Long-term smoking cessation and heart rate dynamics in an aging healthy cohort: Is it possible to fully recover?

AIM: To evaluate the long-term influence of smoking cessation on the regulation of the autonomic cardiovascular system in an aging general population, using the subpopulation of lifelong non-smokers as control group. METHODS: We analyzed 1481 participants aged ≥50 years from the SAPALDIA cohort. In each participant, heart rate variability and heart rate dynamics were characterized by means of various quantitative analyzes of the inter-beat interval time series generated from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable linear regression models in order to evaluate the association with smoking status and time elapsed since smoking cessation. The models were adjusted for known confounding factors and stratified by the time elapsed since smoking cessation. RESULTS: Our findings indicate that smoking triggers adverse changes in the regulation of the cardiovascular system, even at low levels of exposure since current light smokers exhibited significant changes as compared to lifelong non-smokers. Moreover, there was evidence for a dose-response effect. Indeed, the changes observed in current heavy smokers were more marked as compared to current light smokers. Furthermore, full recovery was achieved in former smokers (i.e., normalization to the level of lifelong non-smokers). However, while light smokers fully recovered within the 15 first years of cessation, heavy former smokers might need up to 15-25 years to fully recover. CONCLUSION: This study supports the substantial benefits of smoking cessation, but also warns of important long-term alterations caused by heavy smoking.

The role of conserved PEX3 regions in PEX19-binding and peroxisome biogenesis.

The human peroxins PEX3 and PEX19 are essential for peroxisome biogenesis. They mediate the import of membrane proteins as well as the de novo formation of peroxisomes. PEX19 binds newly synthesized peroxisomal membrane proteins post-translationally and directs them to peroxisomes by engaging PEX3, a protein anchored in the peroxisomal membrane. After protein insertion into the lipid bilayer, PEX19 is released back to the cytosol. Crystallographic analysis provided detailed insights into the PEX3-PEX19 interaction and identified three highly conserved regions, the PEX19-binding region, a hydrophobic groove and an acidic cluster, on the surface of PEX3. Here, we used site-directed mutagenesis and biochemical and functional assays to determine the role of these regions in PEX19-binding and peroxisome biogenesis. Mutations in the PEX19-binding region reduce the affinity for PEX19 and destabilize PEX3. Furthermore, we provide evidence for a crucial function of the PEX3-PEX19 complex during de novo formation of peroxisomes in peroxisome-deficient cells, pointing to a dual function of the PEX3-PEX19 interaction in peroxisome biogenesis. The maturation of preperoxisomes appears to require the hydrophobic groove near the base of PEX3, presumably by its involvement in peroxisomal membrane protein insertion, while the acidic cluster does not appear to be functionally relevant.

Identification of the kinesin KifC3 as a new player for positioning of peroxisomes and other organelles in mammalian cells.

The attachment of organelles to the cytoskeleton and directed organelle transport is essential for cellular morphology and function. In contrast to other cell organelles like the endoplasmic reticulum or the Golgi apparatus, peroxisomes are evenly distributed in the cytoplasm, which is achieved by binding of peroxisomes to microtubules and their bidirectional transport by the microtubule motor proteins kinesin-1 (Kif5) and cytoplasmic dynein. KifC3, belonging to the group of C-terminal kinesins, has been identified to interact with the human peroxin PEX1 in a yeast two-hybrid screen. We investigated the potential involvement of KifC3 in peroxisomal transport. Interaction of KifC3 and the AAA-protein (ATPase associated with various cellular activities) PEX1 was confirmed by in vivo colocalization and by coimmunoprecipitation from cell lysates. Furthermore, knockdown of KifC3 using RNAi resulted in an increase of cells with perinuclear-clustered peroxisomes, indicating enhanced minus-end directed motility of peroxisomes. The occurrence of this peroxisomal phenotype was cell cycle phase independent, while microtubules were essential for phenotype formation. We conclude that KifC3 may play a regulatory role in minus-end directed peroxisomal transport for example by blocking the motor function of dynein at peroxisomes. Knockdown of KifC3 would then lead to increased minus-end directed peroxisomal transport and cause the observed peroxisomal clustering at the microtubule-organizing center.

