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It has long been known that chronic metabolic disease is associated with a parallel increase in the risk for developing peripheral vascular disease. Although more clinically relevant, our understanding about reversing established vasculopathy is limited compared with our understanding of the mechanisms and development of impaired vascular structure/function under these conditions. Using the 13-wk-old obese Zucker rat (OZR) model of metabolic syndrome, where microvascular dysfunction is sufficiently established to contribute to impaired skeletal muscle function, we imposed a 7-wk intervention of chronic atorvastatin treatment, chronic treadmill exercise, or both. By 20 wk of age, untreated OZRs manifested a diverse vasculopathy that was a central contributor to poor muscle performance, perfusion, and impaired O2 exchange. Atorvastatin or exercise, with the combination being most effective, improved skeletal muscle vascular metabolite profiles (i.e., nitric oxide, PGI2, and thromboxane A2 bioavailability), reactivity, and perfusion distribution at both individual bifurcations and within the entire microvascular network versus responses in untreated OZRs. However, improvements to microvascular structure (i.e., wall mechanics and microvascular density) were less robust. The combination of the above improvements to vascular function with interventions resulted in an improved muscle performance and O2 transport and exchange versus untreated OZRs, especially at moderate metabolic rates (3-Hz twitch contraction). These results suggest that specific interventions can improve specific indexes of function from established vasculopathy, but either this process was incomplete after 7-wk duration or measures of vascular structure are either resistant to reversal or require better-targeted interventions. [ABSTRACT FROM AUTHOR]

Purpose: A growing body of epidemiologic evidence links oral health, periodontal disease and cardiovascular health. While underlying pathophysiologic mechanisms are unclear, several studies have suggested a sub-acute inflammatory state, also implicated in the etiology of cardiovascular disease. The objective of the current study was to investigate associations between self-reported dental hygiene (brushing, flossing, preventive care and overall dental health), cardiovascular disease risk factors and systemic inflammation. Methods: 128 adults from 5 different rural counties in West Virginia participated in a comprehensive, community-based health screening that included anthropometric assessments, collection of a blood specimen and completion of a questionnaire about dental hygiene practices and oral health. Results: Univariate analysis demonstrated multiple statistically significant associations between self-reported dental hygiene and cardiovascular disease risk factors and markers of systemic inflammation. In regression analysis, after controlling for demographic and cardiovascular disease risk factor covariates, self-reported dental hygiene demonstrated statistically significant and independent associations with adiponectin, fibrinogen, C-reactive protein (CRP) and cellular adhesion molecule-1 (sICAM-1). Conclusion: This study demonstrated associations between dental hygiene and systemic inflammation, independent from BMI and blood cholesterol. Future studies should investigate whether periodontal-related systemic inflammation begins before the onset of clinical disease. Results from this and other studies highlight the importance of dental hygiene in overall systemic health, and are beginning to collectively suggest that regular dental hygiene care is an integral part of comprehensive health care. [ABSTRACT FROM AUTHOR]

Background: The C8 Health Project was created, authorized, and funded as part of the settlement agreement reached in the case of Jack W. Leach, et al. v. E.I. du Pont de Nemours & Company (no. 01-C-608 W.Va., Wood County Circuit Court, filed 10 April 2002). The settlement stemmed from the perfluorooctanoic acid (PFOA, or C8) contamination of drinking water in six water districts in two states near the DuPont Washington Works facility near Parkersburg, West Virginia. Objectives: This study reports on the methods and results from the C8 Health Project, a population study created to gather data that would allow class members to know their own PFOA levels and permit subsequent epidemiologic investigations. Methods: Final study participation was 69,030, enrolled over a 13-month period in 2005-2006. Extensive data were collected, including demographic data, medical diagnoses (both self-report and medical records review), clinical laboratory testing, and determination of serum concentrations of 10 perfluorocarbons (PFCs). Here we describe the processes used to collect, validate, and store these health data. We also describe survey participants and their serum PFC levels. Results: The population geometric mean for serum PFOA was 32.91 ng/mL, 500% higher than previously reported for a representative American population. Serum concentrations for perfluorohexane sulfonate and perfluorononanoic acid were elevated 39% and 73% respectively, whereas perfluorooctanesulfonate was present at levels similar to those in the U.S. population. Conclusions: This largest known population study of community PFC exposure permits new evaluations of associations between PFOA, in particular, and a range of health parameters. These will contribute to understanding of the biology of PFC exposure. The C8 Health Project also represents an unprecedented effort to gather basic data on an exposed population; its achievements and limitations can inform future legal settlements for populations exposed to environmental contaminants. [ABSTRACT FROM AUTHOR]

