Identification of predictive factors of diabetic ketoacidosis in type 1 diabetes using a subgroup discovery algorithm.

AIM: To identify predictive factors for diabetic ketoacidosis (DKA) by retrospective analysis of registry data and the use of a subgroup discovery algorithm. MATERIALS AND METHODS: Data from adults and children with type 1 diabetes and more than two diabetes-related visits were analysed from the Diabetes Prospective Follow-up Registry. Q-Finder, a supervised non-parametric proprietary subgroup discovery algorithm, was used to identify subgroups with clinical characteristics associated with increased DKA risk. DKA was defined as pH less than 7.3 during a hospitalization event. RESULTS: Data for 108 223 adults and children, of whom 5609 (5.2%) had DKA, were studied. Q-Finder analysis identified 11 profiles associated with an increased risk of DKA: low body mass index standard deviation score; DKA at diagnosis; age 6-10 years; age 11-15 years; an HbA1c of 8.87% or higher (≥ 73 mmol/mol); no fast-acting insulin intake; age younger than 15 years and not using a continuous glucose monitoring system; physician diagnosis of nephrotic kidney disease; severe hypoglycaemia; hypoglycaemic coma; and autoimmune thyroiditis. Risk of DKA increased with the number of risk profiles matching patients' characteristics. CONCLUSIONS: Q-Finder confirmed common risk profiles identified by conventional statistical methods and allowed the generation of new profiles that may help predict patients with type 1 diabetes who are at a greater risk of experiencing DKA.

Demographic characteristics and acute complications among adults with type 1 diabetes: Comparison of two multicentre databases from Germany and the United States.

BACKGROUND: Studies on acute complications in adult T1D were previously reported from the United States (U.S.) and from Germany. The aim was to compare demographic characteristics and patterns of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) between Germany and the U.S. METHODS: Descriptive comparison on individuals aged ≥18 years, with T1D duration ≥2 years were made between the German diabetes-patient registry (DPV) and the U.S. electronic-health-record database (T1PCO). Individuals in both databases were divided into patients with haemoglobin A1c (HbA1c) <7% and HbA1c ≥7%. RESULTS: 5190 (DPV) and 31,430 individuals (T1PCO) fulfilled the inclusion criteria. DPV patients were younger, more often male and had lower body-mass index. In both databases, more males than females had HbA1c <7%. Individuals had higher HbA1c in T1PCO compared to DPV. The relationship between HbA1c and DKA was similar in both databases. SH revealed a U-shaped curve in T1PCO, but no clear pattern was present in DPV. SH events increased with higher age in DPV, but not in T1PCO. CONCLUSION: Patterns of SH differ between Germany and U.S. Differences in capture of SH among the databases cannot be excluded, but differences in health care including patient education and level of care by specialists are likely.

Changes in deceleration capacity of heart rate and heart rate variability induced by ambient air pollution in individuals with coronary artery disease.

BACKGROUND AND OBJECTIVE: Exposure to ambient particles has been shown to be responsible for cardiovascular effects, especially in elderly with cardiovascular disease. The study assessed the association between deceleration capacity (DC) as well as heart rate variability (HRV) and ambient particulate matter (PM) in patients with coronary artery disease (CAD). METHODS: A prospective study with up to 12 repeated measurements was conducted in Erfurt, Germany, between October 2000 and April 2001 in 56 patients with physician-diagnosed ischemic heart disease, stable angina pectoris or prior myocardial infarction at an age of at least 50 years. Twenty-minute ECG recordings were obtained every two weeks and 24-hour ECG recordings every four weeks. Exposure to PM (size range from 10 nm to 2.5 µm), and elemental (EC) and organic (OC) carbon was measured. Additive mixed models were used to analyze the association between PM and ECG recordings. RESULTS: The short-term recordings showed decrements in the high-frequency component of HRV as well as in RMSSD (root-mean-square of successive differences of NN intervals) in association with increments in EC and OC 0-23 hours prior to the recordings. The long-term recordings revealed decreased RMSSD and pNN50 (% of adjacent NN intervals that differed more than 50 ms) in association with EC and OC 24-47 hours prior to the recordings. In addition, highly significant effects were found for DC which decreased in association with PM2.5, EC and OC concurrent with the ECG recordings as well as with a lag of up to 47 hours. CONCLUSIONS: The analysis showed significant effects of ambient particulate air pollution on DC and HRV parameters reflecting parasympathetic modulation of the heart in patients with CAD. An air pollution-related decrease in parasympathetic tone as well as impaired heart rate deceleration capacity may contribute to an increased risk for cardiac morbidity and sudden cardiac death in vulnerable populations.

