Allostatic load (AL) represents the cumulative physiological burden from activation of adaptive response systems. High AL, resulting from multisystemic dysregulation after chronic activation of response systems, is associated with chronic disease risk. Volatile organic compound (VOC) exposure may contribute to this dysregulation, but the impact on AL is unclear. In this study, we evaluated the association between urinary VOC metabolites and AL in 959 adult participants of the Green Heart Louisville Project across four visits (2018 or 2019, 2021, 2022, 2023). We quantified AL using a Mahalanobis Distance-based index (AL-MD) derived from 15 biomarkers spanning cardiovascular, metabolic, immunoinflammatory, and neuroendocrine systems. In spot urine samples, we assessed seven metabolites of six parent VOCs (acrolein (3HPMA), 1,3-butadiene (34HBMA), N,N-dimethylformamide (MCaMA), ethylbenzene/styrene (PGA; MADA), and xylene (2MHA; 3MHA+4MHA)). Quantile-based g-computation was used to estimate the mixture effects on AL adjusting for covariates. A one quartile increase in this VOC metabolite mixture was associated with a 0.10 [0.02, 0.19] standard deviation higher AL-MD score. Effects were more pronounced in middle-aged (40-64 y/o; 0.15 [0.03, 0.26]) and older adults (65+ y/o; 0.14 [-0.06, 0.35]) compared with young adults (25-39 y/o; <0.01 [-0.13, 0.13]). This association was also stronger in males (0.15 [0.01, 0.29]) than females (0.07 [-0.04, 0.18]). Metabolites of acrolein, ethylbenzene/styrene, and xylene were consistent key drivers of physiological dysregulation. These findings suggest that VOC exposure could be a contributor to multisystemic dysregulation, as reflected by higher AL, providing a framework to detect environmental exposure-related subclinical effects linked to higher cardiovascular disease risk.

The Green Heart Project is a community-based trial to evaluate the effects of increasing greenery on urban environment and community health. The study was initiated in 2018 in a low-to-middle-income mixed-race residential area of nearly 28,000 residents in Louisville, KY. The 4 square mile area was surveyed for land use, population characteristics, and greenness, and assigned to 8 paired clusters of demographically- and environmentally matched "target" (T) and adjacent "control" (C), clusters. Ambient levels of ultrafine particles, ozone, oxides of nitrogen, and environmental noise were measured in each cluster. Individual-level data were acquired during in-person exams of 735 participants in Wave 1 (2018-2019) and 545 participants in Wave 2 (2021) to evaluate sociodemographic and psychosocial factors. Blood, urine, nail, and hair samples were collected to evaluate standard cardiovascular risk factors, inflammation, stress, and pollutant exposure. Cardiovascular function was assessed by measuring arterial stiffness and flow-mediated dilation. After completion of Wave 2, more than 8,000 mature, mostly evergreen, trees and shrubs were planted in the T clusters in 2022. Post planting environmental and individual-level data were collected during Wave 3 (2022) from 561 participants. We plan to continue following changes in area characteristics and participant health to evaluate the long-term impact of increasing urban greenery.

Introduction: Living in greener environments has been linked to lower risks of cardiovascular disease, mortality, and mental health disorders. Although these benefits have been attributed to behavioral and psychosocial pathways, emerging evidence suggests that natural environments also influence immune regulation through microbial, biochemical, and stress-modulating mechanisms. Therefore, we examined the association between residential greenspace with circulating levels of immune cells and inflammatory biomarkers. Methods: Adult participants (ages 25-70 years) living in Louisville, KY were enrolled in the Green Heart Study (2018 - 2019). Residential greenness was quantified using leaf area index and NDVI within 100-m and 500-m buffers around participants' homes. Circulating cytokines and immune cells were measured in 624 participants at baseline. Linear regression models were used to estimate associations between greenness and each biomarker, adjusting for socio-demographic and behavioral factors. Results: Most participants were White (77.4%) and female (59%). Leaf area within a 100m buffer was negatively associated with circulating levels of B cells (-11.6% per IQR; 95% CI: -16.6, -6.3), monocytes (-4.7% per IQR; 95% CI: -8.9, -0.3), and natural killer cells (-5.1% per IQR; 95% CI: -9.3, -0.6). Greenness was positively associated with interleukin-4 (IL-4) (9.8% per IQR; 95% CI: 3.3, 16.7), a cytokine promoting Th2-mediated immunoregulation. Other cytokines showed no consistent associations. Conclusion: Residential greenness may improve chronic inflammation and enhance immune responses by modulating both the levels of circulating immune cell populations and the signals that govern their activity. These results provide further evidence that greenness is an important determinant of cardiovascular health.