Objective: The obese Zucker rat (OZR) model of the metabolic syndrome is partly characterized by moderate hypercholesterolemia, in addition to other contributing comorbidities. Previous results suggest that vascular dysfunction in OZR is associated with chronic reduction in vascular nitric-oxide (NO) bioavailability and chronic inflammation, both frequently associated with hypercholesterolemia. As such, we evaluated the impact of chronic cholesterol-reducing therapy on the development of impaired skeletal muscle arteriolar reactivity and microvessel density in OZR and its impact on chronic inflammation and NO bioavailability. Materials and Methods: Beginning at seven weeks of age, male OZR were treated with gemfibrozil, probucol, atorvastatin, or simvastatin (in chow) for 10 weeks. Subsequently, plasma and vascular samples were collected for biochemical/molecular analyses, while arteriolar reactivity and microvessel network structure were assessed by using established methodologies after 3, 6, and 10 weeks of drug therapy. Results: All interventions were equally effective at reducing total cholesterol, although only the statins also blunted the progressive reductions to vascular NO bioavailability, evidenced by greater maintenance of acetylcholine-induced dilator responses, an attenuation of adrenergic constrictor reactivity, and an improvement in agonist-induced NO production. Comparably, while minimal improvements to arteriolar wall mechanics were identified with any of the interventions, chronic statin treatment reduced the rate of microvessel rarefaction in OZR. Associated with these improvements was a striking statin-induced reduction in inflammation in OZR, such that numerous markers of inflammation were correlated with improved microvascular reactivity and density. However, using multivariate discriminant analyses, plasma RANTES (regulated on activation, normal T-cell expressed and secreted), interleukin-10, monocyte chemoattractant protein-1, and tumor necrosis factor alpha were determined to be the strongest contributors to differences between groups, although their relative importance varied with time. Conclusions: While the positive impact of chronic statin treatment on vascular outcomes in the metabolic syndrome are independent of changes to total cholesterol, and are more strongly associated with improvements to vascular NO bioavailability and attenuated inflammation, these results provide both a spatial and temporal framework for targeted investigation into mechanistic determinants of vasculopathy in the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background: Reducing health inequalities among older adults is crucial to ensuring healthy aging is within reach for all. The current study provides a timely update on demographic- and geographic-related inequalities in healthy aging among older adults residing in Canadian communities. Methods: Data was extracted from the Canadian Health Survey on Seniors [2019–2020] for ~6 million adults aged 65 years and older residing in 10 provinces of Canada. Healthy aging was defined by two indices: 1] health-related quality of life and 2] functional health. Poisson regression models and spatial mapping were used to demonstrate inequalities among age, race, and sex categories, and health regions. Results: Approximately 90.3% of individuals reported less than perfect quality of life and 18.8% reported less than perfect functional health. The prevalence of less than perfect quality of life was higher for females [PR 1.14, 95% CI;1.02–1.29] and for older adults aged ≥80 years as compared to males and older adults aged ≤79 years [PR 1.66, 95% CI;1.49–1.85]. Similarly, the prevalence of less than perfect functional health was higher for females [PR 1.58, 95% CI;1.32–1.89] and for older adults aged ≥80 years [PR 2.71, 95% CI;2.59–2.84]. Spatial mapping showed that regions of lower quality of life were concentrated in the Prairies and Western Ontario, whereas regions of higher quality of life were concentrated in Quebec. Conclusions: Amongst older individuals residing in Canadian communities, less than perfect quality of life and functional health is unequally distributed among females, older adults aged ≥80 years, and those residing in the Prairie regions specifically. Newer policy should focus on interventions targeted at these subpopulations to ensure that healthy aging in within reach for all Canadians. [ABSTRACT FROM AUTHOR]

Introduction: Acquisition of a deeper understanding of microvascular function across physiological and pathological conditions can be complicated by poor accessibility of the vascular networks and the necessary sophistication or intrusiveness of the equipment needed to acquire meaningful data. Laser Doppler fluximetry (LDF) provides a mechanism wherein investigators can readily acquire large amounts of data with minor inconvenience for the subject. However, beyond fairly basic analyses of erythrocyte perfusion (fluximetry) data within the cutaneous microcirculation (i.e., perfusion at rest and following imposed challenges), a deeper understanding of microvascular perfusion requires a more sophisticated approach that can be challenging for many investigators. Methods: This manuscript provides investigators with clear guidance for data acquisition from human subjects for full analysis of fluximetry data, including levels of perfusion, single- and multiscale Lempel-Ziv complexity (LZC) and sample entropy (SampEn), and wavelet-based analyses for the major physiological components of the signal. Representative data and responses are presented from a recruited cohort of healthy volunteers, and computer codes for full data analysis (MATLAB) are provided to facilitate efforts by interested investigators. Conclusion: It is anticipated that these materials can reduce the challenge to investigators integrating these approaches into their research programs and facilitate translational research in cardiovascular science. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the leading cause of death in the U.S. Reducing the population burden of CVD will require an increased focus on understanding how to promote and support population-level cardiovascular health (CVH), which will include the ability to measure the presence of CVH, not merely the presence or absence of CVD. Recently, the American Heart Association developed a comprehensive metric designed to measure CVH at the population level. The metric includes smoking, body mass index, physical activity, diet, cholesterol, blood pressure, and blood glucose. The purpose of this study was to assess how population-level CVH is related to the availability of health care providers and services within the county. Data from the Behavioral Risk Factor Surveillance System were used to calculate age-adjusted CVH for each county in 2009. Federal Information Processing Standards codes were used to obtain scores for counties with a sample size of 15 or more. Data on county-level health care services and providers were abstracted from the Area Resource File. The main outcomes were age-standardized mean CVH score. In total, 2236 counties were included in the analysis. Mean CVH score was 3.49 (0.39 SD). After adjustment for county population, county-level CVH score was positively correlated to per capita primary care physicians (rho=0.33, p<0.0001) and nurse practitioners (rho=0.106, p<0.0001). County CVH was also positively and significantly correlated to cardiovascular disease specialists (rho=0.220, p<0.0001). The number of per capita physicians assistants and dieticians / nutritionists were also positively associated with county CVH (rho=0.232, p<0.0001; rho=0.112, p=0.003, respectively). In assessing the effect of the availability of health care facilities, county CVH was positively associated with per capita county-level long term hospital beds, nursing home beds, and community mental health centers (rho/pvalues respectively: 0.122/<0.0001; 0.062/p=0.003; 0.078/<0.0001) but negatively associated with per capita county-level beds in skilled nursing facilities, home health agencies and federally qualified health centers (rho/p-values respectively: -0.189/<0.0001; -0.086/<0.0001; -0.065/0.002). Further study is needed to understand the marginal impact of health care providers and facilities on county CVH. [ABSTRACT FROM AUTHOR]

