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Background: Lower birthweight is associated with increased susceptibility to cardiome-tabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults. Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15–75). Metabolic associations with birthweight were assessed by linear regression mod-els adjusted for sex, gestational age and age at blood sampling. The metabolic associ-ations with birthweight were compared with the corresponding associations with adult body mass index (BMI). Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R2 ¼ 0.77) as-sessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood. Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood. This study was supported by the Strategic Research Funding from the University of Oulu, Finland, the Sigrid Juselius Foundation, the Novo Nordisk Foundation, the Yrjo¨ Jahnsson Foundation, the Finnish Diabetes Research Foundation, the Finnish Medical Foundation, the Paulo Foundation, Biocenter Oulu, Finland, and the UK Medical Research Council via the University of Bristol Integrative Epidemiology Unit (IEU; MC_UU_12013/1 and MC_UU_12013/5). The Cardiovascular Risk in Young Finns Study is supported by the Academy of Finland (grants 286284, 134309, 126925, 121584, 124282, 129378, 117787 and 41071), Finnish Foundation for Cardiovascular Research, Oulu, Helsinki, Kuopio, Tampere, and Turku University Central Hospital Medical Funds, the Paavo Nurmi Foundation, the Juho Vainio Foundation, the Finnish Cultural Foundation and the Finnish Funding Agency for Technology and Innovation. The Northern Finland Birth Cohorts of 1966 and 1986 have received financial support from Academy of Finland, University Hospital Oulu, Biocenter Oulu, University of Oulu, the European Commission (EURO-BLCS, Framework 5 Award QLG1-CT-2000-01643, ENGAGE project and grant agree-ment HEALTH-F4-2007-201413, EurHEALTHAgeing (277849), European Regional Developmental Fund), EU H2020-PHC-2014 (grant no. 633595), DynaHEALTH, NHLBI grant 5R01HL087679-02 through the STAMPEED programme (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), Stanley Foundation, the UK Medical Research Council and Wellcome Trust. The UK Medical Research Council and Wellcome Trust (grant: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. The con-tribution of D.A.L to this study is supported by grants from the US National Institute of Health (R01 DK10324), European Research Council (ObesityDevelop: grant no. 669545) and UK National Institute for Health Research (NF-SI-0166-10196). F.D., D.A.L., G.D.S. and M.A.K. work in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1 and MC_UU_12013/5). The FinnTwin-12 and FinnTwin-16 studies have received support from the National Institute on Alcohol Abuse and Alcoholism (R37-AA12502, R01-AA09203 and K05-AA00145). The views expressed in this paper are those of the authors and not necessarily any funding body. Conflict of interest: P.W., A.J.K., P.S. and M.A.K. are shareholders of Brainshake Ltd, a company offering NMR-based metabolic profiling (www.brainshake.fi). P.W., T.T., M.T., P.S. and A.J.K. re-port employment relation with Brainshake Ltd. D.A.L. has received funding for biomarker research, unrelated to this paper, from Roche Diagnostics and Ferring Pharmaceuticals. K.A. is currently em-ployed by GSK. No other authors reported disclosures.

Aims To critically evaluate the clinical implications of the use of non-fasting rather than fasting lipid profiles and to provide guidance for the laboratory reporting of abnormal non-fasting or fasting lipid profiles. Methods and results Extensive observational data, in which random non-fasting lipid profiles have been compared with those determined under fasting conditions, indicate that the maximal mean changes at 1–6 h after habitual meals are not clinically significant [+0.3 mmol/L (26 mg/dL) for triglycerides; −0.2 mmol/L (8 mg/dL) for total cholesterol; −0.2 mmol/L (8 mg/dL) for LDL cholesterol; +0.2 mmol/L (8 mg/dL) for calculated remnant cholesterol; −0.2 mmol/L (8 mg/dL) for calculated non-HDL cholesterol]; concentrations of HDL cholesterol, apolipoprotein A1, apolipoprotein B, and lipoprotein(a) are not affected by fasting/non-fasting status. In addition, non-fasting and fasting concentrations vary similarly over time and are comparable in the prediction of cardiovascular disease. To improve patient compliance with lipid testing, we therefore recommend the routine use of non-fasting lipid profiles, while fasting sampling may be considered when non-fasting triglycerides >5 mmol/L (440 mg/dL). For non-fasting samples, laboratory reports should flag abnormal concentrations as triglycerides ≥2 mmol/L (175 mg/dL), total cholesterol ≥5 mmol/L (190 mg/dL), LDL cholesterol ≥3 mmol/L (115 mg/dL), calculated remnant cholesterol ≥0.9 mmol/L (35 mg/dL), calculated non-HDL cholesterol ≥3.9 mmol/L (150 mg/dL), HDL cholesterol ≤1 mmol/L (40 mg/dL), apolipoprotein A1 ≤1.25 g/L (125 mg/dL), apolipoprotein B ≥1.0 g/L (100 mg/dL), and lipoprotein(a) ≥50 mg/dL (80th percentile); for fasting samples, abnormal concentrations correspond to triglycerides ≥1.7 mmol/L (150 mg/dL). Life-threatening concentrations require separate referral when triglycerides >10 mmol/L (880 mg/dL) for the risk of pancreatitis, LDL cholesterol >13 mmol/L (500 mg/dL) for homozygous familial hypercholesterolaemia, LDL cholesterol >5 mmol/L (190 mg/dL) for heterozygous familial hypercholesterolaemia, and lipoprotein(a) >150 mg/dL (99th percentile) for very high cardiovascular risk. Conclusion We recommend that non-fasting blood samples be routinely used for the assessment of plasma lipid profiles. Laboratory reports should flag abnormal values on the basis of desirable concentration cut-points. Non-fasting and fasting measurements should be complementary but not mutually exclusive., published version, peerReviewed

Epidemiological data indicate that women with preeclampsia are more likely to develop cardiovascular disease (CVD) later in life. Population-based studies relate preeclampsia to an increased risk of later chronic hypertension (RR, 2.00 to 8.00) and cardiovascular morbidity/mortality (RR, 1.3 to 3.07), compared with normotensive pregnancy. Women who develop preeclampsia before 36 weeks of gestation or have multiple hypertensive pregnancies are at highest risk (RR, 3.4 to 8.12). The underlying mechanism for the remote effects of preeclampsia is complex and probably multifactorial. Many risk factors are shared by CVD and preeclampsia, including endothelial dysfunction, obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia. Therefore, it has been proposed that the metabolic syndrome may be a possible underlying mechanism common to CVD and preeclampsia. Follow-up and counseling of women with a history of preeclampsia may offer a window of opportunity for prevention of future disease.

