Cardiovascular effects of short-term exposure to air pollution : exploring potential pathways and susceptible subgroups
Author: Ljungman, Petter
Date: 2009-05-15
Location: Sal Ihre, Södersjukhuset
Time: 09.00
Department: Institutionen för klinisk forskning och utbildning, Södersjukhuset / Department of Clinical Science and Education, Södersjukhuset
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Abstract
Cardiovascular disease is the most common cause of mortality globally,
with a number of contributing risk factors. Ambient air pollution
represents a universally present risk factor with a substantial
preventive potential. Although the relationship between exposure to air
pollution and all-cause mortality, or even cardiovascular mortality, has
been relatively well established, the details of how, when, who and even
how much remain unclear.
This thesis focuses on understanding associations between short-term exposure to air pollution and cardiovascular disease, with special attention to ischemic heart disease and ventricular arrhythmias.
In the first paper we conducted a case-crossover study with 660 first-time myocardial infarctions in Stockholm, interviewed shortly after diagnosis to determine time of disease onset. Air pollution levels 2 and 24 hours preceding the time of onset were compared in the same individual with 3-4 equally long control periods without myocardial infarction matched by time of day and day of week within the same calendar month. No associations were found between air pollution levels and myocardial infarction in the main analyses or in subgroup analyses.
Atherosclerosis is an inflammatory disease leading to a number of cardiac disorders including myocardial infarction. Low-grade inflammation, measured by slight increases in blood markers such as interleukin-6 (IL-6), has been associated with poorer prognosis for heart disease and mortality. In a multi-center study involving 6 European cities and 1003 myocardial infarction survivors we conducted repeated (5.8 in average) blood sampling for inflammatory markers including IL-6, and genotyped for single nucleotide polymorphisms (SNPs) in inflammatory genes. In the second paper results are presented for associations between interleukin-6 (IL6) genotypes and mean IL-6 plasma levels using mixed model analyses with random intercepts. Four SNPs showed associations with IL-6 levels with eg 6.3% (95% confidence interval 1.7-11.2%) increased IL-6 per minor alleleof an IL6 SNP labeled rs1800795. In the third paper we analyzed the effect modification of selected SNPs in theIL6 gene and the fibrinogen alpha- (FGA) and beta-chain (FGB) genes on the IL-6 response to preceding air pollution levels. We found associations demonstrating gene-environment interaction effects for an IL6 SNP and a FGB SNP. Strongest effects were found when patients with the minor alleles of FGB rs1800790 were exposed to carbon monoxide in the 6-11 hour exposure-window prior to sampling. In homozygotes for this allele a 10% (4.6-16%) increased mean IL-6 was observed per 0.64 mg/m3 increase of pollutant.
In the fourth paper we studied the relationship between air pollution levels 2 and 24 hours preceding ventricular arrhythmias in 211 patients with implantable cardioverter defibrillators in Stockholm and Gothenburg using a similar methodology as in Paper I. We found associations for ventricular arrhythmias and 2 hour exposure to particulate pollution indicating an odds ratio of 1.31 (1.00-1.72) per 13.2 μg/m3 PM10. Interaction analyses showed strongest effects for events occurring closer to the monitoring station, outdoors and in Gothenburg.
Conclusions: Air pollution exposure was not associated with the onset of myocardial infarction in our sample. Four strongly correlated polymorphisms in the IL6 gene were associated with plasma IL-6 levels implicating that variants in the IL6 gene affect the inflammatory status of myocardial infarction survivors and potentially their future prognosis. The air pollution effect on IL-6 levels was modified by variations in the IL6 and FGB genes. This suggests that if inflammation is a pathway for the air pollution effect on heart disease, these genetic variations may lead to some people being more susceptible to air pollution than others. Particulate air pollution was associated with ventricular arrhythmias already after 2 hours of exposure giving further support to the hypotheses that air pollution may contribute to dysfunctional autonomic regulation of the electrical conduction of the heart and be an important alternative explanation for the cardiovascular mortality seen in association with air pollution.
This thesis focuses on understanding associations between short-term exposure to air pollution and cardiovascular disease, with special attention to ischemic heart disease and ventricular arrhythmias.
In the first paper we conducted a case-crossover study with 660 first-time myocardial infarctions in Stockholm, interviewed shortly after diagnosis to determine time of disease onset. Air pollution levels 2 and 24 hours preceding the time of onset were compared in the same individual with 3-4 equally long control periods without myocardial infarction matched by time of day and day of week within the same calendar month. No associations were found between air pollution levels and myocardial infarction in the main analyses or in subgroup analyses.
