Showing papers by "Diederick E. Grobbee published in 2008"

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

Abstract: BACKGROUND: In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. METHODS: We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. RESULTS: After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). CONCLUSIONS: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Abstract: Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD)(1-4) and type 2 diabetes (T2D)(5-7), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) 1.31, P = 1.2 x 10(-12)) and intracranial aneurysm (OR = 1.29, P = 2.5 x 10(-6)), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men - A randomized controlled trial

Abstract: Context Serum testosterone levels decline significantly with aging. Testosterone supplementation to older men might beneficially affect the aging processes. ObjectiveTo investigate the effect of testosterone supplementation on functional mobility, cognitive function, bone mineral density, body composition, plasma lipids, quality of life, and safety parameters in older men with low normal testosterone levels.Design, Setting, and ParticipantsDouble-blind, randomized, placebo-controlled trial of 237 healthy men between the ages of 60 and 80 years with a testosterone level lower than 13.7 nmol/L conducted from January 2004 to April 2005 at a university medical center in the Netherlands.InterventionParticipants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for 6 months.Main Outcome Measures Functional mobility (Stanford Health Assessment Questionnaire, timed get up and go test, isometric handgrip strength, isometric leg extensor strength), cognitive function (8 different cognitive instruments), bone mineral density of the hip and lumbar spine (dual-energy x-ray absorptiometry scanning), body composition (total body dual-energy x-ray absorptiometry and abdominal ultrasound of fat mass), metabolic risk factors (fasting plasma lipids, glucose, and insulin), quality of life (Short-Form Health 36 Survey and the Questions on Life Satisfaction Modules), and safety parameters (serum prostate-specific antigen level, ultrasonographic prostate volume, International Prostate Symptom score, serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, hemoglobin, and hematocrit). Results A total of 207 men completed the study. During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P = .07). Quality-of-life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected. ConclusionTestosterone supplementation during 6 months to older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects.Trial Registration isrctn.org Identifier: ISRCTN23688581

Prevalence of incidental findings in computed tomographic screening of the chest: a systematic review.

Abstract: Objective To perform a systematic review on the prevalence of incidental findings in computed tomographic (CT) screening studies of the chest. Methods We selected CT screening studies of the chest (screening for coronary artery disease [CAD] [coronary calcium and CT coronary angiography] and lung cancer screening). Screening protocols, descriptions of baseline characteristics, range of incidental findings, and recommendations for follow-up were abstracted. Results Eleven chest CT screening studies were identified. The proportion of people with at least 1 imaging abnormality requiring follow-up varied widely between studies (3%-41.5%). This was largely due to considerable variation in follow-up recommendations for incidental findings across studies. Analyzed by subgroup, 7.7% (confidence interval, 7.0%-8.3%) of 6421 participants in CAD screening had further investigations compared with 14.2% (confidence interval, 13.2%-15.2%) of 4531 participants in lung cancer screening. Conclusions In this review, 7.7% and 14.2% of patients undergoing either CAD or lung cancer screening with CT were found to have clinically significant incidental findings requiring additional investigations.

Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity A Pooled Analysis of the Rating Atherosclerotic Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) Trials

Abstract: Background - Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results - Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P=0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. Conclusions - These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.

Gender and outcome in adult congenital heart disease

Abstract: Background— Gender differences in prognosis have frequently been reported in cardiovascular disease but less so in congenital heart disease. We investigated whether gender is associated with outcome in adult patients with congenital heart disease. Methods and Results— From the CONgenital CORvitia (CONCOR) national registry for adults with congenital heart disease, 7414 patients were identified. All outcomes before entry into the registry and during subsequent follow-up were recorded, and differences between men and women were analyzed with the underlying congenital heart defect taken into account. Median age at the end of follow-up was 35 years (range, 17 to 91 years); 49.8% were female. No gender difference in mortality was found. Women had a 33% higher risk of pulmonary hypertension (odds ratio [OR]=1.33; 95% CI, 1.07 to 1.65; P=0.01), a 33% lower risk of aortic outcomes (OR=0.67; 95% CI, 0.50 to 0.90; P=0.007), a 47% lower risk of endocarditis (OR=0.53; 95% CI, 0.40 to 0.70; P<0.001), and a 55% lower r...