We examine the variations in the pace of old-age (80+) mortality decline in seven European countries, from 1950 to 1999. Marked variations were found between countries, periods and sexes. While mortality declines were strong in France and England and Wales, modest or no mortality declines were seen in the 1950s and 1960s in the Nordic countries, and since the 1980s in Denmark, the Netherlands and Norway (men only). For non-smoking-related mortality, a high and consistent pace of mortality decline was observed. Mortality decline stagnated among men born between 1890 and 1899, but persisted among women born between 1847 and 1937. The pace of old-age mortality decline correlated with the pace of mortality decline at ages 60-69 among the same cohorts, but only among men and not for non-smoking-related mortality. Smoking, thus, seems more important than other factors originating earlier in life. Our results furthermore indicate substantial future declines in old-age mortality.

Objective: The purpose of this study was to assess the relationship between road traffic noise exposure at home and the prevalence of hypertension. Methods: We conducted cross-sectional analyses in a large random sample (N = 40,856) of inhabitants of Groningen City, and in a subsample (the Prevention of Renal and Vascular End-Stage Disease [PREVEND]) study cohort, N = 8592. Results: Before adjustment for confounders, road traffic noise exposure was associated with self-reported use of antihypertensive medication in the city of Groningen sample (odds ratio [OR] = 1.31 per 10-dB increase in L-den). Adjusted odds ratios were significant for the subjects between 45 and 55 years old in the full model when adjusted for PM10 (OR = 1.19) and at higher exposure (L-den > 55 dB) only (OR = 1.21; with adjustment for PM10, OR = 1.31). In the PREVEND cohort, the unadjusted odds ratio was 1.35 for hypertension (systolic and diastolic blood pressure > 140 and > 90 mm Hg, respectively, or use of antihypertensive medication). Again, the adjusted odds ratio was significant for subjects between 45 and 55 years old (OR = 1.27; with adjustment for PM10, OR = 1.39). Conclusions: Exposure to road traffic noise may be associated with hypertension in subjects who are between 45 and 55 years old. Associations seemed to be stronger at higher noise levels.

The endogenous fibrinolytic system describes a complex process resulting in the hydrolytic cleavage of fibrin by plasmin to promote clot dissolution and generate fibrin degradation products. This system helps protect the circulation from intravascular fibrin formation and thrombosis that would otherwise lead to vessel occlusion and tissue ischemia[1;2]. The efficacy of plasminogen activation and fibrin degradation is largely determined by the balance between local concentrations of tissue-type plasminogen activator (t-PA) and it’s cognate inhibitor, plasminogen activator inhibitor type 1 (PAI-1). There is substantial evidence indicating that plasma t-PA and PAI-1 are regulated in part by the renin-angiotensin system (RAS)[3]. Angiotensin II promotes the synthesis of PAI-1 in vitro[4;5]. Furthermore, ACE inhibitors have been shown to reduce plasma PAI-1 levels in patients post-myocardial infarction[6], in hypertensive subjects[7], and in postmenopausal females[8]. Conversely, bradykinin is a potent stimulator for t-PA in humans[9], and ACE-inhibition augments bradykinin induced t-PA release from the arterial vasculature[10;11]. Interactions between the RAS, bradykinin and fibrinolytic systems on t-PA and PAI-1 levels may explain at least part of the relationship between those systems and cardiovascular disease and the beneficial effects of ACE-inhibition on thrombotic events. Indeed, prior studies demonstrated interactions between genes from the fibrinolytic system and RAS on levels of t-PA and PAI-1[12–14]. However, these studies were either performed in selected high-risk populations or had small sample sizes. In addition, no study has yet investigated the interplay between genes from the RAS, bradykinin, and fibrinolytic systems on plasma levels of t-PA and PAI-1 in a single study. Therefore, the aim of the present study was to investigate the effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma levels of t-PA and PAI-1 in a large population-based sample, explicitly examining two-way epistatic interactions.

Epidemiological data indicate that women with preeclampsia are more likely to develop cardiovascular disease (CVD) later in life. Population-based studies relate preeclampsia to an increased risk of later chronic hypertension (RR, 2.00 to 8.00) and cardiovascular morbidity/mortality (RR, 1.3 to 3.07), compared with normotensive pregnancy. Women who develop preeclampsia before 36 weeks of gestation or have multiple hypertensive pregnancies are at highest risk (RR, 3.4 to 8.12). The underlying mechanism for the remote effects of preeclampsia is complex and probably multifactorial. Many risk factors are shared by CVD and preeclampsia, including endothelial dysfunction, obesity, hypertension, hyperglycemia, insulin resistance, and dyslipidemia. Therefore, it has been proposed that the metabolic syndrome may be a possible underlying mechanism common to CVD and preeclampsia. Follow-up and counseling of women with a history of preeclampsia may offer a window of opportunity for prevention of future disease.

Background Age, sex, and blood pressure could modify the associations of total cholesterol (and its main two fractions, HDL and LDL cholesterol) with vascular mortality. This meta-analysis combined prospective studies of vascular mortality that recorded both blood pressure and total cholesterol at baseline, to determine the joint relevance of these two risk factors. Methods Information was obtained from 61 prospective observational studies, mostly in western Europe or North America, consisting of almost 900000 adults without previous disease and with baseline measurements of total cholesterol and blood pressure. During nearly 12 million person years at risk between the ages of 40 and 89 years, there were more than 55000 vascular deaths (34000 ischaemic heart disease [IHD], 12000 stroke, 10000 other). Information about HDL cholesterol was available for 150000 participants, among whom there were 5000 vascular deaths (3000 IHD, 1000 stroke, 1000 other). Reported associations are with usual cholesterol levels (ie, corrected for the regression dilution bias). Findings 1 mmol/L lower total cholesterol was associated with about a half (hazard ratio 0 . 44 [95% CI 0.42-0.48]), a third (0.66 [0.65-0.68]), and a sixth (0.83 [0.81-0.85]) lower IHD mortality in both sexes at ages 40-49, 50-69, and 70-89 years, respectively, throughout the main range of cholesterol in most developed countries, with no apparent threshold. The proportional risk reduction decreased with increasing blood pressure, since the absolute effects of cholesterol and blood pressure were approximately additive. Of various simple indices involving HDL cholesterol, the ratio total/HDL cholesterol was the strongest predictor of IHD mortality (40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol). Total cholesterol was weakly positively related to ischaemic and total stroke mortality in early middle age (40-59 years), but this finding could be largely or wholly accounted for by the association of cholesterol with blood pressure. Moreover, a positive relation was seen only in middle age and only in those with below-average blood pressure; at older ages (70-89 years) and, particularly, for those with systolic blood pressure over about 145 mm Hg, total cholesterol was negatively related to haemorrhagic and total stroke mortality. The results for other vascular mortality were intermediate between those for IHD and stroke. Interpretation Total cholesterol was positively associated with IHD mortality in both middle and old age and at all blood pressure levels. The absence of an independent positive association of cholesterol with stroke mortality, especially at older ages or higher blood pressures, is unexplained, and invites further research. Nevertheless, there is conclusive evidence from randomised trials that statins substantially reduce not only coronary event rates but also total stroke rates in patients with a wide range of ages and blood pressures.

