentrations over a 24-hour period. Results  Mean (SD) urinary 8-iso PGF₂ excretion rates were higher in the 21 patients with diabetes (482 [206] pg/mg of creatinine) compared with controls (275 [85] pg/mg of creatinine). In univariate analysis, only MAGE (r = 0.86; P<.001) and AUCpp (r = 0.55; P = .009) showed significant correlations with urinary 8-iso PGF₂ excretion rates. Relationships between 8-iso PGF₂ excretion rates and either MAGE or AUCpp remained significant after adjustment for the other markers of diabetic control in multiple linear regression analysis (multiple R² = 0.72 for the model including MAGE and multiple R² = 0.41 for the model including AUCpp). Standardized regression coefficients were 0.830 (P<.001) for MAGE and 0.700 (P = .003) for AUCpp. Conclusions  Glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia. The present data suggest that interventional trials in type 2 diabetes should target not only hemoglobin A_1c and mean glucose concentrations but also acute glucose swings.      

Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials

Context  Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V₂-receptor antagonist, shows promise in this condition. Objective  To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure. Design, Setting, and Patients  Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied. Intervention  Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission. Main Outcome Measures  Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge). Results  Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension. Conclusion  In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events. Trial Registration  clinicaltrials.gov Identifier: NCT00071331      

Comparison of review articles published in peer-reviewed and throwaway journals

Context  To compare the quality, presentation, readability, and clinical relevance of review articles published in peer-reviewed and "throwaway" journals. Methods  We reviewed articles that focused on the diagnosis or treatment of a medical condition published between January 1 and December 31, 1998, in the 5 leading peer-reviewed general medical journals and high-circulation throwaway journals. Reviewers independently assessed the methodologic and reporting quality, and evaluated each article's presentation and readability. Clinical relevance was evaluated independently by 6 physicians. Results  Of the 394 articles in our sample, 16 (4.1%) were peer-reviewed systematic reviews, 135 (34.3%) were peer-reviewed nonsystematic reviews, and 243 (61.7%) were nonsystematic reviews published in throwaway journals. The mean (SD) quality scores were highest for peer-reviewed articles (0.94 [0.09] for systematic reviews and 0.30 [0.19] for nonsystematic reviews) compared with throwaway journal articles (0.23 [0.03], F_2,391 = 280.8, P<.001). Throwaway journal articles used more tables (P = .02), figures (P = .01), photographs (P<.001), color (P<.001), and larger font sizes (P<.001) compared with peer-reviewed articles. Readability scores were more often in the college or higher range for peer-reviewed journals compared with the throwaway journal articles (104 [77.0%] vs 156 [64.2%]; P = .01). Peer-reviewed article titles were judged less relevant to clinical practice than throwaway journal article titles (P<.001). Conclusions  Although lower in methodologic and reporting quality, review articles published in throwaway journals have characteristics that appeal to physician readers.      

Comparison of Lifestyle and Structured Interventions to Increase Physical Activity and Cardiorespiratory Fitness: A Randomized Trial

Context  Even though the strong association between physical inactivity and ill health is well documented, 60% of the population is inadequately active or completely inactive. Traditional methods of prescribing exercise have not proven effective for increasing and maintaining a program of regular physical activity. Objective  To compare the 24-month intervention effects of a lifestyle physical activity program with traditional structured exercise on improving physical activity, cardiorespiratory fitness, and cardiovascular disease risk factors. Design  Randomized clinical trial conducted from August 1, 1993, through July 31, 1997. Participants  Sedentary men (n = 116) and women (n = 119) with self-reported physical activity of less than 36 and 34 kcal/kg per day, respectively. Interventions  Six months of intensive and 18 months of maintenance intervention on either a lifestyle physical activity or a traditional structured exercise program. Main Outcome Measures  Primary outcomes were physical activity assessed by the 7-Day Physical Activity Recall and peak oxygen consumption (VO_2peak) by a maximal exercise treadmill test. Secondary outcomes were plasma lipid and lipoprotein cholesterol concentrations, blood pressure, and body composition. All measures were obtained at baseline and at 6 and 24 months. Results  Both the lifestyle and structured activity groups had significant and comparable improvements in physical activity and cardiorespiratory fitness from baseline to 24 months. Adjusted mean changes (95% confidence intervals [CIs]) were 0.84 (95% CI, 0.42-1.25 kcal/kg per day; P<.001) and 0.69 (95% CI, 0.25-1.12 kcal/kg day; P = .002) for activity, and 0.77 (95% CI, 0.18-1.36 mL/kg per minute; P = .01) and 1.34 (95% CI, 0.72-1.96 mL/kg per minute; P<.001) for VO_2peak for the lifestyle and structured activity groups, respectively. There were significant and comparable reductions in systolic blood pressure (-3.63 [95% CI, -5.54 to -1.72 mm Hg; P<.001] and -3.26 [95% CI, -5.26 to -1.25 mm Hg; P = .002]) and diastolic blood pressure (-5.38 [95% CI, -6.90 to -3.86 mm Hg; P<.001] and -5.14 [95% CI, -6.73 to -3.54 mm Hg; P<.001) for the lifestyle and structured activity groups, respectively. Neither group significantly changed their weight (-0.05 [95% CI, -1.05 to 0.96 kg; P = .93] and 0.69 [95% CI, -0.37 to 1.74 kg; P = .20]), but each group significantly reduced their percentage of body fat (-2.39% [95% CI, -2.92% to -1.85%; P<.001] and -1.85% [95% CI, -2.41% to -1.28%; P<.001]) in the lifestyle and structured activity groups, respectively. Conclusions  In previously sedentary healthy adults, a lifestyle physical activity intervention is as effective as a structured exercise program in improving physical activity, cardiorespiratory fitness, and blood pressure.      

Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial

Context  -Blockers have been shown to decrease cardiovascular risk in patients with hypertension and type 2 diabetes mellitus (DM); however, some components of the metabolic syndrome are worsened by some -blockers. Objective  To compare the effects of -blockers with different pharmacological profiles on glycemic and metabolic control in participants with DM and hypertension receiving renin-angiotensin system (RAS) blockade, in the context of cardiovascular risk factors. Design, Setting, and Participants  A randomized, double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) conducted between June 1, 2001, and April 6, 2004, at 205 US sites that compared the effects of carvedilol and metoprolol tartrate on glycemic control. The 1235 participants were aged 36 to 85 years with hypertension (>130/80 mm Hg) and type 2 DM (glycosylated hemoglobin [HbA_1c], 6.5%-8.5%) and were receiving RAS blockers. Participants were followed up for 35 weeks. Interventions  Participants were randomized to receive a 6.25- to 25-mg dose of carvedilol (n = 498) or 50- to 200-mg dose of metoprolol tartrate (n = 737), each twice daily. Open-label hydrochlorothiazide and a dihydropyridine calcium antagonist were added, if needed, to achieve blood pressure target. Main Outcome Measures  Difference between groups in mean change from baseline HbA_1c following 5 months of maintenance therapy. Additional prespecified comparisons included change from baseline HbA_1c in individual treatment groups, treatment effect on insulin sensitivity, and microalbuminuria. Results  The 2 groups differed in mean change in HbA_1c from baseline (0.13%; 95% confidence interval [CI], –0.22% to –0.04%; P = .004; modified intention-to-treat analysis). The mean (SD) HbA_1c increased with metoprolol (0.15% [0.04%]; P<.001) but not carvedilol (0.02% [0.04%]; P = .65). Insulin sensitivity improved with carvedilol (–9.1%; P = .004) but not metoprolol (–2.0%; P = .48); the between-group difference was –7.2% (95% CI, –13.8% to –0.2%; P = .004). Blood pressure was similar between groups. Progression to microalbuminuria was less frequent with carvedilol than with metoprolol (6.4% vs 10.3%; odds ratio, 0.60; 95% CI, 0.36-0.97; P = .04). Conclusions  Both -blockers were well tolerated; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 -blockers on clinical outcomes need to be compared in long-term clinical trials.      

Effect of Prolonged Methylprednisolone Therapy in Unresolving Acute Respiratory Distress Syndrome: A Randomized Controlled Trial

Context.— No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome (ARDS) and mortality remains greater than 50%. Objective.— To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS. Design.— Randomized, double-blind, placebo-controlled trial. Setting.— Medical intensive care units of 4 medical centers. Participants.— Twenty-four patients with severe ARDS who had failed to improve lung injury score (LIS) by the seventh day of respiratory failure. Interventions.— Sixteen patients received methylprednisolone and 8 received placebo. Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days. Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment. Main Outcome Measures.— Primary outcome measures were improvement in lung function and mortality. Secondary outcome measures were improvement in multiple organ dysfunction syndrome (MODS) and development of nosocomial infections. Results.— Physiological characteristics at the onset of ARDS were similar in both groups. At study entry (day 9 [SD, 3] of ARDS), the 2 groups had similar LIS, ratios of PaO₂ to fraction of inspired oxygen (FIO₂), and MODS scores. Changes observed by study day 10 for methylprednisolone vs placebo were as follows: reduced LIS (mean [SEM], 1.7 [0.1] vs 3.0 [0.2]; P<.001); improved ratio of PaO₂ to FIO₂ (mean [SEM], 262 [19] vs 148 [35]; P<.001); decreased MODS score (mean [SEM], 0.7 [0.2] vs 1.8 [0.3]; P<.001); and successful extubation (7 vs 0; P=.05). For the treatment group vs the placebo group, mortality associated with the intensive care unit was 0 (0%) of 16 vs 5 (62%) of 8 (P=.002) and hospital-associated mortality was 2 (12%) of 16 vs 5 (62%) of 8 (P=.03). The rate of infections per day of treatment was similar in both groups, and pneumonia was frequently detected in the absence of fever. Conclusions.— In this study, prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality.      

