A review of air pollution as a driver of cardiovascular disease risk across the diabetes spectrum.

The prevalence of diabetes is estimated to reach almost 630 million cases worldwide by the year 2045; of current and projected cases, over 90% are type 2 diabetes. Air pollution exposure has been implicated in the onset and progression of diabetes. Increased exposure to fine particulate matter air pollution (PM2.5) is associated with increases in blood glucose and glycated hemoglobin (HbA1c) across the glycemic spectrum, including normoglycemia, prediabetes, and all forms of diabetes. Air pollution exposure is a driver of cardiovascular disease onset and exacerbation and can increase cardiovascular risk among those with diabetes. In this review, we summarize the literature describing the relationships between air pollution exposure, diabetes and cardiovascular disease, highlighting how airborne pollutants can disrupt glucose homeostasis. We discuss how air pollution and diabetes, via shared mechanisms leading to endothelial dysfunction, drive increased cardiovascular disease risk. We identify portable air cleaners as potentially useful tools to prevent adverse cardiovascular outcomes due to air pollution exposure across the diabetes spectrum, while emphasizing the need for further study in this particular population. Given the enormity of the health and financial impacts of air pollution exposure on patients with diabetes, a greater understanding of the interventions to reduce cardiovascular risk in this population is needed.

Environmental Impacts on Cardiovascular Health and Biology: An Overview.

Environmental stressors associated with human activities (eg, air and noise pollution, light disturbance at night) and climate change (eg, heat, wildfires, extreme weather events) are increasingly recognized as contributing to cardiovascular morbidity and mortality. These harmful exposures have been shown to elicit changes in stress responses, circadian rhythms, immune cell activation, and oxidative stress, as well as traditional cardiovascular risk factors (eg, hypertension, diabetes, obesity) that promote cardiovascular diseases. In this overview, we summarize evidence from human and animal studies of the impacts of environmental exposures and climate change on cardiovascular health. In addition, we discuss strategies to reduce the impact of environmental risk factors on current and future cardiovascular disease burden, including urban planning, personal monitoring, and mitigation measures.

Vascular endothelium as a target for perfluroalkyl substances (PFAs).

INTRODUCTION: Perfluoroalkyl substances (PFAs) are ubiquitous, anthropogenic organic compounds that have been linked with cardiovascular disease and cardiovascular risk factors. Older, long-chain PFAs have been phased out due to adverse cardiometabolic health effect and replaced by newer short-chain PFAs. However, emerging research suggests that short-chain PFAs may also have adverse cardiovascular effects. Non-invasive measures of vascular function can detect preclinical cardiovascular disease and serve as a useful surrogate for early CVD risk. We hypothesized that serum concentrations of PFAs would be associated with noninvasive measures of vascular function, carotid-femoral pulse wave velocity (PWV) and brachial artery reactivity testing (BART), in adults with non-occupational exposure to PFAs. METHODS: We measured serum concentrations of 14 PFAs with hybrid solid-phase extraction and ultrahigh-performance liquid chromatography-tandem mass spectrometry in 94 adult outpatients with no known cardiovascular disease. We collected clinical and demographic data; and measured vascular function, PWV and BART, using standard protocols. We assessed associations of individual PFAs with log-transformed BART and PWV using linear regression. We used weighted quantile sum regression to assess effects of correlated PFA mixtures on BART and PWV. RESULTS: Ten PFAs were measured above the limit of detection in >50% of participants. Each standard deviation increase in concentration of perfluoroheptanoic acid (PFHpA) was associated with 15% decrease in BART (95% CI: -28.5, -0.17). The weighted index of a mixture of PFAs with correlated concentrations was inversely associated with BART: each tertile increase in the weighted PFA mixture was associated with 25% lower BART, with 73% of the effect driven by PFHpA. In contrast, no PFAs or mixtures were associated with PWV. CONCLUSIONS: Serum concentration of PFHpA, a new, short-chain PFA, was associated with impaired vascular function among outpatients without CVD. Our findings support a potential adverse cardiovascular effect of newer, short-chain PFAs.

Portable air cleaner use and biomarkers of inflammation: A systematic review and meta-analysis.

Fine particulate matter air pollution (PM2.5) is a major contributor to cardiovascular morbidity and mortality, potentially via increased inflammation. PM2.5 exposure increases inflammatory biomarkers linked to cardiovascular disease, including CRP, IL-6 and TNFα. Portable air cleaners (PACs) reduce individual PM2.5 exposure but evidence is limited regarding whether PACs also reduce inflammatory biomarkers. We performed a systematic review and meta-analysis of trials evaluating the use of PACs to reduce PM2.5 exposure and inflammatory biomarker concentrations. We identified English-language articles of randomized sham-controlled trials evaluating high efficiency particulate air filters in non-smoking, residential settings measuring serum CRP, IL-6 and TNFα before and after active versus sham filtration, and performed meta-analysis on the extracted modeled percent change in biomarker concentration across studies. Of 487 articles identified, we analyzed 14 studies enrolling 778 participants that met inclusion criteria. These studies showed PACs reduced PM2.5 by 61.5 % on average. Of the 14 included studies, 10 reported CRP concentrations in 570 participants; these showed active PAC use was associated with 7 % lower CRP (95 % CI: -14 % to 0.0 %, p = 0.05). Nine studies of IL-6, with 379 participants, showed active PAC use was associated with 13 % lower IL-6 (95 % CI: [-23 %, -3 %], p = 0.009). Six studies, with 269 participants, reported TNF-α and demonstrated no statistical evidence of difference between active and sham PAC use. Portable air cleaners that reduce PM2.5 exposure can decrease concentrations of inflammatory biomarkers associated with cardiovascular disease. Additional studies are needed to evaluate clinical outcomes and other biomarkers.

