Long-term exposure to air pollution and risk of stroke by ecoregions: The REGARDS study.

Several cohort studies have found associations between long-term exposure to air pollution and stroke risk. However, it is unclear whether the surrounding ecology may modify these associations. This study evaluates associations of air pollution with stroke risk by ecoregions, which are areas of similar type, quality, and quantity of environmental resources in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. We assessed the incidence of stroke in 26,792 participants (45+ yrs) from the REGARDS study, a prospective cohort recruited across the contiguous United States. One-yr and 3-yr means of PM2.5, PM10, O3, NO2, SO2, and CO were estimated at baseline using data from the Center for Air, Climate, & Energy Solution, and assigned to participants at the census block group level. Incident stroke was ascertained through September 30, 2020. Relations of air pollutants with the risk of incident stroke were estimated using Cox proportional hazards models, adjusting for relevant demographics, behavioral risk factors, and neighborhood urbanicity. Models were stratified by EPA designated ecoregions. A 5.4 µg/m3 (interquartile range) increase in 1-yr PM10 was associated with a hazard ratio (95 %CI) for incident stroke of 1.07 (1.003, 1.15) in the overall study population. We did not find evidence of positive associations for PM2.5, O3, NO2, SO2, and CO in the fully adjusted models. In our ecoregion-specific analysis, associations of PM2.5 with stroke were stronger in the Great Plains ecoregion (HR = 1.44) than other ecoregions, while associations for PM10 were strongest in the Eastern Temperate Forests region (HR = 1.15). The associations between long-term exposure to air pollution and risk of stroke varied by ecoregion. Our results suggests that the type, quality, and quantity of the surrounding ecology can modify the effects of air pollution on risk of stroke.

Smoking-associated Electrocardiographic Abnormalities Predict Cardiovascular Mortality: Insights from NHANES.

Background­: Smoking is associated with arrhythmia and sudden cardiac death, but the biological mechanisms remain unclear. Abnormal electrocardiogram (ECG) durations of ventricular repolarization (QT interval), atrial depolarization (P wave), and atrioventricular depolarization (PR interval and segment), predict cardiac arrhythmia and mortality. Objectives­: To elucidate how smoking affects cardiac excitation, we assessed in a nationally representative sample (NHANES III) associations between cotinine, abnormalities in P duration, PR interval, PR segment, rate-corrected QT (QTc), QRS duration, and JT interval, and long-term mortality. Methods­: We analyzed data from 5,633 adults using survey-weighted multinomial logistic regression to estimate associations between tobacco use (>15 ng/ml serum cotinine) and short (<5th percentile) or long (>95th percentile) ECG intervals, relative to reference (5 - 95th percentile). Results­: After adjustment for demographics, risk factors, and conduction-altering medications, smoking was associated with a higher odds of short PR interval, PR segment, and QRS, and long JT. Broader ECG effects of smoking were also assessed by survey-weighted linear regression of continuous cotinine and ECG intervals, which revealed cotinine inversely associated with PR segment and QTc. Over a 22-year follow-up, many ECG abnormalities predicted cardiovascular mortality in smokers, including long JT, QRS, and QTc, and short QRS. Conclusions­: Smoking increases likelihood for rapid atrioventricular conduction, rapid ventricular depolarization, and slow ventricular repolarization. The ventricular electrophysiologic abnormalities associated with smoking also predict cardiovascular mortality in smokers; however, traditional ECG measures of cardiac risk like QTc can overlook these ventricular defects and their independent predictive value in smokers.

Anti-inflammatory mechanisms in cancer research: Characterization of a distinct M2-like macrophage model derived from the THP-1 cell line.