Premature atrial contractions in the general population: frequency and risk factors.

BACKGROUND: Premature atrial contractions (PACs) are independent predictors of atrial fibrillation, stroke, and death. However, little is known about PAC frequency in the general population and its association with other cardiovascular risk factors. METHODS AND RESULTS: We performed a cross-sectional analysis among participants of the population-based Swiss cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA). 24-hour Holter electrocardiograms to assess PAC prevalence and frequency were performed in a random sample of 1742 participants aged ≥50 years. The median (interquartile range) number of PACs per hour was 0.8 (0.4-1.8), 1.1 (0.5-2.4), 1.4 (0.7-4.6), 2.3 (0.8-6.9), and 2.6 (1.2-6.5) among participants aged 50 to 55, 55 to 60, 60 to 65, 65 to 70, and ≥70 years, respectively (P<0.0001). Only 18 (1.0%) participants did not have at least 1 PAC during Holter monitoring. In multivariable negative binomial regression models, PAC frequency was significantly associated with age (risk ratio [RR] per SD 1.80; P<0.0001), height (RR per SD 1.52; P<0.0001), prevalent cardiovascular disease (RR 2.40; P<0.0001), log-transformed N-terminal pro B-type natriuretic peptides (RR per SD 1.27; P<0.0001), physical activity ≥2 hours per day (RR 0.69; P=0.002), and high-density lipoprotein cholesterol (RR per SD 0.80; P=0.0002). Hypertension and body mass index were not significantly related to PAC frequency. CONCLUSIONS: To our knowledge, this is the first study to assess risk factors for PAC frequency in the general population aged ≥50 years. PACs are common, and their frequency is independently associated with age, height, history of cardiovascular disease, natriuretic peptide levels, physical activity, and high-density lipoprotein cholesterol. The underlying mechanisms of these relationships need to be addressed in future studies.

Impact of road traffic noise annoyance on health-related quality of life: results from a population-based study.

PURPOSE: To estimate the impact of traffic-related noise annoyance on health-related quality of life (HrQoL) in a population-based study and potential effect modification by gender. METHODS: The study included 5,021 participants of the Swiss Cohort Study of Air Pollution and Lung Disease in Adults second survey. The association between traffic-related noise annoyance, measured on an 11-point scale, and HrQoL, based on SF-36 scores, was investigated by multivariate regression analysis. Effect sizes were calculated, and interactions by gender and chronic disease status examined. RESULTS: Thirteen percentage of the study population reported high annoyance due to traffic. Women were more likely to report high noise annoyance (adjOR 1.23; 95%CI 1.01-1.48). Except for general health, all SF-36 scores showed a significant negative association with noise annoyance. The respective effect sizes ranged between 0.13 and 0.54. Significant effect modification by gender and chronic disease status was present in specific SF-36 domains. CONCLUSION: This paper presents first evidence of an inverse relationship of noise annoyance and HrQoL in a general population. Although the estimated effects are small to moderate for individuals, they may add up to a relevant public health impact.

Comparing the lung cancer burden of ambient particulate matter using scenarios of air quality standards versus acceptable risk levels.

OBJECTIVES: Ambient particulate matter (PM) is regulated with science-based air quality standards, whereas carcinogens are regulated with a number of "acceptable" cases. Given that PM is also carcinogenic, we identify differences between approaches. METHODS: We assessed the lung cancer deaths for Switzerland attributable to exposure to PM up to 10 µm (PM10) and to five particle-bound carcinogens. For PM10, we used an epidemiological approach based on relative risks with four exposure scenarios compared to two counterfactual concentrations. For carcinogens, we used a toxicological approach based on unit risks with four exposure scenarios. RESULTS: The lung cancer burden using concentrations from 2010 was 10-14 times larger for PM10 than for the five carcinogens. However, the burden depends on the underlying exposure scenarios, counterfactual concentrations and number of carcinogens. All scenarios of the toxicological approach for five carcinogens result in a lower burden than the epidemiological approach for PM10. CONCLUSIONS: Air quality standards-promoted so far by the WHO Air Quality Guidelines-provide a more appealing framework to guide health risk-oriented clean air policymaking than frameworks based on a number of "acceptable" cases.

