Quartz is a form of crystalline quartz composed of silicon and oxygen. It is a mineral which occurs frequently in the earth's crust.1 Quartz exposure is common in occupations such as mining, stone crushing, and foundry processing.1 Other professions at risk of exposure are in the construction industry; jobs that involve processes that make glass, brick, tile, cement, and ceramics are also considered at risk.1 It is estimated that more than three million workers in Europe are exposed in their occupation every year, of which 85,000 are in Sweden.2,3 Some quartz polymorphs can after processing occur as nanoparticles which can be inhaled and possibly enter the bloodstream.1,4 Nanoparticles have in laboratory studies been found to cross the pulmonary epithelium through pores in the alveolar-blood barrier, macrophage mediated phagocytosis, endocytosis by epithelial and endothelial cells, and autophagy in pericytes.5,6 Quartz nanoparticles cause neutrophil recruitment which induces an inflammatory response in the cardiac tissue causing pericardial edema, bradycardia, and dysfunction in cardiac contraction.7 The inflammatory response increases the risk of blood clotting due to activation of plasma fibrinogen and procoagulants.8
Occupational quartz exposure increases overall mortality from cardiovascular diseases (CVD) and increases the activity of the adaptive immune system through a cascade of immunological processes.8,9 Studies have shown associations between quartz exposure and several diseases, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, lung cancer, and CVD.10–14
There is a positive exposure-response relationship between cumulative quartz exposure and death from all causes with an increased hazard ratio by 1.026 for every increase in 1 mg/m3- year of exposure.13 A high cumulative exposure increases the risk of developing lung cancer and mortality from total heart disease and pulmonary heart disease.10,13 A meta-analysis showed a significant increase in relative risk for lung cancer with cumulative quartz exposure above 1.84 mg/m3-year, and indicated that the risk plateaus at exposures greater than 6 mg/m3-year.15 The risk of developing lung cancer increases with employment length above 10 years and especially with a long latency time of over 20 years.12 The occupational exposure limit for respirable quartz is 0.1 mg/m3-year in Sweden as in many other countries16 although it is known that exposure levels below 0.1 mg/m3-year increases mortality from heart disease, including both pulmonary and ischemic heart disease.10
Atrial fibrillation (AF) is a chronic progressive condition and the most common cardiac arrhythmia; it occurs in three different forms: paroxysmal, persistent, and permanent.17 Paroxysmal cases have recurrence episodes of AF with spontaneous termination back to sinus rhythm.18 Persistent AF has more sustained episodes and needs termination with pharmacological treatment or electrical cardioversion.18 In permanent AF, cardioversion is inappropriate and management is down to heart rate control and antithrombotic treatment.18 AF arises from chaotic electrical conduction disturbances in the atria leading to the absence of atrial contraction causing irregular heart rhythm. The change in the heart's ability to contract increases the risk of blood clotting, heart failure, stroke, dementia, and all-cause mortality.17,19–22
The impact on all-cause mortality on nontreated versus treated AF patients with anticoagulants in quartz-exposed individuals is unknown; but treatment with warfarin in patients with AF reduces the relative risk of suffering from stroke by 62% and 26% for all-cause mortality.23
Symptomatic AF is associated with reduced quality of life due to reduced cardiac performance with increased fatigue.24 In Sweden, the prevalence is above 3% in the adult population, and 6000 people with AF suffered from a stroke in 2013.25,26 Apart from the suffering and death, stroke is also a large economic cost for both patients and society. The socioeconomic lifetime costs in Sweden are estimated to be over 1.66 billion USD for the 21,800 individuals who suffered from a stroke in 2009; this figure includes the cost for hospitalization, rehabilitation, and loss of productivity because of reduced work capacity.25 AF might be triggered by: autonomic dysfunction, inflammation, oxidative stress, ionic remodeling, altered calcium homeostasis, atrial pressure changes, and atrial ischemia.24,27,28 The underlying mechanism for the development of AF through particle exposure is not fully understood, but there are three different theories: an inflammatory response, autonomic dysfunction, or translocation with cardiotoxicity and hypoxemia.29
A previous Swedish study that used SMRs found an increase in total mortality after quartz exposure for CVD (SMR 1.4; 95% CI 1.3–1.6) and stroke (SMR 1.6, 95% CI 1.2–2.1).21 In this study, we want to analyze if quartz exposure increases the risk of developing AF, which itself greatly increases the risk of suffering from CVD and ischemic stroke.8,20,22
The aim is to analyze the association between occupational quartz exposure and the risk of developing AF and overall mortality.
