Tim S. Nawrot

Cadmium stress: an oxidative challenge

At the cellular level, cadmium (Cd) induces both damaging and repair processes in which the cellular redox status plays a crucial role. Being not redox-active, Cd is unable to generate reactive oxygen species (ROS) directly, but Cd-induced oxidative stress is a common phenomenon observed in multiple studies. The current review gives an overview on Cd-induced ROS production and anti-oxidative defense in organisms under different Cd regimes. Moreover, the Cd-induced oxidative challenge is discussed with a focus on damage and signaling as downstream responses. Gathering these data, it was clear that oxidative stress related responses are affected during Cd stress, but the apparent discrepancies observed in between the different studies points towards the necessity to increase our knowledge on the spatial and temporal ROS signature under Cd stress. This information is essential in order to reveal the exact role of Cd-induced oxidative stress in the modulation of downstream responses under a diverse array of conditions.

Prevalence, Persistence, and Clinical Significance of Masked Hypertension in Youth

Masked hypertension, an elevated daytime ambulatory blood pressure in the presence of a normal office blood pressure, confers an increased cardiovascular risk to adults. We investigated the prevalence, persistence, and clinical significance of masked hypertension in children and adolescents. We enrolled 592 youths (6 to 18 years old). Youths with masked hypertension (n=34) and a random sample of the normotensive participants (n=200) were followed-up. In a nested case-control study, we compared echocardiographic left ventricular mass among cases with persistent masked hypertension and normotensive controls. At baseline, mean age was 10.2 years; 535 youths were normotensive on office and daytime ambulatory blood pressure measurement (90.4%), and 45 had masked hypertension (7.6%). Compared with normotensive controls, participants with masked hypertension had a higher ambulatory pulse rate, were more obese, and were 2.5-times more likely to have a parental history of hypertension. Among 34 patients with masked hypertension (median follow-up 37 months), 18 became normotensive, 13 had persistent masked hypertension, and 3 had sustained hypertension. Patients with persistent masked hypertension (n=17) or who progressed from masked to sustained hypertension (n=3) had a higher left ventricular mass index (34.9 versus 29.6 g/m2.7; P=0.023) and a higher percentage with left ventricular mass index above the 95th percentile (30% versus 0%; P=0.014) than normotensive controls. In children and adolescents, masked hypertension is a precursor of sustained hypertension and left ventricular hypertrophy. This condition warrants follow-up and, once it becomes persistent, is an indication for blood pressure-lowering treatment.

Public health importance of triggers of myocardial infarction: a comparative risk assessment

BACKGROUND Acute myocardial infarction is triggered by various factors, such as physical exertion, stressful events, heavy meals, or increases in air pollution. However, the importance and relevance of each trigger are uncertain. We compared triggers of myocardial infarction at an individual and population level. METHODS We searched PubMed and the Web of Science citation databases to identify studies of triggers of non-fatal myocardial infarction to calculate population attributable fractions (PAF). When feasible, we did a meta-regression analysis for studies of the same trigger. FINDINGS Of the epidemiologic studies reviewed, 36 provided sufficient details to be considered. In the studied populations, the exposure prevalence for triggers in the relevant control time window ranged from 0.04% for cocaine use to 100% for air pollution. The reported odds ratios (OR) ranged from 1.05 to 23.7. Ranking triggers from the highest to the lowest OR resulted in the following order: use of cocaine, heavy meal, smoking of marijuana, negative emotions, physical exertion, positive emotions, anger, sexual activity, traffic exposure, respiratory infections, coffee consumption, air pollution (based on a difference of 30 μg/m3 in particulate matter with a diameter <10 μm [PM10]). Taking into account the OR and the prevalences of exposure, the highest PAF was estimated for traffic exposure (7.4%), followed by physical exertion (6.2%), alcohol (5.0%), coffee (5.0%), a difference of 30 μg/m3 in PM10 (4.8%), negative emotions (3.9%), anger (3.1%), heavy meal (2.7%), positive emotions (2.4%), sexual activity (2.2%), cocaine use (0.9%), marijuana smoking (0.8%) and respiratory infections (0.6%). Interpretation In view of both the magnitude of the risk and the prevalence in the population, air pollution is an important trigger of myocardial infarction, it is of similar magnitude (PAF 5-7%) as other well accepted triggers such as physical exertion, alcohol, and coffee. Our work shows that ever-present small risks might have considerable public health relevance. FUNDING The research on air pollution and health at Hasselt University is supported by a grant from the Flemish Scientific Fund (FWO, Krediet aan navorsers/G.0873.11), tUL-impulse financing, and bijzonder onderzoeksfonds (BOF) and at the Katholieke Universiteit Leuven by the sustainable development programme of BELSPO (Belgian Science Policy).