Glutathione S-transferase polymorphisms, passive smoking, obesity, and heart rate variability in nonsmokers.

BACKGROUND: Disturbances of heart rate variability (HRV) may represent one pathway by which second-hand smoke (SHS) and air pollutants affect cardiovascular morbidity and mortality. The mechanisms are poorly understood. OBJECTIVES: We investigated the hypothesis that oxidative stress alters cardiac autonomic control. We studied the association of polymorphisms in oxidant-scavenging glutathione S-transferase (GST) genes and their interactions with SHS and obesity with HRV. METHODS: A total of 1,133 nonsmokers > 50 years of age from a population-based Swiss cohort underwent ambulatory 24-hr electrocardiogram monitoring and reported on lifestyle and medical history. We genotyped GSTM1 and GSTT1 gene deletions and a GSTP1 (Ile105Val) single nucleotide polymorphism and analyzed genotype-HRV associations by multiple linear regressions. RESULTS: Homozygous GSTT1 null genotypes exhibited an average 10% decrease in total power (TP) and low-frequency-domain HRV parameters. All three polymorphisms modified the cross-sectional associations of HRV with SHS and obesity. Homozygous GSTM1 null genotypes with > 2 hr/day of SHS exposure exhibited a 26% lower TP [95% confidence interval (CI), 11 to 39%], versus a reduction of -5% (95% CI, -22 to 17%) in subjects with the gene and the same SHS exposure compared with GSTM1 carriers without SHS exposure. Similarly, obese GSTM1 null genotypes had, on average, a 22% (95% CI, 12 to 31%) lower TP, whereas with the gene present obesity was associated with only a 3% decline (95% CI, -15% to 10%) compared with nonobese GSTM1 carriers. CONCLUSIONS: GST deficiency is associated with significant HRV alterations in the general population. Its interaction with SHS and obesity in reducing HRV is consistent with an impact of oxidative stress on the autonomous nervous system.

Differences in heart rate variability associated with long-term exposure to NO2.

BACKGROUND: Heart rate variability (HRV), a measure of cardiac autonomic tone, has been associated with cardiovascular morbidity and mortality. Short-term studies have shown that subjects exposed to higher traffic-associated air pollutant levels have lower HRV. OBJECTIVE: Our objective was to investigate the effect of long-term exposure to nitrogen dioxide on HRV in the Swiss cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA). METHODS: We recorded 24-hr electrocardiograms in randomly selected SAPALDIA participants >or= 50 years of age. Other examinations included an interview investigating health status and measurements of blood pressure, body height, and weight. Annual exposure to NO2 at the address of residence was predicted by hybrid models (i.e., a combination of dispersion predictions, land-use, and meteorologic parameters). We estimated the association between NO2 and HRV in multivariable linear regression models. Complete data for analyses were available for 1,408 subjects. RESULTS: For women, but not for men, each 10-microg/m3 increment in 1-year averaged NO2 level was associated with a decrement of 3% (95% CI, -4 to -1) for the standard deviation of all normal-to-normal RR intervals (SDNN), -6% (95% CI, -11 to -1) for nighttime low frequency (LF), and -5% (95% CI, -9 to 0) for nighttime LF/high-frequency (HF) ratio. We saw no significant effect for 24-hr total power (TP), HF, LF, or LF/HF or for nighttime SDNN, TP, or HF. In subjects with self-reported cardiovascular problems, SDNN decreased by 4% (95% CI, -8 to -1) per 10-microg/m3 increase in NO2. CONCLUSIONS: There is some evidence that long-term exposure to NO2 is associated with cardiac autonomic dysfunction in elderly women and in subjects with cardiovascular disease.

Effects of passive smoking on heart rate variability, heart rate and blood pressure: an observational study.