Objective: To analyse preventive interventions of women with cardiovascular risk factors postpartum. Methods: 3.5 years postpartum, women with history of hypertension in pregnancy were invited for a questionnaire, 1 year after a cardiovascular risk assessment. Results: Two hundred and fifty-seven women completed the questionnaire. At risk factor analyses, 35% had hypertension, 37% abnormal lipid-or glucose levels, 63% BMI >= 25 and 19% smoked. One year later, 36% of women with hypertension used anti-hypertensives, 0% of women with abnormal laboratory findings used anticholesterol and 1% anti-diabetes medication, 31% of the obese women achieved BMI reduction (>= 5%), 42% of the women who smoked, quit. Conclusion: A minority improved their risk profile.

Microalbuminuria has been shown to be a strong predictor of cardiovascular morbidity and mortality in diabetic and hypertensive patients, but also in the general population. Moreover, several reports suggest that reduction of urinary albumin excretion (UAE) is associated with improvement of cardiovascular prognosis. Reduction of UAE can be achieved by lowering arterial blood pressure, but blockers of the renin-angiotensin system (RAS) with their specific renal actions have demonstrated to be able to reduce UAE more than might be expected from reduction of blood pressure alone. Consequently, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also provide superior cardiovascular protection, especially in subjects with higher levels of albuminuria, but evidence is still scarce. The ability of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to reduce UAE and provide cardiovascular protection suggests that the RAS may play a central role. New developments in this area include the use of aldosterone antagonists in albuminuric/proteinuric subjects, and the development of oral renin inhibitors. Combinations of the aforementioned drugs may have the ability to fully block the RAS, potentially avoiding all detrimental effects of this hormonal cascade. However, combination therapy is expected to also increase the incidence of side effects, such as hyperkalaemia and acute renal insufficiency. The current knowledge of microalbuminuria represents the proverbial tip of the iceberg, and future studies should focus on the underlying pathophysiological mechanism of urinary albumin excretion in relation to cardiovascular protection. Only then can a better understanding of the problem be achieved and the optimal pharmacological approach be ascertained.

Microalbuminuria has been shown to be a strong predictor of cardiovascular morbidity and mortality in diabetic and hypertensive patients, but also in the general population. Moreover, several reports suggest that reduction of urinary albumin excretion (UAE) is associated with improvement of cardiovascular prognosis. Reduction of UAE can be achieved by lowering arterial blood pressure, but blockers of the renin-angiotensin system (RAS) with their specific renal actions have demonstrated to be able to reduce UAE more than might be expected from reduction of blood pressure alone. Consequently, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also provide superior cardiovascular protection, especially in subjects with higher levels of albuminuria, but evidence is still scarce. The ability of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to reduce UAE and provide cardiovascular protection suggests that the RAS may play a central role. New developments in this area include the use of aldosterone antagonists in albuminuric/proteinuric subjects, and the development of oral renin inhibitors. Combinations of the aforementioned drugs may have the ability to fully block the RAS, potentially avoiding all detrimental effects of this hormonal cascade. However, combination therapy is expected to also increase the incidence of side effects, such as hyperkalaemia and acute renal insufficiency. The current knowledge of microalbuminuria represents the proverbial tip of the iceberg, and future studies should focus on the underlying pathophysiological mechanism of urinary albumin excretion in relation to cardiovascular protection. Only then can a better understanding of the problem be achieved and the optimal pharmacological approach be ascertained.

Excretion of albumin in the urine is highly variable, ranging from nondetectable quantities to milligrams of albumin and even grams of albumin. Microalbuminuria is defined as low levels of urinary albumin excretion of 30 to 300 mg/d. Microalbuminuria is highly prevalent; in hypertensive and diabetic populations, its prevalence varies from 10 to 40%. It is interesting that microalbuminuria also is found frequently in seemingly healthy individuals (5 to 7%). The variable excretion of albumin in the urine is related to the risk for the individual to develop cardiovascular (CV) disease: Absence or very low levels of albuminuria is associated with low CV risk, whereas the CV risk increases markedly with increasing amount of albumin in the urine (even within the now considered normal range). The predictive power of urinary albumin levels for CV risk is independent of other CV risk factors and not only is present in individual with diabetes and/or hypertension but also in healthy individuals. Treatments that lower albuminuria are associated with CV protection, as demonstrated in randomized, controlled trials of patients with diabetes as well as in patients with hypertension. There is preliminary evidence that albuminuria lowering is CV protective in healthy individuals with an elevated albumin excretion rate. Differences between individuals in their level of albumin excretion are already observed at a very early age (just after birth). In fact, the interindividual variability seems to be relatively constant in the first 5 decades of life, indicating that microalbuminuria is not necessarily a consequence of vascular damage at later age. Higher levels of urinary albumin seem to reflect the ordinary interindividual variability in (renal and systemic) endothelial function. Experimental data show that between strains and even within strains, rats at young age show a remarkable difference in individual endothelial function, and this is strongly related to the susceptibility of that rat to organ damage. In conclusion, albuminuria seems to be a sensitive marker very early in life for the susceptibility of an individual to CV disease. It therefore may be an ideal target for early primary prevention using CV-protective therapy regimens.

The assessment of myocardial viability has become an important aspect of the diagnostic and prognostic work-up of patients with ischemic cardiomyopathy. Although revascularization may be considered in patients with sufficient viable myocardium, patients with predominantly scar tissue should be treated medically. Patients with left ventricular dysfunction who have viable myocardium are the patients at highest risk because of the potential for ischemia but at the same time benefit most from revascularization. It is important to identify viable myocardium in these patients, and radionuclide myocardial scintigraphy is an excellent tool for this. Single-photon emission computed tomography perfusion scintigraphy (SPECT), whether using (201)thallium, Tc-99m-sestamibi, or Tc-99m-tetrofosmin, in stress and/or rest protocols, has consistently been shown to be an effective modality for identifying myocardial viability and guiding appropriate management. Metabolic and perfusion imaging with positron emission tomography (PET) radiotracers frequently adds additional information and is a powerful tool for predicting which patients will have an improved outcome from revascularization. New techniques in the nuclear cardiology field, like attenuation corrected SPECT, dual isotope simultaneous acquisition (DISA) SPECT and gated FDG PET are promising and will further improve the detection of myocardial viability. Also the combination of multislice computed tomography scanners with PET opens possibilities of adding coronary calcium scoring and non-invasive coronary angiography to myocardial perfusion imaging and quantification. Evaluation of the clinical role of these creative new possibilities warrants investigation.