Ambulatory Arterial Stiffness Index Derived From 24-Hour Ambulatory Blood Pressure Monitoring

We hypothesized that 1 minus the slope of diastolic on systolic pressure during 24-hour ambulatory monitoring (ambulatory arterial stiffness index [AASI]) might reflect arterial stiffness. We compared AASI with established measures of arterial stiffness and studied its distribution in Chinese and European populations. We used 90207 SpaceLabs monitors and the SphygmoCor device to measure AASI, central and peripheral pulse pressures, the central (CAIx) and peripheral (PAIx) systolic augmentation indexes, and aortic pulse wave velocity. In 166 volunteers, the correlation coefficient between AASI and pulse wave velocity was 0.51 (P<0.0001). In 348 randomly recruited Chinese subjects, AASI correlated (P<0.0001) with CAIx (r=0.48), PAIx (r=0.50), and central pulse pressure (r=0.50). AASI increased with age and mean arterial pressure but decreased with body height. Both before and after adjustment for arterial wave reflections by considering height and heart rate as covariates, AASI correlated more (P<0.0001) closely with CAIx and PAIx than 24-hour pulse pressure. Among normotensive subjects, the 95th percentile of AASI was 0.55 in Chinese and 0.57 in 1617 Europeans enrolled in the International Database on Ambulatory Blood Pressure Monitoring. The upper boundary of the 95% prediction interval of AASI in relation to age ranged from 0.53 at 20 years to 0.72 at 80 years. In conclusion, AASI is a new index of arterial stiffness that can be easily measured under ambulatory conditions. Pending additional validation in outcome studies, normal values of AASI are probably <0.50 and 0.70 in young and older subjects, respectively.

Telomere length and possible link to X chromosome

BACKGROUND Because telomeres are eroded during mitosis, telomere length indicates the replicative history of human somatic cells. Clinical markers of ageing--such as pulse pressure and survival--are associated with telomere length. On the basis of findings of studies in twins, telomere length seems to be familial, but little is known about its mode of inheritance. We aimed to investigate the inheritance of telomere length. METHODS We measured terminal restriction fragment (TRF) length in white-blood-cell DNA taken from individuals from the family-based cohort of the Flemish Study on Environment, Genes, and Health Outcomes. FINDINGS We recorded no correlation in sex and age adjusted TRF length between spouses (r=-0.05; p=0.70) nor between fathers and sons (r=-0.16; p=0.35). By contrast, we noted robust correlations in TRF length between fathers and daughters (r=0.60; p<0.0001); between mothers and sons (r=0.41; p=0.0017) and daughters (r=0.59; p<0.0001); and among siblings (r> or =0.61; p< or =0.0004). INTERPRETATION X-linked inheritance of TRF length is the most probable explanation for our findings. Pending confirmation, our observations suggest that the process of ageing might be an X-linked trait.

Carotid Intima-Media Thickness and Antihypertensive Treatment A Meta-Analysis of Randomized Controlled Trials

Background and Purpose— Hypertension promotes carotid intima-media thickening. We reviewed the randomized controlled trials that evaluated the effects of an antihypertensive drug versus placebo or another antihypertensive agent of a different class on carotid intima-media thickness. Methods— We searched the PubMed and the Web of Science databases for randomized clinical trials, published in English before 2005, and included 22 trials. Results— In 8 trials including 3329 patients with diabetes or coronary heart disease, antihypertensive treatment initiated with an angiotensin-converting enzyme (ACE) inhibitor, a &bgr;-blocker, or a calcium-channel blocker (CCB), compared with placebo or no-treatment, reduced the rate of intima-media thickening by 7 &mgr;m/year (P=0.01). In 9 trials including 4564 hypertensive patients, CCBs, ACE inhibitors, an angiotensin II receptor blocker or an &agr;-blocker, compared with diuretics or &bgr;-blockers, in the presence of similar blood pressure reductions, decreased intima-media thickening by 3 &mgr;m/year (P=0.03). The overall beneficial effect of the newer over older drugs was largely attributable to the decrease of intima-media thickening by 5 &mgr;m/year (P=0.007) in 4 trials of CCBs involving 3619 patients. In 5 trials including 287 patients with hypertension or diabetes, CCBs compared with ACE inhibitors did not differentially affect blood pressure, but attenuated intima-media thickening by 23 &mgr;m/year (P=0.02). The treatment induced changes in carotid intima-media thickness correlated with the changes in lumen diameter (P=0.02), but not with the differences in achieved blood pressure (P>0.53). Conclusions— CCBs reduce carotid intima-media thickening. This mechanism might contribute to their superior protection against stroke.

Obesity is associated with increased arterial stiffness from adolescence until old age.