A major challenge facing public health is the increased incidence and prevalence of the metabolic syndrome, a clinical condition characterized by excess adiposity, impaired glycaemic control, dyslipidaemia and moderate hypertension. The greatest concern for this syndrome is the profound increase in risk for development of peripheral vascular disease (PVD) in afflicted persons. However, ongoing studies suggest that reductions in bulk blood flow to skeletal muscle may not be the primary contributor to the premature muscle fatigue that is a hallmark of PVD. Compelling evidence has been provided suggesting that an increasingly spatially heterogeneous and temporally stable distribution of blood flow at successive arteriolar bifurcations in metabolic syndrome creates an environment where a large number of the pre-capillary arterioles have low perfusion, low haematocrit, and are increasingly confined to this state, with limited ability to adapt perfusion in response to a challenged environment. Single pharmacological interventions are unable to significantly restore function owing to a divergence in their spatial effectiveness, although combined therapeutic approaches to correct adrenergic dysfunction, elevated oxidant stress and increased thromboxane A2 improve perfusion-based outcomes. Integrated, multi-target therapeutic interventions designed to restore healthy network function and flexibility may provide for superior outcomes in subjects with metabolic syndrome-associated PVD. [ABSTRACT FROM AUTHOR]

To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague- Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk. [ABSTRACT FROM AUTHOR]

Research involving human subjects in ambulatory settings is a critical link in the chain comprising translational research, spanning preclinical research to human subject and patient cohort studies. There are presently a wide array of techniques and approaches available to investigators wishing to study blood flow, perfusion, and vascular structure and function in human subjects. In this multi-sectioned review, we discuss capillaroscopy, carotid intima-media thickness, flow-mediated dilation, laser Doppler flowmetry, near-infrared spectroscopy, peripheral arterial tonometry, pulse wave velocity, retinal fundus imaging, and vascular plethysmography. Each section contains a general overview and the physical basis of the technique followed by a discussion of the procedures involved and the necessary equipment, with attention paid to specific requirements or limitations. Subsequently, we detail which aspects of vascular function can be studied with a given technique, the analytical approach to the collected data, and the appropriate application and limitation(s) to the interpretation of the data collected. Finally, a modified scoping review provides a summary of how each assessment technique has been applied in previous studies. It is anticipated that this review will provide an efficient source of information and insight for preclinical investigators seeking to add translational aspects to their research programs. [ABSTRACT FROM AUTHOR]

Evolution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-α levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-α blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the development and progression of colorectal cancer (CRC). However, the link between these compounds and CRC remains unknown. In this cross-sectional study, we investigated the association of CRC diagnosis to PFOA and PFOS blood levels in a large Appalachian population. Methods Participants were 47,359 adults ≥ 21 years of age and residing in six PFOA-contaminated water districts in the mid-Ohio Valley (N = 47,151 cancer-free adults, 208 cases of primary CRC). All participants completed a comprehensive health survey between 2005 and 2006; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history was assessed via self report and cancer diagnosis confirmed via chart review. Results CRC showed a strong inverse, dose--response association with PFOS serum levels (odds ratio (OR) adjusted for potential confounders = 0.2, 95% confidence interval (CI) 0.2,0.3) for highest vs. lowest quartile of PFOA, P-trend < 0.00001) and a significant, but more modest inverse association with PFOA (adjusted OR = 0.6 (CI 0.4,0.9) for highest vs. lowest quartile, P-trend = 0.001). These inverse associations were stronger in those diagnosed within the previous 6 years and resident in the same water district for a minimum of 10-15 years preceding assessment. The relationship between PFOA and CRC was also more pronounced in men and leaner adults, and showed a stronger linear trend at lower exposure levels. Conclusions In this large cross-sectional study, we found a strong, inverse association between PFOS and likelihood of CRC diagnosis and a significant, although more modest inverse association between PFOA and CRC. If confirmed in prospective investigations, these findings may aid in identifying new strategies for CRC prevention and treatment and inform future studies regarding mechanisms underlying CRC pathogenesis. [ABSTRACT FROM AUTHOR]