Objectives: To assess, in a population-based study, whether secular trends in cardiovascular disease mortality in seven European countries were correlated with past trends in infant mortality rate (IMR) in these countries.Study Design and Setting: Data on ischemic heart disease (IHD) and stroke mortality in 1950-1999 in the Netherlands, England & Wales, France, and four Nordic countries were analyzed. We used Poisson regression to describe trends in mortality according to birth cohort, for the cohorts born between 1860 and 1939. Pearson correlation coefficients were calculated to determine associations between IMR and IHD, or stroke mortality.Results: IHD mortality increased for successive cohorts up to 1900, and then started to decline. Stroke mortality levels were virtually stable among birth cohorts up to 1880, but declined rapidly among later cohorts. A strong positive association was found between cohort-specific IMR levels and stroke mortality rates. There were no strong cohort-wise associations between IMR and IHD mortality.Conclusion: These results support other studies in suggesting that living conditions in early childhood may influence population levels of stroke mortality. Future studies should determine the contribution of specific early life factors to the mortality decline in IHD and especially stroke. (C) 2006 Elsevier Inc. All rights reserved.

Background: Dispositional optimism, defined in terms of life engagement and generalized positive outcome expectancies for one?s future, may be related to lower cardiovascular mortality. We aimed to determine whether dispositional optimism is a stable trait over time and whether it is independently related to lower cardiovascular mortality in elderly men. Methods: In a cohort study with a follow-up of 15 years, we included 545 (61.4%) of 887 men, aged 64 to 84 years, who were free of preexisting cardiovascular disease and cancer and who had complete data on cardiovascular risk factors and sociodemographic characteristics. Dispositional optimism was assessed using a 4-item questionnaire in 1985, 1990, 1995, and 2000. In Cox proportional hazards models, the first 2 years of observation were excluded. Results: Optimism scores significantly decreased over 15 years, but showed temporal stability (reliability coefficients, 0.72 over 5 years and 0.78 over 15 years. Optimists in 1985 had a hazard ratio for cardiovascular mortality of 0.45 (top tertile vs lowest tertile; 95% confidence interval, 0.29-0.68), adjusted for classic cardiovascular risk factors. The risk of cardiovascular death was inversely associated with increased tertiles of dispositional optimism (for trend). Similar results were obtained using 1990 data after additional adjustment for depression (assessed ) by the Zung Self-rating Depression Scale). Conclusion: Dispositional optimism is a relatively stable trait over 15 years and shows a graded and inverse association with the risk of cardiovascular death

Rosiglitazone therapy improves insulin sensitivity and glucose uptake in patients with uncomplicated type 2 diabetes. In coronary artery disease (CAD), glucose is an important source of energy and preserved myocardial glucose uptake is essential for the viability of jeopardized myocardium. The aim was to test whether rosiglitazone changes myocardial metabolism in type 2 diabetic patients with CAD. We studied 54 patients (38 men and 16 women) with type 2 diabetes (HbA(1c) 7.2 + 0.9%) and CAD. Myocardial glucose uptake was measured with [F-18]fluoro-2-deoxy-D-glucose positron emission tomography in ischemic (evaluated by single-photon emission tomography and coronary angiography) and nonischemic regions during euglycemic-hyperinsulinemic clamp before and after a 16-week intervention period with rosiglitazone (n = 27) or placebo (n = 27). Rosiglitazone significantly improved glycemic control (P

Both reduced filtration power and increased excretion of albumin in the urine are powerful markers for renal and cardiovascular progressive function loss. These risk markers indicate the risk above and beyond the conventional existing risk markers/factors. The risk is substantial, because both reduced filtration and microalbuminuria are highly prevalent in the general population, matching in prevalence with the most well-known risk factor, hypertension. Therapeutic interventions to preserve renal and cardiovascular function, such as with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, are highly effective, particularly in those patients that have reduced filtration power. In addition, short-term reduction of albuminuria that follows the renin-angiotensin-aldosterone-system intervention appears to be predictive of long-term cardiovascular and renal protection. In conclusion, estimated glomerular filtration rate as well as albumin excretion in the urine are powerful predictors for cardiovascular and renal outcome and should be used as such. Intervention and prevention could be aimed at not only at reducing conventional risk markers, but also at reducing albuminuria.

Both reduced filtration power and increased excretion of albumin in the urine are powerful markers for renal and cardiovascular progressive function loss. These risk markers indicate the risk above and beyond the conventional existing risk markers/factors. The risk is substantial, because both reduced filtration and microalbuminuria are highly prevalent in the general population, matching in prevalence with the most well-known risk factor, hypertension. Therapeutic interventions to preserve renal and cardiovascular function, such as with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, are highly effective, particularly in those patients that have reduced filtration power. In addition, short-term reduction of albuminuria that follows the renin-angiotensin-aldosterone-system intervention appears to be predictive of long-term cardiovascular and renal protection. In conclusion, estimated glomerular filtration rate as well as albumin excretion in the urine are powerful predictors for cardiovascular and renal outcome and should be used as such. Intervention and prevention could be aimed at not only at reducing conventional risk markers, but also at reducing albuminuria.

Objective: To assess the association of depression following myocardial infarction (MI) and cardiovascular prognosis. Methods: The authors performed a meta-analysis of references derived from MEDLINE, EMBASE, and PSYCINFO (1975-2003) combined with crossreferencing without language restrictions. The authors selected prospective studies that determined the association of depression with the cardiovascular outcome of MI patients, defined as mortality and cardiovascular events within 2 years from index MI. Depression had to be assessed within 3 months after MI using established psychiatric instruments. A quality assessment was performed. Results: Twenty-two papers met the selection criteria. These studies described follow up (on average, 13.7 months) of 6367 MI patients (16 cohorts). Post-MI depression was significantly associated with all-cause mortality (odds ratio [OR], fixed 2.38; 95% confidence interval [CI], 1.76-3.22; p

Objective: Different from the general observed decline in old-age mortality, for The Netherlands and Norway there have been reports of stagnation in the decline since the 1980s. We detect periods of stagnation in recent old-age mortality trends, and explore for which causes of death the recent stagnation is most apparent.Study Design and Setting: We applied Poisson regression analysis to total and cause-specific mortality data by age (80+), period (1950-1999), and sex for seven European low-mortality countries.Results: We found large heterogeneity in the pace of decline in the countries under investigation, with periods of stagnation being widespread. In the 1980s and 1990s, stagnation was observed in Denmark, The Netherlands, and Norway (males). Continued mortality decline was observed especially in France. Although smoking has had a marked influence on the trends in old-age mortality, the role of smoking in the recent stagnation seems only modest and restricted to Norway. Mortality from cardiovascular diseases showed important crossnational variations in the pace of decline. Mortality from diseases specifically related to old age increased recently in all countries, except France.Conclusion: Old-age mortality seems highly plastic and susceptible to many factors, with both favorable and unfavorable effects on trends over time. (C) 2004 Elsevier Inc. All rights reserved.