Objective To our knowledge, only two previous studies have investigated the age dependence of the relationship between the characteristics of large arteries and excessive body weight. We therefore investigated whether the relationship between arterial stiffness and body mass index (BMI) was consistent across an age range from 10 to 86 years. Methods Using a cross-sectional population-based design, we randomly recruited 1306 individuals (median age 43.9 years; 50.5% women). Using a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries and carotid–femoral pulse wave velocity. We analysed men and women separately while adjusting for significant covariates, including age, mean arterial pressure, heart rate, current smoking, alcohol intake and use of antihypertensive drugs. Results Before and after adjustment, arterial diameter increased with BMI in all territories, with an opposite trend for arterial distensibility. In men and women, the relationships of brachial and femoral properties with BMI were consistent across the whole age range. In men and women, carotid distensibility decreased more with BMI at young than old age. In middle-aged and older women, but not in men of any age, pulse wave velocity increased with higher BMI. Conclusions Across a wide age range, the diameter and stiffness of muscular arteries increased with higher BMI. In elastic arteries, the relationship between arterial stiffness and BMI was more complex and varied with sex and age. The mechanisms underlying the influence of adiposity on the properties of muscular and elastic arteries and the reversibility of these associations by weight reduction at young age need further clarification.

Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers

BACKGROUND Human exposure to chemicals is normally monitored by measurement of environmental pollutants in external media. We investigated whether biomarkers in adolescents can show exposure to, and health effects of, common environmental pollutants. METHODS We recruited 200 17-year-old adolescents (120 girls) from a rural control area and from two suburbs polluted by a lead smelter and two waste incinerators. We measured biomarkers of exposure and of effect in blood and urine samples, and obtained questionnaire data. School doctors measured testicular volume and staged sexual maturation. FINDINGS Internal exposure was mostly within current standards. Concentrations of lead and cadmium in blood, PCBs (polychlorinated biphenyls) and dioxin-like compounds in serum samples, and metabolites of VOCs (volatile organic compounds) in urine were higher in one or both suburbs than in the control area. Children who lived near the waste incinerators matured sexually at an older age than others, and testicular volume was smaller in boys from the suburbs than in controls. Biomarkers of glomerular or tubular renal dysfunction in individuals were positively correlated with blood lead. Biomarkers of DNA damage were positively correlated with urinary metabolites of PAHs (polycyclic aromatic hydrocarbons) and VOCs. Interpretation Biomarkers can be used to detect environmental exposure to pollutants and measure their biological effects before overt disease develops. Our findings suggest that current environmental standards are insufficient to avoid measurable biological effects.

C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension.

OBJECTIVES Our aim was to investigate in a prospective study a potential role of C-reactive protein (CRP) in predicting the outcome in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND CRP is a well-known marker of inflammation and tissue damage, widely recognized as a risk predictor of cardiovascular and coronary heart diseases. METHODS Plasma levels of CRP have been measured in consecutive patients diagnosed with PAH and CTEPH, at the time of right heart catheterization. RESULTS Circulating CRP levels were increased in CTEPH and PAH patients compared with those in control subjects (4.9 mg l(-1), 95% confidence interval [CI]: 3.9 to 6.2 mg l(-1); 4.4 mg l(-1), 95% CI: 3.5 to 5.4 mg l(-1); and 2.3 mg l(-1), 95% CI: 1.9 to 2.7 mg l(-1), respectively; p < 0.0001). In PAH patients, CRP levels correlated with New York Heart Association functional class (r = 0.23), right atrial pressure (r = 0.25), and 6-min walking distance (r = -0.19) and were significantly higher in nonsurvivors than in survivors (p = 0.003). All PAH, idiopathic PAH, and patients naive for disease-specific medication with CRP levels >5.0 mg l(-1) had a significantly lower survival rate (p = 0.02, p = 0.009, and p < 0.05, respectively). In CTEPH patients, circulating CRP levels significantly decreased 12 months after pulmonary endarterectomy (n = 23, 4.0 mg l(-1), 95% CI: 2.8 to 5.8 mg l(-1), to 1.6 mg l(-1), 95% CI: 2.2 to 3.0 mg l(-1); p = 0.004). PAH patients normalizing their CRP levels under treatment (n = 29), assigned as responders, had a significantly higher survival rate (p < 0.05). The proportion of patients treated with a parenteral prostacyclin-analogue was significantly higher among the responders than the nonresponders (55% vs. 17%, p = 0.002). CONCLUSIONS This is the first evidence of a role of an inflammatory marker, such as CRP, in predicting outcome and response to therapy in PAH.

A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV1) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005–2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV1, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV1 with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092–0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV1 (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV1 in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV1 and reduces BOS 2 yrs after LTx.