Ambient Air Pollution and Atherosclerosis: Insights Into Dose, Time, and Mechanisms.

Ambient air pollution due to particulate matter ≤2.5 µ is the leading environmental risk factor contributing to global mortality, with a preponderant majority of these deaths attributable to atherosclerotic cardiovascular disease (ASCVD) causes such as stroke and myocardial infarction. Epidemiological studies in humans have provided refined estimates of exposure risk, with evidence suggesting that risk association with particulate matter ≤2.5 levels and ASCVD continues at levels well below air quality guidelines in North America and Europe. Mechanistic studies in animals and humans have provided a framework of understanding of the duration and pathways by which air pollution exposure may predispose to atherosclerosis. Although acute exposure to particulate matter ≤2.5 is associated with oxidative stress and inflammation, system transmission of signals from the lungs to extrapulmonary sites may involve direct translocation of components, biologic intermediates, and autonomic nervous system activation. End-organ effector pathways such as endothelial barrier disruption/dysfunction, thrombosis, vasoconstriction/increased blood pressure, and plaque instability, may contribute to ASCVD. The strength of the association of air pollution with ASCVD offers an opportunity to mitigate its consequences. Although elimination of anthropogenic sources of air pollution with a switch to clean energy provides the ultimate solution, this may not be possible in the interim and may require personal protection efforts and an integrated approach to managing risk posed by air pollution for ASCVD.

Association between ambient air pollution and county-level cardiovascular mortality in the United States by social deprivation index.

BACKGROUND: Air pollution and socioeconomic status have both been strongly associated with cardiovascular (CV) outcomes. We sought to determine if socioeconomic status modifies the risk association between fine particulate matter air pollution (PM2.5) and CV mortality. METHODS: We linked county-level age-adjusted CV mortality data from Multiple Cause of Death files (2000-2016, ICD10: I00-I99) with 2015 Social Deprivation Index (SDI), a validated estimate of socioeconomic status, and modelled spatial and temporal mean annual PM2.5 exposures (2012-2018). Higher SDI suggests greater deprivation and lower socioeconomic status. Associations between PM2.5 and age adjusted CV mortality were estimated using linear models. RESULTS: A total of 5,769,315 cardiovascular deaths from 2012-2018 across 3106 United States counties were analyzed. Both PM2.5 (ß (SE) 7.584 (0.938), P < .001) and SDI scores (ß (SE) 0.591 (0.140), P < .001) were independently associated with age-adjusted CV mortality (R2 = 0.341). The association between PM2.5 and CV mortality were stronger among counties with highest SDI, P value for interaction = .012. CONCLUSION: Social deprivation and PM2.5 exposures were independently associated with county level age-adjusted CV mortality. The associations between PM2.5 and CV mortality were stronger in counties with high vs low social deprivation. SDI and PM2.5 represent potential targets to reduce CV mortality disparities and interventions to reduce PM2.5 exposure may be most impactful in communities of low socioeconomic status.

Ambient Air Pollution and Atherosclerosis: Recent Updates.

PURPOSE OF REVIEW: During the past century, exposure to particulate matter (PM) air pollution < 2.5 µm in diameter (PM2.5) has emerged as an all-pervading element of modern-day society. This increased exposure has come at the cost of heightened risk for cardiovascular (CV) morbidity and mortality. Not only can short-term PM2.5 exposure trigger acute CV events in susceptible individuals, but longer-term exposure over years augments CV risk to a greater extent in comparison with short-term exposure. The purpose of this review is to examine the available evidence for how ambient air pollution exposure may precipitate events at various time frames. RECENT FINDINGS: Recent epidemiological studies have demonstrated an association between ambient PM2.5 exposure and the presence and progression of atherosclerosis in humans. Multiple animal exposure experiments over two decades have provided strong corroborative evidence that chronic exposure in fact does enhance the progression and perhaps vulnerability characteristics of atherosclerotic lesions. Evidence from epidemiological studies including surrogates of atherosclerosis, human translational studies, and mechanistic investigations utilizing animal studies have improved our understanding of how ambient air pollution may potentiate atherosclerosis and precipitate cardiovascular events. Even so, future research is needed to fully understand the contribution of different constituents in ambient air pollution-mediated atherosclerosis as well as how other systems may modulate the impact of exposure including adaptive immunity and the gut microbiome. Nevertheless, due to the billions of people continually exposed to PM2.5, the long-term pro-atherosclerotic effects of this ubiquitous air pollutant are likely to be of enormous and growing global public health importance.

Evidence-Based Medical Management of Peripheral Artery Disease.