BACKGROUND:Volatile organic compounds (VOCs) are ubiquitous gaseous chemicals emitted from multiple sources and present in both indoor and outdoor air. VOC exposures have been linked to detrimental cardiometabolic effects; nevertheless, the underlying mechanisms remain unclear. In this study, we evaluated the relationship between VOC exposure and sympathetic activation. METHODS:Participants (n=696, age 25-70 years) were recruited between 2018 and 2021 in Louisville, KY. Clean catch, spot urine samples were obtained. Urinary metabolites of VOCs and monoamines were quantified using UPLC-MS/MS. The associations of creatinine-adjusted, log-transformed urinary constituents were examined using adjusted multivariable linear regression models for individual metabolites and quantile-based g-computation for overall mixture models. Final models were adjusted for demographics, stress, smoking status, medication use, and urine collection time. RESULTS:Higher urinary levels of several VOC metabolites were associated with higher urinary levels of monoamines and their metabolites. A quartile increase in the overall VOC metabolite mixture was associated with 27% [18%, 37%] (serotonin) to 54% [36%, 73%] (epinephrine) higher urinary parent monoamine concentrations. For phase I monoamine metabolites, concentrations were 25% [16%, 35%] (vanillylmandelic acid) to 37% [29%, 46%] (3-methoxytyramine) higher per quartile increase in VOC metabolite mixture. CONCLUSIONS:Our results suggest that exposure to VOCs is associated with elevated sympathetic activation. Individual and mixture analyses identified robust associations with metabolites of N,N-dimethylformamide, 1,3-butadiene, ethylbenzene/styrene, propylene oxide, and crotonaldehyde. Elevated sympathetic tone may be a significant contributor to the negative cardiometabolic outcomes associated with VOC exposure.

Background Living in areas with more greenness has been associated with beneficial health outcomes. However, few studies have examined associations of greenness with incidence of stroke, and it is unclear how these associations may vary with the type of vegetation and surrounding ecology. This study evaluated associations between greenness and incidence of stroke by the major ecological regions in the United States. Methods and Results We assessed the incidence of stroke in 27 369 participants from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, a prospective cohort recruited across the contiguous United States. Greenness was estimated by the normalized difference vegetation index and enhanced vegetation index (EVI) at multiple buffers around home addresses. Participants were assigned to ecoregions using their baseline residence. We estimated the association between residential greenness and incidence of stroke using covariate‐adjusted Cox proportional hazards models. Models were stratified by ecoregions to assess how associations varied by areas with unique vegetation and ecology. We observed 1581 incident cases of stroke during the study period. In the full study population, there was suggestive evidence of a protective association between greenness and stroke incidence (hazard ratio [HR], 0.989 [95% CI, 0.946–1.033]) for a 0.1 increase in normalized difference vegetation index within 250 m. Similar results were obtained using enhanced vegetation index and larger radii. In our analysis by ecoregions, we found greenness was associated with lower stroke risk in the Eastern Temperate Forests region (HR, 0.946 [95% CI, 0.898–0.997]), but higher risk in the Great Plains (HR, 1.442 [95% CI, 1.124–1.849]) and Mediterranean California regions (HR, 1.327 [95% CI, 1.058–1.664]). Conclusions Vegetation may lower the risk of stroke; however, benefits may be limited to certain contexts of the natural environment.

