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The endothelial microvasculature is essential for the regulation of vasodilation and vasoconstriction, and improved functioning of the endothelium is linked to improved outcomes for individuals with coronary artery disease (CAD). People with endothelial dysfunction exhibit a loss of NO-mediated vasodilation, achieving vasodilation instead through mitochondria-derived H 2 O 2 . Mitochondrial dynamics is an important autoregulatory mechanism that contributes to mitochondrial and endothelial homeostasis and plays a role in formation of reactive oxygen species (ROS), including H 2 O 2 . Dysregulation of mitochondrial dynamics leads to increased ROS production, decreased ATP production, impaired metabolism, activation of pathological signal transduction, impaired calcium sensing, and inflammation. We hypothesize that dysregulation of endothelial mitochondrial dynamics plays a crucial role in the endothelial microvascular dysfunction seen in individuals with CAD. Therefore, proper regulation of endothelial mitochondrial dynamics may be a suitable treatment for individuals with endothelial microvascular dysfunction and we furthermore postulate that improving this microvascular dysfunction will directly improve outcomes for those with CAD.

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., Competing Interests: None

Microvascular disease plays a critical role in systemic end-organ dysfunction, and treatment of microvascular pathologies may greatly reduce cardiovascular morbidity and mortality. The Call for Papers collection: New Developments in Translational Microcirculatory Research highlights key advances in our understanding of the role of microvessels in the development of chronic diseases as well as therapeutic strategies to enhance microvascular function. This Mini Review provides a concise summary of these advances and draws from other relevant research to provide the most up-to-date information on the influence of cutaneous, cerebrovascular, coronary, and peripheral microcirculation on the pathophysiology of obesity, hypertension, cardiovascular aging, peripheral artery disease, and cognitive impairment. In addition to these disease- and location-dependent research articles, this Call for Papers includes state-of-the-art reviews on coronary endothelial function and assessment of microvascular health in different organ systems, with an additional focus on establishing rigor and new advances in clinical trial design. These articles, combined with original research evaluating cellular, exosomal, pharmaceutical, exercise, heat, and dietary interventional therapies, establish the groundwork for translating microcirculatory research from bench to bedside. Although numerous studies in this collection are focused on human microcirculation, most used robust preclinical models to probe mechanisms of pathophysiology and interventional benefits. Future work focused on translating these findings to humans are necessary for finding clinical strategies to prevent and treat microvascular dysfunction.

Background: In the United States, African Americans (AAs) have greater risk for Class III obesity and cardiovascular disease (CVD). Previous reports suggest that AAs have a different immune cell profile when compared to Caucasians., Methods: The immune cell profile of AAs was characterized by flow cytometry using two experimental setups: ex vivo (N = 40) and in vitro (N = 10). For ex vivo experiments, PBMC were treated with participant serum to understand how lipid contents may contribute to monocyte phenotypic differences. For in vitro experiments, monocytes were low-density lipoprotein (LDL)- or vehicle-treated for four hours and subsequently analyzed by flow cytometry and RT-qPCR., Results: When PBMCs were treated with participant sera, subsequent multivariable regression analysis revealed that serum triglycerides and LDL levels were associated with monocyte subset differences. In vitro LDL treatment of monocytes induced a phenotypic switch in monocytes away from classical monocytes accompanied by subset-specific chemokine receptor CCR2 and CCR5 expression changes. These observed changes are partially translation-dependent as determined by co-incubation with cycloheximide., Conclusions: LDL treatment of monocytes induces a change in monocyte subsets and increases CCR2/CCR5 expression in a subset-specific manner. Understanding the molecular mechanisms could prove to have CVD-related therapeutic benefits, especially in high-risk populations with hyperlipidemia and increased risk for CVD., (Published by Elsevier B.V.)

There are approximately 38 million people globally living with Human immunodeficiency virus 1 (HIV-1) and given the tremendous success of combination antiretroviral therapy (cART) this has dramatically reduced mortality and morbidity with prevention benefits. However, HIV-1 persists during cART within the human body and re-appears upon cART interruption. This HIV-1 reservoir remains a barrier to cure with cellular sites of viral persistence not fully understood. In this study we provide evidence corroborating a recently published article in STM demonstrating the role of platelets as a novel cellular disseminator of HIV-1 particles in the setting of viral suppression. Using classical transmission electron microscopy with and without immunogold labeling, we visualize HIV-1 in both platelets and monocytes in cART suppressed HIV donors. Our study suggests that due to the close proximity of platelets and monocytes an alternative life cycle of HIV-1 cycling within monocytes and platelets without the need of active replication under cART occurs. Our findings are supported by the lack of detectable HIV-1 particles in platelets derived from HIV uninfected donors or the 'Berlin' patient suggesting that platelets may serve as an underappreciated hidden bearer for HIV-1 and should be considered in HIV remission studies and trials.