Associations between PM2.5 and heart rate variability are modified by particle composition and beta-blocker use in patients with coronary heart disease.

BACKGROUND: It has been hypothesized that ambient particulate air pollution is able to modify the autonomic nervous control of the heart, measured as heart rate variability (HRV). Previously we reported heterogeneous associations between particulate matter with aerodynamic diameter < 2.5 microm (PM2.5) and HRV across three study centers. OBJECTIVES: We evaluated whether exposure misclassification, effect modification by medication, or differences in particle composition could explain the inconsistencies. METHODS: Subjects with coronary heart disease visited clinics biweekly in Amsterdam, the Netherlands; Erfurt, Germany; and Helsinki, Finland for 6-8 months. The standard deviation (SD) of NN intervals on an electrocardiogram (ECG; SDNN) and high frequency (HF) power of HRV was measured with ambulatory ECG during paced breathing. Outdoor levels of PM2.5 were measured at a central site. In Amsterdam and Helsinki, indoor and personal PM2.5 were measured during the 24 hr preceding the clinic visit. PM2.5 was apportioned between sources using principal component analyses. We analyzed associations of indoor/personal PM2.5, elements of PM2.5, and source-specific PM2.5 with HRV using linear regression. RESULTS: Indoor and personal PM2.5 were not associated with HRV. Increased outdoor PM2.5 was associated with decreased SDNN and HF at lags of 2 and 3 days only among persons not using beta-blocker medication. Traffic-related PM2.5 was associated with decreased SDNN, and long-range transported PM2.5 with decreased SDNN and HF, most strongly among persons not using beta blockers. Indicators for PM2.5 from traffic and long-range transport were also associated with decreased HRV. CONCLUSIONS: Our results suggest that differences in the composition of particles, beta-blocker use, and obesity of study subjects may explain some inconsistencies among previous studies on HRV.

Air pollution and inflammatory response in myocardial infarction survivors: gene-environment interactions in a high-risk group.

Ambient air pollution has been associated with an increased risk of hospital admission and mortality in potentially susceptible subpopulations, including myocardial infarction (MI) survivors. The multicenter epidemiological study described in this report was set up to study the role of air pollution in eliciting inflammation in MI survivors in six European cities, Helsinki, Stockholm, Augsburg, Rome, Barcelona, and Athens. Outcomes of interest are plasma concentrations of the proinflammatory cytokine interleukin 6 (IL-6) and the acute-phase proteins C-reactive protein (CRP) and fibrinogen. In addition, the study was designed to assess the role of candidate gene polymorphisms hypothesized to lead to a modification of the short-term effects of ambient air pollution. In total, 1003 MI survivors were recruited and assessed with at least 2 repeated clinic visits without any signs of infections. In total, 5813 blood samples were collected, equivalent to an average of 5.8 repeated clinic visits per subject (97% of the scheduled 6 repeated visits). Subjects across the six cities varied with respect to risk factor profiles. Most of the subjects were nonsmokers, but light smokers were included in Rome, Barcelona, and Athens. Substantial inter- and intraindividual variability was observed for IL-6 and CRP. The study will permit assessing the role of cardiovascular disease risk factors, including ambient air pollution and genetic polymorphisms in candidate genes, in determining the inter- and the intraindividual variability in plasma IL-6, CRP, and fibrinogen concentrations in MI survivors.

Runs of ventricular and supraventricular tachycardia triggered by air pollution in patients with coronary heart disease.