Perfluorocarbons from common household products such as food containers, stain-resistant protection for clothing, furniture and carpets, paints, and fire-fighting foams are found in soil, water, plants, animal and human serum worldwide. Previous research has shown a significant association between these chemicals and thyroid disease in women. The present data from the C8 Health Project assessed thyroid function in a cross-sectional analysis of 52,296 adults with a year or more of exposure to perfluorooctanoate (PFOA) from drinking water. Outcomes were: thyroxine, T3 uptake, and thyroid stimulating hormone (TSH). Analyses were stratified by gender and age group (< 20 - < 50 years and > 50). Both PFOA and perfluorooctane sulfonate (PFOS) were associated with significant elevations in serum thyroxine and a significant reduction in T3 uptake in all participants. There were also significant gender/PFOS interactions for T3 uptake and thyroxine, as well as gender/PFOA interactions for T3 uptake. Results provide evidence for disruption of thyroid function related to these common chemicals and possible mechanisms are discussed. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are compounds that do not occur in nature but have been widely used since World War II and persist indefinitely in the environment. They are present in the serum of Americans with median levels of 4 ng/mL and 21 ng/mL, respectively. PFOA has been positively associated with cholesterol in several studies of workers. A cross-sectional study of lipids and PFOA and PFOS was conducted among 46,294 community residents aged 18 years or above, who drank water contaminated with PFOA from a chemical plant in West Virginia. The mean levels of serum PFOA and PFOS in 2005–2006 were 80 ng/mL (median, 27 ng/mL) and 22 ng/mL (median, 20 ng/mL), respectively. All lipid outcomes except high density lipoprotein cholesterol showed significant increasing trends by increasing decile of either compound; high density lipoprotein cholesterol showed no association. The predicted increase in cholesterol from lowest to highest decile for either compound was 11–12 mg/dL. The odds ratios for high cholesterol (≥240 mg/dL), by increasing quartile of PFOA, were 1.00, 1.21 (95% confidence interval (CI): 1.12, 1.31), 1.33 (95% CI: 1.23, 1.43), and 1.40 (95% CI: 1.29, 1.51) and were similar for PFOS quartiles. Because these data are cross-sectional, causal inference is limited. Nonetheless, the associations between these compounds and lipids raise concerns, given their common presence in the general population. [ABSTRACT FROM PUBLISHER]

The increasing prevalence and severity of clinical depression are strongly correlated with vascular disease risk, creating a comorbid condition with poor outcomes but demonstrating a sexual disparity whereby female subjects are at lower risk than male subjects for subsequent cardiovascular events. To determine the potential mechanisms responsible for this protection against stress/depression-induced vasculopathy in female subjects, we exposed male, intact female, and ovariectomized (OVX) female lean Zucker rats to the unpredictable chronic mild stress (UCMS) model for 8 wk and determined depressive symptom severity, vascular reactivity in ex vivo aortic rings and middle cerebral arteries (MCA), and the profile of major metabolites regulating vascular tone. While all groups exhibited severe depressive behaviors from UCMS, severity was significantly greater in female rats than male or OVX female rats. In all groups, endothelium-dependent dilation was depressed in aortic rings and MCAs, although myogenic activation and vascular (MCA) stiffness were not impacted. Higher-resolution results from pharmacological and biochemical assays suggested that vasoactive metabolite profiles were better maintained in female rats with normal gonadal sex steroids than male or OVX female rats, despite increased depressive symptom severity (i.e., higher nitric oxide and prostacyclin and lower H2O2 and thromboxane A2 levels). These results suggest that female rats exhibit more severe depressive behaviors with UCMS but are partially protected from the vasculopathy that afflicts male rats and female rats lacking normal sex hormone profiles. Determining how female sex hormones afford partial vascular protection from chronic stress and depression is a necessary step for addressing the burden of these conditions on cardiovascular health. [ABSTRACT FROM AUTHOR]

