Social Determinants of Health in Cardio-Oncology: Multi-Level Strategies to Overcome Disparities in Care: JACC: CardioOncology State-of-the-Art Review.

Addressing the need for more equitable cardio-oncology care requires attention to existing disparities in cardio-oncologic disease prevention and outcomes. This is particularly important among those affected by adverse social determinants of health (SDOH). The intricate relationship of SDOH, cancer diagnosis, and outcomes from cardiotoxicities associated with oncologic therapies is influenced by sociopolitical, economic, and cultural factors. Furthermore, mechanisms in cell signaling and epigenetic effects on gene expression link adverse SDOH to cancer and the CVD-related complications of oncologic therapies. To mitigate these disparities, a multifaceted strategy is needed that includes attention to health care access, policy, and community engagement for improved disease screening and management. Interdisciplinary teams must also promote cultural humility and competency and leverage new health technology to foster collaboration in addressing the impact of adverse SDOH in cardio-oncologic outcomes.

Health and Economic Value of Eliminating Socioeconomic Disparities in US Youth Physical Activity.

Importance: There are considerable socioeconomic status (SES) disparities in youth physical activity (PA) levels. For example, studies show that lower-SES youth are less active, have lower participation in organized sports and physical education classes, and have more limited access to PA equipment. Objective: To determine the potential public health and economic effects of eliminating disparities in PA levels among US youth SES groups. Design and Setting: An agent-based model representing all 6- to 17-year-old children in the US was used to simulate the epidemiological, clinical, and economic effects of disparities in PA levels among different SES groups and the effect of reducing these disparities. Main Outcomes and Measures: Anthropometric measures (eg, body mass index) and the presence and severity of risk factors associated with weight (stroke, coronary heart disease, type 2 diabetes, or cancer), as well as direct and indirect cost savings. Results: This model, representing all 50 million US children and adolescents 6 to 17 years old, found that if the US eliminates the disparity in youth PA levels across SES groups, absolute overweight and obesity prevalence would decrease by 0.826% (95% CI, 0.821%-0.832%), resulting in approximately 383 000 (95% CI, 368 000-399 000) fewer cases of overweight and obesity and 101 000 (95% CI, 98 000-105 000) fewer cases of weight-related diseases (stroke and coronary heart disease events, type 2 diabetes, or cancer). This would result in more than $15.60 (95% CI, $15.01-$16.10) billion in cost savings over the youth cohort's lifetime. There are meaningful benefits even when reducing the disparity by just 25%, which would result in $1.85 (95% CI, $1.70-$2.00) billion in direct medical costs averted and $2.48 (95% CI, $2.04-$2.92) billion in productivity losses averted. For every 1% in disparity reduction, total productivity losses would decrease by about $83.8 million, and total direct medical costs would decrease by about $68.7 million. Conclusions and Relevance: This study quantified the potential savings from eliminating or reducing PA disparities, which can help policymakers, health care systems, schools, funders, sports organizations, and other businesses better prioritize investments toward addressing these disparities.

Association of neighborhood gentrification with prostate cancer and immune markers in African American and European American men.

BACKGROUND: Prior studies showed that neighborhood deprivation increases the risk of lethal prostate cancer. However, the role of neighborhood gentrification in prostate cancer development and outcome remains poorly understood. We examined the relationships of gentrification with prostate cancer and serum proteome-defined inflammation and immune function in a diverse cohort. METHODS: The case-control study included 769 cases [405 African American (AA), 364 European American (EA) men] and 1023 controls (479 AA and 544 EA), with 219 all-cause and 59 prostate cancer-specific deaths among cases. Geocodes were linked to a neighborhood gentrification index (NGI) derived from US Census data. Cox and logistic regression, and MANOVA, were used to determine associations between NGI, as continuous or quintiles (Q), and outcomes. RESULTS: Adjusting for individual socioeconomic status (SES), continuous NGI was positively associated with prostate cancer among all men (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.01-1.14). AA and low-income men experienced the highest odds of prostate cancer when residing in tracts with moderate gentrification, whereas EA men experienced reduced odds of regional/metastatic cancer with increased gentrification in SES-adjusted analyses. Continuous NGI also associated with mortality among men presenting with localized disease and low-income men in SES-adjusted Cox regression analyses. NGI was not associated with serum proteome-defined chemotaxis, inflammation, and tumor immunity suppression. CONCLUSIONS: Findings show that neighborhood gentrification associates with prostate cancer and mortality in this diverse population albeit associations were heterogenous within subgroups. The observations suggest that changing neighborhood socioeconomic environments may affect prostate cancer risk and outcome, likely through multifactorial mechanisms.