Objectives: Little is understood about associations between neighborhood characteristics and depression, a cardiovascular disease (CVD) risk factor, in diverse populations. We examined relationships between perceived/objective neighborhood characteristics, depression, and CVD markers within the Washington, DC CV Health/Needs Assessment, an evaluation among predominantly African-American (AA) adults in resource-limited DC communities., Method: Factor analysis of overall neighborhood environment perception (NEP) identified three NEP sub-scores:1) violence; 2) physical/social environment; 3) social cohesion (higher score = more favorable perception). Objective neighborhood characteristics were measured by geospatially-derived scores of walkability, transportation, and crime. Depression was defined by the revised Center for Epidemiologic Studies Depression Scale (CESD-R). We used linear-regression modeling to examine neighborhood measures and CESD-R associations. To investigate a subsequent connection with CVD risk, we examined relationships between CESD-R and CVD-associated cytokines in a population subset., Results: Participants ( N  = 99; mean age = 59.06; 99% AA) had a mean CESD-R score = 5.8(SD = 8.88). In adjusted models, CESD-R scores decreased by 0.20 units ( p  = 0.01) for every overall NEP unit-increase. Perceived physical/social environment (β = -0.34, p  = 0.04) and social cohesion (β = -0.82, p  = 0.01) were related to CESD-R while perceived violence was not (β = -0.28, p  = 0.1). Of objective neighborhood environment measures (i.e. walk, transit, bike, personal crime, and property crime scores), only property crime score was associated with depression (β = 4.99, p  < 0.03). In population subset ( n  = 42), higher CESD-R associated with higher IL-1β (β = 21.25, p  < 0.01) and IL-18 (β = 0.006, p  = 0.01)., Conclusion: Favorable neighborhood perceptions are related to lower depressive symptoms in a predominantly AA cohort from Washington, DC resource-limited communities. Neighborhood perceptions appear to be strongly associated with depressive symptoms compared to objective characteristics. Increasing CESD-R scores were related to higher pro-inflammatory markers. Improving neighborhood perceptions may be beneficial to psychological well-being and CV health for urban minority residents.

Background: Neighborhoods and the microbiome are linked to cardiovascular disease (CVD), yet investigations to identify microbiome-related factors at neighborhood levels have not been widely investigated. We sought to explore relationships between neighborhood deprivation index (NDI) and the microbial metabolite, trimethylamine-N-oxide. We hypothesized that inflammatory markers and dietary intake would be mediators of the relationship., Methods: African-American adults at risk for CVD living in the Washington, DC area were recruited to participate in a cross-sectional community-based study. US census-based neighborhood deprivation index (NDI) measures (at the census-tract level) were determined. Serum samples were analyzed for CVD risk factors, cytokines, and the microbial metabolite, trimethylamine-N-oxide (TMAO). Self-reported dietary intake based on food groups was collected., Results: Study participants ( n = 60) were predominantly female (93.3%), with a mean (SD) age of 60.83 (+/-10.52) years. Mean (SD) NDI was -1.54 (2.94), and mean (SD) TMAO level was 4.99 (9.65) µmol/L. Adjusting for CVD risk factors and BMI, NDI was positively associated with TMAO (β = 0.31, p = 0.02). Using mediation analysis, the relationship between NDI and TMAO was significantly mediated by TNF-α (60.15%) and interleukin)-1 β (IL; 49.96%). When controlling for clustering within neighborhoods, the NDI-TMAO association was no longer significant (β = 5.11, p = 0.11). However, the association between NDI and IL-1 β (β = 0.04, p = 0.004) and TNF-α (β = 0.17, p = 0.003) remained. Neither NDI nor TMAO was significantly associated with daily dietary intake. Conclusion and Relevance: Among a small sample of African-American adults at risk for CVD, there was a significant positive relationship with NDI and TMAO mediated by inflammation. These hypothesis-generating results are initial and need to be confirmed in larger studies.

