Cardiovascular and respiratory effects of air pollution : application of different observational study designs and analysis approaches

The effect of air pollution exposure on human health has been a topic of an increasing volume of research over the past half century. Due to the ubiquitous nature of ambient air pollution exposure and the comparatively weak effects that can be expected, one of the most viable and most utilized avenues of research has been to conduct large scale observational studies. This thesis presents four such studies covering several health outcomes in a variety of populations using a number of different observational study designs and analysis methods. The overarching aim of the thesis was to elucidate challenges that come with observational research on health effects of air pollution and to assess how the studies and their designs address those challenges. In addition, the individual works were described, interpreted, and assessed on the basis of how they met their respective objectives. BAMSE is an ongoing birth cohort in Stockholm of over 4,000 children who were recruited between 1994 and 1996 and are followed with respect to their respiratory health and development of allergies, as well as their environmental exposures. An association was seen between exposure to traffic generated air pollution during their first year of life and early onset persistent wheezing during their first four years of life, as well as lung function (measured by peak expiratory flow) and allergic sensitization at age 4. HEAPSS was a European five-center register-based study of more than 25,000 first-time acute myocardial infarction (MI) survivors who were followed with respect to re-infarction and mortality, linking the health events to the daily air pollution levels. Daily all-cause mortality among the MI survivors was linked to increased levels of both ultrafine and larger particles during the days preceding the deaths. ALVA was a study of 211 patients in Stockholm and Gothenburg with implantable cardioverter defibrillators, devices implanted in the chest of the patients and designed to recognize and treat ventricular arrhythmias. Since the devices record the exact time when they have treated an arrhythmia it was possible to very precisely determine the time of an event and link it to the air pollution levels immediately before that time. An association was indicated between particulate air pollution levels in the two hours immediately preceding the event and the onset of ventricular arrhythmia. The Swedish Onset study comprised 660 first-time MI survivors in Stockholm and was designed to identify triggers for the onset of MI through very detailed interviews conducted shortly after the event about the time leading up to the MI. This allowed for very accurate determination of the exact time of the events and that information could be linked to the air pollution levels preceding that time. We did not observe any association between air pollution exposure and the onset of first-time non-fatal MI. Major challenges included study design, exposure and outcome assessment, potential confounding and selection bias, as well as study power and analytical strategies. All four studies used state-of-the-art designs and were conducted with great care for data quality and effort was made to rule out that the observed results were due to misrepresentation of exposures or outcomes, uncontrolled confounding, selection bias, or other unintended effects. All four studies had sample sizes that were comparatively small, which yielded rather imprecise estimates of the weak air pollution effects, and each study have some results that cannot easily be explained. In summary, all four studies met their respective objectives to assess how air pollution exposure affect the respective health outcomes and were designed, conducted, analyzed, presented, and interpreted in a manner that allow them to effectively contribute to the collective scientific evidence of health effects of air pollution

Association of faecal elastase 1 with non-fasting triglycerides in type 2 diabetes.

AIMS: Intestinal absorption of esterified fatty acids depends on exocrine pancreatic function and influences plasma triglycerides levels. The aim was to investigate the association of reduced exocrine pancreatic function (low fecal elastase-1; FE1) with plasma triglycerides in type 2 diabetes and controls without diabetes. METHODS: FE1 (μg/g stool) and non-fasting plasma triglyceride measurements were undertaken in 544 type 2 diabetes patients (age: 63 ± 8 years) randomly selected from diabetes registers in Cambridgeshire (UK), and 544 matched controls (age, sex, practice) without diabetes. Linear regression models were fitted using FE1 as dependent and log-triglycerides as independent variable adjusting for sex, age, body mass index, alcohol consumption, serum lipase, HbA1c, and smoking. RESULTS: FE1 concentrations were lower (mean ± SD: 337 ± 204 vs. 437 ± 216 μg/g, p < 0.05) and plasma triglycerides were higher (geometric mean */: standard deviation factor: 2.2*/:1.9 vs. 1.6*/:1.8 mmol/l, p < 0.05) in type 2 diabetes compared to controls, respectively. Within the category of type 2 diabetes and controls separately, a 10% increase in plasma triglycerides was associated with 4.5 μg/g higher FE1 concentrations (p < 0.01) after adjusting for confounders. In contrast, in diabetes patients and controls with pathological FE1 (<100 μg/g), low FE1 levels were associated with high plasma triglycerides (significant only in controls). CONCLUSIONS: Non-fasting triglycerides were positively related to FE1 in both type 2 diabetes and controls suggesting that impairment of exocrine pancreas function is influencing plasma triglycerides. Marked loss of exocrine pancreatic function had the opposite effect, resulting in higher levels of plasma triglycerides.The analysis of the Cambridgeshire study was supported by an unrestricted grant from AstraZeneca, Sweden.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.pan.2016.03.01