Advantages of the nested case-control design in diagnostic research.

Abstract: Despite its benefits, it is uncommon to apply the nested case-control design in diagnostic research. We aim to show advantages of this design for diagnostic accuracy studies. We used data from a full cross-sectional diagnostic study comprising a cohort of 1295 consecutive patients who were selected on their suspicion of having deep vein thrombosis (DVT). We draw nested case-control samples from the full study population with case:control ratios of 1:1, 1:2, 1:3 and 1:4 (per ratio 100 samples were taken). We calculated diagnostic accuracy estimates for two tests that are used to detect DVT in clinical practice. Estimates of diagnostic accuracy in the nested case-control samples were very similar to those in the full study population. For example, for each case:control ratio, the positive predictive value of the D-dimer test was 0.30 in the full study population and 0.30 in the nested case-control samples (median of the 100 samples). As expected, variability of the estimates decreased with increasing sample size. Our findings support the view that the nested case-control study is a valid and efficient design for diagnostic studies and should also be (re)appraised in current guidelines on diagnostic accuracy research.

CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction.

Abstract: Aims Inhibition of cholesteryl ester transfer protein (CETP) increases HDL-cholesterol. However, its combination with statins may increase mortality by factors incompletely understood. We previously observed that patients with intrinsically low CETP levels (carriers of the TaqIB -B2 allele) may have less benefit from statin therapy, and here tested this pharmacogenetic hypothesis on long-term outcomes. Methods and results We performed a 10-year follow-up analysis in 812 coronary artery disease (CAD) patients (REGRESS cohort), treated with statins after an initial 2-year study period. Carriers of TaqIB -B2 showed reduced CETP levels and higher HDL-cholesterol ( P < 0.001 for both). Despite these lower CETP and higher HDL-cholesterol levels, hazard ratios per B2 copy were 1.59 ( P = 0.01) for atherosclerotic disease death, 1.53 ( P = 0.03) for ischaemic heart disease death, and 1.30 ( P = 0.04) for all-cause mortality. Haplotype-effects analysis provided even stronger basis for the genetics involved: one risk-haplotype was identified that was highly significantly associated with these endpoints. Conclusion In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality. This suggests that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels. This effect may need consideration when administering CETP inhibition to CAD patients.

The risk of severe postoperative pain: modification and validation of a clinical prediction rule.

Abstract: risk). RESULTS: Modification of the original rule to enhance prediction in outpatients included reclassification of the predictor “type of surgery,” addition of the predictor “surgical setting” (ambulatory surgery: yes/no) and addition of interaction terms between surgical setting and the other predictors. One-third of the patients in the Utrecht cohort reported severe postoperative pain (36%), compared to 62% of the patients in the Amsterdam cohort. The distribution of most predictors was similar in the two cohorts, although the patients in the Utrecht cohort were slightly older, more often underwent ambulatory surgery and had large expected incision sizes less often than patients in the Amsterdam cohort. The modified prediction rule showed good calibration, when an adjusted intercept was used for the lower incidence in the Utrecht cohort. The discrimination was reasonable (area under the Receiver Operating Characteristic curve 0.65 [95% confidence interval 0.57–0.73]).

