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.

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.

Electronic Cigarette Solvents, JUUL E-Liquids, and Biomarkers of Exposure: In Vivo Evidence for Acrolein and Glycidol in E-Cig-Derived Aerosols.

Despite the increasing popularity of e-cigarettes, their long-term health effects remain unknown. In animal models, exposure to e-cigarette has been reported to result in pulmonary and cardiovascular injury, and in humans, the acute use of e-cigarettes increases heart rate and blood pressure and induces endothelial dysfunction. In both animal models and humans, cardiovascular dysfunction associated with e-cigarettes has been linked to reactive aldehydes such as formaldehyde and acrolein generated in e-cigarette aerosols. These aldehydes are known products of heating and degradation of vegetable glycerin (VG) present in e-liquids. Here, we report that in mice, acute exposure to a mixture of propylene glycol:vegetable glycerin (PG:VG) or to e-cigarette-derived aerosols significantly increased the urinary excretion of acrolein and glycidol metabolites─3-hydroxypropylmercapturic acid (3HPMA) and 2,3-dihydroxypropylmercapturic acid (23HPMA)─as measured by UPLC-MS/MS. In humans, the use of e-cigarettes led to an increase in the urinary levels of 23HPMA but not 3HPMA. Acute exposure of mice to aerosols derived from PG:13C3-VG significantly increased the 13C3 enrichment of both urinary metabolites 13C3-3HPMA and 13C3-23HPMA. Our stable isotope tracing experiments provide further evidence that thermal decomposition of vegetable glycerin in the e-cigarette solvent leads to generation of acrolein and glycidol. This suggests that the adverse health effects of e-cigarettes may be attributable in part to these reactive compounds formed through the process of aerosolizing nicotine. Our findings also support the notion that 23HPMA, but not 3HPMA, may be a relatively specific biomarker of e-cigarette use.

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.

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.

Cardiac mesenchymal cells from failing and nonfailing hearts limit ventricular dilation when administered late after infarction.

Although cell therapy-mediated cardiac repair offers promise for treatment/management of heart failure, lack of fundamental understanding of how cell therapy works limits its translational potential. In particular, whether reparative cells from failing hearts differ from cells derived from nonfailing hearts remains unexplored. Here, we assessed differences between cardiac mesenchymal cells (CMC) derived from failing (HF) versus nonfailing (Sham) hearts and whether the source of donor cells (i.e., from HF vs. Sham) limits reparative capacity, particularly when administered late after infarction. To determine the impact of the donor source of CMCs, we characterized the transcriptional profile of CMCs isolated from sham (Sham-CMC) and failing (HF-CMC) hearts. RNA-seq analysis revealed unique transcriptional signatures in Sham-CMC and HF-CMC, suggesting that the donor source impacts CMC. To determine whether the donor source affects reparative potential, C57BL6/J female mice were subjected to 60 min of regional myocardial ischemia and then reperfused for 35 days. In a randomized, controlled, and blinded fashion, vehicle, HF-CMC, or Sham-CMC were injected into the lumen of the left ventricle at 35 days post-MI. An additional 5 weeks later, cardiac function was assessed by echocardiography, which indicated that delayed administration of Sham-CMC and HF-CMC attenuated ventricular dilation. We also determined whether Sham-CMC and HF-CMC treatments affected ventricular histopathology. Our data indicate that the donor source (nonfailing vs. failing hearts) affects certain aspects of CMC, and these insights may have implications for future studies. Our data indicate that delayed administration of CMC limits ventricular dilation and that the source of CMC may influence their reparative actions.NEW & NOTEWORTHY Most preclinical studies have used only cells from healthy, nonfailing hearts. Whether donor condition (i.e., heart failure) impacts cells used for cell therapy is not known. We directly tested whether donor condition impacted the reparative effects of cardiac mesenchymal cells in a chronic model of myocardial infarction. Although cells from failing hearts differed in multiple aspects, they retained the potential to limit ventricular remodeling.

Defining the Human Envirome: An Omics Approach for Assessing the Environmental Risk of Cardiovascular Disease.