AIMS: Macrophages play an essential role in cancer development. Tumor-associated macrophages (TAMs) have predominantly M2-like attributes that are associated with tumor progression and poor patient survival. Numerous methods have been reported for differentiating and polarizing macrophages in vitro, but there is no standardized and validated model for creating TAMs. Primary cells show varying cytokine responses depending on their origin and functional studies utilizing these cells may lack generalization and validity. A distinct cell line-derived TAM-like M2 subtype is required to investigate the mechanisms mediated by anti-inflammatory TAMs in vitro. Our previous work demonstrated a standardized protocol for creating an M2 subtype derived from a human THP-1 cell line. The cell expression profile, however, has not been validated. The aim of this study was to characterize and validate the TAM-like M2 subtype macrophage created based on our protocol to introduce them as a standardized model for cancer research. METHODS AND RESULTS: Using qRT-PCR and ELISA, we demonstrated that proinflammatory, anti-inflammatory, and tumor-associated marker expression changed during THP-1-derived marcrophage development in vitro, mimicking a TAM-related profile (e.g., TNFα, IL-1ß). The anti-inflammatory marker IL-8/CXCL8, however, is most highly expressed in young M0 macrophages. Flow cytometry showed increased expression of CD206 in the final TAM-like M2 macrophage. Single-cell RNA-sequencing analysis of primary human monocytes and colon cancer tissue macrophages demonstrated that cell line-derived M2 macrophages resembled a TAM-related gene profile. CONCLUSIONS: The THP-1-derived M2 macrophage based on a standardized cell line model represents a distinct anti-inflammatory TAM-like phenotype with an M2a subtype profile. This model may provide a basis for in vitro investigation of functional mechanisms in a variety of anti-inflammatory settings, particularly colon cancer development.

Greenness and equity: Complex connections between intra-neighborhood contexts and residential tree planting implementation.

Associations between neighborhood greenness and socioeconomic status (SES) are established, yet intra-neighborhood context and SES-related barriers to tree planting remain unclear. Large-scale tree planting implementation efforts are increasingly common and can improve human health, strengthen climate adaptation, and ameliorate environmental inequities. Yet, these efforts may be ineffective without in-depth understanding of local SES inequities and barriers to residential planting. We recruited 636 residents within and surrounding the Oakdale Neighborhood of Louisville, Kentucky, USA, and evaluated associations of individual and neighborhood-level sociodemographic indicators with greenness levels at multiple scales. We offered no-cost residential tree planting and maintenance to residents within a subsection of the neighborhood and examined associations of these sociodemographic indicators plus baseline greenness levels with tree planting adoption among 215 eligible participants. We observed positive associations of income with Normalized Difference Vegetation Index (NDVI) and leaf area index (LAI) within all radii around homes, and within yards of residents, that varied in strength. There were stronger associations of income with NDVI in front yards but LAI in back yards. Among Participants of Color, associations between income and NDVI were stronger than with Whites and exhibited no association with LAI. Tree planting uptake was not associated with income, education, race, nor employment status, but was positively associated with lot size, home value, lower population density, and area greenness. Our findings reveal significant complexity of intra-neighborhood associations between SES and greenness that could help shape future research and equitable greening implementation. Results show that previously documented links between SES and greenspace at large scales extend to residents' yards, highlighting opportunities to redress greenness inequities on private property. Our analysis found that uptake of no-cost residential planting and maintenance was nearly equal across SES groups but did not redress greenness inequity. To inform equitable greening, further research is needed to evaluate culture, norms, perceptions, and values affecting tree planting acceptance among low-SES residents.

Exposure to Volatile Organic Compounds Is Associated with Hypertension in Black Adults: The Jackson Heart Study.