While it is known that chronic stress and clinical depression are powerful predictors of poor cardiovascular outcomes, recent clinical evidence has identified correlations between the development of metabolic disease and depressive symptoms, creating a combined condition of severely elevated cardiovascular disease risk. In this study, we used the obese Zucker rat (OZRs) and the unpredictable chronic mild stress (UCMS) model to determine the impact of preexisting metabolic disease on the relationship between chronic stress/depressive symptoms and vascular function. Additionally, we determined the impact of metabolic syndrome on sex-based protection from chronic stress/depressive effects on vascular function in female lean Zucker rats (LZRs). In general, vasodilator reactivity was attenuated under control conditions in OZRs compared with LZRs. Although still impaired, conduit arterial and resistance arteriolar dilator reactivity under control conditions in female OZRs was superior to that in male or ovariectomized (OVX) female OZRs, largely because of better maintenance of vascular nitric oxide and prostacyclin levels. However, imposition of metabolic syndrome in combination with UCMS in OZRs further impaired dilator reactivity in both vessel subtypes to a similarly severe extent and abolished any protective effect in female rats compared with male or OVX female rats. The loss of vascular protection in female OZRs with UCMS was reflected in vasodilator metabolite levels, which closely matched those in male and OVX female OZRs subjected to UCMS. These results suggest that presentation of metabolic disease in combination with depressive symptoms can overwhelm the vasoprotection identified in female rats and, thereby, may reflect a severe impairment to normal endothelial function. [ABSTRACT FROM AUTHOR]

While it is known that chronic stress and clinical depression are powerful predictors of poor cardiovascular outcomes, recent clinical evidence has identified correlations between the development of metabolic disease and depressive symptoms, creating a combined condition of severely elevated cardiovascular disease risk. In this study, we used the obese Zucker rat (OZRs) and the unpredictable chronic mild stress (UCMS) model to determine the impact of preexisting metabolic disease on the relationship between chronic stress/depressive symptoms and vascular function. Additionally, we determined the impact of metabolic syndrome on sex-based protection from chronic stress/depressive effects on vascular function in female lean Zucker rats (LZRs). In general, vasodilator reactivity was attenuated under control conditions in OZRs compared with LZRs. Although still impaired, conduit arterial and resistance arteriolar dilator reactivity under control conditions in female OZRs was superior to that in male or ovariectomized (OVX) female OZRs, largely because of better maintenance of vascular nitric oxide and prostacyclin levels. However, imposition of metabolic syndrome in combination with UCMS in OZRs further impaired dilator reactivity in both vessel subtypes to a similarly severe extent and abolished any protective effect in female rats compared with male or OVX female rats. The loss of vascular protection in female OZRs with UCMS was reflected in vasodilator metabolite levels, which closely matched those in male and OVX female OZRs subjected to UCMS. These results suggest that presentation of metabolic disease in combination with depressive symptoms can overwhelm the vasoprotection identified in female rats and, thereby, may reflect a severe impairment to normal endothelial function. NEW & NOTEWORTHY This study addresses the protection from chronic stress- and depression-induced vascular dysfunction identified in female compared with male or ovariectomized female rats. We determined the impact of preexisting metabolic disease, a frequent comorbidity of clinical depression in humans, on that vascular protection. With preexisting metabolic syndrome, female rats lost all protection from chronic stress/depressive symptoms and became phenotypically similar to male and ovariectomized female rats, with comparably poor vasoactive dilator metabolite profiles. [ABSTRACT FROM AUTHOR]

The increasing prevalence and severity of clinical depression are strongly correlated with vascular disease risk, creating a comorbid condition with poor outcomes but demonstrating a sexual disparity whereby female subjects are at lower risk than male subjects for subsequent cardiovascular events. To determine the potential mechanisms responsible for this protection against stress/depression-induced vasculopathy in female subjects, we exposed male, intact female, and ovariectomized (OVX) female lean Zucker rats to the unpredictable chronic mild stress (UCMS) model for 8 wk and determined depressive symptom severity, vascular reactivity in ex vivo aortic rings and middle cerebral arteries (MCA), and the profile of major metabolites regulating vascular tone. While all groups exhibited severe depressive behaviors from UCMS, severity was significantly greater in female rats than male or OVX female rats. In all groups, endothelium-dependent dilation was depressed in aortic rings and MCAs, although myogenic activation and vascular (MCA) stiffness were not impacted. Higher-resolution results from pharmacological and biochemical assays suggested that vasoactive metabolite profiles were better maintained in female rats with normal gonadal sex steroids than male or OVX female rats, despite increased depressive symptom severity (i.e., higher nitric oxide and prostacyclin and lower H2O2 and thromboxane A2 levels). These results suggest that female rats exhibit more severe depressive behaviors with UCMS but are partially protected from the vasculopathy that afflicts male rats and female rats lacking normal sex hormone profiles. Determining how female sex hormones afford partial vascular protection from chronic stress and depression is a necessary step for addressing the burden of these conditions on cardiovascular health. NEW & NOTEWORTHY This study used a translationally relevant model for chronic stress and elevated depressive symptoms to determine how these factors impact conduit and resistance arteriolar function in otherwise healthy rats. While chronic stress leads to an impaired vascular reactivity associated with elevated oxidant stress, inflammation, and reduced metabolite levels, we demonstrated partial protection from vascular dysfunction in female rats with normal sex hormone profiles compared with male or ovariectomized female rats. [ABSTRACT FROM AUTHOR]