The cardiovascular and pulmonary disease risks of the use of electronic nicotine delivery systems (ENDS) are uncertain. We recently showed that ENDS solvent-derived aerosol (propylene glycol and vegetable glycerin, PG:VG) exposure induced a transient receptor potential ankyrin-1 (TRPA1)-dependent endothelial dysfunction (ED) in healthy female mice. As thermal degradation of PG:VG generates aldehydes, we hypothesized that acrolein (AC), a constituent of ENDS-derived aerosol and a known TRPA1 agonist, was responsible, in part, for the observed TRPA1-dependent pulmonary and vascular effects of PG:VG. To test this, female wild-type (WT) and TRPA1 null mice were exposed by inhalation to either filtered air or AC alone, and biomarkers of exposure and of harm were measured. Compared with their genotype-matched air control group, JUUL Virginia Tobacco (VT), PG:VG, and AC alone exposures (6 h) significantly increased urinary levels of the AC metabolite, 3-hydroxypropyl mercapturic acid (3HPMA), in both female WT and TRPA1 null mice. AC exposures at 1 and 3 ppm led to the rapid onset and reversal (upon cessation) of ‘respiratory braking’ in female WT but not in TRPA1 null mice indicating a TRPA1 dependence. As AC stimulated TRPA1-dependent respiratory braking, we measured urinary monoamines and their metabolites after exposure as a proxy of nervous system activation. In WT mice, AC exposure suppressed levels of dopamine, metanephrine, serotonin (5HT), and 5HT metabolite (5HIAA), whereas in TRPA1 null mice only 5HT was equally suppressed by AC. To assess vascular effects, mice were exposed for 4 days to Air or AC (6 h/day, 1 ppm), and aortic function was measured ex vivo. Although endothelial-dependent relaxation was similar in air control and AC-exposed mice, aortic sensitivity to an NO donor was enhanced significantly and equally by AC in both WT and TRPA1 null mice reflective of a TRPA1-independent and compensatory effect. Collectively, AC exposure at a level present in ENDS aerosols stimulated both TRPA1-dependent and -independent pulmonary, vascular, and systemic effects. These data suggest that ENDS use may increase cardiovascular and pulmonary disease risk, in part, via AC present in ENDS-derived aerosols yet independent of either nicotine or flavorants. The level of AC present in ENDS aerosols should be lowered to an amount where it does not induce biomarkers of vascular, pulmonary, and systemic harm to mitigate potential long-term disease risk. Vascular dysfunction in mid-thoracic aorta ex vivo following short-term exposure to acrolein (AC, 1 ppm, 6 h/day × 4 days) in female WT mice was similarly exposed female TRPA1 null mice indicating a TRPA1-independent effect. TRPA1-dependent nervous system-mediated respiratory braking response in wild-type mice (WT; represented by lightning bolt) was absent in female TRPA1 null mice exposed acutely to AC. Short-term AC exposure induced a ‘compensatory relaxation’ in thoracic aorta of both WT and TRPA1 null mice indicating a TRPA1-independent effect. Irritant compounds such as AC in ENDS-derived aerosols simultaneously promote both ED and ‘vascular compensation’ through TRPA1-dependent and -independent mechanisms that are perhaps, in part, dependent on changes in circulating monoamines. These findings suggest exposures to ENDS-derived aerosols have complex effects on the vasculature and thus, long-term ENDS use likely increases CVD risk. Created in BioRender.

