Environmental Pollution and Cardiovascular Disease: Part 1 of 2: Air Pollution.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Over the past 50 years, there has been a substantial decline in the incidence of CVD and related mortality in high-income countries, largely due to the mitigation of modifiable risk factors such as smoking, hypertension, and diabetes. However, a significant burden of CVD remains in low- to middle-income countries, despite their lower prevalence of traditional risk factors; other environmental factors, particularly pollution, play a significant role in this attributable risk. Mounting evidence underscores a strong association between pollution and adverse health effects, including CVD. This article is part 1 of a 2-part state-of-the-art review and discusses air pollution and its adverse effects on CVD, highlighting pathophysiological mechanisms and methods to reduce air pollution and exposure to these pollutants.

Clinical Outcomes of Aortic Stenosis in Amyloidosis: A United States National Cohort Study.

BACKGROUND: Literature regarding outcomes associated with surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) among amyloidosis (AM) with aortic stenosis (AS) is limited. OBJECTIVES: We aim to study the mortality and in-hospital clinical outcomes among AM with AS associated with SAVR or TAVR. METHODS: We performed a retrospective study of all hospitalisation encounters associated with a diagnosis of AM with AS, using the Nationwide Readmissions Database for the years 2012-2019. Primary outcomes were in-hospital mortality, and 30-day readmissions. RESULTS: A total of 4,820 index hospitalisations of AS (mean age 78.35±10.11; female 37.76%) among AM were reported. Total 464 patients had mechanical intervention, 251 patients (54.1%) TAVR and 213 patients (45.9%) SAVR. A total of 317 patients (6.77%) with AS died; TAVR 4.4%, SAVR 11.9% (p=0.01) and 6.66% died among the subgroup who did not have any mechanical intervention. Higher complication rates were observed among patients who had SAVR than those who had TAVR including acute kidney injury (39.8% vs 22.4%; p=0.01), septic shock (12.1% vs 4.4%; p=0.05) and cardiogenic shock (22% vs 4.4%; p<0.001). Acute heart failure was higher among patients who had TAVR (40.2% vs 27.5%; p=0.04) than those who had SAVR. All conduction block and ischaemic stroke were similar between the two groups (p=0.09 and p=0.1). The overall 30-day readmission rate among AM with AS encounters was 16.82%, higher among TAVR compared to SAVR subgroups (21.25% vs 11.17%; p=0.001). CONCLUSIONS: Among AM with AS hospitalisations, TAVR had mortality benefits compared to SAVR and non-mechanical intervention subgroups. Moreover, higher 30-day mortality rate were observed among SAVR subgroup, which may suggest that TAVR should be strongly considered in AM patients complicated by AS.

Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis.

OBJECTIVE: Recent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent. METHODS: Patients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up 18F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta. RESULTS: 115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups-ΔTNFi: -0.24 (SD=0.51), Δtriple therapy: -0.19 (SD=0.51)-without difference between groups (difference in Δs: -0.02, 95% CI -0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (ß=0.04, 95% CI -0.03 to 0.10). CONCLUSION: We found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy. TRIAL REGISTRATION NUMBER: NCT02374021.

The combined effect of air and transportation noise pollution on atherosclerotic inflammation and risk of cardiovascular disease events.

BACKGROUND: Air pollution and noise exposures individually associate with major adverse cardiovascular events (MACE) via a mechanism involving arterial inflammation (ArtI); however, their combined impact on ArtI and MACE remains unknown. We tested whether dual (vs. one or neither) exposure associates with greater ArtI and MACE risk and whether MACE risk is mediated via ArtI. METHODS: Individuals (N = 474) without active cancer or known cardiovascular disease with clinical 18F-FDG-PET/CT imaging were followed for 5 years for MACE. ArtI was measured. Average air pollution (particulate matter ≤ 2.5 µm, PM2.5) and transportation noise exposure were determined at individual residences. Higher exposures were defined as noise > 55 dBA (World Health Organization cutoff) and PM2.5 ≥ sample median. RESULTS: At baseline, 46%, 46%, and 8% were exposed to high levels of neither, one, or both pollutants; 39 experienced MACE over a median 4.1 years. Exposure to an increasing number of pollutants associated with higher ArtI (standardized ß [95% CI: .195 [.052, .339], P = .008) and MACE (HR [95% CI]: 2.897 [1.818-4.615], P < .001). In path analysis, ArtI partially mediated the relationship between pollutant exposures and MACE (P < .05). CONCLUSION: Air pollution and transportation noise exposures contribute incrementally to ArtI and MACE. The mechanism linking dual exposure to MACE involves ArtI.

Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome.