Atherosclerosis is an inflammatory disease leading to a number of cardiac disorders including myocardial infarction. Low-grade inflammation, measured by slight increases in blood markers such as interleukin-6 (IL-6), has been associated with poorer prognosis for heart disease and mortality. In a multi-center study involving 6 European cities and 1003 myocardial infarction survivors we conducted repeated (5.8 in average) blood sampling for inflammatory markers including IL-6, and genotyped for single nucleotide polymorphisms (SNPs) in inflammatory genes. In the second paper results are presented for associations between interleukin-6 (IL6) genotypes and mean IL-6 plasma levels using mixed model analyses with random intercepts. Four SNPs showed associations with IL-6 levels with eg 6.3% (95% confidence interval 1.7-11.2%) increased IL-6 per minor alleleof an IL6 SNP labeled rs1800795. In the third paper we analyzed the effect modification of selected SNPs in theIL6 gene and the fibrinogen alpha- (FGA) and beta-chain (FGB) genes on the IL-6 response to preceding air pollution levels. We found associations demonstrating gene-environment interaction effects for an IL6 SNP and a FGB SNP. Strongest effects were found when patients with the minor alleles of FGB rs1800790 were exposed to carbon monoxide in the 6-11 hour exposure-window prior to sampling. In homozygotes for this allele a 10% (4.6-16%) increased mean IL-6 was observed per 0.64 mg/m3 increase of pollutant.
In the fourth paper we studied the relationship between air pollution levels 2 and 24 hours preceding ventricular arrhythmias in 211 patients with implantable cardioverter defibrillators in Stockholm and Gothenburg using a similar methodology as in Paper I. We found associations for ventricular arrhythmias and 2 hour exposure to particulate pollution indicating an odds ratio of 1.31 (1.00-1.72) per 13.2 μg/m3 PM10. Interaction analyses showed strongest effects for events occurring closer to the monitoring station, outdoors and in Gothenburg.
Conclusions: Air pollution exposure was not associated with the onset of myocardial infarction in our sample. Four strongly correlated polymorphisms in the IL6 gene were associated with plasma IL-6 levels implicating that variants in the IL6 gene affect the inflammatory status of myocardial infarction survivors and potentially their future prognosis. The air pollution effect on IL-6 levels was modified by variations in the IL6 and FGB genes. This suggests that if inflammation is a pathway for the air pollution effect on heart disease, these genetic variations may lead to some people being more susceptible to air pollution than others. Particulate air pollution was associated with ventricular arrhythmias already after 2 hours of exposure giving further support to the hypotheses that air pollution may contribute to dysfunctional autonomic regulation of the electrical conduction of the heart and be an important alternative explanation for the cardiovascular mortality seen in association with air pollution.
List of papers:
I. Berglind N, Ljungman P, Möller J, Hallqvist J, Nyberg N, Rosenqvist M, Pershagen G, Bellander T (2009). "Air pollution exposure - a trigger for myocardial infarction?". [Submitted]
II. Ljungman P, Bellander T, Nyberg F, Lampa E, Jacquemin B, Kolz M, Lanki T, Mitropoulos J, Müller M, Picciotto S, Pistelli R, Rückerl R, Koenig W, Peters A; for the AIRGENE Study Group (2009). "DNA variants, plasma levels and variability of Interleukin-6 in myocardial infarction survivors: Results from the AIRGENE study." Thromb Res 124(1): 57-64.
Fulltext (DOI)
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View record in Web of Science®
III. Ljungman P, Bellander T, Schneider A, Breitner S, Forastiere F, Hampel R, Illig T, Jacquemin B, Katsouyanni K, von Klot S, Koenig W, Lanki T, Nyberg F, Pekkanen J, Pistelli R, Pitsavos C, Rosenqvist M, Sunyer J, Peters A (2009). "Modification of the interleukin-6 response to air pollution by interleukin-6 and fibrinogen polymorphisms." [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Ljungman PL, Berglind N, Holmgren C, Gadler F, Edvardsson N, Pershagen G, Rosenqvist M, Sjögren B, Bellander T (2008). "Rapid effects of air pollution on ventricular arrhythmias." Eur Heart J 29(23): 2894-901.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Berglind N, Ljungman P, Möller J, Hallqvist J, Nyberg N, Rosenqvist M, Pershagen G, Bellander T (2009). "Air pollution exposure - a trigger for myocardial infarction?". [Submitted]
II. Ljungman P, Bellander T, Nyberg F, Lampa E, Jacquemin B, Kolz M, Lanki T, Mitropoulos J, Müller M, Picciotto S, Pistelli R, Rückerl R, Koenig W, Peters A; for the AIRGENE Study Group (2009). "DNA variants, plasma levels and variability of Interleukin-6 in myocardial infarction survivors: Results from the AIRGENE study." Thromb Res 124(1): 57-64.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Ljungman P, Bellander T, Schneider A, Breitner S, Forastiere F, Hampel R, Illig T, Jacquemin B, Katsouyanni K, von Klot S, Koenig W, Lanki T, Nyberg F, Pekkanen J, Pistelli R, Pitsavos C, Rosenqvist M, Sunyer J, Peters A (2009). "Modification of the interleukin-6 response to air pollution by interleukin-6 and fibrinogen polymorphisms." [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Ljungman PL, Berglind N, Holmgren C, Gadler F, Edvardsson N, Pershagen G, Rosenqvist M, Sjögren B, Bellander T (2008). "Rapid effects of air pollution on ventricular arrhythmias." Eur Heart J 29(23): 2894-901.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Issue date: 2009-04-24
Rights:
Publication year: 2009
ISBN: 978-91-7409-454-1
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