Peripheral artery disease is an atherosclerotic disease of the lower extremities associated with high cardiovascular mortality. Management of this condition may include lifestyle modifications, medical management, endovascular repair, or surgery. The medical approach to peripheral artery disease is multifaceted and includes cholesterol reduction, antiplatelet therapy, anticoagulation, peripheral vasodilators, blood pressure management, exercise therapy, and smoking cessation. Adherence to this regimen can reduce limb-related complications like critical limb ischemia and amputation, as well as systemic complications of atherosclerosis like stroke and myocardial infarction. Relative to coronary artery disease, peripheral artery disease is an undertreated condition. In this article, we explore the evidence behind medical therapies for the management of peripheral artery disease.

Predicting time to castration resistance in hormone sensitive prostate cancer by a personalization algorithm based on a mechanistic model integrating patient data.

BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer death of men worldwide. In hormone-sensitive prostate cancer (HSPC), androgen deprivation therapy (ADT) is widely used, but an eventual failure on ADT heralds the passage to the castration-resistant prostate cancer (CRPC) stage. Because predicting time to failure on ADT would allow improved planning of personal treatment strategy, we aimed to develop a predictive personalization algorithm for ADT efficacy in HSPC patients. METHODS: A mathematical mechanistic model for HSPC progression and treatment was developed based on the underlying disease dynamics (represented by prostate-specific antigen; PSA) as affected by ADT. Following fine-tuning by a dataset of ADT-treated HSPC patients, the model was embedded in an algorithm, which predicts the patient's time to biochemical failure (BF) based on clinical metrics obtained before or early in-treatment. RESULTS: The mechanistic model, including a tumor growth law with a dynamic power and an elaborate ADT-resistance mechanism, successfully retrieved individual time-courses of PSA (R(2) = 0.783). Using the personal Gleason score (GS) and PSA at diagnosis, as well as PSA dynamics from 6 months after ADT onset, and given the full ADT regimen, the personalization algorithm accurately predicted the individual time to BF of ADT in 90% of patients in the retrospective cohort (R(2) = 0.98). CONCLUSIONS: The algorithm we have developed, predicting biochemical failure based on routine clinical tests, could be especially useful for patients destined for short-lived ADT responses and quick progression to CRPC. Prospective studies must validate the utility of the algorithm for clinical decision-making.

Socioeconomic Deprivation and Premature Cardiovascular Mortality in the United States.

OBJECTIVE: To determine the variability in county cardiovascular (CV) premature mortality explained by integrated metrics of socioeconomic deprivation and to explore temporal trends in CV mortality by county socioeconomic deprivation. METHODS: This is a cross-sectional analysis of US county-level death certificate data from 1999 to 2018 of age-adjusted premature (25 to 64 years) CV mortality. Integrated metrics of socioeconomic deprivation (Social Deprivation Index [SDI] and county Area Deprivation Index [ADI]) were associated with mortality using linear regression analysis. Relative change in county CV mortality from 1999 to 2018 was associated with indices using linear regression analysis. RESULTS: Counties with higher quartile SDI and ADI had significantly higher total, non-Hispanic Black/African American, and female premature CV mortality (P<.001). Both SDI and ADI were significantly associated with CV mortality by linear regression (P<.001) explaining 40% and 44% of county variability in CV mortality, respectively. Counties with lower deprivation indices experienced a larger decreased in premature CV mortality (P<.001). CONCLUSION: This study demonstrates an association between multiple integrated metrics of socioeconomic deprivation and premature cardiovascular mortality and shows potentially worsening disparities.

Anisocytosis is associated with myocardial fibrosis and exercise capacity in heart failure with preserved ejection fraction.

BACKGROUND: Red Blood Cell Distribution Width (RDW), a measure of variability in size of circulating red blood cells and is a marker of inflammation. OBJECTIVES: We sought to test the hypothesis that RDW reflects an inflammatory milieu permissive for cardiac fibrosis in those with Heart Failure and preserved ejection fraction (HFpEF). METHODS: We analyzed the association between RDW and fibrosis in two separate cohorts. Cohort 1 (n = 200) was a retrospective analysis of blood biomarkers measured in the RELAX trial (Clinicaltrials.gov NCT00763867) and Cohort 2 (n = 160) included a single center cohort of patients with preserved ventricular function referred for cardiac magnetic resonance imaging (cMRI). Linear regression was used to adjust for potential confounders, and a mediation analysis used to explore relationships with exercise intolerance (peak VO2 max). RESULTS: Within Cohort 1, anisocytosis (RDW > 14.5) was prevalent (49.5%) and was associated with greater baseline clinical comorbidities, a lower Peak VO2 and more frequent heart failure hospitalizations. The RDW was associated with biomarkers of inflammation and cardiac fibrosis. In Cohort 2, RDW was associated with cMRI myocardial fibrosis (extracellular volume; Spearman's rho=0.38, P<0.001) which was independent of age, sex, LV ejection fraction, and hematocrit (P = 0.026). Individuals with both anisocytosis and myocardial fibrosis identified a subgroup of at high risk for 2-year mortality (HR 16.28 [4.30-61.66], P<0.001). CONCLUSIONS: In two independent cohorts of patients with HFpEF, elevated RDW is associated reduced exercise capacity and greater fibrosis as measured by serum biomarkers and cMRI. Additional studies are needed to validate this novel relationship.