Volatile organic compounds (VOCs) are ubiquitous gaseous chemicals present in indoor and outdoor air. These compounds are emitted from several sources such as automobiles, paints, and household items. Human exposures are frequent and expected to increase with climate change. VOC exposures have been linked to negative cardiometabolic effects; however, the underlying mechanisms by which they impact cardiovascular function remain unknown. Exposure to VOCs may stimulate sympathetic nervous system activity. Thus, we aim to investigate the association of urinary VOC metabolites with levels of catecholamines as a biomarker of sympathetic activation. Participants (n=806, age 25-70) were recruited between 2018-2021 from low- to middle-income neighborhoods in Louisville, KY. Clean catch, spot urine samples were obtained during an in-person study visit. Urinary samples were used to quantify metabolites of VOCs and catecholamines using UPLC-MS/MS. The associations of log-transformed, creatinine standardized urinary constituents were examined using adjusted multivariable linear regression models for individual metabolites and quantile-based g computation for overall mixture models. Final models were adjusted for relevant demographic factors, stress, smoking status, medication use, and urine collection time. Detectable levels of acrylamide, acrolein, 1,3-butadiene, crotonaldehyde, N, N-dimethylformamide, propylene oxide, styrene, toluene, and xylene metabolites were present in >80% of urinary samples. In adjusted models, higher concentrations of most VOC metabolites, other than BMA (a metabolite of toluene), were associated with higher levels of urinary catecholamines (p<0.001). Specifically, a 10% increase in 11 individual VOC metabolites was associated with 1.2% to 2.4% higher epinephrine, 0.7% to 1.4% higher norepinephrine, and 0.7% to 1.5% higher dopamine levels. A quartile increase in the overall VOC metabolite mixture was associated with 57% higher epinephrine (95%CI = 41, 76%; p<0.001), 37% higher norepinephrine (95%CI=28, 48%; p<0.001), and 40% dopamine levels (95%CI=31, 48%; p<0.001). Our results suggest that exposure to these ubiquitous volatile compounds is associated with an increase in sympathetic stimulation. Mixture analysis further demonstrated potential additive effects of VOC exposures on autonomic modulation. Hence, an elevated sympathetic tone may in part be responsible for the negative cardiometabolic outcomes related to increased VOC exposure.

BACKGROUND:Volatile organic compounds (VOCs) are ubiquitous environmental pollutants. Exposure to VOCs is associated with cardiovascular disease risk factors, including elevated blood pressure in susceptible populations. However, research in the general population, particularly among nonsmoking adults, is limited. We hypothesized that higher VOC exposure is associated with higher blood pressure and hypertension, among nonsmokers. METHODS:We included 4 cycles of data (2011-2018) of nonsmoking adults (n=4430) from the National Health and Nutrition Examination Survey. Urinary VOC metabolites were measured by ultraperformance liquid chromatography-mass spectrometry, adjusted for urine dilution, and log-transformed. We estimated mean differences in blood pressure using linear models and prevalence ratio of stage 2 hypertension using modified Poisson models with robust standard errors. Models were adjusted for age, sex, race and ethnicity, education, body mass index, estimated glomerular filtration rate, and National Health and Nutrition Examination Survey cycle. RESULTS:Participants were 54% female, with a median age of 48 years, 32.3% had hypertension, and 7.9% had diabetes. The mean differences (95% CI) in systolic blood pressure were 1.61 (0.07-3.15) and 2.46 (1.01-3.92) mm Hg when comparing the highest with the lowest quartile of urinary acrolein (N-acetyl-S-[2-carboxyethyl]-L-cysteine) and 1,3-butadiene (N-acetyl-S-[3,4-dihydroxybutyl]-L-cysteine) metabolites. The prevalence ratios for hypertension were 1.06 (95% CI, 1.02-1.09) and 1.05 (95% CI, 1.01-1.09) when comparing the highest with lowest quartiles of urinary acrolein (N-acetyl-S-[2-carboxyethyl]-L-cysteine) and 1,3-butadiene (N-acetyl-S-[3,4-dihydroxybutyl]-L-cysteine), respectively. CONCLUSIONS:Exposure to VOCs may be a relevant yet understudied environmental contributor to cardiovascular disease risk in the nonsmoking, US population.