BACKGROUND: Exposure to environmental tobacco smoke (ETS) has been shown to increase the risk for cardiovascular diseases and death, and autonomic dysfunction (specifically, reduced heart rate variability (HRV)) is a predictor of increased cardiac risk. This study tests the hypothesis that ETS exposure reduces HRV in the general population and discusses possible pathways. METHODS: This cross-sectional study was conducted between 2001 and 2003 and is part of the SAPALDIA (Swiss Cohort Study on Air Pollution and Lung Diseases in Adults) study. The analysis included 1218 randomly selected non-smokers aged 50 and above who participated in 24-h electrocardiogram recordings. Other examinations included an interview, investigating health status (especially respiratory and cardiovascular health and health relevant behaviours and exposure to ETS) and measurements of blood pressure, body height and weight. RESULTS: Subjects exposed to ETS at home or at work for more than 2 h/day had a difference of -15% in total power (95%CI: -26 to -3%), low frequency power (-28 to -1%), low/high frequency ratio (-26 to -3%) and -18% (-29 to -4%) in ultralow frequency power of HRV compared with subjects not exposed to ETS at home or work. We also found a 2.7% (-0.01 to 5.34%) higher heart rate during the recording in exposed subjects. CONCLUSIONS: Exposure to ETS at home and work is associated with lower HRV and with higher heart rate in an ageing population. Our findings suggest that exposure to ETS increases cardiac risk through disturbances in the autonomic nervous system.

Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991-2003: methods and characterization of participants.

OBJECTIVES: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution. METHODS: The health assessment at recruitment (1991) and at the first reassessment (2001-3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50 years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11 year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates. RESULTS: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6 528 individuals (70%) agreed to the health examination and 5 973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5 kg in 11 years and 28% of smokers in 1991 had quit by the time of the reassessment.

Long-term exposure to traffic-related PM(10) and decreased heart rate variability: is the association restricted to subjects taking ACE inhibitors?

BACKGROUND: Alterations in heart rate variability (HRV) are a potential link between exposure to traffic-related air pollution and cardiovascular mortality. OBJECTIVES: We investigated whether long-term exposure to traffic-related PM(10) (TPM(10)) is associated with HRV in older subjects and/or in participants taking specific cardiovascular treatment or with self-reported heart disease. METHODS: We included 1607 subjects from the general population aged 50 to 72 years. These participants from the SAPALDIA cohort underwent ambulatory 24-hr electrocardiogram monitoring. Associations of average annual exposure to TPM(10) over 10 years with HRV parameters from time and frequency domains were estimated using multivariable mixed linear models. Effect estimates are expressed as percent changes in geometric means. RESULTS: HRV was only associated with TPM(10) in participants under ACE inhibitor therapy (N=94). A 1 µg/m(3) increment, approximately equivalent to an interquartile range, in 10 year average TPM(10) was associated with decrements of 14.5% (95% confidence interval (CI), -25.9 to -1.3) in high frequency (HF) power, of 4.5% (-8.2 to -0.5) in the standard deviation of all normal-to-normal RR intervals (SDNN), of 10.6% (-18.5 to -1.9) in total power (TP) and an increase of 9.2% (0.8 to 20.2) in the LF/HF power ratio. CONCLUSIONS: In the absence of an overall effect our results suggest that alterations in HRV, a measure of autonomic control of the cardiac rhythm, may not be a central mechanism by which long-term exposure to TPM(10) increases cardiovascular mortality. Novel evidence on an effect in persons under ACE inhibitor treatment needs to be confirmed in future studies.

Effect of physical activity on heart rate variability in normal weight, overweight and obese subjects: results from the SAPALDIA study.