Risk Stratification and Treatment of Obesity for Primary and Secondary Prevention of Cardiovascular Disease.

PURPOSE OF REVIEW: In this review, we discuss contemporary and emerging approaches for risk stratification and management of excess adiposity for the primary and secondary prevention of cardiovascular disease. RECENT FINDINGS: Obesity is simultaneously a pandemic-scale disease and major risk factor for the incidence and progression of a wide range of cardiometabolic conditions, but risk stratification and treatment remain clinically challenging. However, sex-, race-, and ethnicity-sensitive anthropometric measures, body composition-focused imaging, and health burden-centric staging systems have emerged as important facilitators of holistic risk prediction. Further, expanding therapeutic approaches, including comprehensive lifestyle programs, anti-obesity pharmacotherapies, device/endoscopy-based interventions, metabolic surgery, and novel healthcare delivery resources offer new empowerment for cardiovascular risk reduction in individuals with obesity. Personalized risk stratification and weight management are central to reducing the lifetime prevalence and impact of cardiovascular disease. Further evidence informing long-term safety, efficacy, and cost-effectiveness of novel approaches targeting obesity are critically needed.

New insights in the mechanisms of weight-loss maintenance: Summary from a Pennington symposium.

Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long-term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight-loss maintenance, and systems-level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight-reduced state.

Social Determinants modulate NK cell activity via obesity, LDL, and DUSP1 signaling.

Adverse social determinants of health (aSDoH) are associated with obesity and related comorbidities like diabetes, cardiovascular disease, and cancer. Obesity is also associated with natural killer cell (NK) dysregulation, suggesting a potential mechanistic link. Therefore, we measured NK phenotypes and function in a cohort of African-American (AA) women from resource-limited neighborhoods. Obesity was associated with reduced NK cytotoxicity and a shift towards a regulatory phenotype. In vitro, LDL promoted NK dysfunction, implicating hyperlipidemia as a mediator of obesity-related immune dysregulation. Dual specific phosphatase 1 (DUSP1) was induced by LDL and was upregulated in NK cells from subjects with obesity, implicating DUSP1 in obesity-mediated NK dysfunction. In vitro, DUSP1 repressed LAMP1/CD107a, depleting NK cells of functional lysosomes to prevent degranulation and cytokine secretion. Together, these data provide novel mechanistic links between aSDoH, obesity, and immune dysregulation that could be leveraged to improve outcomes in marginalized populations.

Lifetime healthcare expenses across demographic and cardiovascular risk groups: The application of a novel modeling strategy in a large multiethnic cohort study.

Objective: To understand the burden of healthcare expenses over the lifetime of individuals and evaluate differences among those with cardiovascular risk factors and among disadvantaged groups based on race/ethnicity and sex. Methods: We linked data from the longitudinal multiethnic Dallas Heart Study, which recruited participants between 2000 and 2002, with inpatient and outpatient claims from all hospitals in the Dallas-Fort Worth metroplex through December 2018, capturing encounter expenses. Race/ethnicity and sex, as well as five risk factors, hypertension, diabetes, hyperlipidemia, smoking, and overweight/obesity, were defined at cohort enrollment. For each individual, expenses were indexed to age and cumulated between 40 and 80 years of age. Lifetime expenses across exposures were evaluated as interactions in generalized additive models. Results: A total of 2184 individuals (mean age, 45±10 years; 61% women, 53% Black) were followed between 2000 and 2018. The mean modeled lifetime cumulative healthcare expenses were $442,629 (IQR, $423,850 to $461,408). In models that included 5 risk factors, Black individuals had $21,306 higher lifetime healthcare spending compared with non-Black individuals (P < .001), and men had modestly higher expenses than women ($5987, P < .001). Across demographic groups, the presence of risk factors was associated with progressively higher lifetime expenses, with significant independent association of diabetes ($28,075, P < .001), overweight/obesity ($8816, P < .001), smoking ($3980, P = .009), and hypertension ($528, P = .02) with excess spending. Conclusion: Our study suggests Black individuals have higher lifetime healthcare expenses, exaggerated by the substantially higher prevalence of risk factors, with differences emerging in older age.