OBJECTIVE: The authors conducted an investigation of the association between air pollution and arrhythmia. METHODS: A prospective panel study (October 2000-April 2001) was conducted in Erfurt, Germany. Fifty-seven men with coronary heart disease were subjected to six 24-hour electrocardiogram recordings. Runs of supraventricular and ventricular tachycardia were associated with continuous ultrafine particle counts (UFP), accumulation mode particle counts (ACP), PM2.5, and gaseous pollutants. Poisson and linear regression models were applied adjusting for trend, weekday, and meteorologic data. RESULTS: Elevated concentrations of UFP, ACP, PM2.5, and nitrogen dioxide increased the risk for supraventricular runs and the number of ventricular runs at almost all lags. Statistically significant associations were found predominantly in the previous 24 to 71 hours and with the 5-day moving average. CONCLUSION: Elevated concentrations of fine and ultrafine particle increased the risk of arrhythmia in men with coronary heart disease.

Particulate air pollution and risk of ST-segment depression during repeated submaximal exercise tests among subjects with coronary heart disease: the Exposure and Risk Assessment for Fine and Ultrafine Particles in Ambient Air (ULTRA) study.

BACKGROUND: Daily variations in ambient particulate air pollution have been associated with cardiovascular mortality and morbidity. We therefore assessed the associations between levels of the 3 main modes of urban aerosol distribution and the occurrence of ST-segment depressions during repeated exercise tests. METHODS AND RESULTS: Repeated biweekly submaximal exercise tests were performed during 6 months among adult subjects with stable coronary heart disease in Helsinki, Finland. Seventy-two exercise-induced ST-segment depressions >0.1 mV occurred during 342 exercise tests among 45 subjects. Simultaneously, particle mass <2.5 microm (PM2.5) and the number concentrations of ultrafine particles (particle diameter 10 to 100 nm [NC(0.01-0.1)]) and accumulation mode particles (100 to 1000 nm [NC(0.1-1)]) were monitored at a central site. Levels of particulate air pollution 2 days before the clinic visit were significantly associated with increased risk of ST-segment depression during exercise test. The association was most consistent for measures of particles reflecting accumulation mode particles (odds ratio 3.29; 95% CI, 1.57 to 6.92 for NC(0.1-1) and 2.84; 95% CI, 1.42 to 5.66 for PM2.5), but ultrafine particles also had an effect (odds ratio 3.14; 95% CI, 1.56 to 6.32), which was independent of PM2.5. Also, gaseous pollutants NO2 and CO were associated with an increased risk for ST-segment depressions. No consistent association was observed for coarse particles. The associations tended to be stronger among subjects who did not use beta-blockers. CONCLUSIONS: The present results suggest that the effect of particulate air pollution on cardiovascular morbidity is at least partly mediated through increased susceptibility to myocardial ischemia.

Repolarization changes induced by air pollution in ischemic heart disease patients.

Epidemiologic studies report associations between particulate air pollution and cardiovascular morbidity and mortality, but the underlying pathophysiologic mechanisms are still unclear. We tested the hypothesis that patients with preexisting coronary heart disease experience changes in the repolarization parameters in association with rising concentrations of air pollution. A prospective panel study was conducted in Erfurt, East Germany, with 12 repeated electrocardiogram (ECG) recordings in 56 males with ischemic heart disease. Hourly particulate and gaseous air pollution and meteorologic data were acquired. The following ECG parameters reflecting myocardial substrate and vulnerability were measured: QT duration, T-wave amplitude, T-wave complexity, and variability of T-wave complexity. Fixed effect regression analysis was used adjusting for subject, trend, weekday, and meteorology. The analysis showed a significant increase in QT duration in response to exposure to organic carbon; a significant decrease in T-wave amplitude with exposure to ultrafine, accumulation mode, and PM2.5 particles (particles < 2.5 microm in aerodynamic diameter); and a corresponding significant increase of T-wave complexity in association with PM2.5 particles for the 24 hr before ECG recordings. Variability of T-wave complexity showed a significant increase with organic and elemental carbon in the same time interval. This study provides evidence suggesting an immediate effect of air pollution on repolarization duration, morphology, and variability representing myocardial substrate and vulnerability, key factors in the mechanisms of cardiac death.

Cardiovascular effects of fine and ultrafine particles.