Parental Smoking and Vascular Damage in Young Adult Offspring: Is Early Life Exposure Critical? The Atherosclerosis Risk in Young Adults Study

Abstract: Objective— Our purpose was to study the association between familial and particularly fetal tobacco smoke exposure and vascular damage in young adulthood. Methods and Results— From a cohort of 732 young adults, birth data were collected and in young adulthood ultrasound measurement of common carotid artery intima-media thickness (CIMT) was performed. Data on parental smoking were obtained by standardized questionnaires. Twenty-nine percent of the mothers smoked during pregnancy. Offspring of mothers who smoked had 13.4 μm thicker CIMT (95% CI: 5.5, 21.3; P=0.001) than offspring of mothers who did not smoke in pregnancy. Adjustment for known CIMT risk factors (participant’s age, gender, BMI, pulse pressure, and LDL-cholesterol) yielded no change (9.4 μm, 95% CI: 1.9, 16.3, P=0.01) nor did adjustment for current smoking of parents (10.6 μm, 95% CI: 0.4 to 20.8, P=0.04), for participants’ current smoking and pack-years (11.5 μm, 95% CI: 3.5 to 19.4, P=0.004) or for parental socioeconomic status (SES; 13.0 μm...

Alcohol consumption and risk of microvascular complications in type 1 diabetes patients: the EURODIAB Prospective Complications Study

Abstract: Aims/hypothesis The aim of this study was to investigate the association between alcohol consumption and risk of microvascular complications (retinopathy, neuropathy, nephropathy) in type 1 diabetes mellitus patients in the EURODIAB Prospective Complications Study.

Is pacifier use a risk factor for acute otitis media? A dynamic cohort study

Abstract: Results. Of the 216 children that used a pacifier at baseline, 76 (35%) developed at least one episode of AOM, and of the 260 children that did not use a pacifier, 82 (32%) developed at least one AOM episode; for recurrent AOM, these figures were 33 (16%) versus 27 (11%), respectively. The adjusted ORs for pacifier use and AOM and recurrent AOM were 1.3 (95% CI 0.9‐1.9) and 1.9 (95% CI 1.1‐3.2), respectively. Conclusion. Pacifier use appears to be a risk factor for recurrent AOM. Parents should be informed about the possible negative effects of using a pacifier once their child has been diagnosed with AOM to avoid recurrent episodes.

Burden and rates of treatment and control of cardiovascular disease risk factors in obesity: the Framingham Heart Study.

Abstract: OBJECTIVE — Obesity is associated with an increased risk for cardiovascular disease (CVD). We sought to determine rates of treatment and control of CVD risk factors among normal weight, overweight, and obese individuals in a community-based cohort. RESEARCH DESIGN AND METHODS — Participants free of CVD ( n = 6,801; mean age 49 years; 54% women) from the Framingham Offspring and Third Generation cohorts who attended the seventh Offspring examination (1998–2001) or first Third Generation (2002–2005) examination were studied. RESULTS — Obese participants with hypertension were more likely to receive antihypertensive treatment (62.3%) than normal weight (58.7%) or overweight (59.0%) individuals ( P = 0.002), but no differences in hypertension control across BMI subgroups among participants with hypertension were observed (36.7% [normal weight], 37.3% [overweight], and 39.4% [obese]; P = 0.48). Rates of lipid-lowering treatment were higher among obese participants with elevated LDL cholesterol (39.5%) compared with normal weight (34.2%) or overweight (36.4%) participants ( P = 0.02), but control rates among those with elevated LDL cholesterol did not differ across BMI categories (26.7% [normal weight], 26.0% [overweight], and 29.2% [obese]; P = 0.11). There were no differences in diabetes treatment among participants with diabetes across BMI groups (69.2% [normal weight], 50.0% [overweight], 55.0% [obese]; P = 0.54), but obese participants with diabetes were less likely to have fasting blood glucose <126 mg/dl (15.7%) compared with normal weight (30.4%) or overweight (20.7%) participants ( P = 0.02). CONCLUSIONS — These findings emphasize the suboptimal rates of treatment and control of CVD risk factors among overweight and obese individuals.

Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density

Abstract: INTRODUCTION: High breast density is one of the strongest known risk factors for developing breast cancer. Insulin-like growth factor I (IGF-I) is a strong mitogen and has been suggested to increas ...