Background: Current primary prevention guidelines for cardiovascular disease (CVD) prioritize risk identification, risk stratification using clinical and risk scores, and risk reduction with lifestyle interventions and pharmacotherapy. Subclinical atherosclerosis is an early indicator of atherosclerotic burden and its timely recognition can slow or prevent progression to CVD. Thus, individuals with subclinical atherosclerosis are a priority for primary prevention. This study takes a practical approach to answering a challenge commonly faced by primary care practitioners: in patients with no known CVD, how can individuals likely to have subclinical atherosclerosis be easily identified using existing clinical data and/or information provided by the patient?Methods: Using NHANES (1999-2004), 6091 men and women aged ≥40 years without any CVD comprised the primary prevention population for this study. Subclinical atherosclerosis was determined via ankle-brachial index (ABI) using established cutoffs (subclinical atherosclerosis defined as ABI (0.91-0.99); normal defined as ABI (1.00-1.30)). Three common scores were calculated: the Framingham Risk Score (FRS), the Metabolic Syndrome (MetS), and the Cardiovascular Health Index (CVHI). Logistic regression analysis assessed the association between these scores and subclinical atherosclerosis. The sensitively and specificity of these scores in identifying subclinical atherosclerosis was determined.Results: In eligible participants, 3.8% had subclinical atherosclerosis. Optimum and average CVHI was associated with decreased odds for subclinical atherosclerosis. High, but not intermediate-risk, FRS was associated with increased odds for subclinical atherosclerosis. MetS was not associated with subclinical atherosclerosis. Of the 3 scores, CVHI was the most sensitive in identifying subclinical atherosclerosis and had the lowest number of missed cases. The FRS was the most specific but least sensitive of the 3 scores, and had almost 10-fold more missed cases vs. the CVHI. The MetS had "middle" sensitivity and specificity, and 10-fold more missed cases vs. the CVHI.Conclusions: Results from this study suggest that routine administration of the CVHI in a primary prevention population would yield the benefits of identifying patients with existing subclinical CVD not identified through traditional CVD risk factors or scores, and bring physical activity and nutrition to the forefront of provider-patient discussions about lifestyle factors critical to maintaining and prolonging cardiovascular health. [ABSTRACT FROM AUTHOR]

Background/Objective: An abnormal ankle-brachial index (ABI) strongly correlates with higher mortality in patients with cardiovascular disease however, the inverse link has not been established for cardiovascular (CV) health. The American Heart Association (AHA) aims to improve CV health by 20% by 2020 and has thus proposed the use of CV health metrics (Life's Simple 7 or LS7). This study examines the relationship of abnormally low ABI with CV health. Methods: We evaluated 5,308 men and women aged ≥40 years, without history of CVD or diabetes mellitus (DM), participating in NHANES from 1999-2004. Abnormally low ABI was defined as ABI< 1.00 which included borderline low [0.91-0.99] and low ABI [<=0.90]). LS7 was scored on a 0-14 point scale and calculated based on poor, intermediate and ideal categories of 7 health components: diet, BMI, smoking, physical activity, blood pressure, glucose and cholesterol. LS7 scores were categorized as inadequate (0-7points), average (8-11) and optimum (12-14) CV health. Ordinal logistic regression models identified associations between abnormal ABI and CV health, with adjustments for sex, age, race/ethnicity, socioeconomic status and hs-CRP. Results: The mean (95% CI) LS7 score was 7.4 (7.3-7.5), with the majority of the population (75.3%) clustered at the lower end of average CV health. Adjusted models demonstrated that, compared to those with inadequate CV health, those with average CV health experienced 28% lower odds of abnormal ABI (OR 0.72, 95% CI; 0.52-0.97). Further improving CV health from inadequate to optimum was associated with 78% lower odds of abnormal ABI (OR 0.22, 95% CI; 0.09-0.57). On examining individual components, only blood pressure was found to be significantly associated with lower odds of abnormal ABI. Those with intermediate, as compared to poor, blood pressure readings showed 32% lower odds of abnormal ABI (OR 0.68, 95% CI; 0.48-0.94) while those with ideal blood pressure showed a 61% lower odds of abnormal ABI (OR 0.39, 95% CI; 0.21-0.72). Discussion/Conclusion: Although those with average CV health experienced lower odds of abnormal ABI, improving CV health to optimum can significantly lower these odds. This suggests that optimizing cardiovascular health, particularly in those who have not yet been affected by CVD or DM, can significantly slow or prevent progression of systemic atherosclerosis. [ABSTRACT FROM AUTHOR]

