Health position paper and redox perspectives - Disease burden by transportation noise.

Transportation noise is a ubiquitous urban exposure. In 2018, the World Health Organization concluded that chronic exposure to road traffic noise is a risk factor for ischemic heart disease. In contrast, they concluded that the quality of evidence for a link to other diseases was very low to moderate. Since then, several studies on the impact of noise on various diseases have been published. Also, studies investigating the mechanistic pathways underlying noise-induced health effects are emerging. We review the current evidence regarding effects of noise on health and the related disease-mechanisms. Several high-quality cohort studies consistently found road traffic noise to be associated with a higher risk of ischemic heart disease, heart failure, diabetes, and all-cause mortality. Furthermore, recent studies have indicated that road traffic and railway noise may increase the risk of diseases not commonly investigated in an environmental noise context, including breast cancer, dementia, and tinnitus. The harmful effects of noise are related to activation of a physiological stress response and nighttime sleep disturbance. Oxidative stress and inflammation downstream of stress hormone signaling and dysregulated circadian rhythms are identified as major disease-relevant pathomechanistic drivers. We discuss the role of reactive oxygen species and present results from antioxidant interventions. Lastly, we provide an overview of oxidative stress markers and adverse redox processes reported for noise-exposed animals and humans. This position paper summarizes all available epidemiological, clinical, and preclinical evidence of transportation noise as an important environmental risk factor for public health and discusses its implications on the population level.

Amygdalar activity measured using FDG-PET/CT at head and neck cancer staging independently predicts survival.

IMPORTANCE: The mechanisms underlying the association between chronic stress and higher mortality among individuals with cancer remain incompletely understood. OBJECTIVE: To test the hypotheses that among individuals with active head and neck cancer, that higher stress-associated neural activity (ie. metabolic amygdalar activity [AmygA]) at cancer staging associates with survival. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center (Massachusetts General Hospital, Boston). PARTICIPANTS: 240 patients with head and neck cancer (HNCA) who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging. MEASUREMENTS: 18F-FDG uptake in the amygdala was determined by placing circular regions of interest in the right and left amygdalae and measuring the mean tracer accumulation (i.e., standardized uptake value [SUV]) in each region of interest. Amygdalar uptake was corrected for background cerebral activity (mean temporal lobe SUV). RESULTS: Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1.7-5.1). AmygA associated with heightened bone marrow activity, leukocytosis, and C-reactive protein (P<0.05 each). In adjusted and unadjusted analyses, AmygA associated with subsequent mortality (HR [95% CI]: 1.35, [1.07-1.70], P = 0.009); the association persisted in stratified subset analyses restricted to patients with advanced cancer stage (P<0.001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P = 0.01). The median progression-free survival was 25 months in patients with higher AmygA (upper tertile) as compared with 36.5 months in other individuals (HR for progression or death [95%CI], 1.83 [1.24-2.68], P = 0.001). CONCLUSIONS AND RELEVANCE: AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality and cancer progression among patients with HNCA. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival.

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.

Heightened splenic and bone marrow uptake of 18F-FDG PET/CT is associated with systemic inflammation and subclinical atherosclerosis by CCTA in psoriasis: An observational study.

BACKGROUND AND AIMS: Psoriasis is an immune-mediated inflammatory disease with increased risk of myocardial infarction. Preclinical studies in psoriasis models show an association between chronic inflammation and immune cell proliferation in the spleen and bone marrow (BM). We sought to test the hypothesis that splenic and BM 18F-fluorodeoxyglucose (18F-FDG) uptake is heightened in psoriasis and that higher uptake associates with systemic inflammation and subclinical atherosclerotic disease measures in this cohort. METHODS: Multimodality imaging and biomarker assays were performed in 240 participants (210 with psoriasis and 30 healthy). Splenic and BM uptake was obtained using 18F-FDG positron emission tomography/computed tomography (PET/CT). Coronary artery plaque characteristics including non-calcified burden (NCB) and lipid rich necrotic core (LRNC) were quantified using a dedicated software for CT angiography. All analyses were performed with StataIC 16 (Stata Corp., College Station, TX, USA). RESULTS: Splenic and BM 18F-FDG uptake was increased in psoriasis (vs. healthy volunteers) and significantly associated with proatherogenic lipids, immune cells and systemic inflammation. Higher splenic 18F-FDG uptake associated with higher total coronary burden (ß = 0.37; p<0.001), NCB (ß = 0.39; p<0.001), and LRNC (ß = 0.32; p<0.001) in fully adjusted models. Similar associations were seen for BM 18F-FDG uptake in adjusted models (ß = 0.38; ß = 0.41; ß = 0.24; respectively, all p<0.001). CONCLUSIONS: Heightened splenic and BM uptake of 18F-FDG is associated with proatherogenic lipids, immune cells, inflammatory markers and coronary artery disease. These findings provide insights into atherogenic mechanisms in psoriasis and suggest that immune cell proliferation in the spleen and BM is associated with subclinical atherosclerosis.

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.

Stress-Associated Neurobiological Pathway Linking Socioeconomic Disparities to Cardiovascular Disease.