Both genetic and environmental factors contribute to the development of cardiovascular disease, but in comparison with genetics, environmental factors have received less attention. Evaluation of environmental determinants of cardiovascular disease is limited by the lack of comprehensive omics approaches for integrating multiple environmental exposures. Hence, to understand the effects of the environment as a whole (envirome), it is important to delineate specific domains of the environment and to assess how, individually and collectively; these domains affect cardiovascular health. In this review, we present a hierarchical model of the envirome; defined by 3 consecutively nested domains, consisting of natural, social, and personal environments. Extensive evidence suggests that features of the natural environment such as sunlight, altitude, diurnal rhythms, vegetation, and biodiversity affect cardiovascular health. However, the effects of the natural environment are moderated by the social environment comprised of built environments, agricultural and industrial activities, pollutants and contaminants, as well as culture, economic activities, and social networks that affect health by influencing access to healthcare, social cohesion, and socioeconomic status. From resources available within society, individuals create personal environments, characterized by private income, wealth and education, and populated by behavioral and lifestyle choices relating to nutrition, physical activity, sleep, the use of recreational drugs, and smoking. An understanding of the interactions between different domains of the envirome and their integrated effects on cardiovascular health could lead to the development of new prevention strategies and deeper insights into etiologic processes that contribute to cardiovascular disease risk and susceptibility.

National secular trends in ambient air volatile organic compound levels and biomarkers of exposure in the United States.

BACKGROUND: Exposure to air pollution is a leading cause of global mortality. Volatile organic compounds (VOCs) are constituents of ambient air that could exert adverse health effects. OBJECTIVE: To examine the relationship between VOC levels in ambient air and individual-level exposure to VOCs, as assessed by urinary VOC metabolites. METHODS: Secular trends in 11 ambient air VOCs (2005-2013) and individual-level metabolites of 14 VOCs (2005-2014) were assessed using National Monitoring Programs (NMP) and National Health and Nutrition Examination Survey (NHANES) data, respectively. To isolate environmental exposure, individuals reporting exposure to tobacco smoke were excluded. Quantile regression models were used to assess secular trends in VOC exposure, and survey-weighted regression models were built to identify factors associated with VOC exposure. RESULTS: All annual levels of ambient VOCs decreased from 2005 to 2013 (Range: 12.5%-77.2%). However, 11 of the corresponding VOC metabolites increased during the same time (Range: 0.3%-53.6%). There was a proportional change in patterns of VOC exposure across NHANES waves, with the middle quantiles of exposure showing the largest increase. VOC exposures were significantly associated with age, sex, race, education, and physical inactivity, but not with secular VOC trends. DISCUSSION: In the United States, individual-level exposure to several VOCs increased between 2005 and 2014 despite a decline in ambient air VOC levels. This inverse relationship suggests that ambient VOCs are not the primary source of VOC exposure, therefore, decreasing ambient VOCs alone may not be sufficient to protect against the adverse health effects associated with VOC exposure.

Exposure to airborne fine particulate matter is associated with impaired endothelial function and biomarkers of oxidative stress and inflammation.

Epidemiological evidence suggests that exposure to air pollution is a leading risk factor for cardiovascular disease (CVD). However, there is little direct evidence linking exposure to vascular dysfunction. We conducted a cross-sectional study of 100 participants, recruited from the University of Louisville Clinics. Endothelial function was assessed by calculating the reactive hyperemia index (RHI). Oxidative stress was indexed by measuring urinary levels of isoprostanes (n = 91). Inflammatory biomarkers were measured in the plasma (n = 80). Daily average PM2.5 levels were obtained from regional monitoring stations. Adjusted associations between PM2.5 levels and measured outcomes were tested using generalized linear models. The average age of participants was 48 years (44% male, 62% white); 52% had a diagnosis of hypertension, and 44% had type-2 diabetes. A 12.4% decrease in RHI was associated with 10 µg/m3 increase in PM2.5 (95% CI: 21.0, -2.7). The F-2 isoprostane metabolite showed a positive association of 28.4% (95% CI: 2.7, 60.3) per 10 µg/m3 increase in PM2.5. Positive associations were observed with angiopoietin 1 (17.4%; 95% CI: 2.8, 33.8), vascular endothelial growth factor (10.4%; 95% CI: 0.6, 21.0), placental growth factor (31.7%; 95% CI: 12.2, 54.5), intracellular adhesion molecule-1 (24.6%; 95% CI: 1.6, 52.8), and matrix metalloproteinase-9 (30.3%; 95% CI: 8.0, 57.5) per 10 µg/m3 increase in PM2.5. Additionally, a 10 µg/m3 increase in PM2.5 was associated with 15.9% decrease in vascular cell adhesion molecule-1 (95% CI: 28.3, -1.3). These findings suggest that exposure to PM2.5 is associated with impaired vascular function, which may result from oxidative stress and inflammation, thereby leading to a pro-atherogenic state.