BACKGROUND: The prevalence of hypertension is higher among Black adults than among White and Hispanic adults. Nevertheless, reasons underlying the higher rates of hypertension in the Black population remain unclear but may relate to exposure to environmental chemicals such as volatile organic compounds (VOCs). METHODS: We evaluated the associations of blood pressure (BP) and hypertension with VOC exposure in non-smokers and smokers in a subgroup of the Jackson Heart Study (JHS), consisting of 778 never smokers and 416 age- and sex-matched current smokers. We measured urinary metabolites of 17 VOCs by mass spectrometry. RESULTS: After adjusting for covariates, we found that amoong non-smokers, metabolites of acrolein and crotonaldehyde were associated with a 1.6 mm Hg (95%CI: 0.4, 2.7; p = 0.007) and a 0.8 mm Hg (95%CI: 0.01, 1.6; p = 0.049) higher systolic BP, and the styrene metabolite was associated with a 0.4 mm Hg (95%CI: 0.09, 0.8, p = 0.02) higher diastolic BP. Current smokers had 2.8 mm Hg (95% CI 0.5, 5.1) higher systolic BP. They were at higher risk of hypertension (relative risk = 1.2; 95% CI, 1.1, 1.4), and had higher urinary levels of several VOC metabolites. Individuals who smoke had higher levels of the urinary metabolites of acrolein, 1,3-butadiene, and crotonaldehyde and were associated with higher systolic BP. The associations were stronger among participants who were <60 years of age and male. Using Bayesian kernel machine regression to assess the effects of multiple VOC exposures, we found that the relationship between VOCs and hypertension among non-smokers was driven primarily by acrolein and styrene in non-smokers, and crotonaldehyde in smokers. CONCLUSIONS: Hypertension in Black individuals may be attributed, in part, to VOC exposure from the environment or tobacco smoke.

The Relationship between Perceptions and Objective Measures of Greenness.

Exposure to greenness has been studied through objective measures of remote visualization of greenspace; however, the link to how individuals interpret spaces as green is missing. We examined the associations between three objective greenspace measures with perceptions of greenness. We used a subsample (n = 175; 2018-2019) from an environmental cardiovascular risk cohort to investigate perceptions of residential greenness. Participants completed a 17-item survey electronically. Objective measurements of greenness within 300 m buffer around participants home included normalized difference vegetation index (NDVI), tree canopy and leaf area index. Principal component analysis reduced the perceived greenspaces to three dimensions reflecting natural vegetation, tree cover and built greenspace such as parks. Our results suggest significant positive associations between NDVI, tree canopy and leaf area and perceived greenness reflecting playgrounds; also, associations between tree canopy and perceived greenness reflecting tree cover. These findings indicate that the most used objective greenness measure, NDVI, as well as tree canopy and leaf area may most align with perceptions of parks, whereas tree canopy alone captures individuals' perceptions of tree cover. This highlights the need for research to understand the complexity of green metrics and careful interpretation of data based on the use of subjective or objective measures of greenness.

Community-Based Evaluation of the Associations Between Well-Being and Cardiovascular Disease Risk.

Background Although the effects of psychological health and optimism have been extensively investigated, data from community-based cohorts assessing the association between psychological health and cardiovascular disease risk factors are sparse, and the concurrent relationship between subjective well-being and cardiovascular health has not been studied. Methods and Results The current cross-sectional study examined the association between well-being and cardiovascular risk factors among 719 individuals living in a middle- to low-income neighborhood. After adjusting for age, sex, race, body mass index, education, smoking status, and exercise status, we found that higher levels of well-being were significantly associated with lower odds of dyslipidemia (odds ratio [OR], 0.7 [95% CI, 0.55-0.85]) and hypertension (OR, 0.8 [95% CI, 0.63-0.92]). Greater well-being was also significantly associated with lower triglyceride levels (mean difference [Mdiff], 7.6 [-14.31 to -0.78]), very low-density lipoprotein (Mdiff, 0.9 [-1.71 to -0.16]), total cholesterol to high-density lipoprotein ratio (Mdiff, 3.9 [-6.07 to -1.73]), higher high-density lipoprotein levels (Mdiff, 1.6 [0.46-2.75]), and lower Framingham Risk Scores (Mdiff, -7.1% [-10.84% to -3.16%]). Well-being also moderated the association between age and arterial stiffness. The strongest association between arterial stiffness and age was found for those with the lowest well-being scores; there was no association between age and arterial stiffness at high levels of well-being. Conclusions In a community-based cohort, individuals reporting higher levels of well-being have lower odds of hypertension and dyslipidemia as well as lower rates of age-dependent increase in vascular stiffness. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03670524.

E-cigarettes and their lone constituents induce cardiac arrhythmia and conduction defects in mice.