Background:Volatile organic compounds (VOCs) are ubiquitous environmental pollutants. Exposure to VOCs is associated with cardiovascular disease (CVD) risk factors, including elevated blood pressure (BP) in susceptible populations. However, research in the general population, particularly among non-smoking adults, is limited. We hypothesized that higher VOC exposure is associated with higher BP and hypertension, among non-smokers. Methods:We included four cycles of data (2011-2018) of non-smoking adults (n=4,430) from the National Health and Nutrition Examination Survey (NHANES). Urinary VOC metabolites were measured by ultra-performance liquid chromatography-mass spectrometry, adjusted for urine dilution, and log-transformed. We estimated mean differences in BP using linear models and prevalence ratio of stage 2 hypertension using modified Poisson models with robust standard errors. Models were adjusted for age, sex, race and ethnicity, education, body mass index, estimated glomerular filtration rate and NHANES cycle. Results:Participants were 54% female, with a median age of 48 years, 32.3% had hypertension, and 7.9% had diabetes. The mean differences (95% CI) in systolic BP were 1.61 (0.07, 3.15) and 2.46 (1.01, 3.92) mmHg when comparing the highest to lowest quartile of urinary acrolein (CEMA) and 1,3-butadiene (DHBMA) metabolites. The prevalence ratios (PR) for hypertension were 1.06 (1.02, 1.09) and 1.05 (1.01, 1.09) when comparing the highest to lowest quartiles of urinary acrolein (CEMA) and 1,3-butadiene (DHBMA), respectively. Conclusions:Exposure to VOCs may be relevant yet understudied environmental contributors to CVD risk in the non-smoking, US population.

Introduction: Peripheral artery disease (PAD) is a significant cause of cardiovascular morbidity and mortality, characterized by atherosclerosis in the skeletal muscle. Currently no mechanism-based therapeutics are available for this diseased population. In the muscle, histidyl dipeptides, such as carnosine (ranging between 5-10 mM) possess the abilities to bind with toxic lipid peroxidation products, such as acrolein. Preclincial studies show carnosine is depleted in the ischemic leg, increasing intramuscular carnosine improves angiogenesis, and blood flow in the ischemic leg. In humans, carnosine levels are increased in the muscle with carnosine supplementation. However, little is known whether carnosine levels are affected in PAD patients and its effect on their walking ability. Hypothesis: Carnosine supplementation will improve walking ability of PAD patients. Methods: We recruited normal (males: n=48; females: n=52; age: 50 ±10 years) and PAD subjects (males: n=52; females: n=41; age: 67±8 years; ankle brachial index (ABI): 0.65±0.18 measured urinary histidyl dipeptides, histidyl dipeptide-aldehyde conjugates, and oxidative stress markers: N-Acetyl-S-(3-hydroxypropyl)-L-Cysteine (3-HPMA) and N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA), both are acrolein metabolites. PAD subjects (n=7; n=5 females and n=2 males; ABI: 0.68±0.08, age: 63±8 years) were supplemented with carnosine 2 g/day for 3 months, measured distance covered in a six-minute walk test (6MWT), ABI, blood profile at baseline and after completion. Results: In PAD subjects urinary carnosine was decreased (normal: 20±29 vs PAD:11±14 nmoles/mg creatinine, p<0.024), carnosine aldehdye conjugates were increased (carnosine propanal: 1.46±1.27 vs normal 0.56±1.08 nmoles/mg creatinine, p<0.0001; and carnosine propanol: 4.66±2.80 vs normal 1.52±1.21 nmoles/mg creatinine, p<0.0001). Oxidative stress markers were increased in the PAD subjects (CEMA: 341±210 vs normal: 119±86 ng/mg creatinine, p<0.0004 and 3HPMA: 6.57±6.32 ng/mg protien vs normal: 5.49±5.28 ng/mg creatinine, p<0.001). Following carnosine supplementation, blood profile was unchanged. Distance covered in 6MWT increased by 166±204 feet (before: 577±129 vs 743±152 feet after, p<0.048) and there was an increasing trend in ABI (before: 0.68±0.08 vs 0.80±0.19; after, p<0.18). Conclusion: Urinary carnosine could serve as a biomarker to evaluate PAD pathology and carnosine supplementation may improve walking ability of PAD patients.