Comparison of different methods in analyzing short-term air pollution effects in a cohort study of susceptible individuals

BACKGROUND: Short-term fluctuations of ambient air pollution have been associated with exacerbation of cardiovascular disease. A multi-city study was designed to assess the probability of recurrent hospitalization in a cohort of incident myocardial infarction survivors in five European cities. The objective of this paper is to discuss the methods for analyzing short-term health effects in a cohort study based on a case-series. METHODS: Three methods were considered for the analyses of the cohort data: Poisson regression approach, case-crossover analyses and extended Cox regression analyses. The major challenge of these analyses is to appropriately consider changes within the cohort over time due to changes in the underlying risk following a myocardial infarction, slow time trends in risk factors within the population, dynamic cohort size and seasonal variation. RESULTS: Poisson regression analyses, case-crossover analyses and Extended Cox regression analyses gave similar results. Application of smoothing methods showed the capability to adequately model the complex time trends. CONCLUSION: From a practical point of view, Poisson regression analyses are less time-consuming, and therefore might be used for confounder selection and most of the analyses. However, replication of the results with Cox models is desirable to assure that the results are independent of the analytical approach used. In addition, extended Cox regression analyses would allow a joint estimation of long-term and short-term health effects of time-varying exposures

Interactions between Glutathione S-Transferase P1, Tumor Necrosis Factor, and Traffic-Related Air Pollution for Development of Childhood Allergic Disease

BACKGROUND: Air pollutants may induce airway inflammation and sensitization due to generation of reactive oxygen species. The genetic background to these mechanisms could be important effect modifiers. OBJECTIVE: Our goal was to assess interactions between exposure to air pollution and single nucleotide polymorphisms (SNPs) in the beta2-adrenergic receptor (ADRB2), glutathione S-transferase P1 (GSTP1), and tumor necrosis factor (TNF) genes for development of childhood allergic disease. METHODS: In a birth cohort originally of 4,089 children, we assessed air pollution from local traffic using nitrogen oxides (traffic NO(x)) as an indicator based on emission databases and dispersion modeling and estimated individual exposure through geocoding of home addresses. We measured peak expiratory flow rates and specific IgE for inhalant and food allergens at 4 years of age, and selected children with asthma symptoms up to 4 years of age (n = 542) and controls (n = 542) for genotyping. RESULTS: Interaction effects on allergic sensitization were indicated between several GSTP1 SNPs and traffic NO(x) exposure during the first year of life (p(nominal) &lt; 0.001-0.06). Children with Ile105Val/Val105Val genotypes were at increased risk of sensitization to any allergen when exposed to elevated levels of traffic NO(x) (for a difference between the 5th and 95th percentile of exposure: odds ratio = 2.4; 95% confidence interval, 1.0-5.3). In children with TNF-308 GA/AA genotypes, the GSTP1-NO(x) interaction effect was even more pronounced. We observed no conclusive interaction effects for ADRB2. CONCLUSION: The effect of air pollution from traffic on childhood allergy appears to be modified by GSTP1 and TNF variants, supporting a role of genes controlling the antioxidative system and inflammatory response in allergy

Air Pollution Exposure—A Trigger for Myocardial Infarction?

The association between ambient air pollution exposure and hospitalization for cardiovascular events has been reported in several studies with conflicting results. A case-crossover design was used to investigate the effects of air pollution in 660 first-time myocardial infarction cases in Stockholm in 1993–1994, interviewed shortly after diagnosis using a standard protocol. Air pollution data came from central urban background monitors. No associations were observed between the risk for onset of myocardial infarction and two-hour or 24-hour air pollution exposure. No evidence of susceptible subgroups was found. This study provides no support that moderately elevated air pollution levels trigger first-time myocardial infarction

Air Pollution and Inflammation (Interleukin-6, C-Reactive Protein, Fibrinogen) in Myocardial Infarction Survivors