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.

E2f1 deletion attenuates infarct-induced ventricular remodeling without affecting O-GlcNAcylation.

Several post-translational modifications figure prominently in ventricular remodeling. The beta-O-linkage of N-acetylglucosamine (O-GlcNAc) to proteins has emerged as an important signal in the cardiovascular system. Although there are limited insights about the regulation of the biosynthetic pathway that gives rise to the O-GlcNAc post-translational modification, much remains to be elucidated regarding the enzymes, such as O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which regulate the presence/absence of O-GlcNAcylation. Recently, we showed that the transcription factor, E2F1, could negatively regulate OGT and OGA expression in vitro. The present study sought to determine whether E2f1 deletion would improve post-infarct ventricular function by de-repressing expression of OGT and OGA. Male and female mice were subjected to non-reperfused myocardial infarction (MI) and followed for 1 or 4 week. MI significantly increased E2F1 expression. Deletion of E2f1 alone was not sufficient to alter OGT or OGA expression in a naïve setting. Cardiac dysfunction was significantly attenuated at 1-week post-MI in E2f1-ablated mice. During chronic heart failure, E2f1 deletion also attenuated cardiac dysfunction. Despite the improvement in function, OGT and OGA expression was not normalized and protein O-GlcNAcyltion was not changed at 1-week post-MI. OGA expression was significantly upregulated at 4-week post-MI but overall protein O-GlcNAcylation was not changed. As an alternative explanation, we also performed guided transcriptional profiling of predicted targets of E2F1, which indicated potential differences in cardiac metabolism, angiogenesis, and apoptosis. E2f1 ablation increased heart size and preserved remote zone capillary density at 1-week post-MI. During chronic heart failure, cardiomyocytes in the remote zone of E2f1-deleted hearts were larger than wildtype. These data indicate that, overall, E2f1 exerts a deleterious effect on ventricular remodeling. Thus, E2f1 deletion improves ventricular remodeling with limited impact on enzymes regulating O-GlcNAcylation.

Carnosine protects cardiac myocytes against lipid peroxidation products.

Endogenous histidyl dipeptides such as carnosine (ß-alanine-L-histidine) form conjugates with lipid peroxidation products such as 4-hydroxy-trans-2-nonenal (HNE and acrolein), chelate metals, and protect against myocardial ischemic injury. Nevertheless, it is unclear whether these peptides protect against cardiac injury by directly reacting with lipid peroxidation products. Hence, to examine whether changes in the structure of carnosine could affect its aldehyde reactivity and metal chelating ability, we synthesized methylated analogs of carnosine, balenine (ß-alanine-Nτ-methylhistidine) and dimethyl balenine (DMB), and measured their aldehyde reactivity and metal chelating properties. We found that methylation of Nτ residue of imidazole ring (balenine) or trimethylation of carnosine backbone at Nτ residue of imidazole ring and terminal amine group dimethyl balenine (DMB) abolishes the ability of these peptides to react with HNE. Incubation of balenine with acrolein resulted in the formation of single product (m/z 297), whereas DMB did not react with acrolein. In comparison with carnosine, balenine exhibited moderate acrolein quenching capacity. The Fe2+ chelating ability of balenine was higher than that of carnosine, whereas DMB lacked chelating capacity. Pretreatment of cardiac myocytes with carnosine increased the mean lifetime of myocytes superfused with HNE or acrolein compared with balenine or DMB. Collectively, these results suggest that carnosine protects cardiac myocytes against HNE and acrolein toxicity by directly reacting with these aldehydes. This reaction involves both the amino group of ß-alanyl residue and the imidazole residue of L-histidine. Methylation of these sites prevents or abolishes the aldehyde reactivity of carnosine, alters its metal-chelating property, and diminishes its ability to prevent electrophilic injury.

Comparison of Urinary Biomarkers of Exposure in Humans Using Electronic Cigarettes, Combustible Cigarettes, and Smokeless Tobacco.

