Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case-Control Study in Sweden

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been associated with elevated cholesterol levels. However, data on incident cardiovascular disease (CVD) is lacking.

Objectives: We investigated the association of exposure to PFAS with risk of myocardial infarction and stroke and, subsidiary, with baseline blood lipids.

Methods: This population-based nested case-control study included first incident myocardial infarction and stroke cases with matched controls from two Swedish cohorts: the Swedish Mammography Cohort-Clinical (SMC-C) and the Cohort of 60-year-olds (60YO). Baseline blood sampling occurred during 2003-2009 and 1997-1999 with follow-up through 2017 and 2014 for the SMC-C and the 60YO, respectively. Eight plasma PFAS concentrations were measured using targeted liquid chromatography-triple quadrupole mass spectrometry. Five of these were quantifiable in both cohorts; individual values and their standardized sum were categorized into tertiles based on the controls. First incident myocardial infarction ($n=345$) and ischemic stroke ($n=354$) cases were ascertained via linkage to the National Inpatient Register and the Cause of Death Register. Controls were randomly selected from each cohort after matching for age, sex, and sample date. Baseline blood lipids were measured in plasma or serum after overnight fasting.

Results: Among the 1,528 case-control subjects, the mean (standard deviation) age was 66 (7.7) y and 67% of them were women. In multivariable-adjusted analyses, the third tertile of the standardized sum of five PFAS associated with higher cholesterol and lower triglyceride levels among controls at baseline ($n=631$). The corresponding results were $\text{odds ratios}=0.70$ [95% confidence interval (CI): 0.53, 0.93] for CVD, 0.60 (95% CI: 0.39, 0.92) for myocardial infarction, and 0.83 (95% CI: 0.46, 1.50) for stroke.

Discussion: This study indicated that exposure to PFAS, although associated with increased cholesterol levels, did not associate with an increased risk of myocardial infarction, stroke, or their composite end point. The findings improve our knowledge on potential health effects of environmental contaminants in the CVD context. https://doi.org/10.1289/EHP9791.

Figure 1.

Flow chart of the prospective nested case–control design and the cross-sectional assessment of lipids using two pooled Swedish cohorts, SMC-C and 60YO. For MI in the SMC-C, there is a 1:1 match in four cases, due to missing missing/broken samples. For lipid analyses, controls without a matched case (due to missing/broken samples) that were excluded from the CVD/MI/stroke analyses were included in the lipid analyses, whereas controls used in both MI and stroke data sets were used only once. Controls on lipid-lowering medication at baseline and missing lipid concentrations were excluded ($n=5$ additional for LDL analyses). Note: 60YO, Cohort of 60-year-olds; CVD, cardiovascular disease; LDL, low-density lipoprotein; MI, myocardial infarction; SMC-C, Swedish Mammography Cohort-Clinical cohort.

Figure 2.

Multivariable-adjusted cross-sectional associations in controls between baseline PFAS plasma concentrations and total cholesterol, LDL, HDL, triglycerides, apoB, and apoA1 of two Swedish pooled cohorts (SMC-C baseline: 2003–2009 and 60YO baseline: 1997–1999), estimated using linear mixed effects models—apoB, apoA1, PFHpA, and PFOA results are from the 60YO cohort alone. Adjusted $\mathrm{\beta }\text{-coefficients}$ (95% CIs) are presented according to PFAS tertiles (using Tertile 1 as reference), as well as by 1-SD increment in natural log-transformed plasma PFAS concentrations (ng/mL). Models were adjusted for age, sex, sampling date, education, BMI, diabetes, hypertension, family history of CVD, smoking habits, physical activity, and healthy diet score. Individual PFAS were standardized (rescaled with $\text{mean}=0$ and $\text{SD}=1$) and summed ($\mathrm{\Sigma }\text{PFAS}$). Note: 60YO, Cohort of 60-year-olds; BMI, body mass index; apo, apolipoprotein; Chol, cholesterol; CI, confidence interval; CVD, cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PFDA, perfluorodecanoic acid; PFAS, per- and polyfluoroalkyl substances; PFHpA, perfluoroheptanoic acid; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; PFUnDA, perfluoroundecanoic acid; SD, standard deviation; SMC-C, Swedish Mammography Cohort-Clinical cohort; Trig, triglycerides.

Figure 3.

Multivariable-adjusted risk of myocardial infarction, presented as pooled ORs (95% CIs) from two Swedish cohorts (SMC-C: $n=398$ and 60YO: $n=422$) using random effects meta-analysis, comparing the third tertile of each PFAS with the first tertile—PFHpA and PFOA results are from the 60YO cohort alone. Estimations adjusted according to Model 2: sex, age, sampling date, education, BMI, diabetes, hypertension, family history of CVD, smoking habits, physical activity, and healthy diet score. Individual PFAS were standardized (rescaled with $\text{mean}=0$ and $\text{SD}=1$) and summed ($\mathrm{\Sigma }\text{PFAS}$). Note: 60YO, Cohort of 60-year-olds; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; OR, odds ratio; PFAS, per- and polyfluoroalkyl substances; PFDA, perfluorodecanoic acid; PFHpA, perfluoroheptanoic acid; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; PFUnDA, perfluoroundecanoic acid; SD, standard deviation; SMC-C, Swedish Mammography Cohort-Clinical cohort.

Figure 4.

Multivariable-adjusted risk of stroke, presented as pooled ORs (95% CIs) from two Swedish cohorts (SMC-C: $n=344$ and 60YO: $n=364$) using random effects meta-analysis, comparing the third tertile of each PFAS with the first tertile—PFHpA and PFOA results are from the 60YO cohort alone. Estimations adjusted according to Model 2: sex, age, sampling date, education, BMI, diabetes, hypertension, family history of CVD, smoking habits, physical activity, and healthy diet score. Individual PFAS were standardized (rescaled with $\text{mean}=0$ and $\text{SD}=1$) and summed ($\mathrm{\Sigma }\text{PFAS}$). Note: 60YO, Cohort of 60-year-olds; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; OR, odds ratio; PFAS, per- and polyfluoroalkyl substances; PFDA, perfluorodecanoic acid; PFHpA, perfluoroheptanoic acid; PFHxS, perfluorohexane sulfonic acid; PFNA, perfluorononanoic acid; PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonate; PFUnDA, perfluoroundecanoic acid; SD, standard deviation; SMC-C, Swedish Mammography Cohort-Clinical cohort.