AIMS: Activity in the amygdala, a brain centre involved in the perception of and response to stressors, associates with: (i) heightened sympathetic nervous system and inflammatory output and (ii) risk of cardiovascular disease. We hypothesized that the amygdalar activity (AmygA) ratio is heightened among individuals who develop Takotsubo syndrome (TTS), a heart failure syndrome often triggered by acute stress. We tested the hypotheses that (i) heightened AmygA precedes development of TTS and (ii) those with the highest AmygA develop the syndrome earliest. METHODS AND RESULTS: Individuals (N=104, median age 67.5 years, 72% female, 86% with malignancy) who underwent clinical 18 F-FDG-PET/CT imaging were retrospectively identified: 41 who subsequently developed TTS and 63 matched controls (median follow-up 2.5 years after imaging). AmygA was measured using validated methods. Individuals with (vs. without) subsequent TTS had higher baseline AmygA (P=0.038) after adjusting for TTS risk factors. Further, AmygA associated with the risk for subsequent TTS after adjustment for risk factors [standardized hazard ratio (95% confidence interval): 1.643 (1.189, 2.270), P=0.003]. Among the subset of individuals who developed TTS, those with the highest AmygA (>mean + 1 SD) developed TTS ∼2 years earlier after imaging vs. those with lower AmygA (P=0.028). CONCLUSION: Higher AmygA associates with an increased risk for TTS among a retrospective population with a high rate of malignancy. This heightened neurobiological activity is present years before the onset of TTS and may impact the timing of the syndrome. Accordingly, heightened stress-associated neural activity may represent a therapeutic target to reduce stress-related diseases, including TTS.

Inflammation of the periodontium associates with risk of future cardiovascular events.

BACKGROUND: While growing evidence suggests a link between periodontal disease (PD) and cardiovascular disease (CVD), the independence of this association and the pathway remain unclear. Herein, we tested the hypotheses that: (1) inflammation of the periodontium (PDinflammation ) predicts future CVD independently of disease risk factors shared between CVD and PD, and (2) the mechanism linking the two diseases involves heightened arterial inflammation. METHODS: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) imaging was performed in 304 individuals (median age 54 years; 42.4% male) largely for cancer screening; individuals without active cancer were included. PDinflammation and arterial inflammation were quantified using validated 18 F-FDG-PET/CT methods. Additionally, we evaluated the relationship between PDinflammation and subsequent major adverse cardiovascular events (MACE) using Cox models and log-rank tests. RESULTS: Thirteen individuals developed MACE during follow-up (median 4.1 years). PDinflammation associated with arterial inflammation, remaining significant after adjusting for PD and CVD risk factors (standardized ß [95% CI]: 0.30 [0.20-0.40], P < 0.001). PDinflammation predicted subsequent MACE (standardized HR [95% CI]: 2.25 [1.47 to 3.44], P <0.001, remaining significant in multivariable models), while periodontal bone loss did not. Furthermore, mediation analysis suggested that arterial inflammation accounts for 80% of the relationship between PDinflammation and MACE (standardized log odds ratio [95% CI]: 0.438 [0.019-0.880], P = 0.022). CONCLUSION: PDinflammation is independently associated with MACE via a mechanism that may involve increased arterial inflammation. These findings provide important support for an independent relationship between PDinflammation and CVD.

Brief Report: Lower Socioeconomic Status Associates With Greater Systemic and Arterial Inflammation in HIV.

OBJECTIVES: In the general population, the lower socioeconomic status (SES) associates with greater systemic and arterial inflammation and a greater risk of cardiovascular disease. Because arterial inflammation is heightened in individuals living with HIV, we tested the hypothesis that SES associates with arterial inflammation in this population. SETTINGS: Prospective cohort study. METHODS: Men living with HIV were recruited. Arterial inflammation and leukopoietic activity (ie, bone marrow activity) were measured using 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Zip code-level SES measures were derived from the US Census Bureau. Linear regression and mediation analyses were used to assess associations between SES, arterial inflammation, leukopoietic activity, C-reactive protein (CRP), and interleukin-6. RESULTS: Thirty-nine virologically suppressed men living with HIV were studied (mean ± SD age 50.5 ± 11.1 years). The median CD4 count was 663 cells/mm3 (interquartile range: 399-922); 82% were receiving antiretroviral therapies. Local median income inversely associated with arterial inflammation [standardized ß (95% confidence interval): -0.42 (-0.76 to -0.08)] after adjusting for age, Framingham risk score, statin use, antiretroviral use, and nadir CD4 count. The high-school graduation rate independently associated with arterial inflammation [-0.45 (-0.78 to -0.12)] and CRP [-0.49 (-0.86 to -0.012)]. Mediation analysis demonstrated the impact of SES on arterial inflammation was partially mediated by heightened circulating inflammatory levels: ↓SES (as high school graduation rate) →↑CRP →↑arterial inflammation accounting for 44% of the total effect (P < 0.05). CONCLUSION: In individuals living with HIV, lower SES independently associated with higher leukopoietic activity, circulating markers of inflammation, and arterial inflammation. Furthermore, the link between SES and arterial inflammation was mediated by increased systemic inflammation.

A leucopoietic-arterial axis underlying the link between ambient air pollution and cardiovascular disease in humans.

AIMS: Air pollution [i.e. particulate matter with diameter <2.5 µm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE. METHODS AND RESULTS: Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual's home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE. CONCLUSIONS: Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series.