E-cigarette use has surged, but the long-term health effects remain unknown. E-cigarette aerosols containing nicotine and acrolein, a combustion and e-cigarette byproduct, may impair cardiac electrophysiology through autonomic imbalance. Here we show in mouse electrocardiograms that acute inhalation of e-cigarette aerosols disturbs cardiac conduction, in part through parasympathetic modulation. We demonstrate that, similar to acrolein or combustible cigarette smoke, aerosols from e-cigarette solvents (vegetable glycerin and propylene glycol) induce bradycardia, bradyarrhythmias, and elevations in heart rate variability during inhalation exposure, with inverse post-exposure effects. These effects are slighter with tobacco- or menthol-flavored aerosols containing nicotine, and in female mice. Yet, menthol-flavored and PG aerosols also increase ventricular arrhythmias and augment early ventricular repolarization (J amplitude), while menthol uniquely alters atrial and atrioventricular conduction. Exposure to e-cigarette aerosols from vegetable glycerin and its byproduct, acrolein, diminish heart rate and early repolarization. The pro-arrhythmic effects of solvent aerosols on ventricular repolarization and heart rate variability depend partly on parasympathetic modulation, whereas ventricular arrhythmias positively associate with early repolarization dependent on the presence of nicotine. Our study indicates that chemical constituents of e-cigarettes could contribute to cardiac risk by provoking pro-arrhythmic changes and stimulating autonomic reflexes.

Pyridine nucleotide redox potential in coronary smooth muscle couples myocardial blood flow to cardiac metabolism.

Adequate oxygen delivery to the heart during stress is essential for sustaining cardiac function. Acute increases in myocardial oxygen demand evoke coronary vasodilation and enhance perfusion via functional upregulation of smooth muscle voltage-gated K+ (Kv) channels. Because this response is controlled by Kv1 accessory subunits (i.e., Kvß), which are NAD(P)(H)-dependent aldo-keto reductases, we tested the hypothesis that oxygen demand modifies arterial [NAD(H)]i, and that resultant cytosolic pyridine nucleotide redox state influences Kv1 activity. High-resolution imaging mass spectrometry and live-cell imaging reveal cardiac workload-dependent increases in NADH:NAD+ in intramyocardial arterial myocytes. Intracellular NAD(P)(H) redox ratios reflecting elevated oxygen demand potentiate native coronary Kv1 activity in a Kvß2-dependent manner. Ablation of Kvß2 catalysis suppresses redox-dependent increases in Kv1 activity, vasodilation, and the relationship between cardiac workload and myocardial blood flow. Collectively, this work suggests that the pyridine nucleotide sensitivity and enzymatic activity of Kvß2 controls coronary vasoreactivity and myocardial blood flow during metabolic stress.

Mortality risk associated with greenness, air pollution, and physical activity in a representative U.S. cohort.

Several cohort studies suggest greenness is associated with decreased mortality risk. Potential confounding by or interactions between physical activity and air pollution remains unclear. This study evaluates associations of greenness, air pollution, and physical activity with mortality risk and investigates confounding and effect modification across these key risk factors. National Health Interview Survey (NHIS) data covering 1997-2014 were linked to the National Death Index to generate a cohort of 403,748 individuals with 39,528 deaths. Greenness, represented by census-tract Normalized Difference Vegetation Index (NDVI) for the seasonal period of May-October, was averaged over the years 2003-2016. Air pollution was estimated by census-tract level PM2.5 concentrations from 1999 to 2015. Cox Proportional Hazard Models were used to estimate hazard ratios (HR) for differences in greenness, air pollution, and physical activity. Alternative models that evaluated potential confounding and stratified models that evaluated effect modification were examined. Mortality risks were associated with PM2.5 (HR = 1.14, 95% CI: 1.09-1.19 per 10 µg/m3) and physical inactivity (1.49, 1.44-1.54 relative to sufficiently active), but not with greenness (1.01, 0.99-1.03 per IQR). The PM2.5-mortality association was mitigated at high levels of greenness (1.05, 0.91-1.22). There was no strong evidence of confounding between air pollution, physical activity, and greenness. However, stratified analysis suggested effect modification for PM2.5 and NDVI by physical activity. A significant protective greenness-mortality association was observed for only highly active individuals (0.91, 0.86-0.96). Also, relatively high PM2.5-mortality HRs were observed for more physically active individuals (1.25, 1.12-1.40). PM2.5 air pollution and physical inactivity are robustly associated with mortality risk. Greenness may be most beneficial and air pollution relatively harmful to highly active individuals. This analysis provides evidence that, in addition to not smoking, being physically active and living in a clean, green environment contributes to improved health and reduced risk of mortality.