MATERIAL AND METHODS
There were 5237 cases aged between 20 and 65 in the study period between 2005 and 2016, diagnosed for the first time with AF (I 48) as defined by the International Classification of Diseases (ICD 10). These cases have been obtained from the National Board of Health and Welfare's Outpatient Register and Inpatient Register (SoS). All the cases have one linked control from the Statistics Sweden population register regarding age, gender, and county. The controls in this study were originally obtained for a larger study and therefore have the same exclusion criteria: that is, not allowed to be first-degree relatives, have autoimmune diseases—Sarcoidosis-D86, Bechterews-M45, Seropositive rheumatoid arthritis-M05, other artritis-M06, Crohn disease-K50, or Ulcerative colitis-K51.
The total population of 10,474 included both cases with AF and controls, and who for a period in their lives had worked at an occupation with quartz exposure. The total population consisted of 4074 females and 6400 males. In the male population 1001 individuals and in the female population 99 were exposed to quartz. The females’ mean age at diagnosis was 62.29 ± 8.05; the figure for males was 59.61 ± 9.15. The first exclusion criterion was female gender (4074) due to the low proportion of quartz-exposed individuals in the population. The second exclusion criterion was working in an occupation without possible quartz exposure 5 years prior to AF diagnosis (892 males) (Fig. 1) because of the risk of other unknown occupational exposure. A total of 4966 individuals were excluded based on this criterion, leaving a male study population of 5508 (Fig. 1).
The occupation and employment length of the individuals in the study population was obtained from the Statistics Sweden (SCB) database. That information was thereafter linked to a Swedish job-exposure matrix (JEM) with time-specific estimates of respirable quarts exposure for different occupational codes. Personal exposure was calculated based on the length of employment for each occupation a person had, and the prevalence and level of respirable quartz given for each occupation.30,31
The information collected from the SCB was linked to the Cause of Death Register and Emigration Register to detect those who died or had migrated during the study period.
The study protocol is approved by the Ethical Review Authority board in Uppsala (Dnr 2017/252). This retrospective register study was made on a population level, and no individual data can be distinguished from the study population. The data were anonymized by SoS and SCB before our acquisition.
Data Processing and Analysis
The background data for the study population are presented with descriptive statistics and contains number of individuals, numbers of years with quartz exposure, mean years exposed to quartz, numbers of deaths and mean age at death for the cases and controls.
A conditional logistic regression model was used to compare the OR as an estimate of risk complemented with 95% confidence intervals (CI 95%), between quartz-exposed case and control. Separate regression models evaluated the OR stratified by numbers of years exposed and age from unexposed, 0 to 1, 2 to 5, 6 to 10 to greater than 10 years and age when diagnosed divided into two groups 20 to 55 or 55 to 65. The OR was also evaluated with a conditional logistic regression analysis with mean quartz exposure mg/m3. Individual quartz exposures (mg/m3) were used to calculate dose responses. Exposure to respirable quartz was thus defined as the average exposure per year in mg/m3 and categorized into three dose groups: 0 mg/m3, 0.01 to 0.05 mg/m3 and 0.051+ mg/m3. An independent T test was used to evaluate mean age at death between exposed and unexposed in the case and control population; a two-sided P value < 0.05 was considered statistically significant.
Mortality was assessed with SMR with 95% CI on the assumption of a Poisson distribution of the population. Person-years at risk was calculated and stratified by gender, 5-year age groups, and 1-year calendar periods. The expected number of deaths for these strata was calculated with the use of the general Swedish population.