Associations of Cumulative Perceived Stress with Cardiovascular Risk Factors and Outcomes: Findings from The Dallas Heart Study.

Background: Data remain sparse regarding the impact of chronic stress on cardiovascular disease (CVD) risk factors and outcomes. Prior work has been limited by incomplete assessments of perceived stress and focus on single stress domains. We evaluated the association between a composite measure of perceived stress and CVD risk factors and outcomes. Methods: Participants from the Dallas Heart Study phase 2 (2007-2009) without prevalent CVD who completed questionnaire assessments of perceived stress were included (n=2685). Individual perceived stress subcomponents (generalized stress, psychosocial, financial, and neighborhood stress) were standardized and integrated into a single cumulative stress score (CSS) with equal weighting for each component. Associations between CSS and demographics, psychosocial variables and cardiac risk factors were assessed in univariable and multivariable analyses. Cox proportional hazards models were used to determine associations of the CSS with atherosclerotic CVD (ASCVD) and Global CVD (ASCVD, heart failure, and atrial fibrillation) after adjustment for demographics and traditional risk factors. Results: Median age of the study population was 48 years, 55% were female, 49% Black and 15% Hispanic/Latinx. CSS was higher among participants who were younger, female, Black or Hispanic, and those with lower income and educational attainment (p<.0001 for each). Higher CSS was associated with self-report of racial/ethnic discrimination, lack of health insurance and last medical contact > one year previously (p<.0001 for each). In multivariable regression models adjusting for age, gender, race/ethnicity, income and education, higher CSS associated with hypertension, smoking, and higher body mass index, waist circumference Hemoglobin A1C, hs-CRP and sedentary time (p< 0.01 for each). Over a median follow-up of 12.4 years, higher CSS associated with ASCVD (adjusted HR 1.22 per SD, 95% CI 1.01-1.47) and Global CVD (HR 1.20, 95% CI 1.03-1.40). No interactions were seen between CSS, demographic factors, and outcomes. Conclusion: Composite multidimensional assessments of perceived stress may help to identify individuals at risk for CVD who may be targeted for stress mitigation or enhanced prevention strategies. These approaches may be best focused on vulnerable populations, given the higher burden of stress in women, Black and Hispanic individuals, and those with lower income and education. WHAT IS NEW?: A novel measure of cumulative stress was created that integrates generalized, psychosocial, financial, and neighborhood perceived stress.Cumulative stress was higher among women, Black and Hispanic participants, younger individuals and persons with lower income and educational attainment and was associated with adverse health behaviors and increased burden of cardiovascular disease (CVD) risk factors.In a diverse cohort, higher cumulative stress associated with incident CVD after adjustment for demographics and traditional risk factors. No interactions were seen based on demographic factors. CLINICAL IMPLICATIONS: Although associations of chronic stress with CVD were similar across demographic subgroups, the higher burden of stress among younger individuals, women, Black and Hispanic participants, and those with lower SES suggests that CVD risk associated with higher stress affects marginalized groups disproportionately.Cumulative Stress is associated with modifiable risk factors and health behaviors. Future studies should explore targeting behavioral modification and risk factor reduction programs, as well as stress reduction strategies, to individuals with high cumulative stress.Additional research is needed to uncover mechanisms that underly the association between chronic stress and cardiovascular disease.

Neighborhood socioeconomic deprivation and individual-level socioeconomic status are associated with dopamine-mediated changes to monocyte subset CCR2 expression via a cAMP-dependent pathway.