BACKGROUND: Numerous studies have found that ambient air pollution has been associated with cardiovascular disease exacerbation. OBJECTIVES: Given previous findings, we hypothesized that particulate air pollution might induce systemic inflammation in myocardial infarction (MI) survivors, contributing to an increased vulnerability to elevated concentrations of ambient particles. METHODS: A prospective longitudinal study of 1,003 MI survivors was performed in six European cities between May 2003 and July 2004. We compared repeated measurements of interleukin 6 (IL-6), fibrinogen, and C-reactive protein (CRP) with concurrent levels of air pollution. We collected hourly data on particle number concentrations (PNC), mass concentrations of particulate matter (PM) &lt; 10 microm (PM(10)) and &lt; 2.5 microm (PM(2.5)), gaseous pollutants, and meteorologic data at central monitoring sites in each city. City-specific confounder models were built for each blood marker separately, adjusting for meteorology and time-varying and time-invariant covariates. Data were analyzed with mixed-effects models. RESULTS: Pooled results show an increase in IL-6 when concentrations of PNC were elevated 12-17 hr before blood withdrawal [percent change of geometric mean, 2.7; 95% confidence interval (CI), 1.0-4.6]. Five day cumulative exposure to PM(10) was associated with increased fibrinogen concentrations (percent change of arithmetic mean, 0.6; 95% CI, 0.1-1.1). Results remained stable for smokers, diabetics, and patients with heart failure. No consistent associations were found for CRP. CONCLUSIONS: Results indicate an immediate response to PNC on the IL-6 level, possibly leading to the production of acute-phase proteins, as seen in increased fibrinogen levels. This might provide a link between air pollution and adverse cardiac events

The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naïve patients with type 2 diabetes mellitus: a randomized controlled trial

Abstract Background The aim of this study was to assess efficacy and safety of saxagliptin monotherapy for up to 76 weeks in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control, with main efficacy assessment at 24 weeks. Methods 365 treatment-naïve patients with T2DM (HbA1c 7.0%–10.0%) were treated with saxagliptin 2.5 mg q.A.M., saxagliptin 2.5 mg q.A.M. with possible titration to saxagliptin 5 mg, saxagliptin 5 mg q.A.M., saxagliptin 5 mg q.P.M., or placebo. After week 24, patients in all groups were eligible for titration to saxagliptin 10 mg based on HbA1c ≥7%, and all unrescued placebo patients began blinded metformin 500 mg/day. Rescue with open-label metformin was available for patients with inadequate glycemic control. Results At week 24, placebo-subtracted mean HbA1c reduction from baseline (LOCF) was significantly greater in the saxagliptin treatment groups vs placebo, and remained greater through week 76. Serious adverse events (AEs) and discontinuations due to AEs were similar in saxagliptin and control groups; incidence of confirmed hypoglycemia was low across all treatment groups (saxagliptin-treated, 2 [0.7]; control, 1 [1.4]). Conclusions In treatment-naïve patients with T2DM, saxagliptin monotherapy demonstrated statistically significant improvement in HbA1c compared with placebo at 24 weeks and was generally well tolerated for up to 76 weeks. Trial registration ClinicalTrials.gov Identifier: NCT00316082</p

Daily intake of magnesium and calcium from drinking water in relation to myocardial infarction

Background: A decreased risk for cardiovascular disease has been related to the hardness of drinking water, particularly high levels of magnesium. However, the evidence is still uncertain, especially in relation to individual intake from water. Methods: We used data from the Stockholm Heart Epidemiology Program, a population-based case-control study conducted during 1992-1994, to study the association between myocardial infarction and the daily intake of drinking water magnesium and calcium. Our analyses are based on 497 cases age 45-70 years, and 677 controls matched on age, sex, and hospital catchment area. Individual data on magnesium, calcium, and hardness of the domestic drinking water were assessed from waterwork registers or analyses of well water. Results: After adjustment for the matching variables and smoking, hypertension, socioeconomic status, job strain, body mass index, diabetes, and physical inactivity, the odds ratio for myocardial infarction was 1.09 (95% confidence interval ϭ 0.81-1.46) associated with a tap water hardness above the median (Ͼ4.4 German hardness degrees) and 0.88 (0.67-1.15) associated with a water magnesium intake above the median (Ͼ1.86 mg/d). There was no apparent sign of any exposure-response pattern related to water intake of magnesium or calcium. Conclusions: This study does not support previous reports of a protective effect on myocardial infarction associated with consumption of drinking water with higher levels of hardness, magnesium, or calcium