Environmental exposure to volatile organic compounds is associated with endothelial injury.

OBJECTIVE: Volatile organic compounds (VOCs) are airborne toxicants abundant in outdoor and indoor air. High levels of VOCs are also present at various Superfund and other hazardous waste sites; however, little is known about the cardiovascular effects of VOCs. We hypothesized that ambient exposure to VOCs exacerbate cardiovascular disease (CVD) risk by depleting circulating angiogenic cells (CACs). APPROACH AND RESULTS: In this cross-sectional study, we recruited 603 participants with low-to-high CVD risk and measured 15 subpopulations of CACs by flow cytometry and 16 urinary metabolites of 12 VOCs by LC/MS/MS. Associations between CAC and VOC metabolite levels were examined using generalized linear models in the total sample, and separately in non-smokers. In single pollutant models, metabolites of ethylbenzene/styrene and xylene, were negatively associated with CAC levels in both the total sample, and in non-smokers. The metabolite of acrylonitrile was negatively associated with CD45dim/CD146+/CD34+/AC133+ cells and CD45+/CD146+/AC133+, and the toluene metabolite with AC133+ cells. In analysis of non-smokers (n = 375), multipollutant models showed a negative association with metabolites of ethylbenzene/styrene, benzene, and xylene with CD45dim/CD146+/CD34+ cells, independent of other VOC metabolite levels. Cumulative VOC risk score showed a strong negative association with CD45dim/CD146+/CD34+ cells, suggesting that total VOC exposure has a cumulative effect on pro-angiogenic cells. We found a non-linear relationship for benzene, which showed an increase in CAC levels at low, but depletion at higher levels of exposure. Sex and race, hypertension, and diabetes significantly modified VOC associated CAC depletion. CONCLUSION: Low-level ambient exposure to VOCs is associated with CAC depletion, which could compromise endothelial repair and angiogenesis, and exacerbate CVD risk.

Fine particulate matter air pollution and aortic perivascular adipose tissue: Oxidative stress, leptin, and vascular dysfunction.

Exposure to fine particulate matter (PM2.5 ) air pollution increases blood pressure, induces vascular inflammation and dysfunction, and augments atherosclerosis in humans and rodents; however, the understanding of early changes that foster chronic vascular disease is incomplete. Because perivascular adipose tissue (PVAT) inflammation is implicated in chronic vascular diseases, we investigated changes in aortic PVAT following short-term air pollution exposure. Mice were exposed to HEPA-filtered or concentrated ambient PM2.5 (CAP) for 9 consecutive days, and the abundance of inflammatory, adipogenic, and adipokine gene mRNAs was measured by gene array and qRT-PCR in thoracic aortic PVAT. Responses of the isolated aorta with and without PVAT to contractile (phenylephrine, PE) and relaxant agonists (acetylcholine, ACh; sodium nitroprusside, SNP) were measured. Exposure to CAP significantly increased the urinary excretion of acrolein metabolite (3HPMA) as well as the abundance of protein-acrolein adducts (a marker of oxidative stress) in PVAT and aorta, upregulated PVAT leptin mRNA expression without changing mRNA levels of several proinflammatory genes, and induced PVAT insulin resistance. In control mice, PVAT significantly depressed PE-induced contractions-an effect that was dampened by CAP exposure. Pulmonary overexpression of extracellular dismutase (ecSOD-Tg) prevented CAP-induced effects on urinary 3HPMA levels, PVAT Lep mRNA, and alterations in PVAT and aortic function, reflecting a necessary role of pulmonary oxidative stress in all of these deleterious CAP-induced changes. More research is needed to address how exactly short-term exposure to PM2.5 perturbs PVAT and aortic function, and how these specific genes and functional changes in PVAT could lead over time to chronic inflammation, endothelial dysfunction, and atherosclerosis.