Patients at increased risk of coronary artery disease (CAD) frequently exhibit an atherogenic lipoprotein phenotype characterized by elevated plasma levels of both triglyceride-rich lipoproteins (TRL) and small, dense LDL and low concentrations of HDL cholesterol. Recently, in a large observational study, the calculated non-HDL plasma cholesterol concentration (the sum of the cholesterol contents of LDL, intermediate-density lipoprotein [IDL], and very-low-density lipoprotein [VLDL]) was a stronger predictor of cardiovascular events than plasma cholesterol alone.1–3 Improvement in the predictability of CAD on inclusion of VLDL and IDL cholesterol emphasizes the proatherogenic nature of TRL and their remnant particles. The atherogenic lipoprotein phenotype has been defined by Austin et al4 as the presence of a predominance of small, dense LDL particles, elevated plasma triglyceride (TG) levels, and low plasma HDL cholesterol levels in the lipoprotein profile, which is associated with an approximately 3-fold increased risk of atherosclerotic disease.5–8 It is now commonly accepted that small, dense LDL particles are the products of the intravascular remodeling of TG-rich VLDL particles after interaction primarily with lipoprotein lipase, hepatic lipase, and cholesterol ester transfer protein9,10 (Figure). The atherogenic lipoprotein phenotype is strongly linked to obesity, insulin resistance, familial combined hyperlipidemia (FCHL), hypertension, and abnormalities in postprandial lipid metabolism.7,11,12 Epidemiological data from the Framingham study have already revealed that plasma TG concentration is an important independent risk indicator of CAD in women13; additional evidence supporting this observation was obtained by Yarnell et al14 in a 10-year follow-up study and confirmed by others.15,16 In the PROCAM (Prospective Cardiovascular Munster) study,17 this relationship was dependent on plasma HDL cholesterol concentration. Criqui et al,18 however, could not demonstrate an independent relationship between plasma TG and cardiovascular mortality in a North American population participating in the Lipid Research Clinics Follow-up. …

Since the discovery of the polymorphism in the angiotensin converting enzyme (ACE) and the consequences of this polymorphism on the activity levels of the enzyme, numerous association studies have been performed. However, these investigations do not often adhere to the most stringent criteria for such studies. The initial study reporting a positive association of the ACE polymorphism and myocardial infarction showed an increased risk of the DD genotype. This initial association was eventually refuted by a large, well conducted association study, which found a risk ratio of 1.02 after combining their own data with all published data. Although such large, well conducted association studies have not been performed in left ventricular (LV) hypertrophy, the association between DD genotype and hypertrophy is more convincing with a 192% excess risk of LV hypertrophy in untreated hypertensives. The role of ACE genotype in LV growth is well established, especially in athletes. In heart failure, large studies or meta-analyses have not been performed, because most studies have selected different end-points. This hampers a proper meta-analysis of the results obtained in associations with heart failure. As most association studies do not fulfill the criteria for good association studies and use too small sample sizes, it remains important to perform a meta-analysis to add meaning to the results of such studies. Above all, it is important to obey the rules set for association studies, large sample size, small P values, report associations that make biological sense and alleles that affect the gene product in a physiologically meaningful way. (C) 2003 Elsevier Science Ltd. All rights reserved.

Since the discovery of the polymorphism in the angiotensin converting enzyme (ACE) and the consequences of this polymorphism on the activity levels of the enzyme, numerous association studies have been performed. However, these investigations do not often adhere to the most stringent criteria for such studies. The initial study reporting a positive association of the ACE polymorphism and myocardial infarction showed an increased risk of the DD genotype. This initial association was eventually refuted by a large, well conducted association study, which found a risk ratio of 1.02 after combining their own data with all published data. Although such large, well conducted association studies have not been performed in left ventricular (LV) hypertrophy, the association between DD genotype and hypertrophy is more convincing with a 192% excess risk of LV hypertrophy in untreated hypertensives. The role of ACE genotype in LV growth is well established, especially in athletes. In heart failure, large studies or meta-analyses have not been performed, because most studies have selected different end-points. This hampers a proper meta-analysis of the results obtained in associations with heart failure. As most association studies do not fulfill the criteria for good association studies and use too small sample sizes, it remains important to perform a meta-analysis to add meaning to the results of such studies. Above all, it is important to obey the rules set for association studies, large sample size, small P values, report associations that make biological sense and alleles that affect the gene product in a physiologically meaningful way. (C) 2003 Elsevier Science Ltd. All rights reserved.

Bilirubin, the principal tetrapyrrole, bile pigment and catabolite of haem, is an emerging biomarker of disease resistance, which may be related to several recently documented biological functions. Initially believed to be toxic in infants, the perception of bilirubin has undergone a transformation: it is now considered to be a molecule that may promote health in adults. Data from the last decade demonstrate that mildly elevated serum bilirubin levels are strongly associated with reduced prevalence of chronic diseases, particularly cardiovascular diseases (CVDs), as well as CVD-related mortality and risk factors. Recent data also link bilirubin to other chronic diseases, including cancer and Type 2 diabetes mellitus, and to all-cause mortality. Therefore, there is evidence to suggest that bilirubin is a biomarker for reduced chronic disease prevalence and a predictor of all-cause mortality, which is of important clinical significance. In the present review, detailed information on the association between bilirubin and all-cause mortality, as well as the pathological conditions of CVD, cancer, diabetes and neurodegenerative diseases, is provided. The mechanistic background concerning how bilirubin and its metabolism may influence disease prevention and its clinical relevance is also discussed. Given that the search for novel biomarkers of these diseases, as well as for novel therapeutic modalities, is a key research objective for the near future, bilirubin represents a promising candidate, meeting the criteria of a biomarker, and should be considered more carefully in clinical practice as a molecule that might provide insights into disease resistance. Clearly, however, greater molecular insight is warranted to support and strengthen the conclusion that bilirubin can prevent disease, with future research directions also proposed.