Introduction: Extreme-heat events increase mortality, and excessive deaths due to heat waves are overwhelmingly cardiovascular in origin. However, many previous studies only consider ambient temperature, which fails to capture the actual heat stress experienced by populations. Hot weather can interfere with a variety of biological processes including the promotion of systemic inflammatory responses, which play a critical role in the progression of cardiovascular disease (e.g., atherosclerosis). Our objective was to assess how short-term heat exposures are related to markers of inflammation and the immune response using physiologically-relevant heat metrics that capture additional meteorological conditions. Methods: Adult participants, aged 20-70 years, were recruited from a neighborhood in Louisville, KY during the summer months of 2018 and 2019. Circulating cytokines and immune cells were measured in 624 participants at baseline. Heat metrics, including temperature, net effective temperature, and Universal Thermal Climate Index (UTCI) were calculated as the 24hr mean on the day of participants’ clinical visit. Linear regression models were used to estimate associations between heat metrics and each biomarker, adjusting for socio-demographic and behavioral factors. Results: Participants were predominantly female (59%) and White (77%), with an average age of 49.5 years. The median daily temperature during study visits was 24.5 degrees C (IQR=3.8 degrees). The mean daily UTCI was positively associated with total circulating monocytes (4.2% per IQR; 95% CI: 0.3, 8.3), and classical monocytes (CD14 hi CD16 lo ), while nonclassical monocytes (CD14 lo CD16 hi ) displayed a negative association. We also observed positive associations with eosinophils 9.5% per IQR (95% CI: 0.6, 19.1) and Natural Killer T-Cells 9.9% per IQR (95% CI:2.8, 17.5), and a negative association with B-cells -6.8% per IQR (95% CI: -12.1, -1.1). In our cytokine analysis, UTCI was positively associated with TNF-alpha 7.0% per IQR (95% CI:2.8, 11.4) as well as IL-5 and MIP-1α. Similar, but attenuated associations were observed using daily temperature and other heat metrics. Conclusion: Short-term heat exposure may trigger an inflammatory response characterized by innate immune activation as evidenced by our results of higher total monocytes, classical monocytes, and TNF-alpha. Moreover, short-term heat exposure may impair adaptive immune response. These results suggest that exposure to high temperatures may increase susceptibility to infectious agents, environmental exposures, and accelerate the progression of cardiovascular disease.

Introduction: Accumulating evidence suggests that cardiovascular disease (CVD) risk is associated with climatic variables and the impact of these factors is likely to be increasing with changes in the global climate. Nevertheless, the underlying physiological mechanisms remain unclear, and it remains unknown whether urban greenspaces could contribute to climatic resilience by mitigating these mechanisms. Moreover, to-date most studies assessing CVD risk consider only ambient temperature, which may not fully capture physiologically relevant thermal conditions. Accordingly, using varied measures of heat, our objective was to assess how short-term heat exposure is related to arterial stiffness, and whether these associations are modified by area greenness. Methods: Adult participants, aged 25-70 years, were recruited from a neighborhood in Louisville, KY during the summer months of 2018 and 2019. Arterial Stiffness was measured by augmentation index (AIX) via pulse wave analysis in 714 participants. We assessed 7 heat metrics, including ambient temperature, dew point temperature, net effective temperature, Heat Index, and Universal Thermal Climate Index (UTCI), calculated as the 24h mean on the day of participants’ visit. Greenness surrounding participants’ homes was assessed by tree canopy within a 500m buffer. Linear regression was used to estimate associations between heat metrics and arterial stiffness, adjusting for socio-demographic and behavioral factors. Subgroup analysis was performed by tertiles of greenness. Results: Participants were predominantly female (61%) and White (77%), with an average age of 49.5 years. The median daily temperature during study visits was 24.4°C (range=12.2 to 28.9°C) and the median daily UTCI was 26.1°C (IQR=5.4°C). The strongest association between heat metrics and AIX was observed for UTCI (2.0% per IQR; 95% CI:0.4, 3.6), followed by net effective temperature (1.8% per IQR; 95% CI: 0.1, 3.6), while dew point temperature had the weakest association (0.6% per IQR; 95% CI: -0.8, 2.0). Stratifying our analysis by tertiles of tree canopy, we observed significant associations between heat metrics and AIX in low canopy areas, with a dose response decrease in associations among medium and high canopy areas. Conclusion: Increased arterial stiffness could be an important contributor to excessive CVD risk associated with physiologically relevant measures of heat exposure, which could be mitigated by surrounding greenspaces.