A neurobiological mechanism linking transportation noise to cardiovascular disease in humans.

AIMS: Chronic noise exposure associates with increased cardiovascular disease (CVD) risk; however, the role of confounders and the underlying mechanism remain incompletely defined. The amygdala, a limbic centre involved in stress perception, participates in the response to noise. Higher amygdalar metabolic activity (AmygA) associates with increased CVD risk through a mechanism involving heightened arterial inflammation (ArtI). Accordingly, in this retrospective study, we tested whether greater noise exposure associates with higher: (i) AmygA, (ii) ArtI, and (iii) risk for major adverse cardiovascular disease events (MACE). METHODS AND RESULTS: Adults (N = 498) without CVD or active cancer underwent clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging. Amygdalar metabolic activity and ArtI were measured, and MACE within 5 years was adjudicated. Average 24-h transportation noise and potential confounders were estimated at each individual's home address. Over a median 4.06 years, 40 individuals experienced MACE. Higher noise exposure (per 5 dBA increase) predicted MACE [hazard ratio (95% confidence interval, CI) 1.341 (1.147-1.567), P < 0.001] and remained robust to multivariable adjustments. Higher noise exposure associated with increased AmygA [standardized ß (95% CI) 0.112 (0.051-0.174), P < 0.001] and ArtI [0.045 (0.001-0.090), P = 0.047]. Mediation analysis suggested that higher noise exposure associates with MACE via a serial mechanism involving heightened AmygA and ArtI that accounts for 12-26% of this relationship. CONCLUSION: Our findings suggest that noise exposure associates with MACE via a mechanism that begins with increased stress-associated limbic (amygdalar) activity and includes heightened arterial inflammation. This potential neurobiological mechanism linking noise to CVD merits further evaluation in a prospective population.

Psychosocial Stress and Cardiovascular Disease.

PURPOSE OF REVIEW: This manuscript reviews the epidemiological data linking psychosocial stress to cardiovascular disease (CVD), describes recent advances in understanding the biological pathway between them, discusses potential therapies against stress-related CVD, and identifies future research directions. RECENT FINDINGS: Metabolic activity of the amygdala (a neural center that is critically involved in the response to stress) can be measured on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) yielding a neurobiological signal that independently predicts subsequent CVD events. Furthermore, a serial pathway from ↑amygdalar activity → ↑hematopoietic tissue activity → ↑arterial inflammation → ↑CVD events has been elucidated, providing new insights into the mechanism linking stress to CVD. Psychosocial stress and stress conditions are independently associated with CVD in a manner that depends on the degree and duration of stress as well as the individual response to a stressor. Nevertheless, the fundamental biology remains incompletely defined, and stress is often confounded by adverse health behaviors. Thus, most clinical guidelines do not yet recognize psychosocial stress as an independent CVD risk factor or advocate for its treatment in CVD prevention. Clarification of this neurobiological pathway provides a better understanding of the underlying pathophysiology and suggests opportunities to develop novel preventive strategies and therapies.

Machine Learning Applications in Head and Neck Radiation Oncology: Lessons From Open-Source Radiomics Challenges.

Radiomics leverages existing image datasets to provide non-visible data extraction via image post-processing, with the aim of identifying prognostic, and predictive imaging features at a sub-region of interest level. However, the application of radiomics is hampered by several challenges such as lack of image acquisition/analysis method standardization, impeding generalizability. As of yet, radiomics remains intriguing, but not clinically validated. We aimed to test the feasibility of a non-custom-constructed platform for disseminating existing large, standardized databases across institutions for promoting radiomics studies. Hence, University of Texas MD Anderson Cancer Center organized two public radiomics challenges in head and neck radiation oncology domain. This was done in conjunction with MICCAI 2016 satellite symposium using Kaggle-in-Class, a machine-learning and predictive analytics platform. We drew on clinical data matched to radiomics data derived from diagnostic contrast-enhanced computed tomography (CECT) images in a dataset of 315 patients with oropharyngeal cancer. Contestants were tasked to develop models for (i) classifying patients according to their human papillomavirus status, or (ii) predicting local tumor recurrence, following radiotherapy. Data were split into training, and test sets. Seventeen teams from various professional domains participated in one or both of the challenges. This review paper was based on the contestants' feedback; provided by 8 contestants only (47%). Six contestants (75%) incorporated extracted radiomics features into their predictive model building, either alone (n = 5; 62.5%), as was the case with the winner of the "HPV" challenge, or in conjunction with matched clinical attributes (n = 2; 25%). Only 23% of contestants, notably, including the winner of the "local recurrence" challenge, built their model relying solely on clinical data. In addition to the value of the integration of machine learning into clinical decision-making, our experience sheds light on challenges in sharing and directing existing datasets toward clinical applications of radiomics, including hyper-dimensionality of the clinical/imaging data attributes. Our experience may help guide researchers to create a framework for sharing and reuse of already published data that we believe will ultimately accelerate the pace of clinical applications of radiomics; both in challenge or clinical settings.