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16 -17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease is the leading cause of death in the United States, so improving cardiovascular health (CVH) is a key population health goal. As part of public health efforts to achieve this, the American Heart Association recently developed a comprehensive CVH metric that incorporates smoking, body mass index, physical activity, diet, cholesterol, blood pressure, and blood glucose. The objectives of the current study were to measure CVH in all US counties and identify key socioeconomic determinants of county-level CVH. Methods: Data from the Behavioral Risk Factor Surveillance System were used to determine calculate CVH for each county in 2009. Federal Information Processing Standards codes were used to obtain scores for counties with a sample size of 15 or more; 62% (1948 of 3142) of United States counties had available data. The main outcomes were age-standardized mean CVH score and percentage of poor or ideal health. Data on county-level socioeconomic indicators were abstracted from the Area Resource File. Results and Conclusions: Overall, 18% of the population had poor CVH, 77% had intermediate, and 5% had ideal. Between counties the average overall CVH varied from 2.13 to 4.80, the percentage of ideal health varied from 0% to 46%, and the percentage of poor health varied from 1% to 76%. Counties with the poorest health were in the Midwest and Southern regions. There is a moderate positive relationship between mean CVH and per capita income (r=0.355) and a weak positive relationship between mean CVH and percent urban population (r=0.245). In conclusion, there are few counties with a substantial percentage of their population with ideal health, there is a wide range of cardiovascular health status within the United States, and there is some association of increasing CVH with increasing income and urbanization. [ABSTRACT FROM AUTHOR]

Highlights: [•] A cross-sectional study was performed on 815 children from 8years of NHANES data. [•] PFOA and PFOS were the exposures examined; dyslipidemia was the outcome variable. [•] PFOA and PFOS were positively associated with high total cholesterol and LDL-C. [•] Even low PFAS levels were associated with elevated serum lipid levels in children. [Copyright &y& Elsevier]

R4012 --> 686.7 --> Breast Cancer (BC) is the most common malignancy affecting women worldwide [1]. Adjuvant radiation therapy (RT) of the breast plays a vital role in BC treatment and has been shown to improve overall survival [2]. Due to increased survivorship, the cardiac sequelae that develop due to BC treatments have become more apparent. Radiation therapy, a common BC treatment, exposes the heart to radiation due to its presence in the irradiation field. Although modern RT techniques aim to reduce cardiac radiation exposure, research suggests the persistence of cardiac damage. This scoping review aims to establish the types of cardiovascular disease (CVD) that manifest post‐RT, and create a timeline for early radiation‐induced cardiotoxicity detection and surveillance. A scoping review was conducted utilizing the methodology of the Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐Scr). A literature search was conducted on MEDLINE and EMBASE in Ovid on July 29th, 2021 for papers published from 1995 to July 2021. MeSH/EMTREE terms and keywords were used for the following concepts: Breast Cancer, Radiation Therapy, Cardiovascular, Treatment Outcomes. Search strategies were optimized for each database. After removing duplicates, 1341 papers were sent to title and abstract screening, of which 276 were sent to full‐text review. 160 studies were included for final data extraction. Agreement from two reviewers was required for an article to move to the next stage of screening. Eligibility criteria included primary clinical studies reporting a cardiovascular outcome of interest for patients who underwent BC RT. Even with modern radiotherapy techniques, patients who have undergone BC RT face an increased risk of the development of cardiovascular morbidities. In the long term, the risk of cardiac disease increases with an increase in mean heart radiation dose. Early‐detection studies reveal that changes in cardiac dysfunction can be detected early on, often characterized by a decline in left ventricular ejection fraction. With most RT‐induced cardiac sequelae manifesting years after RT exposure, studies with a shorter follow‐up period often report lower CVD risk. Articles produced contrasting results regarding whether breast cancer radiation laterality increases the risk of CVD, with many indicating no difference while others concluded those with left‐sided radiation therapy have an increased risk. Detection and surveillance, with a combination of both cardiac biomarkers and imaging, is critical at an early stage for all women who have undergone BC RT. With the majority of current surveillance techniques only detecting cardiovascular damage once it is too late, early detection is a critical prerequisite in improving cardiac sequelae prediction and prevention to ultimately improve breast cancer patients' quality of life and care. [1] Sung et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin; 72(3):210‐249 [2] Correa et al. Coronary Artery Findings After Left‐Sided Compared with Right‐Sided Radiation Treatment for Early‐Stage Breast Cancer. J Clin Oncol, 2007; 25(21):3031‐3037 [ABSTRACT FROM AUTHOR]