Social determinants of health (SDoH) include socioeconomic, environmental, and psychological factors that impact health. Neighborhood socioeconomic deprivation (NSD) and low individual-level socioeconomic status (SES) are SDoH that associate with incident heart failure, stroke, and cardiovascular mortality, but the underlying biological mechanisms are not well understood. Previous research has demonstrated an association between NSD, in particular, and key components of the neural-hematopoietic-axis including amygdala activity as a marker of chronic stress, bone marrow activity, and arterial inflammation. Our study further characterizes the role of NSD and SES as potential sources of chronic stress related to downstream immunological factors in this stress-associated biologic pathway. We investigated how NSD, SES, and catecholamine levels (as proxy for sympathetic nervous system activation) may influence monocytes which are known to play a significant role in atherogenesis. First, in an ex vivo approach, we treated healthy donor monocytes with biobanked serum from a community cohort of African Americans at risk for CVD. Subsequently, the treated monocytes were subjected to flow cytometry for characterization of monocyte subsets and receptor expression. We determined that NSD and serum catecholamines (namely dopamine [DA] and norepinephrine [NE]) associated with monocyte C-C chemokine receptor type 2 (CCR2) expression (p < 0.05), a receptor known to facilitate recruitment of monocytes towards arterial plaques. Additionally, NSD associated with catecholamine levels, especially DA in individuals of low SES. To further explore the potential role of NSD and the effects of catecholamines on monocytes, monocytes were treated in vitro with epinephrine [EPI], NE, or DA. Only DA increased CCR2 expression in a dose-dependent manner (p < 0.01), especially on non-classical monocytes (NCM). Furthermore, linear regression analysis between D2-like receptor surface expression and surface CCR2 expression suggested D2-like receptor signaling in NCM. Indicative of D2-signaling, cAMP levels were found to be lower in DA-treated monocytes compared to untreated controls (control 29.78 pmol/ml vs DA 22.97 pmol/ml; p = 0.038) and the impact of DA on NCM CCR2 expression was abrogated by co-treatment with 8-CPT, a cAMP analog. Furthermore, Filamin A (FLNA), a prominent actin-crosslinking protein, that is known to regulate CCR2 recycling, significantly decreased in DA-treated NCM (p < 0.05), indicating a reduction of CCR2 recycling. Overall, we provide a novel immunological mechanism, driven by DA signaling and CCR2, for how NSD may contribute to atherogenesis. Future studies should investigate the importance of DA in CVD development and progression in populations disproportionately experiencing chronic stress due to SDoH.

Interleukin-8 (IL-8) as a Potential Mediator of an Association between Trimethylamine N-Oxide (TMAO) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) among African Americans at Risk of Cardiovascular Disease.

Trimethylamine N-oxide (TMAO)-a microbial metabolite derived from the hepatic-gut axis-is linked to inflammation, hyperlipidemia, and cardiovascular disease (CVD). Proprotein convertase subtilisin/kexin type 9 (PCSK9), which is largely hepatically expressed, blocks low-density lipoprotein (LDL) receptor recycling, also leading to hyperlipidemia. The primary objective of this study was to investigate a previously hypothesized potential relationship between TMAO and PCSK9 in order to explore novel mechanisms linking TMAO and CVD risk. African American adults at risk of CVD living in the Washington DC area were recruited to participate in a cross-sectional community-based study (n = 60, 93% female, BMI = 33). Fasting levels of inflammatory cytokines (i.e., interleukin (IL)-1 beta, tumor necrosis factor-alpha, and interleukin-8), TMAO, and PCSK9 were measured using Luminex and ELISA, respectively. Univariate and multivariate linear regression analyses and structural equation mediation analyses were conducted using STATA. All models were adjusted for body mass index (BMI) and atherosclerotic CVD risk score (ASCVD). A significant association between TMAO and PCSK9 was identified (ß = 0.31, p = 0.02). Both TMAO and PCSK9 were significantly associated with IL-8 (TMAO: ß = 0.45, p = 0.00; PCSK9: ß = 0.23, p = 0.05) in adjusted models. Mediation analysis indicated that 34.77% of the relationship between TMAO and PCSK9 was explained by IL-8. Our findings indicate a potential PCSK9-involved pathway for TMAO and CVD risk, with potential mediation by IL-8.

Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association.