Epidemiological studies of the past decades have provided a strong body of evidence that elevated levels of ambient particulate air pollution (PM) are associated with increased cardiovascular and respiratory morbidity and mortality. Exacerbations of ischemic and/or arrhythmic cardiac diseases have been linked to PM exposure. At a workshop held at the GSF- National Center for Environment and Health in November 2003, relevant epidemiological and toxicological data of the past 5 years were compiled and potential biological pathways discussed. Available clinical and experimental evidence lends support to the following mechanisms mediating cardiovascular effects of inhaled ambient particles: (i) pulmonary and/or systemic inflammatory responses inducing endothelial dysfunction, a pro-coagulatory state and promotion of atherosclerotic lesions, (ii) dysfunction of the autonomic nervous system in response to direct reflexes from receptors in the lungs and/or to local or systemic inflammatory stimuli, and (iii) cardiac malfunction due to ischemic responses in the myocardium and/or altered ion-channel functions in myocardial cells. While an increasing number of studies addressing these questions support the notion that PM exposure is associated with cardiovascular effects, these studies at present provide only a fragmentary and at times inconclusive picture of the complex biological pathways involved. The available data are consistent with the occurrence of a systemic inflammatory response and an alteration of autonomic cardiac control, but evidence on endothelial dysfunction, pro-coagulatory states, and PM-related myocardial malfunction is as yet scarce. Further studies are therefore needed to substantiate our current understanding of the pathophysiological links between PM exposure and adverse cardiovascular outcomes.

Effects of particulate air pollution on blood pressure and heart rate in subjects with cardiovascular disease: a multicenter approach.

Given the hypothesis that air pollution is associated with elevated blood pressure and heart rate, the effect of daily concentrations of air pollution on blood pressure and heart rate was assessed in 131 adults with coronary heart disease in Helsinki, Finland; Erfurt, Germany; and Amsterdam, the Netherlands. Blood pressure was measured by a digital monitor, and heart rate was calculated as beats per minute from an electrocardiogram recording with the patient in supine position. Particle concentrations were measured at central measuring sites. Linear regression was used to model the association between 24-hr mean concentrations of particles and blood pressure and heart rate. Estimates were adjusted for trend, day of week, temperature, barometric pressure, relative humidity, and medication use. Pooled effect estimates showed a small significant decrease in diastolic and systolic blood pressure in association with particulate air pollution; a slight decrease in heart rate was found. Of the three centers, Erfurt revealed the most consistent particle effects. The results do not support findings from previous studies that had shown an increase in blood pressure and heart rate in healthy individuals in association with particles. However, particle effects might differ in cardiac patients because of medication intake and disease status, both affecting the autonomic control of the heart.

Epidemiological evidence on health effects of ultrafine particles.

Evidence from epidemiologic studies linking ambient concentrations of particulate matter to morbidity and mortality influenced the guidelines for air quality standards worldwide. With the improvement of measurement techniques, clearer effects were observed with smaller particle sizes. Based on these effects and results from animal studies on the potential toxicity of ultrafine particles, recent epidemiologic studies focus on the health effects of particles which are less than 100nm in diameter. However, most of the studies are ongoing and only few results have been available so far. Six panel studies with patients suffering from chronic pulmonary diseases have been performed in Germany, Finland and the United Kingdom. Overall, a decrease of peak expiratory flow (PEF) and an increase of daily symptoms and medication use was found for elevated daily particle concentrations. Effects were seen with both fine and ultrafine particles. One large study on daily mortality from Germany showed comparable effects of fine and ultrafine particles in all size classes considered. However, fine particles showed more immediate effects while ultrafine particles showed more delayed effects on mortality. The limited number of epidemiological studies suggest that there are health effects of fine and ultrafine particles which might be independent of each other. If these effects are confirmed by ongoing research, monitoring and regulation of particulate air pollution may need to be revised.

Air pollution and markers of inflammation and coagulation in patients with coronary heart disease.