BACKGROUND: Cigarette smoking is associated with an increase in cardiovascular disease risk, attributable in part to reactive volatile organic chemicals (VOCs). However, little is known about the extent of VOC exposure due to the use of other tobacco products. METHODS: We recruited 48 healthy, tobacco users in four groups: cigarette, smokeless tobacco, occasional users of first generation e-cigarette and e-cigarette menthol and 12 healthy nontobacco users. After abstaining for 48 h, tobacco users used an assigned product. Urine was collected at baseline followed by five collections over a 3-h period to measure urinary metabolites of VOCs, nicotine, and tobacco alkaloids. RESULTS: Urinary levels of nicotine were ≃2-fold lower in occasional e-cigarette and smokeless tobacco users than in the cigarette smokers; cotinine and 3-hydroxycotinine levels were similar in all groups. Compared with nontobacco users, e-cigarette users had higher levels of urinary metabolites of xylene, cyanide, styrene, ethylbenzene, and benzene at baseline and elevated urinary levels of metabolites of xylene, N,N-dimethylformamide, and acrylonitrile after e-cigarette use. Metabolites of acrolein, crotonaldehyde, and 1,3-butadiene were significantly higher in smokers than in users of other products or nontobacco users. VOC metabolite levels in smokeless tobacco group were comparable to those found in nonusers with the exception of xylene metabolite-2-methylhippuric acid (2MHA), which was almost three fold higher than in nontobacco users. CONCLUSIONS: Smoking results in exposure to a range of VOCs at concentrations higher than those observed with other products, and first generation e-cigarette use is associated with elevated levels of N,N-dimethylformamide and xylene metabolites. IMPLICATIONS: This study shows that occasional users of first generation e-cigarettes have lower levels of nicotine exposure than the users of combustible cigarettes. Compared with combustible cigarettes, e-cigarettes, and smokeless tobacco products deliver lower levels of most VOCs, with the exception of xylene, N,N-dimethylformamide, and acrylonitrile, whose metabolite levels were higher in the urine of e-cigarette users than nontobacco users. Absence of anatabine in the urine of e-cigarette users suggests that measuring urinary levels of this alkaloid may be useful in distinguishing between users of e-cigarettes and combustible cigarettes. However, these results have to be validated in a larger cohortcomprised of users of e-cigarettes of multiple brands.

Nicotine Metabolism in Adults With Type 2 Diabetes.

INTRODUCTION: Metabolism of nicotine has implications for addiction and may be altered in people with type 2 diabetes. Thus, our objective was to analyze nicotine metabolism in adults with and without type 2 diabetes who smoke. METHODS: From an existing cross-sectional study, we analyzed nicotine metabolism in urine of 148 smokers, 36 type 2 diabetics (insulin or antidiabetic medication use and/or fasting glucose >126 mg/dL) and 112 non-diabetics. Nicotine metabolism was quantified as the nicotine metabolite ratio (NMR) = trans-3'-hydroxycotinine (3HC) divided by cotinine (COT). COT and 3HC were measured in the participant urine by ultra-performance liquid chromatography-tandem mass spectrometry. Generalized linear models were used to assess whether NMR was associated with diabetic status (yes/no). RESULTS: Participants categorized as high NMR smoked more cigarettes per day (p = .002) and were more likely to be diabetic (p = .022) compared to low NMR. We found no significant difference in total nicotine equivalents defined as the sum of the nicotine, COT, and 3HC (p > .05). In unadjusted models, NMR was 42.5% higher in diabetics versus non-diabetics (95% confidence interval [CI]: 12.9, 79.8; p = .003). In models adjusted for factors significantly different between low versus high NMR participants, mean NMR was 36.5% higher in the diabetics versus non-diabetics (95% CI: 7.8, 72.8; p = .010). Additionally, in models adjusted for known confounders of NMR, NMR was 40.6% higher in diabetics versus non-diabetics (95% CI: 9.9, 80.0; p = .007). CONCLUSIONS: From these data, we infer that type 2 diabetics metabolize nicotine faster, which may increase the potential for nicotine addiction. IMPLICATIONS: Smoking is addictive and this addiction may be related to tobacco metabolism. Individuals with faster metabolism of nicotine tend to smoke more cigarettes for longer periods of time. People with type 2 diabetes may metabolize nicotine faster, which could lead to higher lifetime tobacco burden, increasing the adverse health outcomes associated with increased exposure to tobacco.

Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury.