Empirical comparison of subgroup effects in conventional and individual patient data meta-analyses

Abstract: Objectives: Individual patient data (IPD) meta-analyses have been proposed as a major improvement in meta-analytic methods to study subgroup effects. Subgroup effects of conventional and IPD meta-analyses using identical data have not been compared. Our objective is to compare such subgroup effects using the data of six trials (n = 1,643) on the effectiveness of antibiotics in children with acute otitis media (AOM). Methods: Effects (relative risks, risk differences [RD], and their confidence intervals [Cl]) of antibiotics in subgroups of children with AOM resulting from (i) conventional meta-analysis using summary statistics derived from published data (CMA), (ii) two-stage approach to IPD meta-analysis using summary statistics derived from IPD (IPDMA-2), and (iii) one-stage approach to IPD meta-analysis where IPD is pooled into a single data set (IPDMA-1) were compared. Results: In the conventional meta-analysis, only two of the six studies were included, because only these reported on relevant subgroup effects. The conventional meta-analysis showed larger (age < 2 years) or smaller (age ≥ 2 years) subgroup effects and wider CIs than both IPD meta-analyses (age < 2 years: RD CMA -21 percent, RD IPDMA-1 -16 percent, RD IPDMA-2 -15 percent; age ≥2 years: RD CMA -5 percent, RD IPDMA-1 -11 percent, RD IPDMA-2 -11 percent). The most important reason for these discrepant results is that the two studies included in the conventional meta-analysis reported outcomes that were different both from each other and from the IPD meta-analyses. Conclusions: This empirical example shows that conventional meta-analyses do not allow proper subgroup analyses, whereas IPD meta-analyses produce more accurate subgroup effects. We also found no differences between the one- and two-stage meta-analytic approaches.

Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up

Abstract: The benefits versus the risks of postnatal administration of steroids in preterm-born infants are still debatable. This review examines the literature on postnatal hydrocortisone treatment for chronic lung disease (CLD) in preterm-born infants with a particular focus on the effects of such treatment on long-term neurodevelopmental outcomes. Quantitative published evidence does not point to a clear advantage of treatment with hydrocortisone over dexamethasone with regard to the impact on long-term neurological outcomes. However, in the absence of a randomised comparison, a consensus may soon have to be reached on the basis of the best available evidence whether hydrocortisone should replace dexamethasone in the treatment of CLD.

Peroxisome proliferator-activated receptor gamma-2 P12A polymorphism and risk of acute myocardial infarction, coronary heart disease and ischemic stroke: a case-cohort study and meta-analyses.

Abstract: Background The alanine allele of P12A polymorphism in PPARG gene in a few studies has been associated with a reduced or increased risk of acute myocardial infarction (AMI). Yet, the risk relation has not been confi rmed, and data on ischemic stroke (IS) is scarce. We therefore investigated the role of this polymorphism on occurrence of AMI, coronary heart disease (CHD) and IS.

Estimation of cardiovascular risk: a comparison between the Framingham and the SCORE model in people under 60 years of age.

Abstract: BackgroundThe Framingham Heart Study risk model has been used in the majority of cardiovascular risk management guidelines. Recently, a new model based on the SCORE system has been proposed. We compared both risk models with regard to their ability to predict cardiovascular mortality in the Netherlands.DesignCohort study.MethodsIn a Dutch cohort study of 39 719 persons, three properties of the risk models were investigated: discriminating ability (ranking persons in order of risks, expressed in area under the curve); calibrating ability (prediction of events compared with actual events expressed in goodness of fit); and the number of persons assigned to treatment according to the guideline.ResultsThe discriminative ability of both models was similar: the area under the curve of Framingham was 0.86 and of SCORE 0.85. Calibration of both functions was inadequate. The goodness of fit of the SCORE model was 35 and of the Framingham model 64, whereas a goodness of fit less than 20 is considered acceptable. Usi...