The global obesity epidemic is well established, with increases in obesity prevalence for most countries since the 1980s. Obesity contributes directly to incident cardiovascular risk factors, including dyslipidemia, type 2 diabetes, hypertension, and sleep disorders. Obesity also leads to the development of cardiovascular disease and cardiovascular disease mortality independently of other cardiovascular risk factors. More recent data highlight abdominal obesity, as determined by waist circumference, as a cardiovascular disease risk marker that is independent of body mass index. There have also been significant advances in imaging modalities for characterizing body composition, including visceral adiposity. Studies that quantify fat depots, including ectopic fat, support excess visceral adiposity as an independent indicator of poor cardiovascular outcomes. Lifestyle modification and subsequent weight loss improve both metabolic syndrome and associated systemic inflammation and endothelial dysfunction. However, clinical trials of medical weight loss have not demonstrated a reduction in coronary artery disease rates. In contrast, prospective studies comparing patients undergoing bariatric surgery with nonsurgical patients with obesity have shown reduced coronary artery disease risk with surgery. In this statement, we summarize the impact of obesity on the diagnosis, clinical management, and outcomes of atherosclerotic cardiovascular disease, heart failure, and arrhythmias, especially sudden cardiac death and atrial fibrillation. In particular, we examine the influence of obesity on noninvasive and invasive diagnostic procedures for coronary artery disease. Moreover, we review the impact of obesity on cardiac function and outcomes related to heart failure with reduced and preserved ejection fraction. Finally, we describe the effects of lifestyle and surgical weight loss interventions on outcomes related to coronary artery disease, heart failure, and atrial fibrillation.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in a Community-Based Cohort: Data From the Washington, D.C. Cardiovascular Health and Needs Assessment.

Background: Psychosocial stress correlates with cardiovascular (CV) events; however, associations between physiologic measures of stressors and CVD remain incompletely understood, especially in racial/ethnic minority populations in resource-limited neighborhoods. We examined associations between chronic stress-related neural activity, measured by amygdalar 18Fluorodeoxyglucose (18FDG) uptake, and aortic vascular FDG uptake (arterial inflammation measure) in a community-based cohort. Methods: Forty participants from the Washington, DC CV Health and Needs Assessment (DC-CHNA), a study of a predominantly African-American population in resource-limited urban areas and 25 healthy volunteers underwent detailed phenotyping, including 18FDG PET/CT for assessing amygdalar activity (AmygA), vascular FDG uptake, and hematopoietic (leukopoietic) tissue activity. Mediation analysis was used to test whether the link between AmygA and vascular FDG uptake was mediated by hematopoietic activity. Results: AmygA (1.11 ± 0.09 vs. 1.05 ± 0.09, p = 0.004) and vascular FDG uptake (1.63 ± 0.22 vs. 1.55 ± 0.17, p = 0.05) were greater in the DC-CHNA cohort compared to volunteers. Within the DC-CHNA cohort, AmygA associated with vascular FDG uptake after adjustment for Framingham score and body mass index (ß = 0.41, p = 0.015). The AmygA and aortic vascular FDG uptake relationship was in part mediated by splenic (20.2%) and bone marrow (11.8%) activity. Conclusions: AmygA, or chronic stress-related neural activity, associates with subclinical CVD risk in a community-based cohort. This may in part be mediated by the hematopoietic system. Our findings of this hypothesis-generating study are suggestive of a potential relationship between chronic stress-related neural activity and subclinical CVD in an African American community-based population. Taken together, these findings suggest a potential mechanism by which chronic psychosocial stress, such as stressors that can be experienced in adverse social conditions, promotes greater cardiovascular risk amongst resource-limited, community-based populations most impacted by cardiovascular health disparities. However, larger prospective studies examining these findings in other racially and ethnically diverse populations are necessary to confirm and extend these findings.

Time to listen: a mixed-method study examining community-based views of mobile technology for interventions to promote physical activity.