RATIONALE: Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed. OBJECTIVE: We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury. METHODS AND RESULTS: In adult male C57BL/6 mouse hearts, Gstp1/2 was the most abundant GST transcript followed by Gsta4 and Gstm4.1, and GSTP activity was a significant fraction of the total GST activity. mGstp1/2 deletion reduced total GST activity, but no compensatory increase in GSTA and GSTM or major antioxidant enzymes was observed. Genetic deficiency of GSTP did not alter cardiac function, but in comparison with hearts from wild-type mice, the hearts isolated from GSTP-null mice were more sensitive to I/R injury. Disruption of the GSTP gene also increased infarct size after coronary occlusion in situ. Ischemia significantly increased acrolein in hearts, and GSTP deficiency induced significant deficits in the metabolism of the unsaturated aldehyde, acrolein, but not in the metabolism of 4-hydroxy-trans-2-nonenal or trans-2-hexanal; on ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than wild-type hearts. GSTP deficiency did not affect I/R-induced free radical generation, c-Jun N-terminal kinase activation, or depletion of reduced glutathione. Acrolein exposure induced a hyperpolarizing shift in INa, and acrolein-induced cell death was delayed by SN-6, a Na(+)/Ca(++) exchange inhibitor. Cardiomyocytes isolated from GSTP-null hearts were more sensitive than wild-type myocytes to acrolein-induced protein crosslinking and cell death. CONCLUSIONS: GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes, such as acrolein.

Visual Dysfunctions at Different Stages after Blast and Non-blast Mild Traumatic Brain Injury.

PURPOSE: To assess the prevalence of visual dysfunctions and associated symptoms in war fighters at different stages after non-blast- or blast-induced mild traumatic brain injury (mTBI). METHODS: A comprehensive retrospective review of the electronic health records of 500 U.S. military personnel with a diagnosis of deployment-related mTBI who received eye care at the Landstuhl Regional Medical Center. For analysis, the data were grouped by mechanism of injury, and each group was further divided in three subgroups based on the number of days between injury and initial eye examination. RESULTS: The data showed a high frequency of visual symptoms and visual dysfunctions. However, the prevalence of visual symptoms and visual dysfunctions did not differ significantly between mechanism of injury and postinjury stage, except for eye pain and diplopia. Among visual symptoms, binocular dysfunctions were more common, including higher near vertical phoria, reduced negative fusional vergence break at near, receded near point of convergence, decreased stereoacuity, and reduced positive relative accommodation. CONCLUSIONS: The lack of difference in terms of visual sequelae between subgroups (blast vs. nonblast) suggests that research addressing the assessment and management of mTBI visual sequelae resulting from civilian nonblast events is relevant to military personnel where combat injury results primarily from a blast event.

Residential Proximity to Major Roadways Is Associated With Increased Levels of AC133+ Circulating Angiogenic Cells.

OBJECTIVES: Previous studies have shown that residential proximity to a roadway is associated with increased cardiovascular disease risk. Yet, the nature of this association remains unclear, and its effect on individual cardiovascular disease risk factors has not been assessed. The objective of this study was to determine whether residential proximity to roadways influences systemic inflammation and the levels of circulating angiogenic cells. APPROACH AND RESULTS: In a cross-sectional study, cardiovascular disease risk factors, blood levels of C-reactive protein, and 15 antigenically defined circulating angiogenic cell populations were measured in participants (n=316) with moderate-to-high cardiovascular disease risk. Attributes of roadways surrounding residential locations were assessed using geographic information systems. Associations between road proximity and cardiovascular indices were analyzed using generalized linear models. Close proximity (<50 m) to a major roadway was associated with lower income and higher rates of smoking but not C-reactive protein levels. After adjustment for potential confounders, the levels of circulating angiogenic cells in peripheral blood were significantly elevated in people living in close proximity to a major roadway (CD31(+)/AC133(+), AC133(+), CD34(+)/AC133(+), and CD34(+)/45(dim)/AC133(+) cells) and positively associated with road segment distance (CD31(+)/AC133(+), AC133(+), and CD34(+)/AC133(+) cells), traffic intensity (CD31(+)/AC133(+) and AC133(+) cells), and distance-weighted traffic intensity (CD31(+)/34(+)/45(+)/AC133(+) cells). CONCLUSIONS: Living close to a major roadway is associated with elevated levels of circulating cells positive for the early stem marker AC133(+). This may reflect an increased need for vascular repair. Levels of these cells in peripheral blood may be a sensitive index of cardiovascular injury because of residential proximity to roadways.

Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells.

Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormone-bound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.