Both developmental nutrition and adult nutrition affect life-history traits; however, little is known about whether the effect of developmental nutrition depends on the adult environment experienced. We used the fruit fly to determine whether life-history traits, particularly life span and fecundity, are affected by developmental nutrition, and whether this depends on the extent to which the adult environment allows females to realize their full reproductive potential. We raised flies on three different developmental food levels containing increasing amounts of yeast and sugar: poor, control, and rich. We found that development on poor or rich larval food resulted in several life-history phenotypes indicative of suboptimal conditions, including increased developmental time, and, for poor food, decreased adult weight. However, development on poor larval food actually increased adult virgin life span. In addition, we manipulated the reproductive potential of the adult environment by adding yeast or yeast and a male. This manipulation interacted with larval food to determine adult fecundity. Specifically, under two adult conditions, flies raised on poor larval food had higher reproduction at certain ages – when singly mated this occurred early in life and when continuously mated with yeast this occurred during midlife. We show that poor larval food is not necessarily detrimental to key adult life-history traits, but does exert an adult environment-dependent effect, especially by affecting virgin life span and altering adult patterns of reproductive investment. Our findings are relevant because (1) they may explain differences between published studies on nutritional effects on life-history traits; (2) they indicate that optimal nutritional conditions are likely to be different for larvae and adults, potentially reflecting evolutionary history; and (3) they urge for the incorporation of developmental nutritional conditions into the central life-history concept of resource acquisition and allocation.

Background Patients with a depressive disorder after myocardial infarction (MI) have a significantly increased risk of major cardiac events. The Myocardial INfarction and Depression-Intervention Trial (MIND-IT) investigates whether antidepressive treatment can improve the cardiac prognosis for these patients. The rationale and outline of the study are described. Methods In this multicenter randomized clinical trial, 2140 patients admitted for MI are screened for depressive symptoms with a questionnaire 0, 3, 6, 9, and 12 months after MI. Patients with symptoms undergo a standardized psychiatric interview. Those with a post-MI depressive episode are randomized to intervention (ie, antidepressive treatment; n = 190) or care-as-usual (CAU; n = 130). In the intervention arm, the research diagnosis is to be confirmed by a psychiatrist. First-choice treatment consists of placebo-controlled treatment with mirtazapine. In case of refusal or nonresponse, alternative open treatment with citalopram is offered. In the CAU arm, the patient is not informed about the research diagnosis. Psychiatric treatment outside the study is recorded, but no treatment is offered. Both arms are followed for end points (cardiac death or hospital admission for MI, unstable angina, heart failure, or ventricular tachyarrhythmia) during an average period of 27 months. Analysis is on an intention-to-treat basis. Conclusion The MIND-IT study will show whether treatment of post-MI depression can improve cardiac prognosis. (Am Heart J 2002;144:219-25.)

This study aimed to detect endothelial dysfunction in erectile dysfunction (ED) patients free from cardiovascular diseases or atherosclerotic risk factors and to evaluate acute effects of phosphodiesterase-5 inhibitor tadalafil on endothelial dysfunction and cardiac function. Thirty ED patients and 20 healthy male subjects (mean ages: 48.7 +/- 11.7 and 48.3 +/- 8.7 years, respectively) were enrolled. Endothelium functions were assessed by applanation tonometry. Aortic stiffness and cardiac function were evaluated by transthoracic echocardiography. Pulse pressure was greater in the ED group (P < 0.05), whereas aortic strain and aortic distensibility were significantly lower (P < 0.001). Treatment with tadalafil reduced pulse pressure (P = 0.0179), systolic blood pressure (P = 0.001) and diastolic blood pressure (P = 0.054) and increased aortic distensibility (P = 0.001) and aortic strain (P = 0.003) in the ED group. Tadalafil administration also increased large artery and small artery elasticity indices that were reduced in the ED group at baseline (P = 0.02 and 0.003, respectively). Systemic vascular disease and compromised left ventricular diastolic function (LVDF) were present in ED patients with no known atherosclerotic risk factors and cardiac diseases. Tadalafil positively affected arterial stiffness and LVDF.

BACKGROUND: The main goal of this randomized controlled single-blinded pilot study was to study whether, independent of weight loss, a Palaeolithic-type diet alters characteristics of the metabolic syndrome. Next we searched for outcome variables that might become favourably influenced by a Paleolithic-type diet and may provide new insights in the pathophysiological mechanisms underlying the metabolic syndrome. In addition, more information on feasibility and designing an innovative dietary research program on the basis of a Palaeolithic-type diet was obtained. METHODS: Thirty-four subjects, with at least two characteristics of the metabolic syndrome, were randomized to a two weeks Palaeolithic-type diet (n = 18) or an isoenergetic healthy reference diet, based on the guidelines of the Dutch Health Council (n = 14). Thirty-two subjects completed the study. Measures were taken to keep bodyweight stable. As primary outcomes oral glucose tolerance and characteristics of the metabolic syndrome (abdominal circumference, blood pressure, glucose, lipids) were measured. Secondary outcomes were intestinal permeability, inflammation and salivary cortisol. Data were collected at baseline and after the intervention. RESULTS: Subjects were 53.5 (SD9.7) year old men (n = 9) and women (n = 25) with mean BMI of 31.8 (SD5.7) kg/m2. The Palaeolithic-type diet resulted in lower systolic blood pressure (-9.1 mmHg; P = 0.015), diastolic blood pressure (-5.2 mmHg; P = 0.038), total cholesterol (-0.52 mmol/l; P = 0.037), triglycerides (-0.89 mmol/l; P = 0.001) and higher HDL-cholesterol (+0.15 mmol/l; P = 0.013), compared to reference. The number of characteristics of the metabolic syndrome decreased with 1.07 (P = 0.010) upon the Palaeolithic-type diet, compared to reference. Despite efforts to keep bodyweight stable, it decreased in the Palaeolithic group compared to reference (-1.32 kg; P = 0.012). However, favourable effects remained after post-hoc adjustments for this unintended weight loss. No changes were observed for intestinal permeability, inflammation and salivary cortisol. CONCLUSIONS: We conclude that consuming a Palaeolithic-type diet for two weeks improved several cardiovascular risk factors compared to a healthy reference diet in subjects with the metabolic syndrome. TRIAL REGISTRATION: Nederlands Trial Register NTR3002.

Item does not contain fulltext Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2-10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.

Phospholipase Cgamma2 (PLCgamma2) is a critical regulator of osteoclast differentiation and basal bone resorption, which was demonstrated by Kertesz et al. in agreement with previous reports(1). The role of the PLCgamma isoenzyme in bone resorption and in adhesion receptor signalling of osteoclasts was further emphasized in a recent review(2) reinforcing the statements made by Kertesz et al.,(1). Moreover, Dr. Faccio's group provided genetic evidence that targeting PLCgamma2 can suppress inflammatory osteolysis(3). This article is protected by copyright. All rights reserved.