INTRODUCTION: A mixed-method, co-design approach to studying the adoption of mobile health (mHealth) technology among African-American (AA) women has not been fully explored. Qualitative data may contextualise existing knowledge surrounding perceptions of mHealth among AA women as part of formative work for designing a physical activity application (app). METHODS: A convenience sample of 16 AA women completed an informatics survey prior to participating in focus groups exploring their use of mobile technology and health apps. Survey responses provided frequency data, while iterative transcript analysis of focus groups identified themes. RESULTS: The majority of participants (mean age=62.1 years, SD=6.6) felt comfortable using a tablet/smartphone (75.0%). Most (68.8%) reported using health-related apps, primarily focused on physical activity and nutrition. Focus groups revealed four overarching concepts, including (1) user attachment, (2) technology adoption, (3) potential facilitators and (4) potential barriers. Important features which may serve as facilitators or barriers to future adoption of a mobile app for an mHealth intervention include individual app tailoring and software concerns, respectively. DISCUSSION: Thematic analysis revealed high user attachment to smartphones and described participants' process for adopting new mHealth technology. CONCLUSION: Early engagement of target end users as a part of a broader co-design and community-based participatory research process for developing mHealth technologies may be useful for sustained adoption of these tools in future mHealth behavioural interventions.

Physical activity-mediated associations between perceived neighborhood social environment and depressive symptoms among Jackson Heart Study participants.

BACKGROUND: Little is known about the associations between perceived neighborhood social environment (PNSE) and depressive symptoms among African Americans. Furthermore, the role of physical activity (PA) as a mediator of this association has not been investigated. The two-fold objectives of this study, therefore, were (1) to examine the associations between PNSE and depressive symptoms among African Americans, and (2) to test the degree to which these associations were mediated by total PA. METHODS: We used baseline data from the Jackson Heart Study (JHS), a single-site, prospective, community-based study of African-American adults (n = 2209) recruited from Jackson, Mississippi. PNSE variables included scores for neighborhood violence (i.e., higher score = more violence), problems (higher score = more problems), and social cohesion (higher score = more cohesion). Depressive symptoms were measured by the 20-item Center for Epidemiological Studies Depression (CES-D) score. First, multilevel modeling, controlling for census tract clustering effects, was used to estimate associations between each PNSE variable and CES-D score, adjusting for covariates, including demographic, health-related, and population density. Second, validated, self-reported total PA, based on active living, sport, and home indices, was tested as the mediator. Multivariable linear regressions with bootstrap-generated 95% bias-corrected confidence intervals (BC CIs) were estimated to test for significant unstandardized indirect effects, controlling for all covariates. RESULTS: Our participants were 64.2% female with a mean age of 52.6 (SD = 12.2) and a mean CES-D score of 10.8 (SD = 8.1). In the fully-adjusted model, neighborhood violence and problems were positively related to depressive symptoms (B = 3.59, 95%CI = 0.93, 6.26, and B = 3.06, 95%CI = 1.19, 4.93, respectively). Neighborhood violence and problems were also indirectly related to depressive symptoms via total PA (B = 0.26, 95%BC CI = 0.05, 0.55; and B = 0.15, 95%BC CI = 0.02, 0.34, respectively). Social cohesion was neither directly nor indirectly related to depressive symptoms. CONCLUSIONS: We found that higher levels of perceived neighborhood problems and violence were directly and positively associated with depressive symptoms. These associations may be explained in part by lower total PA levels. Future interventions to reduce depressive symptoms attributed to neighborhood features should consider emphasizing built environment features that facilitate PA increases in conjunction with community efforts to reduce neighborhood violence and problems.

Hyperlipidaemia and IFNgamma/TNFalpha Synergism are associated with cholesterol crystal formation in Endothelial cells partly through modulation of Lysosomal pH and Cholesterol homeostasis.