Effect of Testosterone Supplementation on Functional Mobility, Cognition, and Other Parameters in Older Men

Abstract: CONTEXT Serum testosterone levels decline significantly with aging. Testosterone supplementation to older men might beneficially affect the aging processes. OBJECTIVE To investigate the effect of testosterone supplementation on functional mobility, cognitive function, bone mineral density, body composition, plasma lipids, quality of life, and safety parameters in older men with low normal testosterone levels. DESIGN, SETTING, AND PARTICIPANTS Double-blind, randomized, placebo-controlled trial of 237 healthy men between the ages of 60 and 80 years with a testosterone level lower than 13.7 nmol/L conducted from January 2004 to April 2005 at a university medical center in the Netherlands. INTERVENTION Participants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for 6 months. MAIN OUTCOME MEASURES Functional mobility (Stanford Health Assessment Questionnaire, timed get up and go test, isometric handgrip strength, isometric leg extensor strength), cognitive function (8 different cognitive instruments), bone mineral density of the hip and lumbar spine (dual-energy x-ray absorptiometry scanning), body composition (total body dual-energy x-ray absorptiometry and abdominal ultrasound of fat mass), metabolic risk factors (fasting plasma lipids, glucose, and insulin), quality of life (Short-Form Health 36 Survey and the Questions on Life Satisfaction Modules), and safety parameters (serum prostate-specific antigen level, ultrasonographic prostate volume, International Prostate Symptom score, serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, hemoglobin, and hematocrit). RESULTS A total of 207 men completed the study. During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P = .07). Quality-of-life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected. CONCLUSION Testosterone supplementation during 6 months to older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN23688581.

Survival analysis in heart transplantation: results from an analysis of 1290 cases in a single center

Abstract: Background: The clinical profiles of recipients and donors eligible for the procedure as well as the procedure itself have changed over time. We determined the impact of changes in baseline risk profiles at different transplant periods on outcome, and the time-specific distribution of causes of death. Patients and methods: Adult heart transplantations were performed consecutively on 1290 patients. Three transplant periods were defined: 1989—1993, 1994—1998, and 1999—2004. Results: Recipient age and body mass index, previous cardiac surgery, high urgency status, need of ventricular assist device, waiting time (to transplantation and on ventricular assist device), donor age and body mass index, donor— recipient body mass index mismatch, and ischemic and cardiopulmonary bypass time were significantly different over the three transplant periods.Therewas,however,nosignificantdifferenceinmortalityrisk.Themajorcausesofdeathswere:acuterejection,multiorganfailure,and right heart failure (30 days); infection and acute rejection (31 days to 1 year); malignancy, acute rejection, and cardiac allograft vasculopathy (>1—5 years); cardiac allograft vasculopathy and malignancy (>5—10 years); and malignancy and infection (>10 years). The overall 1-, 5-, 10and 15-year survival was respectively 77%, 67%, 53% and 42%. There was no difference in survival by different transplant periods (p = 0.68). Conclusion: Despite clearly increased baseline risk profiles over time, the outcome of adult heart transplantation remains stable and encouraging. Cardiac allograft vasculopathy, malignancy, and infection threaten the long-term survival. # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Reproductive factors, metabolic factors, and coronary artery calcification in older women.