Statistical calculations were made with STATA version 14.0 and SPSS version 22.
The male study population consisted of 2574 cases diagnosed with AF and as many healthy controls (Table 1). Five hundred and two individuals in total from both groups were exposed to quartz for approximately 6 years; 358 of them died aged about 66 (Table 1). Mean age of AF diagnosis in the case group was 60 ± 9.15.
An increase in the risk of developing AF with statistical significance was seen in the population who had worked in a quartz exposed occupation for up to a year (OR 1.54; CI 95% 1.06–2.24); this further increased in the group 20 to 55 years of age when diagnosed (OR 2.05; CI 95% 1.02–4.10) (Table 2). The group 20 to 55 years of age when diagnosed with AF showed an overall increased risk (OR 1.49; CI 95% 1.08–2.06) no matter the number of years with quartz exposure before diagnosis (Table 2).
For men in age 20 to 55 years there is a significant increase in AF when mean quartz dust (mg/m3) per year is above 0.051+ (Table 3).
Compering date of quartz exposure and date of AF yield (OR 1.54; 95% CI 0.98–2.42) in age group 20 to 55 and (OR 1.02; 95% CI 0.70–1.50) in age group 56 to 65 with mean exposure above 0.05 mg/m3 per year. In lower exposed, 0.01 to 0.05 mg/m3 per year (OR 0.60; 95% CI 0.17–2.03) and (OR 0.70; 95% CI 0.27–1.84) in, respectively, age group.
Men working in quartz exposed occupations 5 years within AF diagnosis die approximately with a mean of 4 years earlier than unexposed men (P = 0.007) (Table 4).
An increase in total mortality with statistical significance was seen for the cases with AF aged between 20 and 55 (SMR 2.04; 95% CI 1.43–2.82) and those between 56 and 65 (SMR 1.51; CI 95% 1.31–1.73) (Table 5). A mortality reduction with statistical significance was seen for the control group aged between 20 and 55 (SMR 0.44; 95% CI 0.19–0.87) and 56 and 65 (SMR 0.75; CI 95% 0.61–0.90) (Table 5). Mortality was increased in the case group with AF for those unexposed (SMR 1.60; CI 95% 1.39–1.81), and a greater increase was seen for individuals exposed to quartz for up to a year (SMR 2.33; CI 95% 1.16–4.16) (Table 5). The unexposed in the control group had reduced mortality (SMR 0.67; CI 0.55–0.82) (Table 5).
The major finding in this study was that individuals aged 20 to 55 with and mean quartz dust exposure above 0.05 mg/m3 have increased risk of developing AF. There is also an increased risk for the group with employment duration less than a year (Tables 2 and 3).
The same two groups show a higher overall mortality than the general Swedish population (Table 5). The lifespan for the cases exposed to quartz was decreased by a mean of 4 years (Table 4). A reduction in total mortality was observed in the control groups due to the exclusion of individuals with autoimmune diseases, which made them healthier than the general Swedish population (Table 5).
This is the first study that we know of which analyses the association between quartz exposure and the risk of developing AF; we have, therefore, not been able to find any opposing or supporting results.
The increased risk of developing AF among those aged 20 to 55 with a short-term employment record of less than a year in an occupation with quartz exposure might reflect the possibility that workers leave their occupation when experiencing AF symptoms in a higher degree than the healthy controls. The underlying cause of AF with the fast onset in the short-term employed might be due to other risk factors such as obesity, physical inactivity, diabetes, alcohol consumption, sleep apnea syndrome, smoking habits, job strain, noise-induced annoyance, shift-work, air pollution, socioeconomic status and lifestyle.32–35 The increased risk in men at age 20 to 55 might reflect that work in quartz exposure also often is physical demanding and therefore people force to change job after received AF. This can explain why no significance increase in AF was found in men above 55. A limitation of the study is the using of JEM for exposure assessment it is not possible to adjust for co-founding factors because limited knowledge of the participates. The increase in all-cause mortality when exposed to quartz in the short-term employed seems to cohere with the result from a previous study, where an increase was seen within six months of employment.11 Even low levels of quartz exposure (below 0.1 mg/m3-year) have been associated with an increase in all-cause mortality (SMR 1.06, 95% CI 1.01–1.11), which supports our result, that is, that even a low amount of quartz exposure increases all-cause mortality.10,13 The same studies also show that a higher cumulative quartz exposure further increases all-cause mortality; this differs from our results where the cumulative exposure in the short-term employed should be low.10,13 The assumption of a low cumulative exposure in the short-term employed group is based on the short time of their exposure and an exposure level below the present occupational exposure limit in Sweden, which is 0.1 mg/m3-year.36 This reflects the fact that the underlying cause might be due to non-occupational lifestyles factors, which we were unable to obtain.