BACKGROUND: Lower socioeconomic status (SES) associates with a higher risk of major adverse cardiac events (MACE) via mechanisms that are not well understood. OBJECTIVES: Because psychosocial stress is more prevalent among those with low SES, this study tested the hypothesis that stress-associated neurobiological pathways involving up-regulated inflammation in part mediate the link between lower SES and MACE. METHODS: A total of 509 individuals, median age 55 years (interquartile range: 45 to 66 years), underwent clinically indicated whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging and met pre-defined inclusion criteria, including absence of known cardiovascular disease or active cancer. Baseline hematopoietic tissue activity, arterial inflammation, and in a subset of 289, resting amygdalar metabolism (a measure of stress-associated neural activity) were quantified using validated 18F-fluorodeoxyglucose positron emission tomography/computed tomography methods. SES was captured by neighborhood SES factors (e.g., median household income and crime). MACE within 5 years of imaging was adjudicated. RESULTS: Over a median 4.0 years, 40 individuals experienced MACE. Baseline income inversely associated with amygdalar activity (standardized ß: -0.157 [95% confidence interval (CI): -0.266 to -0.041]; p = 0.007) and arterial inflammation (ß: -0.10 [95% CI: -0.18 to -0.14]; p = 0.022). Further, income associated with subsequent MACE (standardized hazard ratio: 0.67 [95% CI: 0.47 to 0.96]; p = 0.029) after multivariable adjustments. Mediation analysis demonstrated that the path of: ↓ neighborhood income to ↑ amygdalar activity to ↑ bone marrow activity to ↑ arterial inflammation to ↑ MACE was significant (ß: -0.01 [95% CI: -0.06 to -0.001]; p < 0.05). CONCLUSIONS: Lower SES: 1) associates with higher amygdalar activity; and 2) independently predicts MACE via a serial pathway that includes higher amygdalar activity, bone marrow activity, and arterial inflammation. These findings illuminate a stress-associated neurobiological mechanism by which SES disparities may potentiate adverse health outcomes.

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.

Amygdalar Metabolic Activity Independently Associates With Progression of Visceral Adiposity.

CONTEXT: Epidemiologic data link psychological stress to adiposity. The underlying mechanisms remain uncertain. OBJECTIVES: To test whether (i) higher activity of the amygdala, a neural center involved in the response to stress, associates with greater visceral adipose tissue (VAT) volumes and (ii) this association is mediated by increased bone marrow activity. SETTING: Massachusetts General Hospital, Boston, Massachusetts. PATIENTS: Two hundred forty-six patients without active oncologic, cardiovascular, or inflammatory disease who underwent clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging were studied. VAT imaging was repeated ∼1 year later in 68 subjects. DESIGN: Metabolic activity of the amygdala (AmygA), hematopoietic tissue activity, and adiposity volumes were measured with validated methods. MAIN OUTCOME MEASURE: The relationship between AmygA and baseline and follow-up VAT. RESULTS: AmygA associated with baseline body mass index (standardized ß = 0.15; P = 0.01), VAT (0.19; P = 0.002), and VAT/subcutaneous adipose tissue ratio (0.20; P = 0.002), all remaining significant after adjustment for age and sex. AmygA also associated with bone marrow activity (0.15; P = 0.01), which in turn associated with VAT (0.34; P < 0.001). Furthermore, path analysis showed that 48% of the relationship between AmygA and baseline VAT was mediated by increased bone marrow activity (P = 0.007). Moreover, AmygA associated with achieved VAT after 1 year (P = 0.02) after adjusting for age, sex, and baseline VAT. CONCLUSIONS: These results suggest a neurobiological pathway involving the amygdala and bone marrow linking psychosocial stress to adiposity in humans. Future studies should test whether targeting this mechanism attenuates adiposity and its complications.

Coronary Microvascular Dysfunction and Cardiovascular Risk in Obese Patients.

BACKGROUND: Besides body mass index (BMI), other discriminators of cardiovascular risk are needed in obese patients, who may or may not undergo consideration for bariatric surgery. Coronary microvascular dysfunction (CMD), defined as impaired coronary flow reserve (CFR) in the absence of flow-limiting coronary artery disease, identifies patients at risk for adverse events independently of traditional risk factors. OBJECTIVES: The study sought to investigate the relationship among obesity, CMD, and adverse outcomes. METHODS: Consecutive patients undergoing evaluation for coronary artery disease with cardiac stress positron emission tomography demonstrating normal perfusion (N = 827) were followed for median 5.6 years for events, including death and hospitalization for myocardial infarction or heart failure. RESULTS: An inverted independent J-shaped relationship was observed between BMI and CFR, such that in obese patients CFR decreased linearly with increasing BMI (adjusted p < 0.0001). In adjusted analyses, CFR but not BMI remained independently associated with events (for a 1-U decrease in CFR, adjusted hazard ratio: 1.95; 95% confidence interval: 1.41 to 2.69; p < 0.001; for a 10-U increase in BMI, adjusted hazard ratio: 1.20; 95% confidence interval: 0.95 to 1.50; p = 0.125) and improved model discrimination (C-index 0.71 to 0.74). In obese patients, individuals with impaired CFR demonstrated a higher adjusted rate of events (5.7% vs. 2.6%; p = 0.002), even in those not currently meeting indications for bariatric surgery (6.4% vs. 2.6%; p = 0.04). CONCLUSIONS: In patients referred for testing, CMD was independently associated with elevated BMI and adverse outcomes, and was a better discriminator of risk than BMI and traditional risk factors. CFR may facilitate management of obese patients beyond currently used markers of risk.

Cardiac macrophages promote diastolic dysfunction.

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.

Isolated cardiac sarcoidosis: A focused review of an under-recognized entity.

There is accumulating evidence for the existence of a phenotype of isolated cardiac sarcoidosis (ICS), or sarcoidosis that only involves the heart. In the absence of biopsy-confirmed cardiac sarcoidosis (CS), existing diagnostic criteria require the presence of extra-cardiac sarcoidosis as an inclusion criterion for the diagnosis of CS. Consequently, in the absence of a positive endomyocardial biopsy, ICS is not diagnosable by current guidelines. Therefore, there is uncertainty regarding the epidemiology, pathobiology, clinical characteristics, prognosis, and optimal treatment of ICS. This review will summarize the available data related to the prevalence and prognosis of ICS and will discuss challenges surrounding the diagnosis and management of this under-recognized entity.