RATIONALE: Ambient air pollution has been shown to be associated with cardiovascular morbidity and mortality. OBJECTIVES: A prospective panel study was conducted to study the early physiologic reactions characterized by blood biomarkers of inflammation, endothelial dysfunction, and coagulation in response to daily changes in air pollution in Erfurt, Germany. METHODS: Blood parameters were repeatedly measured in 57 male patients with coronary heart disease during the winter of 2000/2001. Fixed-effects linear and logistic regression models were applied, adjusting for trend, weekday, and meteorologic parameters. MEASUREMENTS: Hourly data on ultrafine particles (UFPs; number concentration of particles from 0.01 to 0.1 microm), mass concentration of particles less than 10 (PM(10)) and 2.5 microm in diameter, elemental and organic carbon, gaseous pollutants, and meteorologic data were collected at central monitoring sites. MAIN RESULTS: Increased levels of C-reactive protein above the 90th percentile were observed for an increase in air pollution concentrations of one interquartile range. The effect was strongest for accumulation mode particles, with a delay of 2 d (odds ratio [OR], 3.2; confidence interval [CI], 1.7, 6.0). Results were consistent for UFPs and PM(10), which also showed a 2-d delayed response (OR, 2.3; CI, 1.3, 3.8; and OR, 2.2; CI, 1.2, 3.8, respectively). However, not all of the blood markers of endothelial dysfunction and coagulation increased consistently in association with air pollutants. CONCLUSION: These results suggest that inflammation as well as parts of the coagulation pathway may contribute to the association between particulate air pollution and coronary events.

Effects of ultrafine and fine particulate and gaseous air pollution on cardiac autonomic control in subjects with coronary artery disease: the ULTRA study.

Previous studies have shown an association between elevated concentrations of particulate air pollution and cardiovascular morbidity and mortality. Therefore, the association between daily variation of ultrafine and fine particulate air pollution and cardiac autonomic control measured as heart rate variability (HRV) was studied in a large multicenter study in Amsterdam, the Netherlands, Erfurt, Germany, and Helsinki, Finland. Elderly subjects (n=37 in Amsterdam, n=47 in both Erfurt and Helsinki) with stable coronary artery disease were followed for 6 months with biweekly clinical visits. During the visits, ambulatory electrocardiogram was recorded during a standardized protocol including a 5-min period of paced breathing. Time and frequency domain analyses of HRV were performed. A statistical model was built for each center separately. The mean 24-h particle number concentration (NC) (1,000/cm(3)) of ultrafine particles (diameter 0.01-0.1 microm) was 17.3 in Amsterdam, 21.1 in Erfurt, and 17.0 in Helsinki. The corresponding values for PM2.5 were 20.0, 23.1, and 12.7 microg/m(3). During paced breathing, ultrafine particles, NO(2), and CO were at lags of 0-2 days consistently and significantly associated with decreased low-to-high frequency ratio (LF/HF), a measure of sympathovagal balance. In a pooled analysis across the centers, LF/HF decreased by 13.5% (95% confidence interval: -20.1%, -7.0%) for each 10,000/cm(3) increase in the NC of ultrafine particles (2-day lag). PM2.5 was associated with reduced HF and increased LF/HF in Helsinki, whereas the opposite was true in Erfurt, and in Amsterdam, there were no clear associations between PM2.5 and HRV. The results suggest that the cardiovascular effects of ambient ultrafine and PM2.5 can differ from each other and that their effect may be modified by the characteristics of the exposed subjects and the sources of PM2.5.

Stability over time of short-term heart rate variability.

Heart rate variability (HRV) is a widely used method to assess cardiac autonomic control. However, the reproducibility of especially short-term HRV has not been properly evaluated. Therefore, we assessed the stability of short-term HRV over a three to four month period. We had seven consecutive electrocardiographic (ECG) recordings from 89 subjects with stable coronary artery disease obtained during a large multicenter study. The HRV assessments were performed from these 40-minute ECG-recordings simulating normal daily activities, i. e., recordings consisting of 5 to 10 minute periods of rest, paced breathing, standing, submaximal exercise and recovery. Both time and frequency domain HRV analyses were conducted from the whole 40-minute recordings and from the 5-minute periods of rest and paced breathing. The coefficient of variation (CV) varied between 5.1-16.7% for the 40-minute and 6.0-37.1% for the 5-minute time domain and 4.4-11.0 % for the 40-minute and 7.2-16.5 % for the 5-minute frequency domain measurements. The mean of the RR intervals and the total power showed the highest stability over time. The most unstable measure was the standard deviation of all NN intervals (SDNN). In conclusion, most short-term HRV measures were highly stable over time indicating low physiological variation. However, the SDNN showed large variability in consecutive recordings.