Introduction: Although both coagulation and fibrinolysis are associated with cardiovascular disease (CVD) the underlying nature and pathways of many of these associations are still unclear. Our aim was to determine which of the current or 5-year prior levels of total fibrinogen, fibrinogen gamma', plasminogen activator inhibitor-1 (PAI-1(act)) and global fibrinolytic potential were the stronger determinant of arterial structure and function. Materials and methods: This prospective study consisted of 2010 Africans over the age of 35 years with 5-year follow-up data available for 1288 participants. Cardiovascular measurements included arterial stiffness, blood pressure and carotid intima media thickness. Results: Fibrinogen gamma' showed stronger associations with blood pressure than total fibrinogen also in the presence of other CVD risk factors. PAI-1(act) was positively associated with blood pressure both cross-sectionally and prospectively, with the longitudinal association being the stronger determinant, also after adjustment for known CVD risk factors. Clot lysis time (CLT) was positively associated, both prospectively and crosssectionally, with intima media thickness and negatively with markers of arterial stiffness but not after adjustment for known CVD risk factors. Conclusions: Fibrinogen gamma' was more strongly associated with CVD function than total fibrinogen. PAI-1(act) was significantly associated with blood pressure with changes in PAI-1 levels preceding changes in blood pressure. Different mechanisms may be at play determining arterial wall stiffness/thickening and blood pressure as observed from the opposing associations with PAI-1act and CLT. CLT was not independently related to cardiovascular measures as its associations were weakened in the presence of other known CVD risk factors. (C) 2014 Elsevier Ltd. All rights reserved.

We studied lipids, apolipoprotein-E (apo-epsilon) genotypes and other coronary artery disease (CAD) risk factors of 67 CAD patients (male/female ratio 5) in Curacao. Compared with 57 controls, male CAD patients had higher cholesterol, triglycerides, LDL-cholesterol, apo-B and decreased HDL-cholesterol and HDL-cholesterol/cholesterol concentrations. Other CAD risk factors were: increased fasting glucose and HbA(lc) concentrations, decreased creatinine clearance, and increased prevalences of lipoprotein (a) concentration >500 mg/l, renal disease, hyperhomocysteinaemia, diabetes mellitus type II (DM-II), positive CAD family history and cigarette smoking. Male CAD patients had higher plasma alpha-tocopherol(eq). Compared with 29 female controls, female CAD patients had higher fasting plasma glucose and HbA(lc) concentrations, and prevalence of DM-II; Predicting factors for CAD development in the whole CAD group were: DM-II, cigarette smoking, apo-epsilon(3)/epsilon(4) and apo-epsilon(4)/epsilon(4). Apo-epsilon(4) was associated with lower HDL- and higher LDL-cholesterol concentrations. There is a need for local studies on improvement of diabetic control, reference values of lipoprotein (a) and homocysteine concentrations, on apolipoprotein (a) phenotypes, causes of hyperhomocysteinaemia, and dietary influences on CAD development in subjects who carry the apo-epsilon(4) allele.

Although plasma concentrations of high-density lipoprotein (HDL) cholesterol correlate inversely with the incidence of atherosclerotic cardiovascular disease, results from recent epidemiological, genetic and pharmacological intervention studies resulted in a shift of concept. Rather than HDL cholesterol mass levels, the functionality of HDL particles is increasingly regarded as potentially clinically important. This review provides an overview of four key functional properties of HDL, namely cholesterol efflux and reverse cholesterol transport; antioxidative activities; anti-inflammatory activities; and the ability of HDL to increase vascular nitric oxide production resulting in vasorelaxation. Currently available assays are put into context with different HDL isolation procedures yielding compositional heterogeneity of the particle. Gathered knowledge on the impact of different disease states on HDL function is discussed together with potential underlying causative factors modulating HDL functionalities. In addition, a perspective is provided regarding how a better understanding of the determinants of (dys)functional HDL might impact clinical practice and the future design of rational and specific therapeutic approaches targeting atherosclerotic cardiovascular disease.

Introduction People born preterm at very low birth weight (VLBW, ≤1500g) have higher rates of risk factors for adult-onset diseases, including cardiovascular diseases and type 2 diabetes. These risks may be mediated through epigenetic modification of genes that are critical to normal growth and development. Methods We measured the methylation level of an imprinted insulin-like-growth-factor 2 (IGF2) locus (IGF2/H19) in young adults born preterm at VLBW and in their peers born at term. We studied 158 VLBW and 161 control subjects aged 18 to 27 years from the Helsinki Study of Very Low Birth Weight Adults. Methylation fraction at two IGF2 differentially methylated regions (DMRs) – IGF2 antisense transcript (IGF2AS, also known as IGF2 DMR0) and last exon of IGF2 (IGF2_05, also known as IGF2 DMR2) – were measured with Sequenom Epityper. We used linear regression and adjustment for covariates to compare methylation fractions at these DMRs between VLBW and control subjects. Results At one IGF2AS CpG site, methylation was significantly lower in VLBW than in control subjects, mean difference −0.017 (95% CI; −0.028, −0.005), P = 0.004. Methylation at IGF2_05 was not different between the groups. Conclusions Methylation of IGF2AS is altered 20 years after preterm birth at VLBW. Altered methylation may be a mechanism of later increased disease risk but more data are needed to indicate causality.

There is a strong need to reduce the risk of cardiovascular disease (CVD) beyond the use of statins that lower low-density lipoprotein cholesterol (LDL-C). The inverse relationship of high-density lipoprotein cholesterol (HDL-C) with cardiovascular disease suggests HDL-C raising therapy as a novel target. This review discusses the role of HDL-C in atherogenesis as well as the promise of cholesteryl ester transfer protein (CETP) inhibition in CVD prevention. While genetic studies show conflicting results on correlations between HDL-C and CVD, experimental studies have yielded sufficient encouraging data to proceed with the development of HDL-C raising strategies. CETP inhibition has been shown to successfully increase HDL-C levels in man. However, the first CETP inhibitor tested in phase III trials increased mortality possibly due to torcetrapib-specific vasopressor effects. More recently, dalcetrapib did not show an effect on CVD outcome while raising HDL-C by 30%, thereby refuting the HDL-C hypothesis. Anacetrapib and evacetrapib are currently tested in phase III clinical trials and have not shown adverse effects thus far. Both compounds not only increase HDL-C by 129-151%, they also decrease LDL-C (36-41%) and anacetrapib lowers Lp(a) (17%). Combined, these effects are anticipated to decrease CVD risk and the results will be revealed in 2017.

To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation. Copyright © ILSI Europe 2013.

Background: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups.Methodology/Principal: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I: A-II levels interacted with high apoE levels in establishing subgroup risk.Conclusions/Significance: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP.