Greenness, air pollution, and mortality risk: A U.S. cohort study of cancer patients and survivors.

BACKGROUND: Several studies suggest that living in areas of high surrounding greenness may be associated with a lower cardiopulmonary mortality risk. However, associations of greenness with specific causes of death in cancer patients and survivors has not been examined and it is unknown whether this relationship is affected by area levels of fine particulate matter air pollution (PM2.5). This study evaluated associations between greenness and PM2.5 on causes of death in a large, U.S.-based cohort of cancer patients and survivors. METHODS: Surveillance, Epidemiology and End Results (SEER) data were used to generate a cohort of 5,529,005 cancer patients and survivors from 2000 to 2016. Census-tract Normalized Difference Vegetation Index (NDVI) during May-October from 2003 to 2016 was population-weighted to act as a county-level greenness measure. County-level PM2.5 exposure was estimated from annual concentrations averaged from 1999 to 2015. Cox Proportional Hazards models were used to estimate the association between greenness, PM2.5, and cause-specific mortality while controlling for age, sex, race, and other individual and county level variables. FINDINGS: An IQR increase in greenness was associated with a decrease in cancer mortality for cancer patients (Hazard ratio of 0.94, 95% CI: 0.93-0.95), but not for cardiopulmonary mortality (0.98, 95% CI: 0.96-1.00). Inversely, an increase in 10 µg/m3 PM2.5 was associated with increased cardiopulmonary mortality (1.24, 95% CI: 1.19-1.29), but not cancer mortality (0.99, 95% CI: 0.97-1.00). Hazard ratios were robust to inclusion of PM2.5 in models with greenness and vice versa. Although exposure estimates were constant over most stratifications, greenness seemed to benefit individuals diagnosed with high survivability cancers (0.92, 95% CI: 0.90-0.95) more than those with low survivability cancers (0.98. 95% CI: 0.96-0.99). INTERPRETATION: Higher levels of greenness are associated with lower cancer mortality in cancer patients. The evidence suggests minimal confounding between greenness and PM2.5 exposures and risk of mortality.

Omega-3 polyunsaturated fatty acids modify the inverse association between systemic inflammation and cardiovascular fitness.

BACKGROUND AND OBJECTIVE: Exercise increases quality of life and lowers all-cause mortality, likely by preventing cardiovascular disease. Although the beneficial effects of exercise are linked with reductions in chronic inflammation, individual responses vary and factors that contribute to the anti-inflammatory effects of cardiovascular fitness remain largely undefined. We sought to investigate the role of fatty acids in the inverse relationship between inflammation and cardiovascular fitness. APPROACH AND RESULTS: In this cross-sectional study using data from 435 participants in NHANES and linear regression models with CRP as the outcome, we observed significant negative interactions between VO2max and omega-3 polyunsaturated fatty acids (PUFAs) but not saturated, monounsaturated, or omega-6 PUFAs. When stratified by omega-3 PUFA tertiles, participants in the medium tertile, but not low tertile, show an enhanced negative association between VO2max and CRP, with a -32.0% difference (95% CI: -44.95, -15.9%) per 10 mL/kg/min of VO2max. Exploratory factor analysis identified five unique dietary fatty acid (FA) profiles. The FA profile consisting predominantly of omega-3 PUFA had the strongest negative association for VO2max and CRP, with a -28.2% difference in CRP (95% CI: -43.4, -8.9) per 10 mL/kg/min of VO2max. We also found that alpha-linolenic acid (ALA) and docosahexaenoic acid (DHA) enhanced the negative association between VO2max and CRP, suggesting that the anti-inflammatory response to VO2max capacity is associated with ALA and DHA levels. Males, Whites, and individuals with lower BMI were more sensitive to the effects of omega-3 PUFAs, while having high SFA levels attenuated the benefit. CONCLUSIONS: This study suggests that omega-3 PUFAs are effect modifiers for VO2max and CRP and that the anti-inflammatory benefits of increasing cardiovascular fitness are associated with omega-3 PUFAs.