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 18 Fluorodeoxyglucose ( 18 FDG) 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 18 FDG 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 (β = 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., Competing Interests: NM is a full-time US government employee and has served as a consultant for Amgen, Eli Lilly, and Leo Pharma receiving grants/other payments; as a principal investigator and/or investigator for AbbVie, Celgene, Janssen Pharmaceuticals, Inc, and Novartis receiving grants and/or research funding and as a principal investigator for the National Institute of Health receiving grants and/or research funding. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Powell-Wiley, Dey, Rivers, Chaturvedi, Andrews, Ceasar, Claudel, Mitchell, Ayers, Tamura, Gutierrez-Huerta, Teague, Oeser, Goyal, Joshi, Collins, Baumer, Chung, Sumner, Playford, Tawakol and Mehta.)

Introduction: Although physical activity (PA) reduces cardiovascular disease (CVD) risk, physical inactivity remains a pressing public health concern, especially among African American (AA) women in the USA. PA interventions focused on AA women living in resource-limited communities with scarce PA infrastructure are needed. Mobile health (mHealth) technology can increase access to PA interventions. We describe the development of a clinical protocol for a multilevel, community-based, mHealth PA intervention for AA women., Methods and Analysis: An mHealth intervention targeting AA women living in resource-limited Washington, DC communities was developed based on the socioecological framework for PA. Over 6 months, we will use a Sequential Multi-Assignment, Randomized Trial approach to compare the effects on PA of location-based remote messaging (named 'tailored-to-place') to standard remote messaging in an mHealth intervention. Participants will be randomised to a remote messaging intervention for 3 months, at which point the intervention strategy will adapt based on individuals' PA levels. Those who do not meet the PA goal will be rerandomised to more intensive treatment. Participants will be followed for another 3 months to determine the contribution of each mHealth intervention to PA level. This protocol will use novel statistical approaches to account for the adaptive strategy. Finally, effects of PA changes on CVD risk biomarkers will be characterised., Ethics and Dissemination: This protocol has been developed in partnership with a Washington, DC-area community advisory board to ensure feasibility and acceptability to community members. The National Institutes of Health Intramural IRB approved this research and the National Heart, Lung, and Blood Institute provided funding. Once published, results of this work will be disseminated to community members through presentations at community advisory board meetings and our quarterly newsletter., Trial Registration Number: NCT03288207., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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; β = 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)., Competing Interests: Declaration of Interest Dr. Mehta has received funding from the National Institutes of Health Intramural Research Program (Z01 HL-06193); and has received research grants from Abbvie, Janssen, Novartis Corp, and Celgene. Dr. Gelfand reports personal fees from BMS, Boehringer Ingelheim, GSK, Lilly, Janssen Biologics, Novartis Corp., UCB (DSMB), Neuroder (DSMB), Dr. Reddy's Labs, Pfizer Inc., and Sun Pharma as well as grants from Abbvie, Boehringer Ingelheim, Janssen, Novartis Corp., Celgene, Ortho Dermatologics, and Pfizer, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier B.V.)

Background: Cardiovascular disease (CVD) is the leading cause of death in the world. Given the role of immune cells in atherosclerosis development and progression, effective methods for characterizing immune cell populations are needed, particularly among populations disproportionately at risk for CVD., Results: By using a variety of antibodies combined in one staining protocol, we were able to identify granulocyte, lymphocyte, and monocyte sub-populations by CD-antigen expression from 500 µl of whole blood, enabling a more extensive comparison than what is possible with a complete blood count and differential (CBC). The flow cytometry panel was established and tested in a total of 29 healthy men and women. As a proof of principle, these 29 samples were split by their race/ethnicity: African-Americans (AA) (N = 14) and Caucasians (N = 15). We found in accordance with the literature that AA had fewer granulocytes and more lymphocytes when compared to Caucasians, though the proportion of total monocytes was similar in both groups. Several new differences between AA and Caucasians were noted that had not been previously described. For example, AA had a greater proportion of platelet adhesion on non-classical monocytes when compared to Caucasians, a cell-to-cell interaction described as crucially important in CVD. We also examined our flow panel in a clinical population of AA women with known CVD risk factors (N = 20). Several of the flow cytometry parameters that cannot be measured with the CBC displayed correlations with clinical CVD risk markers. For instance, Framingham Risk Score (FRS) calculated for each participant correlated with immune cell platelet aggregates (PA) (e.g. T cell PA β = 0.59, p = 0.03 or non-classical monocyte PA β = 0.54, p = 0.02) after adjustment for body mass index (BMI)., Conclusion: A flow cytometry panel identified differences in granulocytes, monocytes, and lymphocytes between AA and Caucasians which may contribute to increased CVD risk in AA. Moreover, this flow panel identifies immune cell sub-populations and platelet aggregates associated with CVD risk. This flow cytometry panel may serve as an effective method for phenotyping immune cell populations involved in the development and progression of CVD.