Abstract: Objective: Metabolic disturbances may explain the increased cardiovascular risk associated with reproductive factors. This cohort study investigated the relationship between reproductive factors and coronary artery calcification in elderly women and whether this relationship could be explained by metabolic disturbances. Design: In total, 568 postmenopausal women were included in this cross-sectional study. Information about the women's reproductive life was obtained by a questionnaire. Metabolic factors were measured during a single visit. Coronary artery calcification was assessed with a multislice computed tomography scanner and dichotomized as absent or present. Logistic regression analysis was used to assess the relationship between reproductive factors and coronary artery calcification. Crude and multivariate adjusted odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. In addition, ORs were adjusted for several metabolic and cardiovascular risk factors. Results: The mean age was 66.9 (± 5.5) years. Women with a history of irregular menstrual cycle lengths, as opposed to women with a history of regular menstrual cycles (26-30 d), had an increased risk of coronary artery calcification; multivariate-adjusted OR = 2.73 (95%CI: 1.24-5.98). Four or more pregnancies, compared with never pregnant, yielded an multivariate-adjusted OR of 1.89 (95% CI: 1.00-3.58). Having four children or more, compared with having no children, yielded a multivariate-adjusted OR of 1.97 (95% CI: 1.00-3.89). Adjustment for metabolic factors and other cardiovascular risk factors did not fully explain theses relationships. Conclusion: Multigravidity (more than four pregnancies), multiparity (more than four births), and irregular menstrual cycle lengths were related to an increased risk of coronary artery disease. These associations could not be explained by metabolic abnormalities.

Mutations in the HFE gene and cardiovascular disease risk: an individual patient data meta-analysis of 53 880 subjects

Abstract: Background—Whether mutations in the hemochromatosis (HFE) gene increase cardiovascular disease risk is still undetermined. The main reason is the low frequency of the mutations, in particular of the compound C282Y/H63D genotype. We combined the data of 11 observational studies for an individual patient data meta-analysis. Methods and Results—Individual patient data were obtained from published as well as unpublished studies that had information available on the C282Y mutation as well as the H63D mutation in relation to coronary heart disease risk. Individual records were provided on each of the 53 880 participants in 11 studies. In total, 10 541 patients with coronary events were documented, of whom 5724 had an acute myocardial infarction. The crude and adjusted association between HFE genotypes and coronary events was examined by logistic regression analysis. We explored potential effect modification of the association between traditional cardiovascular risk factors and coronary events by HFE genotypes. After full adjustment, the odds ratio for coronary heart disease was 1.12 (95% CI, 0.92 to 1.37) for subjects with the compound heterozygous (C282Y/H63D) genotype relative to those with the wild-type/wild-type genotype. The odds ratios for C282Y/C282Y, C282Y/wild-type, H63D/H63D, and H63D/wild-type were 0.78 (95% CI, 0.49 to 1.26), 0.98 (95% CI, 0.90 to 1.07), 1.16 (95% CI, 0.97 to 1.38), and 1.07 (95% CI, 1.00 to 1.14), respectively. There was no evidence for effect modification. Conclusions—The results of this large individual patient data meta-analysis do not support the view that HFE gene mutations are associated with an increased risk of coronary heart disease or acute myocardial infarction. (Circ Cardiovasc Genet. 2008;1:43-50.)

Does the European Clinical Trials Directive really improve clinical trial approval time

Abstract: AIMS To facilitate and improve clinical research within Europe, the European Union (EU) adopted in 2001 the Clinical Trials Directive (EUCTD). The aim of this study was to compare duration between submission of a clinical drug trial application and approval by regulatory authorities in EU countries regulated by EUCTD vs. EU countries regulated by local legislation and, second, to compare the duration of regulatory approval in Europe vs. the USA and Australia. METHODS Application for clinical drug trial initiation was submitted to the regulatory authorities of 14 European countries, to the USA and to Australia. In Europe, 10 countries were regulated by EUCTD and four by local legislation. RESULTS In Europe, the median duration of regulatory procedures was longer in EUCTD countries compared with countries following local legislation (75 vs. 59 days; P 60 days (maximum within EUCTD rules). The long duration of regulatory procedures was the consequence of (i) sequential instead of simultaneous submission of trial application to regulatory authorities, and (ii) involvement of local ethics committees in procedures that should be followed only by central ethics committees. The duration of regulatory procedures was similar in Australia (67 vs. 68 days, P = 0.388), but significantly shorter in the USA (67 vs. 15 days, P <0.001). CONCLUSIONS In this early stage of implementation, EUCTD appears not to shorten the duration of regulatory procedures for clinical trial initiation. Furthermore, Europe lags behind the USA in speed of regulatory procedures.