Endothelin-1 and peak oxygen consumption in patients with heart failure with preserved ejection fraction.

BACKGROUND: Mechanisms of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) are not well understood. Pulmonary hypertension, a common accompaniment in patients with HFpEF, is associated with poor outcomes. While Endothelin -1 (ET-1) plays a mechanistic role in pulmonary hypertension, its role in exercise intolerance in HFpEF is not well established. OBJECTIVE: To explore the association between plasma ET-1 levels and maximal oxygen consumption (pVO2), and their changes over 24 weeks in HFpEF. METHODS: This is a post-hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. We performed linear regressions to assess the relationship between plasma ET-1 and pVO2. We also used linear regressions to determine whether ET-1 was associated with change in peak VO2 (ΔpVO2). RESULTS: A total of 210 patients were included. Baseline plasma ET-1 levels were associated with older age, higher NT-proBNP levels, higher serum creatinine levels, and higher prevalence of atrial fibrillation. Patients with higher ET1 levels also had higher plasma galectin-3 and CITP levels. After multiple adjustments, baseline ET1 levels were associated with lower pVO2 (ß -0.927, SE 0.196, p < 0.001). Over 24 weeks, the change in ET1 levels was associated with the change in pVO2 (multivariable adjusted ß -0.415, SE 0.115, p = 0.018). Baseline ET1 levels did not modify the effect of sildenafil on change in peak VO2. CONCLUSIONS: Plasma ET1 levels are significantly associated with lower exercise oxygen consumption both at baseline and longitudinally over 24 weeks. Future studies should explore Endothelin-1 antagonism to improve exercise tolerance in HFpEF.

Oxidative stress pathways of air pollution mediated toxicity: Recent insights.

Ambient air pollution is a leading environmental cause of morbidity and mortality globally with most of the outcomes of cardiovascular origin. While numerous mechanisms are proposed to explain the link between air pollutants and cardiovascular events, the evidence supports a role for oxidative stress as a critical intermediary pathway in the transduction of systemic responses in the cardiovascular system. Indeed, alterations in vascular function are a critical step in the development of cardiometabolic disorders such as hypertension, diabetes, and atherosclerosis. This review will provide an overview of the impact of particulate and gaseous pollutants on oxidative stress from human and animal studies published in the last five years. We discuss current gaps in knowledge and evidence to date implicating the role of oxidative stress with an emphasis on inhalational exposures. We conclude with the identification of gaps, and an exhortation for further studies to elucidate the impact of oxidative stress in air pollution mediated effects.

Whole blood defensin mRNA expression is a predictive biomarker of docetaxel response in castration-resistant prostate cancer.

This study tested the potential of circulating RNA-based signals as predictive biomarkers for docetaxel response in patients with metastatic castration-resistant prostate cancer (CRPC). RNA was analyzed in blood from six CRPC patients by whole-transcriptome sequencing (total RNA-sequencing) before and after docetaxel treatment using the Illumina's HiSeq platform. Targeted RNA capture and sequencing was performed in an independent cohort of ten patients with CRPC matching the discovery cohort to confirm differential expression of the genes. Response to docetaxel was defined on the basis of prostate-specific antigen levels and imaging criteria. Two-way analysis of variance was used to compare differential gene expression in patients classified as responders versus nonresponders before and after docetaxel treatment. Thirty-four genes with two-fold differentially expressed transcripts in responders versus nonresponders were selected from total RNA-sequencing for further validation. Targeted RNA capture and sequencing showed that 13/34 genes were differentially expressed in responders. Alpha defensin genes DEFA1, DEFA1B, and DEFA3 exhibited significantly higher expression in responder patients compared with nonresponder patients before administration of chemotherapy (fold change >2.5). In addition, post-docetaxel treatment significantly increased transcript levels of these defensin genes in responders (fold change >2.8). Our results reveal that patients with higher defensin RNA transcripts in blood respond well to docetaxel therapy. We suggest that monitoring DEFA1, DEFA1B, and DEFA3 RNA transcripts in blood prior to treatment will be helpful to determine which patients are better candidates to receive docetaxel chemotherapy.

Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer.

BACKGROUND: Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. OBJECTIVE: To identify and evaluate plasma exosomal miRNAs for prognosis in castration-resistant prostate cancer (CRPC). DESIGN, SETTING, AND PARTICIPANTS: RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors. RESULTS AND LIMITATIONS: RNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥ 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate < 0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival (p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 (p = 6.57 × 10(-6)). CONCLUSIONS: Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further evaluation of these candidate miRNAs. PATIENT SUMMARY: In this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant further investigation because the noninvasive blood-based test has great potential in the management of late-stage prostate cancer.