Many studies have demonstrated an association of both a sedentary lifestyle and a high body mass index (BMI) with greater risk for cardiovascular disease. Within the prospective SAPALDIA cohort (Swiss cohort Study on Air Pollution and Lung Diseases in Adults), we investigated whether regular exercise was protective against reduced heart rate variability (HRV), a clinically relevant predictor of cardiovascular morbidity and mortality, and whether adverse effects of obesity and weight gain on HRV were modified by regular exercise. Twenty-four-hour electrocardiograms were recorded in 1,712 randomly selected SAPALDIA participants aged >or=50, for whom BMI was assessed in the years 1991 and 2001-2003. Other examinations included an interview investigating health status (especially respiratory and cardiovascular health and health relevant behaviours including physical activity) and measurements of blood pressure, body height and weight. The association between regular physical activity and HRV and interactions with BMI and BMI change was assessed in multivariable linear regression analyses. Compared to sedentary obese subjects, SDNN (standard deviation of all RR intervals) was 14% (95% CI: 8-20%) higher in sedentary normal weight subjects; 19% (CI: 12-27%) higher in normal weight subjects exercising regularly >or=2 h/week; and 19% (CI: 11-28%) higher in obese subjects exercising regularly >or=2 h/week. Compared with sedentary subjects who gained weight, those who gained weight but did exercise regularly had a 13% higher SDNN (CI: 7-20%). Regular physical exercise has strong beneficial effects on cardiac autonomic nervous function and thus appears to offset the negative effect of obesity on HRV.

Prevalence of renal impairment and its association with cardiovascular risk factors in a general population: results of the Swiss SAPALDIA study.

BACKGROUND: Impaired renal function is evolving as an independent marker of the risk of cardiovascular morbidity and mortality. Little is known about the prevalence of impaired renal function and its relationship to cardiovascular risk factors in the Swiss general population. METHODS: SAPALDIA comprises a random sample of the Swiss population established in 1991, originally to investigate the health effects of long-term exposure to air pollution. Participants were reassessed in 2002/3 and blood measurements were obtained (n = 6317). Renal function was estimated using the Cockcroft-Gault equation and the modified MDRD (four-component) equation incorporating age, race, gender and serum creatinine level. RESULTS: The estimated prevalence of impaired renal function [estimated glomerular filtration rate <60 ml/min/1.73 m(2)] differed substantially between men and women, particularly at higher ages, and amounted to 13% [95% confidence interval (CI) 10-16%] and 36% (95% CI 32-40%) in men and women, respectively, of 65 years or older. Smoking, obesity, blood lipid levels, high systolic blood pressure and hyperuricaemia were all more common in men when compared with women. These cardiovascular risk factors were also associated independently with creatinine in both women and men. Women were less likely to receive cardiovascular drugs, in particular angiotensin-converting enzyme inhibitors and beta-blockers, when compared with men of the same age. CONCLUSION: Moderate renal impairment seems to be prevalent in the general population, with an apparent excess in females which is not explained by conventional cardiovascular risk factors. The unexpected finding questions the validity of the prediction equations, in particular in females.

Heart rate variability in an ageing population and its association with lifestyle and cardiovascular risk factors: results of the SAPALDIA study.

AIMS: (i) To report associations between cardiovascular risk factors and heart rate variability (HRV) in a general population and (ii) to provide normal values for various HRV measurements in a healthy European general population sample aged >or=50. METHODS AND RESULTS: Twenty-four-hour electrocardiograms were recorded in 1742 randomly selected SAPALDIA (Swiss cohort study on Air Pollution and Lung Diseases in Adults) participants aged >or=50. In multivariate regression analyses, women (n=895) had a 6.1% lower standard deviation of all normal RR (NN) intervals (SDNN), a 11.4% lower total power (TP), and a 27.2% lower low-frequency (LF) power than men (n=847). Per unit increase in BMI, SDNN decreased by 0.7% and TP decreased by 1.2%. Persons with high blood pressure had a 9.2% lower LF than normotensive persons and current smokers a 15.5% lower LF than never smokers. Each hour of heavy physical exercise was associated with a 2.0% increase in SDNN, a 3.6% increase in the high frequency (HF) range power and a 4.2% increase in LF power. Higher levels of uric acid, high-sensitive C-reactive protein and non-HDL-cholesterol were associated with lower TP, HF and LF. Percentiles of TP and LF/HF as a function of age were calculated for an asymptomatic subsample of participants (n=499) free of cardioactive medications. CONCLUSION: Heart rate variability in a general population sample shows expected associations with all known cardiovascular risk factors, although not identically for all HRV domains. Together with our percentile estimates for HRV as a function of age, these findings could assist scientists in interpreting 24 h HRV values and factors influencing them in an ageing population.