Background: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the development and progression of colorectal cancer (CRC). However, the link between these compounds and CRC remains unknown. In this cross-sectional study, we investigated the association of CRC diagnosis to PFOA and PFOS blood levels in a large Appalachian population.Methods: Participants were 47,359 adults ≥ 21 years of age and residing in six PFOA-contaminated water districts in the mid-Ohio Valley (N = 47,151 cancer-free adults, 208 cases of primary CRC). All participants completed a comprehensive health survey between 2005 and 2006; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history was assessed via self report and cancer diagnosis confirmed via chart review.Results: CRC showed a strong inverse, dose-response association with PFOS serum levels (odds ratio (OR) adjusted for potential confounders = 0.2, 95% confidence interval (CI) 0.2,0.3) for highest vs. lowest quartile of PFOS, P-trend < 0.00001) and a significant, but more modest inverse association with PFOA (adjusted OR = 0.6 (CI 0.4, 0.9) for highest vs. lowest quartile, P-trend = 0.001). These inverse associations were stronger in those diagnosed within the previous 6 years and resident in the same water district for a minimum of 10-15 years preceding assessment. The relationship between PFOA and CRC was also more pronounced in men and leaner adults, and showed a stronger linear trend at lower exposure levels.Conclusions: In this large cross-sectional study, we found a strong, inverse association between PFOS and likelihood of CRC diagnosis and a significant, although more modest inverse association between PFOA and CRC. If confirmed in prospective investigations, these findings may aid in identifying new strategies for CRC prevention and treatment and inform future studies regarding mechanisms underlying CRC pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) persist in the environment and are found in relatively high concentrations in animal livers. Studies in humans have reported inconsistent associations between PFOA and liver enzymes. Objectives: We examined the cross-sectional association between serum PFOA and PFOS concentrations with markers of liver function in adults. Methods: The C8 Health Project collected data on 69,030 persons; of these, a total of 47,092 adults were included in the present analysis. Linear regression models were fitted for natural log (ln)-transformed values of alanine transaminase (ALT), γ-glutamyltransferase (GGT), and direct bilirubin on PFOA, PFOS, and potential confounders. Logistic regression models were fitted comparing deciles of PFOA or PFOS in relation to high biomarker levels. A multilevel analysis comparing the evidence for association of PFOA with liver function at the individual level within water districts to that at the population level between water districts was also performed. Results: ln-PFOA and ln-PFOS were associated with ln-ALT in linear regression models [PFOA: coefficient, 0.022; 95% confidence interval (CI): 0.018, 0.025; PFOS: coefficient, 0.020; 95% CI: 0.014, 0.026] and with raised ALT in logistic regression models [with a steady increase in the odds ratio (OR) estimates across deciles of PFOA and PFOS; PFOA: OR = 1.10; 95% CI: 1.07, 1.13; PFOS: OR = 1.13; 95% CI: 1.07, 1.18]. There was less consistent evidence of an association of PFOA and GGT or bilirubin. The relationship with bilirubin appears to rise at low levels of PFOA and to fall again at higher levels. Conclusions: These results show a positive association between PFOA and PFOS concentrations and serum ALT level, a marker of hepatocellular damage. [ABSTRACT FROM AUTHOR]

Velan SS, Said N, Durst C, Frisbee S, Frisbee J, Raylman RR, Thomas MA, Rajendran VM, Spencer RG, Alway SE. Distinct patterns of fat metabolism in skeletal muscle of normal-weight, overweight, and obese humans. Am J Physiol Regul Integr Comp Physiol 295: R1060-R1065, 2008. First published July 30, 2008; doi:10.1 152/ajpregu.90367.2008.-The link between body weight, lipid metabolism, and health risks is poorly understood and difficult to study. Magnetic resonance spectroscopy (MRS) permits noninvasive investigation of lipid metabolism. We extended existing two-dimensional MRS techniques to permit quantification of intraand extramyocellular lipid (IMCL and EMCL, respectively) compartments and their degree of unsaturation in human subjects and correlated these results with body mass index (BMI). Using muscle creatine for normalization, we observed a statistically significant (P < 0.01) increase in the IMCL-to-creatine ratio with BMI (n = 8 subjects per group): 5.9 ± 1.7 at BMI < 25, 10.9 ± 1.82 at 25 30. Similarly, the degree of IMCL unsaturation decreased significantly (P < 0.01) with BMI: 1.51 ± 0.08 at BMI < 25, 1.30 ± 0.11 at 25 < BMI < 30, and 0.90 ± 0.14 at BMI> 30. We conclude that important aspects of lipid metabolism can be evaluated by two-dimensional MRS and propose that degree of unsaturation measured noninvasively may serve as a biomarker for lipid metabolic defects associated with obesity. [ABSTRACT FROM AUTHOR]

The obese Zucker rat (OZR) is afflicted with moderate hypercholesterolemia (HC), and previous studies suggest that vascular dysfunction in OZR is associated with chronic loss of nitric oxide (NO) bioavailability and chronic elevation in inflammation, also associated with HC. As such, we evaluated the impact of anti-HC therapy on vascular outcomes in OZR, and effects on inflammation and NO bioavailability. OZR were treated with gemfibrozil, probucol, atorvastatin or simvastatin for 10 weeks. Subsequently, plasma/vascular samples were collected for biochemical/molecular analyses, while vascular reactivity and network structure were assessed. All therapies were effective in reducing cholesterol, though only statins improved indices of NO bioavailability. Similarly, statins caused modest improvements to wall mechanics, these agents strongly attenuated microvascular rarefaction in OZR, and improved active hyperemia in gastrocnemius. Additionally, statin therapy reduced inflammatory state in OZR, such that most measured markers of inflammation were correlated with improved microvascular outcome. However, using discriminant analyses, plasma IL-10, RANTES, IL-Iβ and IL-4 were determined to be the strongest contributors to differences between groups. These results provide a framework for targeted investigation into mechanistic determinants of poor vascular outcomes in the metabolic syndrome. [ABSTRACT FROM AUTHOR]