Association between phonocardiographic third and fourth heart sounds and objective measures of left ventricular function

Context  The third (S₃) and fourth (S₄) heart sounds detected by phonocardiography are considered to represent the criterion standards of the gallop sounds, but their test characteristics have not been explored. Objective  To determine the diagnostic test characteristics of the S₃ and S₄ for prediction of left ventricular dysfunction using a computerized heart sound detection algorithm. Design, Setting, and Participants  Prospective study of 90 adult patients undergoing elective left-sided heart catheterization at a single US teaching hospital between August 2003 and June 2004. The mean age was 62 (SD, 13) years (range, 24-90 years) and 61 (68%) were male. Within a 4-hour period, participants underwent computerized heart sound phonocardiographic analysis, cardiac catheterization, transthoracic echocardiography, and blood sampling for assessment of an S₃/S₄, left ventricular end-diastolic pressure (LVEDP), left ventricular ejection fraction (LVEF), and B-type natriuretic peptide (BNP), respectively. Main Outcome Measures  Diagnostic test characteristics of the computerized phonocardiographic S₃ and S₄ using markers of left ventricular function as criterion standards. Results  Mean (SD) LVEDP was significantly elevated (18.4 [6.9] mm Hg vs 12.1 [7.3] mm Hg; P<.001), mean (SD) LVEF was reduced (49.4% [20.2%] vs 63.6% [14.8%]; P<.001), and median (interquartile range) BNP was elevated (330 [98-1155] pg/mL vs 86 [41-192] pg/mL; P<.001) in those with an S₃, S₄, or both compared with patients without a diastolic heart sound. The sensitivities of these heart sounds to detect an elevated LVEDP, reduced LVEF, or elevated BNP were 41%, 52%, and 32% for an S₃, and 46%, 43%, and 40% for an S₄, respectively. For abnormal levels of the same markers of ventricular function, the specificities of the S₃ were 92%, 87%, and 92%, while the specificities of the S₄ were 80%, 72%, and 78%, respectively. Conclusions  Neither the phonocardiographic S₃ nor the S₄ is a sensitive marker of left ventricular dysfunction. The phonocardiographic S₃ is specific for left ventricular dysfunction and appears to be superior to the moderate specificity of the phonocardiographic S₄.      

Platelet activation in obese women: role of inflammation and oxidant stress

Context  Obesity, in particular abdominal adiposity, is associated with increased cardiovascular morbidity and mortality through mechanisms possibly linking the metabolic disorder to platelet and vascular abnormalities. Objective  To investigate the clinical and biochemical determinants of lipid peroxidation and platelet activation in obese women. Design, Setting, and Participants  Cross-sectional comparison, conducted between September 1999 and September 2001, of urinary 8-iso prostaglandin F₂ (8-iso PGF₂) and 11-dehydrothromboxane B₂ (11-dehyhdro-TxB₂) excretion levels in 93 women: 44 with a body mass index (BMI) higher than 28 and a waist-to-hip ratio (WHR) of 0.86 or higher, android obesity; 25 with a BMI higher than 28 and a WHR lower than 0.86, gynoid obesity; and 24 nonobese women with a BMI lower than 25. An additional study was conducted to determine the short-term effects of weight loss in 20 of the 44 women with android obesity. Intervention  During a 12-week period, 20 women with android obesity followed a weight loss program to reduce caloric intake to about 1200 kcal/d. Main Outcome Measures  Plasma C-reactive protein, insulin and leptin levels, and urinary 8-iso PGF₂ (marker of in vivo lipid peroxidation) and 11-dehyhdro-TxB₂ (marker of in vivo platelet activation) excretion. Weight loss was defined as successful when the initial body weight decreased by at least 5 kg after a 12-week period of caloric restriction. Results  Women with android obesity had higher levels of 8-iso PGF₂ (median [interquartile range {IQR}] 523 [393-685] vs 187 [140-225] pg/mg creatinine) and 11-dehyhdro-TxB₂ (median [IQR], 948 [729-1296] vs 215 [184-253] pg/mg creatinine) than nonobese women (P<.001). Both 8-iso PGF₂and 11-dehyhdro-TxB₂ were higher in women with android obesity than women with gynoid obesity (P<.001). Based on multiple regression analysis, C-reactive protein levels and WHRs of 0.86 or higher predicted the rate of 8-iso PGF₂ excretion independently of insulin and leptin levels. Of 20 women with android obesity, 11 achieved successful weight loss, which was associated with statistically significant reductions in C-reactive protein (median change, 23%; P<.05), 8-iso PGF₂ (median change, 32%; P = .04) and 11-dehydro-TxB₂ (median change, 54%; P = .005). Conclusions  Android obesity is associated with enhanced lipid peroxidation and persistent platelet activation. These abnormalities are driven by inflammatory triggers related to the degree of abdominal adiposity and are, at least in part, reversible with a successful weight-loss program.      

Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder

Context  Various anatomic brain abnormalities have been reported for attention-deficit/hyperactivity disorder (ADHD), with varying methods, small samples, cross-sectional designs, and without accounting for stimulant drug exposure. Objective  To compare regional brain volumes at initial scan and their change over time in medicated and previously unmedicated male and female patients with ADHD and healthy controls. Design, Setting, and Participants  Case-control study conducted from 1991-2001 at the National Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range, 4.5-19 years) recruited from the local community, who contributed 544 anatomic magnetic resonance images. Main Outcome Measures  Using completely automated methods, initial volumes and prospective age-related changes of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate nucleus of the brain were compared in patients and controls. Results  On initial scan, patients with ADHD had significantly smaller brain volumes in all regions, even after adjustment for significant covariates. This global difference was reflected in smaller total cerebral volumes (-3.2%, adjusted F_1,280 = 8.30, P = .004) and in significantly smaller cerebellar volumes (-3.5%, adjusted F_1,280 = 12.29, P = .001). Compared with controls, previously unmedicated children with ADHD demonstrated significantly smaller total cerebral volumes (overall F_2,288 = 6.65; all pairwise comparisons Bonferroni corrected, -5.8%; P = .002) and cerebellar volumes (-6.2%, F_2,288 = 8.97, P<.001). Unmedicated children with ADHD also exhibited strikingly smaller total white matter volumes (F_2,288 = 11.65) compared with controls (-10.7%, P<.001) and with medicated children with ADHD (-8.9%, P<.001). Volumetric abnormalities persisted with age in total and regional cerebral measures (P = .002) and in the cerebellum (P = .003). Caudate nucleus volumes were initially abnormal for patients with ADHD (P = .05), but diagnostic differences disappeared as caudate volumes decreased for patients and controls during adolescence. Results were comparable for male and female patients on all measures. Frontal and temporal gray matter, caudate, and cerebellar volumes correlated significantly with parent- and clinician-rated severity measures within the ADHD sample (Pearson coefficients between -0.16 and -0.26; all P values were <.05). Conclusions  Developmental trajectories for all structures, except caudate, remain roughly parallel for patients and controls during childhood and adolescence, suggesting that genetic and/or early environmental influences on brain development in ADHD are fixed, nonprogressive, and unrelated to stimulant treatment.      

Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss

Context  Weight loss elicits physiological adaptations relating to energy intake and expenditure that antagonize ongoing weight loss. Objective  To test whether dietary composition affects the physiological adaptations to weight loss, as assessed by resting energy expenditure. Design, Study, and Participants  A randomized parallel-design study of 39 overweight or obese young adults aged 18 to 40 years who received an energy-restricted diet, either low–glycemic load or low-fat. Participants were studied in the General Clinical Research Centers of the Brigham and Women’s Hospital and the Children’s Hospital, Boston, Mass, before and after 10% weight loss. The study was conducted from January 4, 2001, to May 6, 2003. Main Outcome Measures  Resting energy expenditure measured in the fasting state by indirect calorimetry, body composition by dual-energy x-ray absorptiometry, cardiovascular disease risk factors, and self-reported hunger. Results  Resting energy expenditure decreased less with the low–glycemic load diet than with the low-fat diet, expressed in absolute terms (mean [SE], 96 [24] vs 176 [27] kcal/d; P = .04) or as a proportion (5.9% [1.5%] vs 10.6% [1.7%]; P = .05). Participants receiving the low–glycemic load diet reported less hunger than those receiving the low-fat diet (P = .04). Insulin resistance (P = .01), serum triglycerides (P = .01), C-reactive protein (P = .03), and blood pressure (P = .07 for both systolic and diastolic) improved more with the low–glycemic load diet. Changes in body composition (fat and lean mass) in both groups were very similar (P = .85 and P = .45, respectively). Conclusions  Changes in dietary composition within prevailing norms can affect physiological adaptations that defend body weight. Reduction in glycemic load may aid in the prevention or treatment of obesity, cardiovascular disease, and diabetes mellitus.      

Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial

Context  Surgical site infection (SSI) in the general surgical population is a significant public health issue. The use of a high fractional inspired concentration of oxygen (FIO₂) during the perioperative period has been reported to be of benefit in selected patients, but its role as a routine intervention has not been investigated. Objective  To determine whether the routine use of high FIO₂ during the perioperative period alters the incidence of SSI in a general surgical population. Design, Setting, and Patients  Double-blind, randomized controlled trial conducted between September 2001 and May 2003 at a large university hospital in metropolitan New York City of 165 patients undergoing major intra-abdominal surgical procedures under general anesthesia. Interventions  Patients were randomly assigned to receive either 80% oxygen (FIO₂ of 0.80) or 35% oxygen (FIO₂ of 0.35) during surgery and for the first 2 hours after surgery. Main Outcome Measures  Presence of clinically significant SSI in the first 14 days after surgery, as determined by clinical assessment, a management change, and at least 3 prospectively defined objective criteria. Results  The study groups were closely matched in a large number of clinical variables. The overall incidence of SSI was 18.1%. In an intention-to-treat analysis, the incidence of infection was significantly higher in the group receiving FIO₂ of 0.80 than in the group with FIO₂ of 0.35 (25.0% vs 11.3%; P = .02). FIO₂ remained a significant predictor of SSI (P = .03) in multivariate regression analysis. Patients who developed SSI had a significantly longer length of hospitalization after surgery (mean [SD], 13.3 [9.9] vs 6.0 [4.2] days; P<.001). Conclusions  The routine use of high perioperative FIO₂ in a general surgical population does not reduce the overall incidence of SSI and may have predominantly deleterious effects. General surgical patients should continue to receive oxygen with cardiorespiratory physiology as the principal determinant.      

Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial

Context  Inhaled nitric oxide has been shown to improve oxygenation in acute lung injury. Objective  To evaluate the clinical efficacy of low-dose (5-ppm) inhaled nitric oxide in patients with acute lung injury. Design and Setting  Multicenter, randomized, placebo-controlled study, with blinding of patients, caregivers, data collectors, assessors of outcomes, and data analysts (triple blind), conducted in the intensive care units of 46 hospitals in the United States. Patients were enrolled between March 1996 and September 1999. Patients  Patients (n = 385) with moderately severe acute lung injury, a modification of the American-European Consensus Conference definition of acute respiratory distress syndrome (ARDS) using a ratio of PaO₂ to FiO₂ of 250, were enrolled if the onset was within 72 hours of randomization, sepsis was not the cause of the lung injury, and the patient had no significant nonpulmonary organ system dysfunction at randomization. Interventions  Patients were randomly assigned to placebo (nitrogen gas) or inhaled nitric oxide at 5 ppm until 28 days, discontinuation of assisted breathing, or death. Main Outcome Measures  The primary end point was days alive and off assisted breathing. Secondary outcomes included mortality, days alive and meeting oxygenation criteria for extubation, and days patients were alive following a successful unassisted ventilation test. Results  An intent-to-treat analysis revealed that inhaled nitric oxide at 5 ppm did not increase the number of days patients were alive and off assisted breathing (mean [SD], 10.6 [9.8] days in the placebo group and 10.7 [9.7] days in the inhaled nitric oxide group; P = .97; difference, –0.1 day [95% confidence interval, –2.0 to 1.9 days]). This lack of effect on clinical outcomes was seen despite a statistically significant increase in PaO₂ that resolved by 48 hours. Mortality was similar between groups (20% placebo vs 23% nitric oxide; P = .54). Days patients were alive following a successful 2-hour unassisted ventilation trial were a mean (SD) of 11.9 (9.9) for placebo and 11.4 (9.8) for nitric oxide patients (P = .54). Days alive and meeting criteria for extubation were also similar: 17.0 placebo vs 16.7 nitric oxide (P = .89). Conclusion  Inhaled nitric oxide at a dose of 5 ppm in patients with acute lung injury not due to sepsis and without evidence of nonpulmonary organ system dysfunction results in short-term oxygenation improvements but has no substantial impact on the duration of ventilatory support or mortality.      

Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome

Context  Previous data support an association between polymorphisms of the ₁- and ₂-adrenergic receptors (ADRB1 and ADRB2) and surrogate end points of response to -adrenergic blocker therapy. However, no associations between these polymorphisms and mortality have been demonstrated. Objective  To evaluate the effect of ADRB1 Arg389Gly (1165 CG), Ser49Gly (145 AG), and ADRB2 Gly16Arg (46 GA), Gln27Glu (79 CG) genotypes on survival among patients discharged with prescribed -blockers after an acute coronary syndrome (ACS). Design, Setting, and Patients  Prospective cohort study of 735 ACS patients admitted to 2 Kansas City, Mo, medical centers between March 2001 and October 2002; 597 patients were discharged with -blocker therapy. Main Outcome Measure  Multivariable-adjusted time to all-cause 3-year mortality. Results  There were 84 deaths during follow-up. There was a significant association between ADRB2 genotype and 3-year mortality among patients prescribed -blocker therapy. For the 79 CG polymorphism, Kaplan-Meier 3-year mortality rates were 16% (35 deaths), 11% (27 deaths), and 6% (4 deaths) for the CC, CG, and GG genotypes, respectively (P = .03; adjusted hazard ratios [AHRs], 0.51 [95% confidence interval {CI}, 0.30-0.87] for CG vs CC and 0.24 (95% CI, 0.09-0.68) for GG vs CC, P = .004). For the ADRB2 46 GA polymorphism, 3-year Kaplan-Meier mortality estimates were 10% (17 deaths), 10% (28 deaths), and 20% (20 deaths) for the GG, GA, and AA genotypes, respectively (P = .005; AHRs, 0.48 [95% CI, 0.27-0.86] for GA vs AA and 0.44 [95% CI, 0.22-0.85] for GG vs AA, P = .02). No mortality difference between genotypes was found among patients not discharged with -blocker therapy for either the 79 CG or 46 GA polymorphisms (P = .98 and P = .49, respectively). The ADRB2 diplotype and compound genotypes were predictive of survival in patients treated with -blockers (P = .04 and P = .002; AHRs, 5.36 [95% CI, 1.83-15.69] and 2.41 [95% CI, 0.86-6.74] for 46 A homozygous and composite heterozygous vs 79 G homozygous, respectively). No association of the ADRB1 variants with mortality was observed in either the -blocker or no -blocker groups. Conclusions  Patients prescribed -blocker therapy after an ACS have differential survival associated with their ADRB2 genotypes. Further assessment of the benefits of -blocker therapy in high-risk genotype groups may be warranted.      

Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation

Context  Although reperfusion therapy, aspirin, -blockers, and angiotensin-converting enzyme inhibitors reduce mortality when used early in patients with acute myocardial infarction (MI), mortality and morbidity remain high. No antithrombotic or newer antiplatelet drug has been shown to reduce mortality in acute MI. Objective  To evaluate the effects of reviparin, a low-molecular-weight heparin, when initiated early and given for 7 days in addition to usual therapy on the primary composite outcome of death, myocardial reinfarction, or strokes at 7 and 30 days. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled trial (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation [CREATE]) of 15 570 patients with ST-segment elevation or new left bundle-branch block, presenting within 12 hours of symptom onset at 341 hospitals in India and China from July 2001 through July 2004. Intervention  Reviparin or placebo subcutaneously twice daily for 7 days. Main Outcome Measure  Primary composite outcome of death, myocardial reinfarction, or stroke at 7 and 30 days. Results  The primary composite outcome was significantly reduced from 854 (11.0%) of 7790 patients in the placebo group to 745 (9.6%) of 7780 in the reviparin group (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96; P = .005). These benefits persisted at 30 days (1056 [13.6%] vs 921 [11.8%] patients; HR, 0.87; 95% CI, 0.79-0.95; P = .001) with significant reductions in 30-day mortality (877 [11.3%] vs 766 [9.8%]; HR, 0.87; 95% CI, 0.79-0.96; P = .005) and reinfarction (199 [2.6%] vs 154 [2.0%]; HR, 0.77; 95% CI, 0.62-0.95; P = .01), and no significant differences in strokes (64 [0.8%] vs 80 [1.0%]; P = .19). Reviparin treatment was significantly better when it was initiated very early after symptom onset at 7 days (<2 hours: HR, 0.70; 95% CI, 0.52-0.96; P = .03; 30/1000 events prevented; 2 to <4 hours: HR, 0.81; 95% CI, 0.67-0.98; P = .03; 21/1000 events prevented; 4 to <8 hours: HR, 0.85; 95% CI, 0.73-0.99; P = .05; 16/1000 events prevented; and 8 hours: HR, 1.06; 95% CI, 0.86-1.30; P = .58; P = .04 for trend). There was an increase in life-threatening bleeding at 7 days with reviparin and placebo (17 [0.2%] vs 7 [0.1%], respectively; P = .07), but the absolute excess was small (1 more per 1000) vs reductions in the primary outcome (18 fewer per 1000) or mortality (15 fewer per 1000). Conclusions  In patients with acute ST-segment elevation or new left bundle-branch block MI, reviparin reduces mortality and reinfarction, without a substantive increase in overall stroke rates. There is a small absolute excess of life-threatening bleeding but the benefits outweigh the risks.      

Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial

Context  Glucose-insulin-potassium (GIK) infusion is a widely applicable, low-cost therapy that has been postulated to improve mortality in patients with acute ST-segment elevation myocardial infarction (STEMI). Given the potential global importance of GIK infusion, a large, adequately powered randomized trial is required to determine the effect of GIK on mortality in patients with STEMI. Objective  To determine the effect of high-dose GIK infusion on mortality in patients with STEMI. Design, Setting, and Participants  Randomized controlled trial conducted in 470 centers worldwide among 20 201 patients with STEMI who presented within 12 hours of symptom onset. The mean age of patients was 58.6 years, and evidence-based therapies were commonly used. Intervention  Patients were randomly assigned to receive GIK intravenous infusion for 24 hours plus usual care (n = 10 091) or to receive usual care alone (controls; n = 10 110). Main Outcome Measures  Mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days after randomization. Results  At 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients (10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95-1.13; P = .45). There were no significant differences in the rates of cardiac arrest (1.5% [151/10 107] in control and 1.4% [139/10 088] in GIK infusion; HR, 0.93; 95% CI, 0.74-1.17; P = .51), cardiogenic shock (6.3% [640/10 107] vs 6.6% [667/10 088]; HR, 1.05; 95% CI, 0.94-1.17; P = .38), or reinfarction (2.4% [246/10 107] vs 2.3% [236/10 088]; HR, 0.98; 95% CI, 0.82-1.17; P = .81). The rates of heart failure at 7 days after randomization were also similar between the groups (16.9% [1711/10 107] vs 17.1% [1721/10 088]; HR, 1.01; 95% CI, 0.95-1.08; P = .72). The lack of benefit of GIK infusion on mortality was consistent in prespecified subgroups, including in those with and without diabetes, in those presenting with and without heart failure, in those presenting early and later after symptom onset, and in those receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous coronary intervention). Conclusion  In this large, international randomized trial, high-dose GIK infusion had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI.      

Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial

Context  Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. Objective  To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI. Design, Setting, and Participants  Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12 092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment. Main Outcome Measures  Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months). Results  Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days. Conclusion  In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes. Trial Registration  ClinicalTrials.gov Identifier NCT00064428      

Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial

Context  Aortic stiffness is increased in Marfan syndrome contributing to aortic dilatation and rupture, the major cause of premature death in this population. Angiotensin-converting enzyme inhibitors have been shown to reduce arterial stiffness. Objective  To determine whether perindopril therapy reduces aortic stiffness and attenuates aortic dilatation in patients with Marfan syndrome. Design, Setting, and Participants  A randomized, double-blind, placebo-controlled trial of 17 patients with Marfan syndrome (mean [SD], 33 [6] years) taking standard -blocker therapy, initiated in January 2004 and completed in September 2006, at Alfred Hospital Marfan Syndrome Clinic, Melbourne, Australia. Intervention  Patients were administered 8 mg/d of perindopril (n = 10) or placebo (n = 7) for 24 weeks. Main Outcome Measures  Indices of arterial stiffness were assessed via systemic arterial compliance, and central and peripheral pulse wave velocities. Aortic root diameters were assessed at 4 sites via transthoracic echocardiography. Results  Perindopril reduced arterial stiffness as indicated by increased systemic arterial compliance (mean [SEM], 0.33 [0.01] mL/mm Hg at baseline to 0.54 [0.04] mL/mm Hg at 24 weeks in perindopril group vs 0.30 [0.01] mL/mm Hg to 0.29 [0.01] mL/mm Hg in placebo group, P = .004), and reduced central (7.6 [0.4] m/s to 5.9 [0.3] m/s in perindopril group, P < .001 vs placebo) and peripheral (10.9 [0.4] m/s to 8.7 [0.4] m/s in perindopril group, P < .001 vs placebo) pulse wave velocities. In addition, perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (P<.01 to P < .001 for all comparisons between groups). Although perindopril marginally reduced mean arterial pressure (from 81 [2] mm Hg to 80 [1] mm Hg in perindopril group vs 83 [2] mm Hg to 84 [3] mm Hg in placebo group, P = .004), the observed changes in both stiffness and left ventricular outflow tract diameter remained significant when mean arterial pressure was included as a covariate. Transforming growth factor (TGF-), which contributes to aortic degeneration in Marfan syndrome, was reduced by perindopril compared with placebo in both latent (59 [6] ng/mL to 45 [3] ng/mL in perindopril group, P = .01 vs placebo) and active (46 [2] ng/mL to 42 [1] ng/mL in perindopril group, P = .02 vs placebo) forms. Conclusions  Perindopril reduced both aortic stiffness and aortic root diameter in patients with Marfan syndrome taking standard -blocker therapy, possibly through attenuation of TGF- signaling. Large clinical trials are needed to assess the clinical benefit of angiotensin II blockade in Marfan syndrome. Trial Registration  clinicaltrials.gov Identifier: NCT00485368      

Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial

Context  Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes. Objective  To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control. Design, Setting, and Participants  Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs. Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes. Interventions  Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care. Main Outcome Measures  Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA_1c] value <6.2% while taking no glycemic therapy). Secondary measures included weight and components of the metabolic syndrome. Analysis was by intention-to-treat. Results  Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2 diabetes was related to weight loss (R² = 0.46, P < .001) and lower baseline HbA_1c levels (combined R² = 0.52, P < .001). There were no serious complications in either group. Conclusions  Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed. Trial Registration  actr.org Identifier: ACTRN012605000159651      

Prophylactic Oral Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularization, Valve Replacement, or Repair: PAPABEAR: a randomized controlled trial

Context  Atrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results. Objective  To determine whether a brief perioperative course of oral amiodarone is an effective and safe prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups. Design, Setting, and Patients  Double-blind randomized controlled trial of 601 patients listed for nonemergent coronary artery bypass graft (CABG) surgery and/or valve replacement/repair surgery between February 1, 1999, and September 26, 2003, at a tertiary care hospital. The patients were followed up for 1 year. Intervention  Oral amiodarone (10 mg/kg daily) or placebo administered 6 days prior to surgery through 6 days after surgery (13 days). Randomization was stratified for subgroups defined by age, type of surgery, and use of preoperative -blockers. Main Outcome Measure  Incidence of atrial tachyarrhythmias lasting 5 minutes or longer that prompted therapy by the sixth postoperative day. Results  Atrial tachyarrhythmias occurred in fewer amiodarone patients (48/299; 16.1%) than in placebo patients (89/302; 29.5%) overall (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.34-0.69; P<.001); in patients younger than 65 years (19 [11.2%] vs 36 [21.1%]; HR, 0.51 [95% CI, 0.28-0.94]; P = .02); in patients aged 65 years or older (28 [21.7%] vs 54 [41.2%]; HR, 0.45 [95% CI, 0.27-0.75]; P<.001); in patients who had CABG surgery only (22 [11.3%] vs 46 [23.6%]; HR, 0.45 [95% CI, 0.26-0.79]; P = .002); in patients who had valve replacement/repair surgery with or without CABG surgery (25 [23.8%] vs 44 [44.1%]; HR, 0.51 [95% CI, 0.31-0.84; P = .008); in patients who received preoperative -blocker therapy (27 [15.3%] vs 42 [25.0%]; HR, 0.58 [95% CI, 0.34-0.99]; P = .03); and in patients who did not receive preoperative -blocker therapy (20 [16.3%] vs 48 [35.8%]; HR, 0.40 [95% CI, 0.22-0.71]; P<.001), respectively. Postoperative sustained ventricular tachyarrhythmias occurred less frequently in amiodarone patients (1/299; 0.3%) than in placebo patients (8/302; 2.6%) (P = .04). Dosage reductions of blinded therapy were more common in amiodarone patients (34/299; 11.4%) than in placebo patients (16/302; 5.3%) (P = .008). There were no differences in serious postoperative complications, in-hospital mortality, or readmission to the hospital within 6 months of discharge or in 1-year mortality. Conclusion  Oral amiodarone prophylaxis of atrial tachyarrhythmias after cardiac surgery is effective and may be safe overall and in important patient subgroups. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00251706