Nrf2-related gene expression and exposure to traffic-related air pollution in elderly subjects with cardiovascular disease: An exploratory panel study.

Gene expression changes are linked to air pollutant exposures in in vitro and animal experiments. However, limited data are available on how these outcomes relate to ambient air pollutant exposures in humans. We performed an exploratory analysis testing whether gene expression levels were associated with air pollution exposures in a Los Angeles area cohort of elderly subjects with coronary artery disease. Candidate genes (35) were selected from published studies of gene expression-pollutant associations. Expression levels were measured weekly in 43 subjects (≤ 12 weeks) using quantitative PCR. Exposures included gaseous pollutants O3, nitrogen oxides (NOx), and CO; particulate matter (PM) pollutants elemental and black carbon (EC, BC); and size-fractionated PM mass. We measured organic compounds from PM filter extracts, including polycyclic aromatic hydrocarbons (PAHs), and determined the in vitro oxidative potential of particle extracts. Associations between exposures and gene expression levels were analyzed using mixed-effects regression models. We found positive associations of traffic-related pollutants (EC, BC, primary organic carbon, PM 0.25-2.5 PAH and/or PM 0.25 PAH, and NOx) with NFE2L2, Nrf2-mediated genes (HMOX1, NQO1, and SOD2), CYP1B1, IL1B, and SELP. Findings suggest that NFE2L2 gene expression links associations of traffic-related air pollution with phase I and II enzyme genes at the promoter transcription level.

Mitochondrial genetic background modifies the relationship between traffic-related air pollution exposure and systemic biomarkers of inflammation.

BACKGROUND: Mitochondria are the main source of reactive oxygen species (ROS). Human mitochondrial haplogroups are linked to differences in ROS production and oxidative-stress induced inflammation that may influence disease pathogenesis, including coronary artery disease (CAD). We previously showed that traffic-related air pollutants were associated with biomarkers of systemic inflammation in a cohort panel of subjects with CAD in the Los Angeles air basin. OBJECTIVE: We tested whether air pollutant exposure-associated inflammation was stronger in mitochondrial haplogroup H than U (high versus low ROS production) in this panel (38 subjects and 417 observations). METHODS: Inflammation biomarkers were measured weekly in each subject (≤ 12 weeks), including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein, interleukin-6 soluble receptor and tumor necrosis factor-soluble receptor II. We determined haplogroup by restriction fragment length polymorphism analysis. Air pollutants included nitrogen oxides (NOx), carbon monoxide (CO), organic carbon, elemental and black carbon (EC, BC); and particulate matter mass, three size fractions (<0.25 µm, 0.25-2.5 µm, and 2.5-10 µm in aerodynamic diameter). Particulate matter extracts were analyzed for organic compounds, including polycyclic aromatic hydrocarbons (PAH), and in vitro oxidative potential of aqueous extracts. Associations between exposures and biomarkers, stratified by haplogroup, were analyzed by mixed-effects models. RESULTS: IL-6 and TNF-α were associated with traffic-related air pollutants (BC, CO, NOx and PAH), and with mass and oxidative potential of quasi-ultrafine particles <0.25 µm. These associations were stronger for haplogroup H than haplogroup U. CONCLUSIONS: Results suggest that mitochondrial haplogroup U is a novel protective factor for air pollution-related systemic inflammation in this small group of subjects.

Ancient mtDNA genetic variants modulate mtDNA transcription and replication.

Although the functional consequences of mitochondrial DNA (mtDNA) genetic backgrounds (haplotypes, haplogroups) have been demonstrated by both disease association studies and cell culture experiments, it is not clear which of the mutations within the haplogroup carry functional implications and which are "evolutionary silent hitchhikers". We set forth to study the functionality of haplogroup-defining mutations within the mtDNA transcription/replication regulatory region by in vitro transcription, hypothesizing that haplogroup-defining mutations occurring within regulatory motifs of mtDNA could affect these processes. We thus screened >2500 complete human mtDNAs representing all major populations worldwide for natural variation in experimentally established protein binding sites and regulatory regions comprising a total of 241 bp in each mtDNA. Our screen revealed 77/241 sites showing point mutations that could be divided into non-fixed (57/77, 74%) and haplogroup/sub-haplogroup-defining changes (i.e., population fixed changes, 20/77, 26%). The variant defining Caucasian haplogroup J (C295T) increased the binding of TFAM (Electro Mobility Shift Assay) and the capacity of in vitro L-strand transcription, especially of a shorter transcript that maps immediately upstream of conserved sequence block 1 (CSB1), a region associated with RNA priming of mtDNA replication. Consistent with this finding, cybrids (i.e., cells sharing the same nuclear genetic background but differing in their mtDNA backgrounds) harboring haplogroup J mtDNA had a >2 fold increase in mtDNA copy number, as compared to cybrids containing haplogroup H, with no apparent differences in steady state levels of mtDNA-encoded transcripts. Hence, a haplogroup J regulatory region mutation affects mtDNA replication or stability, which may partially account for the phenotypic impact of this haplogroup. Our analysis thus demonstrates, for the first time, the functional impact of particular mtDNA haplogroup-defining control region mutations, paving the path towards assessing the functionality of both fixed and un-fixed genetic variants in the mitochondrial genome.