BACKGROUND: Inflammation plays an important role in the development of cardiovascular disease (CVD). Patients with chronic inflammation diseases have high levels of inflammation and early fatal myocardial infarction due to early, unstable coronary plaques. Cholesterol crystals (CC) play a key role in atherogenesis. However, the underlying mechanisms of endothelial cell (EC)-derived CC formation are not well understood in chronic inflammation. METHODS: We utilized a combination of a mouse psoriasis model (K14-Rac1V12 mouse model) and human psoriasis patients to study the effect of inflammatory cytokines on CC formation in ECs. Lysosomal pH, alterations in lipid load and inflammatory proteins were evaluated as potential mechanisms linking inflammatory cytokines to CC formation. Coronary CT angiography was performed (n = 224) to characterize potential IFNγ and TNFα synergism on vascular diseases in vivo. FINDINGS: We detected CC presence in the aorta of K14-Rac1V12 mice on chow diet. IFNγ and TNFα were found to synergistically increase LDL-induced CC formation by almost 2-fold. There was an increase in lysosomal pH accompanied by a 28% loss in pH-dependent lysosomal signal and altered vATPaseV1E1 expression patterns. In parallel, we found that LDL+IFNγ/TNFα treatments increased free cholesterol content within EC and led to a decrease in SOAT-1 expression, an enzyme critically involved cholesterol homeostasis. Finally, the product of IFNγ and TNFα positively associated with early non-calcified coronary burden in patients with psoriasis (n = 224; ß = 0.28, p < 0.001). INTERPRETATION: Our results provide evidence that IFNγ and TNFα accelerate CC formation in endothelial cells in part by altering lysosomal pH and free cholesterol load. These changes promote early atherogenesis and contribute to understanding the burden of CVD in psoriasis. FUNDING: Funding was provided by the Intramural Research Program at NIH (NNM) and the National Psoriasis Foundation (NNM and YB).

Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study.

BACKGROUND: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. METHODS: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) <6 ng/L and NT-proBNP (N-terminal pro-B-type natriuretic peptide) <100 pg/mL), and those with ECG-LVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF. RESULTS: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1-3.5) in those with malignant LVH and 0.9 (95% CI, 0.6-1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. CONCLUSIONS: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study.

OBJECTIVES: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters. BACKGROUND: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques. METHODS: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB. RESULTS: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: ß = 0.20, p = 0.01) and subclinical CVD (VI: ß = 0.31, p < 0.001; NCB: ß = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB. CONCLUSIONS: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact.

Association of Cardiovascular Disease With Premature Mortality in the United States.

Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States. Despite substantial declines in CVD mortality rates during past decades, progress against cardiovascular deaths in midlife has stagnated, with rates increased in some US racial/ethnic groups. Objective: To examine the trends in premature (ages 25-64 years) mortality from CVD from 2000 to 2015 by demographics and county-level factors, including education, rurality, and the prevalence of smoking, obesity, and diabetes. Design, Setting, and Participants: This descriptive study used US national mortality data from the Surveillance, Epidemiology, and End Results data set and included all CVD deaths among individuals ages 25 to 64 years from January 2000 to December 2015. The data analysis began in February 2018. Exposures: Age, sex, race/ethnicity, and county-level factors. Main Outcomes and Measures: Age-standardized mortality rates and average annual percent change (AAPC) in rates by age, sex, race/ethnicity, and county-level factors (in quintiles) and relative risks of CVD mortality across quintiles of each county-level factor. Results: In 2000 to 2015, 2.3 million CVD deaths occurred among individuals age 25 to 64 years in the United States. There were significant declines in CVD mortality for black, Latinx, and Asian and Pacific Islander individuals (AAPC: range, -1.7 to -3.2%), although black people continued to have the highest CVD mortality rates. Mortality rates were second highest for American Indian/Alaskan Native individuals and increased significantly among those aged 25 to 49 years (AAPC: women, 2.1%; men, 1.3%). For white individuals, mortality rates plateaued among women age 25 to 49 years (AAPC, 0.05%). Declines in mortality rates were observed for most major CVD subtypes except for ischemic heart disease, which was stable in white women and increased in American Indian/Alaska Native women, hypertensive heart disease, for which significant increases in rates were observed in most racial/ethnic groups, and endocarditis, for which rates increased in white individuals and American Indian/Alaska Native men. Counties with the highest prevalence of diabetes (quintile 5 vs quintile 1: relative risk range 1.6-1.8 for white individuals and 1.4-1.6 for black individuals) had the most risk of CVD mortality. Conclusions and Relevance: There have been substantial declines in premature CVD mortality in much of the US population. However, increases in CVD mortality before age 50 years among American Indian/Alaska Native individuals, flattening rates in white people, and overall increases in deaths from hypertensive disease suggest that targeted public health interventions are needed to prevent these premature deaths.