Exposure to volatile organic compounds - acrolein, 1,3-butadiene, and crotonaldehyde - is associated with vascular dysfunction.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Exposure to air pollution, specifically particulate matter of diameter ≤2.5 µm (PM2.5), is a well-established risk factor for CVD. However, the contribution of gaseous pollutant exposure to CVD risk is less clear. OBJECTIVE: To examine the vascular effects of exposure to individual volatile organic compounds (VOCs) and mixtures of VOCs. METHODS: We measured urinary metabolites of acrolein (CEMA and 3HPMA), 1,3-butadiene (DHBMA and MHBMA3), and crotonaldehyde (HPMMA) in 346 nonsmokers with varying levels of CVD risk. On the day of enrollment, we measured blood pressure (BP), reactive hyperemia index (RHI - a measure of endothelial function), and urinary levels of catecholamines and their metabolites. We used generalized linear models for evaluating the association between individual VOC metabolites and BP, RHI, and catecholamines, and we used Bayesian Kernel Machine Regression (BKMR) to assess exposure to VOC metabolite mixtures and BP. RESULTS: We found that the levels of 3HPMA were positively associated with systolic BP (0.98 mmHg per interquartile range (IQR) of 3HPMA; CI: 0.06, 1.91; P = 0.04). Stratified analysis revealed an increased association with systolic BP in Black participants despite lower levels of urinary 3HPMA. This association was independent of PM2.5 exposure and BP medications. BKMR analysis confirmed that 3HPMA was the major metabolite associated with higher BP in the presence of other metabolites. We also found that 3HPMA and DHBMA were associated with decreased endothelial function. For each IQR of 3HPMA or DHBMA, there was a -4.4% (CI: -7.2, -0.0; P = 0.03) and a -3.9% (CI: -9.4, -0.0; P = 0.04) difference in RHI, respectively. Although in the entire cohort the levels of several urinary VOC metabolites were weakly associated with urinary catecholamines and their metabolites, in Black participants, DHBMA levels showed strong associations with urinary norepinephrine and normetanephrine levels. DISCUSSION: Exposure to acrolein and 1,3-butadiene is associated with endothelial dysfunction and may contribute to elevated risk of hypertension in participants with increased sympathetic tone, particularly in Black individuals.

Urinary Levels of the Acrolein Conjugates of Carnosine Are Associated with Cardiovascular Disease Risk.

Carnosine is a naturally occurring dipeptide (ß-alanine-L-histidine) which supports physiological homeostasis by buffering intracellular pH, chelating metals, and conjugating with and neutralizing toxic aldehydes such as acrolein. However, it is not clear if carnosine can support cardiovascular function or modify cardiovascular disease (CVD) risk. To examine this, we measured urinary levels of nonconjugated carnosine and its acrolein conjugates (carnosine-propanal and carnosine-propanol) in participants of the Louisville Healthy Heart Study and examined associations with indices of CVD risk. We found that nonconjugated carnosine was significantly associated with hypertension (p = 0.011), heart failure (p = 0.015), those categorized with high CVD risk (p < 0.001), body mass index (BMI; p = 0.007), high sensitivity C-reactive protein (hsCRP; p = 0.026), high-density lipoprotein (HDL; p = 0.007) and certain medication uses. Levels of carnosine-propanal and carnosine-propanol demonstrated significant associations with BMI, blood glucose, HDL and diagnosis of diabetes. Carnosine-propanal was also associated with heart failure (p = 0.045) and hyperlipidemia (p = 0.002), but no associations with myocardial infarction or stroke were identified. We found that the positive associations of carnosine conjugates with diabetes and HDL remain statistically significant (p < 0.05) in an adjusted, linear regression model. These findings suggest that urinary levels of nonconjugated carnosine, carnosine-propanal and carnosine-propanol may be informative biomarkers for the assessment of CVD risk-and particularly reflective of skeletal muscle injury and carnosine depletion in diabetes.