Background -Smoking is associated with arrhythmia and sudden cardiac death, but the biological mechanisms remain unclear. In electrocardiogram (ECG) recordings abnormal durations of ventricular repolarization (QT interval), atrial depolarization (P wave), and atrioventricular depolarization (PR interval and segment), predict cardiac arrhythmia and mortality. Previous analyses of the National Health and Nutrition Examination Survey (NHANES) database for associations between smoking and ECG abnormalities were incomplete. To elucidate how smoking affects cardiac excitation, we assessed in a nationally representative sample (NHANES III) the association between serum cotinine and P duration, PR interval, PR segment, rate-corrected QT (QTc), QRS duration, and JT interval. Methods and Results-We analyzed data from 5,653 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). 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 effects of smoking on ECG were also assessed by survey-weighted linear regression of continuous cotinine and ECG, 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, whereas only short JT predicted mortality in nonsmokers. Conclusions -Smoking increases likelihood for rapid atrioventricular and ventricular depolarization and slow ventricular repolarization, which may promote cardiac arrhythmia and mortality.

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and "respiratory braking"-biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N-1,3-thiazolidine-4-carboxylic acid, TCA; N-1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS.

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 mu g/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.

INTRODUCTION:Previous investigations have reported that individuals living in greener neighborhoods have better cardiovascular health. It is unclear whether the effects reported at large geographic scales persist when examined at an intra-neighborhood level. The effects of greenness have not been thoroughly examined using high-resolution metrics of greenness exposure, and how they vary with spatial scales of assessment or participant characteristics. METHODS:We conducted a cross-sectional assessment of associations between blood pressure and multiple high-resolution measures of residential area greenness in spatially concentrated HEAL Study cohort of the Green Heart Project. We employed generalized linear models, accounting for individual-level covariates, to examine associations between different high-resolution measures of greenness and blood pressure among 667 participants in a 4 sq. mile contiguous neighborhood area in Louisville, KY. RESULTS:In adjusted models, we observed significant inverse associations between residential greenness, measured by leaf area index (LAI), and systolic blood pressure (SBP) within 150-250 m and 500 m of homes, but not for Normalized Difference Vegetation Index (NDVI) or grass cover. Weaker associations were also found with diastolic blood pressure (DBP). Significant positive associations were observed between LAI and SBP among participants who reported being female, White, without obesity, non-exercisers, non-smokers, younger age, of lower income, and who had high nearby roadway traffic. We found few significant associations between grass cover and SBP, but an inverse association in those with obesity, but positive associations for those without obesity. CONCLUSIONS:We found that leaf surface area of trees around participants home is strongly associated with lower blood pressure, with little association with grass cover. These effects varied with participant characteristics and spatial scales. More research is needed to test causative links between greenspace types and cardiovascular health and to develop population-, typology-, and place-based evidence to inform greening interventions.