Quartz exposure has been shown to elevate total mortality from CVD and stroke.8,21 AF increases the relative risk of suffering from CVD and stroke (the most common causes of death among AF patients) by three- and twofold, respectively.20,22 This might be a conclusion in line with our results: that quartz exposure increases total mortality and is most likely to be caused by a cardiovascular event.
AF is a progressive disease due to remodeling and fibrosis with initially short episodes of arrhythmia that gradually become more frequent and longer lasting, ultimately becoming permanent.17,37,38 The fibrosis and remodeling is caused through long-term inflammation with an increase in proinflammatory mediators with oxidative stress damaging the cardiac tissue.29,39
The fast onset of AF displayed in the short-term employed young male population in this study might be explained by three theories of AF pathophysiology: translocation with cardiotoxicity and hypoxemia, autonomic dysfunction or an inflammatory response.29
The first theory (translocation with cardiotoxicity and hypoxemia) is based on ultrafine particles such as quartz, entering the bloodstream through the alveoli with a possible cardiotoxic effect damaging the cardiomyocytes directly.7,40,41
The second theory (autonomic dysfunction) is based on exposure to air pollution that suggests a direct effect on the autonomic regulation of the heart through reflexes from the inflamed lung tissue, direct action or translocation of particles to the myocardium or through inflammation.29,42 This causes an acute autonomic dysfunction affecting the sympathetic and parasympathetic tone and balance.24,29,43–45
The third theory posits an inflammation starting in the lungs and thereafter becoming systemic, as is the case with air pollution.42,46 The systemic inflammation with proinflammatory mediators causes oxidative stress, cardiovascular inflammation, endothelial dysfunction, cardiac ischemia, and increased right atrial pressure.24,27,37,39,46 These three theories—with inflammatory mediators, damage to the cardiomyocytes, and changed autonomic regulation—all cause remodeling of ion channels, disturbed calcium homeostasis, dysfunction of the autonomic tone in the cardiomyocytes promoting rapid atrial electrical disturbances with altered conduction properties of the atria, potentially increasing the vulnerability to developing AF after short-term quartz exposure.28,39,43,44,47
One of the main strengths of this study is the large, nationwide population with different occupations, which diminishes any impacts on the results due to regional and occupation-specific exposures. Another strength is the matched controls regarding age, gender, and county. Adjusted for county will adjust to some extend for socioeconomic and health care factors.48 Furthermore, exposure information was derived from registers and a JEM, meaning that exposure data were collected independently of disease status, preventing reporting bias.
A limitation of our work is that we had no information of risk factors mentioned above, which might impact the risk of AF. Most occupational exposure contains several different particulate matters, not exclusively quartz.
A potential source of error is that application of the JEM resulted in some misclassification of exposure. Within an occupation there will be some degree of variation in the quartz exposure, and may include unexposed individuals. Another weakness of the study is the lack of actual individual exposure data to quartz and other particulate matter. The amount used here is based on a calculation regarding occupation and length of employment taken from the JEM.
Our main conclusion is that quartz dust exposure may be related to increased risk of AF in high exposed (above 0.05 mg/m3 mean quartz dust) in men aged 20 to 55 year. Quartz exposed with AF shows a higher overall mortality and their life expectancy was also decreased.
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