Not all patients treated on the basis of PET-proven viability benefit from revascularization. Myocardial perfusion reserve (MPR) predicts survival in patients not undergoing revascularization. In the present study, we investigated whether MPR is related to survival in ischemic heart disease (IHD) patients after a PET-driven intervention. Methods: Between 1995 and 2003, 119 consecutive patients with chronic IHD underwent a PET-driven revascularization procedure based on ischemia-viability assessment with PET. Patients were followed for all-cause mortality and major cardiovascular events. Results: One hundred nineteen patients underwent a PET-driven revascularization procedure (67 percutaneous coronary interventions, 52 coronary artery bypass grafts) because of angina complaints. The mean age was 67 +/- 11 y (96 men, 23 women); global left ventricle MPR was 1.54 +/- 0.43. MPR intertertile boundaries were 1.34 and 1.67. Significantly more cardiac deaths were observed in the lowest and middle MPR tertiles than in the highest tertile. The age-and sex-corrected hazard ratio for the middle tertile was 8.3 (95% confidence interval, 1.02-68.3) and for the lowest tertile 23.6 (95% confidence interval, 3.1-179) (P = 0.002). After left ventricular ejection fraction (LVEF) and viability were added to the model, MPR remained significant, with hazard ratios of 6.5 (0.8-54.4) and 18.5 (2.3-145.5) (P = 0.004), whereas neither LVEF nor viability reached significance in this model. Comparable results were found for major adverse cardiac events, with hazard ratios of 3.15 (0.82-12.0) and 8.24 (2.36-28.8) (P = 0.002). Conclusion: Patients with IHD revascularized on the basis of PET viability assessment who have a low MPR are at risk for cardiac death and subsequent cardiac events. MPR is a more sensitive predictor for cardiac death than LVEF and extent of viability.

Item does not contain fulltext Aim of the present Consensus Statement is to provide a comprehensive and up to-date document on the pathophysiology, atherogenicity and clinical significance of low density liproproteins (LDL) subclasses. We sub-divided our statement in 2 sections. section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drug and lifestyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions.

Background Low birth weight and slow growth during infancy are associated with increased rates of chronic diseases in adulthood. Associations with risk factors such as fasting glucose and lipids concentrations are weaker than expected based on associations with disease. This could be explained by differences in postprandial responses, which, however, have been little studied. Our aim was to examine the impact of growth during infancy on postprandial responses to a fast-food meal (FF-meal) and a meal, which followed the macro-nutrient composition of the dietary guidelines (REC-meal). Methodology/Principal Findings We recruited 24 overweight 65–75 year-old subjects, 12 with slow growth during infancy (SGI-group) and 12 with normal early growth. All the subjects were born at term. The study meals were isocaloric and both meals were consumed once. Plasma glucose, insulin, triglycerides (TG) and free fatty acids (FFA) were measured in fasting state and over a 4-h period after both meals. Subjects who grew slowly during infancy were also smaller at birth. Fasting glucose, insulin or lipid concentrations did not differ significantly between the groups. The TG responses were higher for the SGI-group both during the FF-meal (P = 0.047) and the REC-meal (P = 0.058). The insulin responses were significantly higher for the SGI-group after the FF-meal (P = 0.036). Glucose and FFA responses did not differ significantly between the groups. Conclusions Small birth size and slow early growth predict postprandial TG and insulin responses. Elevated responses might be one explanation why subjects who were small at birth and experiencing slow growth in infancy are at an increased risk of developing cardiovascular diseases in later life.

Purpose: To evaluate the cardiac toxicity of radiotherapy (RT) in breast cancer (BC) patients employing myocardial perfusion imaging (MPI) with Tc-99 m Tetrofosmin - single photon emission computer tomography (T-SPECT). Materials and methods: We studied 46 BC female patients (28 patients with left and 18 patients with right BC) treated with postoperative RT compared to a control group of 85 age-matched females. The median time of RT to SPECT was 40 months (6-263). Results: Abnormalities in the summed stress score (SSS) were found in 54% of left BC patients, 44.4% of right BC patients, and 32.9% of controls. In left BC patients there were significantly more SSS abnormalities compared to controls (4.0 +/- 3.5 vs 2.6 +/- 2.0, p = 0.05) and possible trend of increased abnormalities of right BC patients (3.7 +/- 3.0 vs 2.6 +/- 2.0, p = 0.14). Multiple regression analysis showed more abnormalities in the MPI of left BC patients compared to controls (SSS, p = 0.0001); Marginal toxicity was also noted in right BC patients (SSS, p = 0.045). No additional toxicity was found in patients that received adjuvant cardiotoxic chemotherapy. All T-SPECT abnormalities were clinically silent. Conclusion: The study suggests that radiation therapy to BC patients result in MPI abnormalities but without apparent clinical consequences. Radiation Oncology

In their recent paper, Drs. Turner and Thompson1 question whether the assumption of a Paleolithic life as the human standard is complete because of its “relying primarily on genetic understandings of the human diet.” According to the authors, the Paleolithic assumption focuses too much on “a single model of human ancestral diets” and on “cultural evolution outpacing genetic evolution” as a “fundamental cause of disease in the modern world,” thereby “resulting in an incomplete view of the flexibility and variability in human dietary behavior and health in the past and present.” We would like to comment on several statements of Drs. Turner and Thompson as follows: 1. Despite the “incomplete view,” all interventions with a Paleolithic-type diet have shown favorable effects, as also noted by the authors, and were even superior to Mediterranean and diabetic diets with regard to cardiovascular disease risk factors, glucose tolerance, and appetite and body weight regulation.2–6 2. A basic misunderstanding may come from the following sentence: “Fetal imprinting and other epigenetic processes during development underscore the importance of the fetal environment in shaping long-term body composition and metabolic health …

Background Adults born preterm with very low birth weight (VLBW

Objective. We evaluated the thyroid function in women with a history of preeclampsia and/or HELLP syndrome at least 2 years after delivery. Design. Observational retrospective study. Setting. University Medical Center Groningen, The Netherlands. Population. Women with a history of preeclampsia and/or HELLP syndrome (n = 310) or uncomplicated pregnancies (n = 363), between January 1990 and February 2003. Methods. Measurement of serum thyroid stimulating hormone (TSH) levels and antibodies to thyroid peroxidase and the use of a questionnaire about relevant history and family history of auto-immune diseases related to thyroid disease. Main outcome measures. Prevalence of primary thyroid dysfunction and antibodies to thyroid peroxidase. Results. Mean serum TSH values were not significantly different between the preeclampsia and control group (1.62 vs. 1.80 mU/l). The percentage of women who have (have had) hypothyroidism and hyperthyroidism, respectively, did not differ significantly between the preeclampsia and the control group (3.3 vs. 6.1% and 10.0 vs. 7.7%). Furthermore the prevalence of antibodies to thyroid peroxidase was not significantly different (6.1 vs. 7.7%). Conclusion. Preeclampsia and/or HELLP syndrome are not associated with an increased risk of thyroid dysfunction in later life.