Residential proximity to greenness mitigates the hemodynamic effects of ambient air pollution.

Residential proximity to greenness is associated with a lower risk of cardiovascular disease (CVD) and all-cause mortality. However, it is unclear whether the beneficial effects of greenness are linked to a reduction in the effects of ambient air pollutants. We measured arterial stiffness in 73 participants with moderate to high CVD risk. Average levels of ambient PM2.5 and ozone were calculated from local monitoring stations. Residential greenness was estimated using satellite-derived normalized difference vegetation index (NDVI) for a 200-m and 1-km radius around each participant's home. Participants were 51% female, average age of 52 yr, and 79% had diagnosed hypertension. In multiple linear regression models, residential NDVI was negatively associated with augmentation index (-3.8% per 0.1 NDVI). Ambient levels of PM2.5 [per interquartile range (IQR) of 6.9 µg/m3] were positively associated with augmentation pressure (3.1 mmHg), pulse pressure (5.9 mmHg), and aortic systolic pressure (8.1 mmHg). Ozone (per IQR of 0.03 ppm) was positively associated with augmentation index (5.5%), augmentation pressure (3.1 mmHg), and aortic systolic pressure (10 mmHg). In areas of low greenness, both PM2.5 and ozone were positively associated with pulse pressure. Additionally, ozone was positively associated with augmentation pressure and systolic blood pressure. However, in areas of high greenness, there was no significant association between indices of arterial stiffness with either PM2.5 or ozone. Residential proximity to greenness is associated with lower values of arterial stiffness. Residential greenness may mitigate the adverse effects of PM2.5 and ozone on arterial stiffness.NEW & NOTEWORTHY Previous studies have linked proximity to green spaces with lower cardiovascular disease risk. However, the mechanisms underlying the salutary effects of green areas are not known. In our study of participants at risk of cardiovascular disease, we found that arterial stiffness was positively associated with short-term exposure to PM2.5, PM10, and ozone and inversely associated with greenness. The association between pollution and arterial stiffness was attenuated in areas of high greenness, suggesting that living green neighborhoods can lessen the adverse cardiovascular effects of air pollution.

Urinary levels of the acrolein conjugates of carnosine are associated with inhaled toxicants.

OBJECTIVE: The inhalation of air-borne toxicants is associated with adverse health outcomes which can be somewhat mitigated by enhancing endogenous anti-oxidant capacity. Carnosine is a naturally occurring dipeptide (ß-alanine-L-histidine), present in high abundance in skeletal and cardiac muscle. This multi-functional dipeptide has anti-oxidant properties, can buffer intracellular pH, chelate metals, and sequester aldehydes such as acrolein. Due to these chemical properties, carnosine may be protective against inhaled pollutants which can contain metals and aldehydes and can stimulate the generation of electrophiles in exposed tissues. Thus, assessment of carnosine levels, or levels of its acrolein conjugates (carnosine-propanal and carnosine-propanol) may inform on level of exposure and risk assessment. METHODS: We used established mass spectroscopy methods to measure levels of urinary carnosine (n = 605) and its conjugates with acrolein (n = 561) in a subset of participants in the Louisville Healthy Heart Study (mean age = 51 ± 10; 52% male). We then determined associations between these measures and air pollution exposure and smoking behavior using statistical modeling approaches. RESULTS: We found that higher levels of non-conjugated carnosine, carnosine-propanal, and carnosine-propanol were significantly associated with males (p < 0.02) and those of Caucasian ethnicity (p < 0.02). Levels of carnosine-propanol were significantly higher in never-smokers (p = 0.001) but lower in current smokers (p = 0.037). This conjugate also demonstrated a negative association with mean-daily particulate air pollution (PM2.5) levels (p = 0.01). CONCLUSIONS: These findings suggest that urinary levels of carnosine-propanol may inform as to risk from inhaled pollutants.